Chemotherapy and Biotherapy Guidelines
Uploaded by
Mohammed GazoChemotherapy and Biotherapy Guidelines
Uploaded by
Mohammed GazoFOURTH EDITION
Chemotherapy
and Biotherapy
Guidelines
AND RECOMMENDATIONS
FOR PRACTICE
Edited by
Martha Polovich, PhD, RN, AOCN®
MiKaela Olsen, MS, RN, AOCNS®
Kristine B. LeFebvre, MSN, RN, AOCN®
FOURTH EDITION
Chemotherapy and
Biotherapy Guidelines
and Recommendations
for Practice
Edited by
Martha Polovich, PhD, RN, AOCN®
MiKaela Olsen, MS, RN, AOCNS®
Kristine B. LeFebvre, MSN, RN, AOCN®
Oncology Nursing Society
Pittsburgh, Pennsylvania
ONS Publications Department
Executive Director, Professional Practice and Programs and Publisher:
Elizabeth Wertz Evans, PhD, RN, MPM, CPHQ, CPHIMS, FHIMSS, FACMPE
Director of Publications: Bill Tony, BA, CQIA
Managing Editor: Lisa M. George, BA
Technical Content Editor: Angela D. Klimaszewski, RN, MSN
Staff Editor II: Amy Nicoletti, BA
Copy Editor: Laura Pinchot, BA
Graphic Designer: Dany Sjoen
Editorial Assistant: Judy Holmes
Copyright © 2014 by the Oncology Nursing Society. All rights reserved. No part of the material protected by this copyright may be repro-
duced or utilized in any form, electronic or mechanical, including photocopying, recording, or by an information storage and retrieval system,
without written permission from the copyright owner. For information, write to the Oncology Nursing Society, 125 Enterprise Drive, Pittsburgh,
PA 15275-1214, or visit www.ons.org/practice-resources/permissions-reprints.
Cover image of cisplatin crystals courtesy of NCI Visuals Online, Larry Ostby, photographer.
Library of Congress Cataloging-in-Publication Data
Chemotherapy and biotherapy guidelines and recommendations for practice. -- Fourth edition / edited by Martha Polovich, MiKaela Olsen, Kris-
tine B. LeFebvre.
p. ; cm.
Includes bibliographical references and index.
ISBN 978-1-935864-33-2
ISBN 978-1-935864-49-3 (E-Book)
I. Polovich, Martha, editor of compilation. II. Olsen, MiKaela M., editor of compilation. III. LeFebvre, Kristine B., editor of compilation. IV. On-
cology Nursing Society, issuing body.
[DNLM: 1. Neoplasms--drug therapy--Outlines. 2. Neoplasms--drug therapy--Practice Guideline. 3. Antineoplastic Agents--administration & dos-
age--Outlines. 4. Antineoplastic Agents--administration & dosage--Practice Guideline. 5. Biological Agents--therapeutic use--Outlines. 6. Biological
Agents--therapeutic use--Practice Guideline. 7. Neoplasms--nursing--Outlines. 8. Neoplasms--nursing--Practice Guideline. QV 18.2]
RC266
616.99’40231--dc23
2013039836
Publisher’s Note
This book is published by the Oncology Nursing Society (ONS). ONS neither represents nor guarantees that the practices described herein
will, if followed, ensure safe and effective patient care. The recommendations contained in this book reflect ONS’s judgment regarding the
state of general knowledge and practice in the field as of the date of publication. The recommendations may not be appropriate for use in all
circumstances. Those who use this book should make their own determinations regarding specific safe and appropriate patient-care practices,
taking into account the personnel, equipment, and practices available at the hospital or other facility at which they are located. The editors
and publisher cannot be held responsible for any liability incurred as a consequence from the use or application of any of the contents of this
book. Figures and tables are used as examples only. They are not meant to be all-inclusive, nor do they represent endorsement of any particular
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mentioned are provided for information only; the hosts are responsible for their own content and availability. Unless otherwise indicated, dollar
amounts reflect U.S. dollars.
ONS publications are originally published in English. Publishers wishing to translate ONS publications must contact ONS about licensing
arrangements. ONS publications cannot be translated without obtaining written permission from ONS. (Individual tables and figures that are
reprinted or adapted require additional permission from the original source.) Because translations from English may not always be accurate or
precise, ONS disclaims any responsibility for inaccuracies in words or meaning that may occur as a result of the translation. Readers relying on
precise information should check the original English version.
Printed in the United States of America
Integrity • Innovation • Stewardship • Advocacy • Excellence • Inclusiveness
Contributors
Editors
Martha Polovich, PhD, RN, AOCN® Kristine B. LeFebvre, MSN, RN, AOCN®
Oncology Nurse Consultant Nurse Planner and Project Manager, Education
Atlanta, Georgia Department
Chapter 5. Nursing Considerations in Cancer Oncology Nursing Society
Treatment; Chapter 8. Infusion-Related Com- Pittsburgh, Pennsylvania
plications Chapter 1. Overview of Cancer and Cancer
Treatment; Chapter 2. Drug Development and
MiKaela Olsen, MS, RN, AOCNS® Clinical Trials; Chapter 11. Competence in Che-
Oncology and Hematology Clinical Nurse Spe- motherapy Administration
cialist
Sidney Kimmel Comprehensive Cancer Center
Johns Hopkins Hospital
Baltimore, Maryland
Chapter 9. Side Effects of Cancer Therapy
Authors
Carol Stein Blecher, RN, MS, AOCN®, APNC, Catherine E. Jansen, PhD, RN, AOCNS®
CBPN-C, CBCN® Oncology Clinical Nurse Specialist
Advanced Practice Nurse/Clinical Educator Kaiser Permanente Medical Center
Trinitas Comprehensive Cancer Center San Francisco, California
Elizabeth, New Jersey Chapter 9. Side Effects of Cancer Therapy
Chapter 7. Pretreatment Care
Anne Katz, PhD, RN
Paul F. Davis, MSN, RN Clinical Nurse Specialist and Sexuality Coun-
Fourth Floor Manager selor
Duke Raleigh Hospital CancerCare Manitoba
Raleigh, North Carolina Manitoba, Canada
Chapter 9. Side Effects of Cancer Therapy Editor, Oncology Nursing Forum
Oncology Nursing Society
Tracy T. Douglas, RN, MSN Pittsburgh, Pennsylvania
BMT Nurse Manager Chapter 9. Side Effects of Cancer Therapy
Sidney Kimmel Comprehensive Cancer Center
Johns Hopkins Hospital Alice S. Kerber, MN, APRN, ACNS-BC,
Baltimore, Maryland AOCN®, APNG
Chapter 9. Side Effects of Cancer Therapy Oncology Clinical Nurse Specialist
Georgia Center for Oncology Research and
Cheryl D. Gilbert, RN, MSN, OCN®, CBPN-IC Education
Nurse Navigator Atlanta, Georgia
Mercy Women’s Center Chapter 5. Nursing Considerations in Cancer
Oklahoma City, Oklahoma Treatment
Chapter 9. Side Effects of Cancer Therapy
iii
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
iv Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Denise Menonna-Quinn, RN-BC, MSN, Stephanie Shields, PharmD
AOCNS® Clinical Specialist
Nurse Transplant Insurance Coordinator/ McKesson Specialty Health
Educator San Francisco, California
John Theurer Cancer Center at Hackensack Chapter 3. Principles of Antineoplastic Therapy
University Medical Center
Hackensack, New Jersey Janice L. Skinner, RN, MS, MSN, CRNP
Chapter 6. Administration Considerations Nurse Practitioner
Transplant and Oncology Infectious Diseases
Paula M. Muehlbauer, RN, MSN, AOCNS® Johns Hopkins School of Medicine
Clinical Nurse Specialist/Academic Educator Baltimore, Maryland
Veterans Affairs San Diego Healthcare System Chapter 9. Side Effects of Cancer Therapy
San Diego, California
Chapter 3. Principles of Antineoplastic Therapy; Michael Smart, RN, BSN, OCN®
Chapter 4. Principles of Biotherapy Oncology Nurse Educator, Charge Nurse
Huntsville Hospital
Carolene B. Robinson, MA, RN, CNS, CBCN®, Huntsville, Alabama
AOCN® Chapter 7. Pretreatment Care
Oncology Clinical Nurse Specialist
UnityPoint Health—Trinity Michael Steinberg, PharmD, BCOP
Moline, Illinois Associate Professor of Pharmacy Practice
Chapter 9. Side Effects of Cancer Therapy Massachusetts College of Pharmacy and
Health Sciences University
Barbara Barnes Rogers, CRNP, MN, AOCN®, Worcester, Massachusetts
ANP-BC Chapter 4. Principles of Biotherapy
Adult Hematology-Oncology Nurse Practitioner
Fox Chase Cancer Center Wendy Stiver, RN, CCM, BSN, MA
Philadelphia, Pennsylvania Clinical Assessment Nurse–Case Manager
Chapter 9. Side Effects of Cancer Therapy Alere Health
Atlanta, Georgia
Lisa Schulmeister, MN, RN, ACNS-BC, OCN®, Chapter 1. Overview of Cancer and Cancer
FAAN Treatment
Oncology Nursing Consultant
New Orleans, Louisiana Barbara J. Wilson, MS, RN, AOCN®, ACNS-
Chapter 8. Infusion-Related Complications BC
Director, Oncology Professional Practice
Nonniekaye Shelburne, CRNP, MS, AOCN® WellStar Kennestone Regional Medical Center
Program Director Marietta, Georgia
National Cancer Institute Chapter 9. Side Effects of Cancer Therapy
Bethesda, Maryland
Chapter 3. Principles of Antineoplastic Therapy; Laura J. Zitella, MS, RN, ACNP-BC, AOCN®
Chapter 4. Principles of Biotherapy Lead Advanced Practice Provider, Hematology
and Oncology Nurse Practitioner
Brenda K. Shelton, MS, RN, CCRN, AOCN® Stanford University Medical Center
Clinical Nurse Specialist Stanford, California
Sidney Kimmel Comprehensive Cancer Center Chapter 10. Post-Treatment Care
Johns Hopkins Hospital
Baltimore, Maryland
Chapter 9. Side Effects of Cancer Therapy
Field Reviewers
Jill Benedeck, BSN, RN, OCN® Amy S. Coghill, MSN, RN, OCN®, CNL
Oncology Nurse Educator Instructional Designer
Centegra Health System Health Care Information Services Division
McHenry, Illinois University of North Carolina Health Care System
Chapel Hill, North Carolina
James Breedon, RN, BSN, OCN®, REMT-P
Nurse Educator S. Gayle Marble, BSN, RN, OCN®
Dendreon Corporation Director, Oncology Service Line Clinical Edu-
Albuquerque, New Mexico cation
Banner Health Clinical Education
Phoenix, Arizona
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Contributors v
Disclosure
Editors and authors of books and guidelines provided by the Oncology Nursing Society are ex-
pected to disclose to the readers any significant financial interest or other relationships with the
manufacturer(s) of any commercial products.
A vested interest may be considered to exist if a contributor is affiliated with or has a financial in-
terest in commercial organizations that may have a direct or indirect interest in the subject matter.
A “financial interest” may include, but is not limited to, being a shareholder in the organization; be-
ing an employee of the commercial organization; serving on an organization’s speakers bureau; or
receiving research from the organization. An “affiliation” may be holding a position on an advisory
board or some other role of benefit to the commercial organization. Vested interest statements ap-
pear in the front matter for each publication.
Contributors are expected to disclose any unlabeled or investigational use of products discussed
in their content. This information is acknowledged solely for the information of the readers.
The contributors provided the following disclosure and vested interest information:
Martha Polovich, PhD, RN, AOCN®: BD, ICU Medical, honoraria
Kristine B. LeFebvre, MSN, RN, AOCN®: American Nurses Credentialing Center, employment or
leadership position
Alice S. Kerber, MN, APRN, ACNS-BC, AOCN®, APNG: Pfizer, honoraria
Barbara Barnes Rogers, CRNP, MN, AOCN®, ANP-BC: Millennium, Seattle Genetics, Teva, hono-
raria
Lisa Schulmeister, MN, RN, ACNS-BC, OCN®, FAAN: American Society of Clinical Oncology QCP™
Program, Intellisphere, consultant
Barbara J. Wilson, MS, RN, AOCN®, ACNS-BC: Amgen, honoraria
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table of Contents
Preface........................................................................................................ ix
Abbreviations Used.......................................................................................... xi
Chapter 1. Overview of Cancer and Cancer Treatment..................................................1
A. Definition of cancer...................................................................................................................1
B. Cancer grading and staging......................................................................................................2
C. Cancer treatment modalities ....................................................................................................3
D. Treatment approaches..............................................................................................................5
E. Treatment strategies.................................................................................................................6
F. Goals of cancer therapy: Treatment planning includes discussion with patients about their goals
of therapy and whether those goals are realistic (Skeel, 2011b)...............................................7
G. Measuring response.................................................................................................................7
H. Factors affecting treatment response .....................................................................................10
References.....................................................................................................................................13
Chapter 2. Drug Development and Clinical Trials..................................................... 17
A. Development of new cytotoxic and other therapeutic agents..................................................17
B. Clinical trials involving humans..............................................................................................17
C. Expedited approval..................................................................................................................23
References.....................................................................................................................................23
Chapter 3. Principles of Antineoplastic Therapy....................................................... 25
A. Life cycle of cells....................................................................................................................25
B. Chemotherapeutic agents.......................................................................................................25
References.....................................................................................................................................48
Chapter 4. Principles of Biotherapy...................................................................... 51
A. Immunology...........................................................................................................................51
B. Types of immune response ....................................................................................................51
C. Cells of the immune system....................................................................................................54
D. Tumor escape mechanisms....................................................................................................55
E. Overview of biologic therapies................................................................................................56
F. Categories of biotherapy ........................................................................................................56
G. Radioimmunotherapy.............................................................................................................58
H. Therapeutic uses for biotherapeutic agents............................................................................60
I. Supportive uses for biotherapeutic agents..............................................................................60
J. Biotherapeutic strategies........................................................................................................60
K. Angiogenesis and antiangiogenic agents................................................................................93
References.....................................................................................................................................94
Chapter 5. Nursing Considerations in Cancer Treatment............................................. 97
A. Ethical issues..........................................................................................................................97
B. Legal issues related to cancer therapy....................................................................................99
C. Safety standards for antineoplastic administration...............................................................100
D. Patient safety........................................................................................................................100
E. Safe handling and disposal of hazardous drugs....................................................................102
References...................................................................................................................................115 vii
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
viii Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Chapter 6. Administration Considerations.............................................................121
A. Routes of administration.......................................................................................................121
B. Adherence to therapy............................................................................................................129
C. Pretreatment nursing assessment........................................................................................130
References...................................................................................................................................133
Chapter 7. Pretreatment Care............................................................................137
A. Patient education..................................................................................................................137
B. Verification and maintenance of treatment as planned..........................................................139
References...................................................................................................................................151
Chapter 8. Infusion-Related Complications...........................................................155
A. Types of infusion complications............................................................................................155
B. Extravasation........................................................................................................................155
C. Irritation................................................................................................................................161
D. Flare reaction........................................................................................................................163
E. Acute infusion reactions.......................................................................................................163
F. Patient and caregiver education ...........................................................................................167
References...................................................................................................................................168
Chapter 9. Side Effects of Cancer Therapy.............................................................171
A. Myelosuppression.................................................................................................................171
B. Gastrointestinal and mucosal side effects.............................................................................190
C. Cutaneous toxicity................................................................................................................231
D. Alopecia ...............................................................................................................................250
E. Cardiovascular toxicity..........................................................................................................255
F. Pulmonary toxicity ...............................................................................................................287
G. Hemorrhagic cystitis.............................................................................................................318
H. Hepatotoxicity.......................................................................................................................321
I. Nephrotoxicity.......................................................................................................................329
J. Neurotoxicity.........................................................................................................................337
K. Cognitive impairment............................................................................................................347
L. Ocular toxicity.......................................................................................................................365
M. Pancreatitis...........................................................................................................................375
N. Fatigue..................................................................................................................................377
O. Alterations in sexuality..........................................................................................................383
P. Reproductive alterations.......................................................................................................388
References...................................................................................................................................391
Chapter 10. Post-Treatment Care .......................................................................437
A. Overview...............................................................................................................................437
B. Survivorship care .................................................................................................................437
C. Late effects of cancer treatment............................................................................................438
D. Types of late effects..............................................................................................................440
E. Risk of late effects for patients with select primary cancers.................................................451
F. Collaborative management ...................................................................................................454
G. Nursing assessment ............................................................................................................455
H. Preventive screening recommendations and follow-up care.................................................455
I. Patient and family education ................................................................................................456
J. Professional education..........................................................................................................456
References...................................................................................................................................457
Chapter 11. Competence in Chemotherapy Administration.........................................461
A. Professional education..........................................................................................................461
B. Policies and procedures........................................................................................................463
C. Sample documentation tools................................................................................................463
References...................................................................................................................................464
Appendices.................................................................................................465
Index.........................................................................................................473
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Preface
Welcome to the fourth edition of the Oncology Nursing Society’s (ONS’s) Chemo-
therapy and Biotherapy Guidelines and Recommendations for Practice. This book comes
more than 30 years after ONS published its first chemotherapy guidelines. Oncology
nursing practice related to pharmacologic cancer treatment has changed significant-
ly over the years. Not only do more patients undergo drug treatment for cancer to-
day compared to patients diagnosed a generation ago, but patients’ survival time has
increased, making them more likely to receive treatment over extended periods of
time. The need for evidence-based guidelines for nurses administering chemothera-
py and biotherapy is greater than ever.
This new edition incorporates a number of significant changes. The content has
been reorganized and is divided into 11 chapters, with references appearing at the
end of each chapter. We hope that this new way of organizing the material will make
it easier to locate information. The section related to nursing considerations now in-
corporates the American Society of Clinical Oncology/ONS Chemotherapy Adminis-
tration Safety Standards (Neuss et al., 2013). All nurses who administer antineoplas-
tic agents must familiarize themselves with and adapt their practices to conform to
these standards. Patient education content has been expanded to emphasize its im-
portance to patient care. The cancer treatment section includes information about
sequencing of chemotherapy agents. The chapter on nursing management of treat-
ment side effects has been updated to reflect existing evidence.
Patients expect nurses to possess the knowledge and skills to provide excellent
care. It is difficult for nurses caring for patients receiving chemotherapy, biotherapy,
and targeted agents to keep up with treatment-related information. These guidelines
are as current as possible with respect to approved drugs, standards of practice, and
available evidence. As always, oncology nurses are encouraged to update their knowl-
edge on an ongoing basis.
The editors want to thank all the contributors to this edition and all the previous
editions of the guidelines. This work builds on the expertise of a whole generation
of “chemo nurses.” We are proud to be a part of this dedicated group of profession-
als. We hope these guidelines serve as an essential resource for practicing oncology
nurses today.
Neuss, M.N., Polovich, M., McNiff, K., Esper, P., Gilmore, T., LeFebvre, K.B., … Jacobson, J. (2013).
2013 updated American Society of Clinical Oncology/Oncology Nursing Society chemothera-
py administration safety standards including standards for the safe administration and manage-
ment of oral chemotherapy. Oncology Nursing Forum, 40, 225–233. doi:10.1188/13.ONF.40-03AP2
ix
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Abbreviations Used
ACE—angiotensin-converting enzyme DHHS—U.S. Department of Health and Human
ADH—antidiuretic hormone Services
AHRQ—Agency for Healthcare Research and DIC—disseminated intravascular coagulation
Quality DLCO—diffusing capacity of the lung for car-
AJCC—American Joint Committee on Cancer bon monoxide
AKI—acute kidney injury DNA—deoxyribonucleic acid
AML—acute myeloid leukemia ECG—electrocardiogram
ANC—absolute neutrophil count ECM—extracellular matrix
APHON—Association of Pediatric Hematology/ ECOG—Eastern Cooperative Oncology Group
Oncology Nurses EGF—epidermal growth factor
APL—acute promyelocytic leukemia EGFR—epidermal growth factor receptor
ARB—angiotensin receptor blocker EGFRI—epidermal growth factor receptor in-
ASCO—American Society of Clinical Oncology hibitor
ASHP—American Society of Health-System 18
F-FDG—fluorine-18 fluorodeoxyglucose
Pharmacists EORTC—European Organization for Research
ATI—acute tubular injury and Treatment of Cancer
ATRA—all-trans-retinoic acid EPO—erythropoietin
AUC—area under the time-versus-concentra- ER—estrogen receptor
tion curve ESA—erythropoiesis-stimulating agent
BMT—bone marrow transplantation estCrCl—estimated creatinine clearance
BSA—body surface area FDA—U.S. Food and Drug Administration
BSC—biologic safety cabinet 5-FU—5-fluorouracil
BUN—blood urea nitrogen 5-HT3—5-hydroxytryptamine-3 (serotonin)
CACI—compounding aseptic containment iso- G—gap phase (G0, G1, G2)
lator G-CSF—granulocyte–colony-stimulating factor
CAM—complementary and alternative medicine GFR—glomerular filtration rate
CBC—complete blood count GI—gastrointestinal
CD—cluster of differentiation GM-CSF—granulocyte macrophage–colony-
CDC—Centers for Disease Control and Pre- stimulating factor
vention GVHD—graft-versus-host disease
CDK—cyclin-dependent kinase Gy—gray (radiation unit)
CHF—congestive heart failure H—histamine (H1, H2)
CI—confidence interval HC—hemorrhagic cystitis
CIN—chemotherapy-induced neutropenia Hct—hematocrit
CINV—chemotherapy-induced nausea and HD—hazardous drug
vomiting HEPA—high-efficiency particulate air
CKD—chronic kidney disease HER2—human epidermal growth factor recep-
CMS—Centers for Medicare and Medicaid Ser- tor 2
vices Hgb—hemoglobin
CN—cranial nerve HIF-1—hypoxia-inducible factor-1
CNS—central nervous system HIV—human immunodeficiency virus
COG—Children’s Oncology Group HL—Hodgkin lymphoma
CrCl—creatinine clearance HPV—human papillomavirus
CSF—colony-stimulating factor HSC—hematopoietic stem cell
CSTD—closed-system transfer device HSCT—hematopoietic stem cell transplantation
CT—computed tomography IARC—International Agency for Research on
CTCAE—Common Terminology Criteria for Ad- Cancer
verse Events IC—informed consent
CTEP—Cancer Therapy Evaluation Program IFN—interferon
(NCI) IFRT—involved-field radiation therapy
CTLA-4—cytotoxic T-lymphocyte antigen 4 Ig—immunoglobulin (IgA, IgD, IgE)
CTZ—chemoreceptor trigger zone IL—interleukin
CVC—central venous catheter ILD—interstitial lung disease
CVD—cardiovascular disease IM—intramuscular
xi
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
xii Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
INR—international normalized ratio PEC—primary engineering control
IP—intraperitoneal PEG—polyethylene glycol
IRB—institutional review board PEP—Putting Evidence Into Practice (ONS)
IT—intrathecal PERCIST—Positron Emission Tomography Re-
IV—intravenous sponse Criteria in Solid Tumors
KPS—Karnofsky Performance Status PET—positron-emission tomography
LFT—liver function test P-gp—P-glycoprotein
LLN—lower limit of normal PPE—personal protective equipment
LVEF—left ventricular ejection fraction PR—progesterone receptor
M—mitosis phase PRES—posterior reversible encephalopathy
mAb—monoclonal antibody syndrome
MASCC—Multinational Association of Support- PT—prothrombin time
ive Care in Cancer PTT—partial thromboplastin time
mcl—microliter QOL—quality of life
MDA—University of Texas MD Anderson Can- RBC—red blood cell
cer Center (classification system) RDI—relative dose intensity
MDR—multidrug resistance RECIST—Response Evaluation Criteria in Sol-
MDS—myelodysplastic syndrome id Tumors
MHC—major histocompatibility complex RIT—radioimmunotherapy
MLL—mixed lineage leukemia RR—relative risk
MMP—matrix metalloproteinase RSO—radiation safety officer
MOPP—mechlorethamine, vincristine, procar- S—synthesis phase
bazine, and prednisone SC—subcutaneous
MRI—magnetic resonance imaging SCr—serum creatinine
mRNA—messenger ribonucleic acid SDS—safety data sheet
mTOR—mammalian target of rapamycin SIADH—syndrome of inappropriate antidiuret-
MUGA—multigated acquisition ic hormone
NCCN—National Comprehensive Cancer Net- SMN—second malignant neoplasm
work TC—cytotoxic T cell
NCI—National Cancer Institute TEC—toxic erythema of chemotherapy
NF-кB—nuclear factor-кB TH—helper T cell (TH1, TH2)
NHL—non-Hodgkin lymphoma TLS—tumor lysis syndrome
NIH—National Institutes of Health TM—memory T cell
NIOSH—National Institute for Occupational TNF—tumor necrosis factor
Safety and Health TNM—tumor, node, metastasis
NK—natural killer Treg—regulatory T cell
NK1—neurokinin-1 TS—suppressor T cell
NKT—nature killer T USP—U.S. Pharmacopeial Convention
NP—nurse practitioner UV—ultraviolet (UVA, UVB)
NRC—U.S. Nuclear Regulatory Commission VAD—vascular access device
NSAID—nonsteroidal anti-inflammatory drug VC—vomiting center
n/v—nausea and vomiting VEGF—vascular endothelial growth factor
OHRP—Office for Human Research Protections VEGFR—vascular endothelial growth factor re-
ONS—Oncology Nursing Society ceptor
OSHA—Occupational Safety and Health Ad- VOD—veno-occlusive disease
ministration VTE—venous thromboembolism
PABA—para-aminobenzoic acid WBC—white blood cell
PDE5—phosphodiesterase-5 WHO—World Health Organization
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 1
Overview of Cancer and
Cancer Treatment
A. Definition of cancer
1. Clinically, cancer is a large group of malignant diseases with some or all
of the following characteristics (Eggert, 2010; Merkle, 2011).
a) Abnormal cell proliferation caused by a series of cellular and/or ge-
netic alterations or translocations
b) Lack of controlled growth and cell division that leads to the forma-
tion of tumors and invasion of tissues in proximity to tumor cells
c) Ability to spread (metastasize) to distant sites and establish second-
ary tumors
d) Ability to involve any tissue of the body
e) Evasion of natural cell death (apoptosis)
2. On the cellular and molecular levels, however, cancer is believed to be only
a few diseases (Eggert & Kasse, 2010) that result from faulty or abnormal
genetic expression caused by changes in deoxyribonucleic acid (DNA).
a) The transcription of DNA into a single strand of messenger ribonu-
cleic acid (mRNA) may be changed.
b) When abnormal mRNA exists, the sequence of amino acids is changed,
resulting in abnormal protein synthesis.
3. Multiple factors often interact, leading to the development of cancer. Normal
cells may undergo changes outlined by Eggert and Kasse (2010) because of
a) Spontaneous transformation: No causative agent is identified, but cel-
lular characteristics are typical of cancer cells.
b) Exposure to chemical or physical carcinogens: Environmental fac-
tors are continuously being studied. Chronic or occupational expo-
sure to substances such as asbestos, benzene, radiation, tobacco, arse-
nic, nickel, and some chemotherapeutic agents is implicated in can-
cer development. The National Institute for Occupational Safety and
Health (NIOSH) and other organizations have identified more than
100 substances as carcinogens, with the listings continually evaluated
and revised (International Agency for Research on Cancer [IARC],
2013; National Toxicology Program, 2011; U.S. Department of Health
and Human Services [DHHS], 2012).
c) Genetic alterations: Mutations are permanent changes in the sequenc-
ing of DNA base pairs resulting in a cell with malignant properties.
Some mutations are of no concern, whereas others lead to tumor for-
mation (Eggert & Kasse, 2010; Merkle, 2011).
(1) A small percentage of cancers are caused by mutations inherit-
ed between generations in germ cells (sperm and ova).
(2) Most cancers are sporadic and caused by a series of acquired
mutations over time.
d) Exposure to viruses: Genetic changes can occur to cells through vi-
ral infections. For example, the human papillomavirus (HPV) is the
primary cause of cervical cancer (Fair, 2011). 1
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
2 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
4. Figure 1 provides a summary of genetic changes that may result in tu-
mor formation. The properties of transformed cells are changes in the
cytology, cell membrane, and growth and development.
Figure 1. Clonal Evolution in Cancer
Variant 1 Variant 2 Variant 3
Normal
P clone T
Selective growth Selective growth Continuing
advantage of clone advantage of clone evolution of
with first mutation with first and second variant
mutations subpopulations
Carcinogen First mutation Second mutation Third mutation
Specific genetic alterations in evolving tumors may range from gene mutations to major chromosomal aberrations. This figure illustrates
a carcinogen-induced genetic change in a progenitor normal cell (P), which produces a cell with selective growth advantage allowing
clonal expansion to begin. In this case, gene mutations produce variant cells. Because they are at a disadvantage metabolically or im-
munologically, most variant cells are nonviable. If one variant has a selective advantage, its progeny become the predominant subpop-
ulation until another variant appears. The sequential selection of variant subpopulations in each tumor (T) differs because of genetic in-
stability, which positively or negatively affects cell proliferation.
Note. From “Biology of Cancer” (p. 7), by C.J. Merkle in C.H. Yarbro, D. Wujcik, and B.H. Gobel (Eds.), Cancer Nursing: Principles and Practice (7th ed.),
2011, Burlington, MA: Jones and Bartlett. Copyright 2011 by Jones and Bartlett. Reprinted with permission.
B. Cancer grading and staging
1. Differentiation and grading: Cellular differentiation is based on how
closely tumor cells resemble normal cells in their structure and maturi-
ty. Differentiation is graded using the following scale.
a) GX—grade cannot be assessed
b) G1—well differentiated (resembles the parent cell)
c) G2—moderately well differentiated
d) G3—poorly differentiated (bears little resemblance to the parent cell)
e) G4—undifferentiated (impossible to tell which cell is the parent)
f) Cells are obtained by biopsy or surgical removal for microscopic ex-
amination by a pathologist. Cancer cells appear different from those
of the surrounding normal tissue. Tumor differentiation can vary over
time, and cells with several grades of differentiation can exist with-
in a single tumor. Tumor grade is a prognostic indicator. The higher
the grade, the more aggressive the tumor (American Joint Commit-
tee on Cancer [AJCC], 2010; Vogel, 2011).
2. Staging: The purpose of staging is to verify the extent of the disease by
assessing the location and size of the primary tumor and determining
if it has spread to other tissues or organs. Staging assists in determining
prognosis, treatment planning, identification of suitable clinical trials,
and treatment response. Staging provides a common language with which
the healthcare team can communicate about a patient’s case. Staging cri-
teria are unique for each type of cancer (AJCC, 2010; National Cancer
Institute [NCI], 2013).
a) AJCC (2010) describes three types of staging: clinical (based on phys-
ical examination, imaging, and biopsy), pathologic (based on infor-
mation obtained during surgery), and restaging (completed upon
disease recurrence).
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 1. Overview of Cancer and Cancer Treatment 3
b) The tumor, node, metastasis (TNM) staging system is maintained
jointly by AJCC and the Union for International Cancer Control. It
is used commonly with solid tumors and classifies cancers by the fol-
lowing three criteria. Additional information about cancer staging is
available online at www.cancerstaging.org (AJCC, 2010; Vogel, 2011).
(1) T—tumor (local involvement, invasion): The primary tumor
is measured to document its size and to determine the depth
of invasion.
(2) N—node (nodal involvement): Lymph nodes in the area of the
primary tumor are examined for evidence of tumor cells. Lymph
node size, number, and location are documented.
(3) M—metastasis: Studies are done to determine if the primary tu-
mor has metastasized to a distant location.
c) Lymphomas, leukemias, and multiple myeloma are hematologic ma-
lignancies that are staged according to other systems. For example, the
Ann Arbor staging classification is used to stage Hodgkin lymphoma
(HL), and the International Staging System is used for multiple my-
eloma (Gospodarowicz, 2009; Tariman & Faiman, 2011; Vogel, 2011).
d) Childhood cancers may be staged by the TNM system or by criteria
from the Children’s Oncology Group (COG), which conducts clini-
cal trials in pediatric oncology (NCI, 2013).
e) Some gynecologic cancers are staged using the International Feder-
ation of Gynecology and Obstetrics, or FIGO, system.
f) Prognostic information is provided by an increasing number of non-
anatomic factors that may predict the effectiveness of specific thera-
pies. Gender, overall health status, and specific biologic properties of
tumor cells are characteristics that may affect patient outcomes and
have been incorporated into some staging algorithms (AJCC, 2010).
C. Cancer treatment modalities
1. Table 1 summarizes the history of cancer therapy. A variety of modali-
ties are used to treat cancer. Treatment may include one or more of the
following interventions.
Table 1. History of Cancer Therapy
Period Events
Pre-20th century 1500s: Heavy metals are used systemically to treat cancers; however, their effectiveness is limited and their
toxicity is great (Burchenal, 1977).
1890s: William Coley, MD, develops and explores the use of Coley toxins, the first nonspecific immunostimu-
lants used to treat cancer.
World War I Sulfur-mustard gas is used for chemical warfare; servicemen who are exposed to nitrogen mustard experi-
ence bone marrow and lymphoid suppression (Gilman, 1963; Gilman & Philips, 1946).
World War II Congress passes National Cancer Act in 1937, establishing the National Cancer Institute (NCI).
Alkylating agents are recognized for their antineoplastic effect (Gilman & Philips, 1946).
Thioguanine and mercaptopurine are developed (Guy & Ingram, 1996).
1946: NCI-identified cancer research areas include biology, chemotherapy, epidemiology, and pathology.
1948: Divisions within NCI and external institutions are identified to conduct research (Zubrod, 1984).
Folic acid antagonists are found to be effective against childhood acute leukemia (Farber et al., 1948).
Antitumor antibiotics are discovered.
1950s 1955: The National Chemotherapy Program, developed with Congressional funding, is founded to develop
and test new chemotherapy drugs.
1957: Interferon is discovered.
The Children’s Cancer Group, the first cooperative group dedicated to finding effective treatments for pediat-
ric cancer, is formed.
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
4 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Table 1. History of Cancer Therapy (Continued)
Period Events
1960s–1970s Development of platinum compounds begins.
Multidrug therapy improves remission rates without severe toxicity; mechlorethamine, vincristine, procarba-
zine, and prednisone (MOPP), the first combination chemotherapy, is used and found to be curative against
Hodgkin disease (Noonan, 2007).
Clinical trials of bacillus Calmette-Guérin and Corynebacterium parvum, nonspecific immunostimulants, be-
gin.
Chemotherapy is used with surgery and radiation as cancer treatment.
Development of hybridoma technology begins.
NCI starts its Biological Response Modifiers Program.
Tamoxifen is synthesized in 1962 and first used in 1969.
1970s The National Cancer Act of 1971 provides funding for cancer research; NCI director is appointed by and re-
ports to the president of the United States.
Doxorubicin phase I trials begin.
Adjuvant chemotherapy begins to be a common cancer treatment (Bonadonna et al., 1985; Fisher et al.,
1986).
1980s Community Clinical Oncology Programs are developed in 1983 to contribute to NCI chemotherapy clinical tri-
als.
Use of multimodal therapies increases (Eilber et al., 1984; Marcial et al., 1988).
Focus turns to symptom management to alleviate dose-limiting toxicities related to neutropenia, nausea and
vomiting, and cardiotoxicity.
Clinical trials for dexrazoxane (ICRF-187) as a cardioprotectant begin (Speyer et al., 1988).
New chemotherapeutic agents are available.
Scientists begin to investigate recombinant DNA technology.
Trials of monoclonal antibodies and cytokines begin.
Effector cells (lymphokine-activated killer cells and tumor-infiltrating lymphocytes) are grown ex vivo.
1986: U.S. Food and Drug Administration (FDA) approves interferon alfa.
1989: FDA approves erythropoietin.
1990s New classifications of drugs (e.g., taxanes) are developed.
In clinical trials, paclitaxel is found to be effective against ovarian and breast cancers (Rowinsky et al., 1992).
FDA approves granulocyte–colony-stimulating factor and granulocyte macrophage–colony-stimulating factor,
interleukin-2, interleukin-11, rituximab, trastuzumab, and denileukin diftitox.
Clinical trials of gene therapy and antiangiogenic agents begin.
FDA approves filgrastim for use in bone marrow transplantation and chemotherapy-induced neutropenia, se-
vere chronic neutropenia, and peripheral blood stem cell transplantation.
FDA approves ondansetron for prevention of chemotherapy-induced nausea and vomiting; other 5-hydroxy-
tryptamine-3 (5-HT3) receptor antagonists are in clinical trials (Perez, 1995).
As a result of improved symptom management, dose intensity becomes a focus.
FDA approves new analogs (e.g., vinorelbine) (Abeloff, 1995).
Scientists focus on the sequencing of agents (Bonadonna et al., 1995).
The genetic basis of cancers becomes an important factor in cancer risk research (e.g., BRCA1 for breast
cancer, renal cell cancer) (Gnarra et al., 1995; Hoskins et al., 1995; Miki et al., 1994).
Aromatase inhibitors are approved for breast cancer treatment. This marks a step forward for hormonal therapy.
2000–present The Children’s Oncology Group, a cooperative group combining the efforts of several groups, is formed to fur-
ther the advancement of cancer treatment for children (www.childrensoncologygroup.org).
Scientists complete a working draft of the human genome (American Society of Clinical Oncology [ASCO],
n.d.).
Theory of immune surveillance continues, and biotherapy is used to target and mount a defense against cer-
tain antigens on malignant cells (e.g., gemtuzumab ozogamicin binds to CD33 on leukemic cells, rituximab
binds to CD20-positive non-Hodgkin lymphoma cells).
Radioimmunotherapy is used to deliver radioactivity directly to select tumor cells, avoiding damage to healthy
tissue (e.g., ibritumomab tiuxetan, tositumomab I-131).
FDA approves targeted therapies attacking epidermal growth factor receptor for lung cancer (gefitinib and er-
lotinib) and colon cancer (cetuximab and panitumumab) (ASCO, n.d.).
FDA approves antiangiogenic agents (bevacizumab was the first) (ASCO, n.d.).
Neurokinin-1 antagonist (aprepitant) is used in combination with other antiemetic drugs to prevent chemother-
apy-induced nausea and vomiting.
Therapeutic vaccine trials are begun for existing cancers (e.g., OncoVAX®, an autologous tumor cell vaccine,
is in phase III studies for stage II colon cancer), and FDA approves a prophylactic vaccine (Gardasil®) for the
prevention of human papillomavirus infections that cause cervical cancer (ASCO, n.d.).
2010: Affordable Care Act is signed into law.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 1. Overview of Cancer and Cancer Treatment 5
2. Surgery (Drake & Lynes, 2010; Gillespie, 2011)
a) Is a precise local treatment
b) May remove all or a portion of the primary tumor
c) Can be used to obtain specimens for cytopathology
d) May be the only treatment a patient requires
e) May be preceded or followed by other modalities
f) May be used in the palliative setting to alleviate or lessen intolera-
ble symptoms
3. Radiation therapy (Gosselin, 2011; Kelvin, 2010)
a) Is a local treatment in which energy is precisely directed at a specif-
ic target
b) May follow surgery to prevent recurrence of the primary tumor
c) Is more effective for some diseases than others
d) Is sometimes used after chemotherapy because radiation can perma-
nently damage bone marrow, making it impossible to give chemother-
apy in the doses needed for curative therapy
e) Is often given in combination with chemotherapy (chemoradiation)
f) May be given as radioimmunotherapy (RIT), combining a radioiso-
tope and a monoclonal antibody (mAb)
4. Chemotherapy/hormonal therapies (Levine, 2010; Tortorice, 2011)
a) Are systemic therapies, rather than local treatments, as drugs are dis-
tributed throughout the body by the bloodstream
b) May be used as single agents or, more commonly, in combination
c) Are limited by toxic effects on normal tissues
d) May have a tumoricidal effect in hormone-sensitive tumors because
of reduction or blockage of the source of the hormone or receptor
site where hormone is active
5. Biotherapy/targeted agents (Lapka & Franson, 2010)
a) Are systemic treatments
b) May modify the patient’s own immune defenses
c) May be so specific as to target a single receptor on the surface of tu-
mor cells or an enzyme within the cell
d) May cause side effects and toxicities different from those of other an-
tineoplastic agents
e) May be combined with other treatment modalities
f) May promote tumor regression
g) May stimulate hematopoiesis
D. Treatment approaches
1. Neoadjuvant therapy: The use of one or more treatment modalities pri-
or to the primary therapy (e.g., chemotherapy before surgery). Goal is
to shrink the primary tumor to improve the effectiveness of surgery or
decrease the likelihood of micrometastases (Otto, 2007). In cases of lo-
cally advanced breast tumors, using neoadjuvant therapy may increase
the possibility for breast conservation.
2. Adjuvant therapy: Therapy following the primary treatment modality
(e.g., chemotherapy or radiation after surgery). The goal of adjuvant
therapy is to target minimal disease or micrometastases for patients at
high risk for recurrence (Otto, 2007).
3. Conditioning or preparative therapy: Administration of chemotherapy,
sometimes with total body irradiation, to eliminate residual disease or
empty the marrow space prior to receiving a stem cell transplant (also
referred to as myeloablation).
a) Myeloablation: Obliteration of bone marrow with chemotherapeutic
agents typically administered in high doses in preparation for periph-
eral blood stem cell or bone marrow transplantation (BMT). Myeloab-
lative therapy does not allow for spontaneous marrow recovery because
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
6 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
of the lethal doses of agents used; therefore, it must be followed by
stem cell transplantation to prevent death. An example of myeloabla-
tive therapy is cyclophosphamide plus total body irradiation or busul-
fan plus cyclophosphamide (National Marrow Donor Program, 2012).
b) Nonmyeloablative: Reduced-intensity conditioning using doses that
are not lethal to bone marrow (Poliquin, 2007). Use of nonmyeloabla-
tive regimens has expanded the number of patients eligible for trans-
plantation (National Marrow Donor Program, 2012).
4. Immunosuppression: Administration of chemotherapy at doses suffi-
cient to blunt a patient’s immune response. This is done prior to trans-
plantation to prevent graft rejection in allogeneic stem cell transplant
recipients. Agents such as methotrexate are given post-transplantation
to prevent graft-versus-host disease (GVHD). Certain agents are given
for immunosuppression to treat noncancerous conditions, such as au-
toimmune diseases.
E. Treatment strategies
1. Combination versus single-agent therapy (Tortorice, 2011): A combina-
tion of drugs is more effective in producing responses and prolonging life
than the same drugs used sequentially. With combination therapy, more
cancer cells are exposed in a sensitive phase, resulting in higher tumor
cell kill. Moreover, “with rare exceptions, . . . single drugs at clinically tol-
erable doses have been unable to cure cancer” (Chu & DeVita, 2013, p. 3).
a) Tumor cell populations are heterogeneous; therefore, a combination
of agents with different mechanisms of action is able to increase the
proportion of cells killed at any one time.
b) Combination agents with different mechanisms of action also reduce
the possibility of drug resistance, theoretically minimizing the chanc-
es for outgrowth of resistant clones (Skeel, 2011a).
c) Agents selected for use in combination chemotherapy have proven
efficacy as single agents.
d) Combination chemotherapy may use the principle of drug synergy to
maximize the effects of another drug. Synergy is affected by the rate of
tumor cell proliferation and by timing of drug administration (sequen-
tial or simultaneous; for example, leucovorin potentiates the cytotoxicity
of 5-fluorouracil [5-FU]) (Brown, in press). Combinations can be used
to provide access to sanctuary sites for reasons such as drug solubility
or affinity of specific tissues for a particular drug type (Skeel, 2011a).
e) Drugs with similar toxicities generally are avoided, although this is
not always possible. For example, both paclitaxel and cisplatin can
cause peripheral neuropathy as single agents but often are used to-
gether (Argyriou et al., 2007).
2. Dosing of chemotherapy
a) Treatment cycles are designed to permit recovery from damage to nor-
mal tissues and organs. Because the average white blood cell (WBC)
nadir is 10–14 days, many regimens are based upon this time frame.
b) Administering a drug such as 5-FU at a steady concentration over a
period of time increases cell kill (Howland & Mycek, 2006).
c) Dose density refers to the drug dose per unit of time. Higher dose den-
sity is achieved by shortening the intervals between treatments (Freter,
2012). Reducing the time between chemotherapy cycles may dimin-
ish tumor regrowth. This strategy has resulted in longer survival for
patients with breast, ovarian, and colon cancers and lymphoma (Tor-
torice, 2011). The prophylactic use of the myeloid growth factor peg-
filgrastim has allowed for administration of dose-dense chemothera-
py regimens that would otherwise result in unacceptable neutropenia
(Burdette-Radoux et al., 2007; von Minckwitz et al., 2007).
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 1. Overview of Cancer and Cancer Treatment 7
d) Dose intensity is the amount of drug that is delivered over time. Nurs-
es should be aware that dose reduction or delay resulting from che-
motherapy side effects, scheduling conflicts, or any other reason re-
duces dose intensity and may negatively affect patient survival (Tor-
torice, 2011). Optimal cell kill is achieved by delivering sufficient dos-
es of chemotherapy at planned intervals.
e) Relative dose intensity is calculated by comparing the received dose
to the planned dose of the standard regimen. Proactively managing
symptoms and educating patients on the importance of maintaining
the prescribed dosing schedule are paramount. (See Chapter 7 for
further discussion of dosing concepts.)
F. Goals of cancer therapy: Treatment planning includes discussion with pa-
tients about their goals of therapy and whether those goals are realistic
(Skeel, 2011b).
1. Prevention (Mahon, 2010)
a) Primary cancer prevention: Measures taken to avoid carcinogen expo-
sure and promote health. Steps taken to prevent disease development
(e.g., avoidance of tobacco products, immunization against HPV).
(1) Chemoprevention: The use of selected pharmacologic agents
to prevent cancer in high-risk individuals, such as the adminis-
tration of tamoxifen to women whose personal health history
indicates they are at a statistically increased risk for developing
breast cancer (Brown, in press).
(2) There has been discussion related to the role of nutritional ep-
idemiology in the identification of nutritional or chemopre-
ventive approaches to colon cancer, but that has yet to be con-
firmed (Marshall, 2009).
b) Secondary cancer prevention: Early detection and treatment of cancer
c) Tertiary cancer prevention: Monitoring for and/or preventing recur-
rence of the original cancer or secondary malignancies
2. Cure: Defined as the prolonged absence of detectable disease. This is the
desired outcome for all patients but is not always achievable.
3. Control: When cure is not possible, the goal is to allow patients to live
longer than if therapy had not been given (Skeel, 2011b). Treatment
often extends life and may prevent the growth of cancer cells without
complete elimination of disease or may reduce existing disease (Gos-
selin, 2011).
4. Palliation: Palliative cancer care is the integration of therapies that ad-
dress the multiple issues that cause suffering in patients with cancer
and their families. In 2009, the American Society of Clinical Oncology
(ASCO) Board of Directors advocated that palliative care be offered to
all patients from the time of diagnosis to death (Ferris et al., 2009). Pal-
liation involves reduction of side effects and symptoms, including pain
(Brown, in press; Gaddis & Gullatte, in press). It may include surgery,
radiation therapy, chemotherapy, or biotherapy, individually or in com-
bination (Otto, 2007).
G. Measuring response
1. Measuring tumor response
a) Objective tumor response is assessed through a quantitative mea-
surement such as surgical examination, imaging studies, or serum
tumor markers. Measurements recorded at the time of diagnosis are
compared to those recorded after treatment completion. In 1981,
the World Health Organization (WHO) first published tumor re-
sponse criteria with overall assessment of tumor burden. Response
to therapy may be measured by survival, disease-free survival, ob-
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
8 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
jective change in tumor size or in tumor product, and subjective
change (Skeel, 2011a). With neoadjuvant therapy, tumor response
and resectability are partial determinants of effectiveness (Skeel,
2011a). The current end point for assessing response to therapy in
solid tumors is measuring change in tumor size (Kumar, Halanaik,
& Dahiya, 2010).
b) Tumor response has historically been classified using the following
system (Wahl, Jacene, Kasamon, & Lodge, 2009).
(1) Complete response: Absence of all signs and symptoms of can-
cer for at least one month using objective criteria (e.g., quanti-
tative bidimensional tumor measurement)
(2) Partial response: At least a 50% reduction of measurable tu-
mor mass for one month without development of new tumors
(3) Stable disease: A reduction in tumor mass of less than 50% or
less than a 25% increase in tumor growth
(4) Progressive disease: Growth of 25% or more or development of
new tumors. Note that this definition of progressive is negative,
in contrast to the standard English usage of the term.
(5) Relapse: After complete response, a new tumor appears or the
original tumor reappears. Following partial response, a new tu-
mor appears or the original tumor increases in size. See Table
2 for further information.
c) Response Evaluation Criteria in Solid Tumors (RECIST) guidelines
were developed in 1999 by an international task force including
the European Organization for Research and Treatment of Cancer
(EORTC), NCI, and the National Cancer Institute of Canada Clin-
ical Trials Group. The criteria were revised in 2008 and notated as
RECIST 1.1.
(1) Guidelines are intended to facilitate communication between re-
searchers and clinicians (Therasse, Eisenhauer, & Buyse, 2006).
(2) Considerable variation exists between the original RECIST and
WHO criteria for evaluating response (Mazumdar, Smith, &
Schwartz, 2004; Schwartz et al., 2006), as well as subsequent edi-
tions of RECIST. These variations create a challenge for evalu-
ating the effectiveness of therapies being studied in clinical tri-
als. For example, RECIST criteria may show tumor progression
more slowly than WHO criteria, and RECIST 1.1 criteria result
in a higher complete response rate than the original RECIST
criteria (Wahl et al., 2009).
2. WHO (Therasse et al., 2000) recognizes that diagnostic technologies
(e.g., computed tomography [CT] scans, magnetic resonance imaging
Table 2. Comparison of WHO and RECIST Criteria for Tumor Response
Response WHO RECIST 1.1
Complete response Absence of all known disease for at least 4 Disappearance of all target lesions
weeks
Partial response ≥ 50% reduction of measurable tumor mass for 30% reduction in the sum of the diameters of target le-
≥ 4 weeks without development of new tumors sions compared to the baseline
Progressive disease Growth of ≥ 25% or more, or development of 20% increase in the sum of diameters of target lesions
new tumors
Stable disease Unable to meet criteria for either partial re- Unable to meet criteria for either partial response or
sponse or progressive disease progressive disease
RECIST—Response Evaluation Criteria in Solid Tumors; WHO—World Health Organization
Note. Based on information from Eisenhauer et al., 2009; Wahl et al., 2009.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 1. Overview of Cancer and Cancer Treatment 9
[MRI]) have led to confusion regarding three-dimensional measurement
of disease. As a result, the reported response criteria vary among research
groups. See Table 2 for a comparison of WHO and RECIST criteria.
3. RECIST 1.1 guidelines
a) Response to a clinical trial is used to decide whether an agent or regi-
men demonstrated results promising enough to warrant further test-
ing (prospective end point).
b) Baseline lesions are characterized as measurable or nonmeasurable.
At baseline, tumors must be measurable in at least one dimension
(using metrics) by calipers or a ruler. Baseline measurements must
be obtained within four weeks of initiating therapy. Lesions may be
measured using CT or MRI, but CT is preferred in most cases because
of variability in MRI scan parameters. In the original RECIST, non-
measurable lesions included bone lesions, ascites, pleural or pericar-
dial effusions, leptomeningeal disease, and inflammatory breast can-
cer. RECIST 1.1 now accepts bone metastases and soft tissue mass-
es measuring 10 mm or larger as target lesions (Costelloe, Chuang,
Madewell, & Ueno, 2010).
c) The same method and technique used at baseline must be used to
evaluate response for reporting and follow-up.
d) If the primary end point is response to treatment, the patient must
have at least one measurable lesion at baseline. If only one measur-
able lesion is present, it must be confirmed by cytology or histology.
e) Measurable lesions, up to 5 per organ or 10 in total, are identified
as target lesions.
(1) Lesions selected are the longest in diameter and suitable for
follow-up measurement.
(2) The sum of the longest diameters for all target lesions is desig-
nated as the baseline sum longest diameter. This sum is used as the
reference to compare response (Skeel, 2011b).
(3) All other nontarget lesions are measured and recorded if possi-
ble. Their presence or absence can be noted for follow-up but
is not included in the response evaluation. For example, effu-
sions cannot be measured, nor can lesions with necrotic cen-
ters (Skeel, 2011b).
f) Using RECIST criteria: See Table 2.
(1) Time to progression is a valuable indicator in cases when treat-
ment results in disease stability despite failure to produce measur-
able shrinkage. This can be used as an indicator of disease status
when there is no measurable disease at the start of therapy, giv-
en the limitations of current RECIST 1.1 criteria (Skeel, 2011b).
(2) Follow-up should be protocol specific.
(a) Every other cycle (six to eight weeks) is reasonable for fol-
low-up.
(b) Patients who discontinue therapy because of deterioration
of their health condition without evidence of progressive
disease are identified as symptomatically deteriorated and not
included in the partial response, stable disease, or progres-
sive disease groups.
(c) At the conclusion of treatment, follow-up tests and schedules
are based on the goal of the study. If time to a specific event,
such as recurrence or death, is the primary end point of the
study, measurements must be compared to the baseline.
(d) The duration of overall response is measured from when
the measurement criteria were met for complete or par-
tial response until the first date a recurrence or progres-
sive disease was measured.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
10 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
(e) The duration of stable disease is the time from initiation of
therapy until the criteria are met for progressive disease.
g) Reporting using RECIST 1.1 results: All patients in a study are as-
sessed at the end of the study. Patients are assigned to one of the fol-
lowing categories.
(1) Complete response
(2) Partial response
(3) Stable disease
(4) Progressive disease
(5) Early death from disease
(6) Early death from toxicity
4. Glucose analog tracer, fluorine-18 fluorodeoxyglucose (18F-FDG),
positron-emission tomography (PET) scans: Used to assess tumor re-
sponse both qualitatively and quantitatively (Costelloe et al., 2010)
with PERCIST (Positron Emission Tomography Response Criteria in
Solid Tumors).
a) Used to capture and report fractional change in standardized up-
take value at intervals during and after treatment (Wahl et al., 2009)
b) 18F-FDG PET scans have lower sensitivity and specificity for non-small
cell lung cancer than previously published (Levitan, 2012).
5. MDA (University of Texas MD Anderson Cancer Center) classification:
Uses key imaging techniques to stratify patients with breast cancer with
bone-only metastases with respect to progression-free survival, overall
survival, and clinical response. Use of this classification may enable bone
lesions to be considered measurable disease (Hamaoka et al., 2010).
6. Measuring patient response: Performance status scales are used as part
of inclusion and exclusion criteria for clinical trials (Vogel, 2011). Table
3 compares three commonly used performance status scales.
a) Karnofsky Performance Status (KPS) scale: Evaluates adult perfor-
mance in terms of percentage; a lower score indicates poorer perfor-
mance (Karnofsky & Burchenal, 1949).
b) Eastern Cooperative Oncology Group (ECOG) and Zubrod scales:
Evaluate adult performance on a 0–5 scale; a higher score indicates
poorer performance (Oken et al., 1982).
c) WHO scale: Developed by the United Nations and includes perfor-
mance and toxicity grading.
d) Lansky Performance Scale: Developed specifically for use in children,
as the KPS scale often is not applicable in pediatric populations (Lan-
sky, List, Lansky, Ritter-Sterr, & Miller, 1987).
e) Quality of life (QOL): A partially independent measure of perfor-
mance determined based on the patient’s own perceptions. It has
been shown to be an independent predictor of tumor response and
survival in some cancers (Skeel, 2011a).
H. Factors affecting treatment response
1. Pretreatment comorbidities and performance status: Patients with co-
morbid conditions and those who have been heavily pretreated may be
less able to tolerate the side effects and toxicities of chemotherapy, thus
affecting dose intensity and treatment planning (Camp-Sorrell, 2011).
After tumor type, performance status or activity level is the most impor-
tant factor to consider when determining appropriate and tolerable
treatment. Patients who have poorer performance scores (e.g., bedrid-
den) may be unable to withstand the rigors of an aggressive treatment
regimen and may experience decreased QOL. Patients who are fully ac-
tive or have mild symptoms respond more frequently to treatment and
survive longer than those who are less active or experience more symp-
toms (Skeel, 2011b).
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 1. Overview of Cancer and Cancer Treatment 11
2. Tumor burden: The inverse relationship between the number of tu-
mor cells and response implies that the smaller the tumor, the higher
the rate of response (Tortorice, 2011). As tumor mass increases, the
growth rate slows, decreasing the effectiveness of antineoplastic ther-
apy. Additionally, large solid tumors may have inadequate blood flow,
which inhibits the ability of the chemotherapy to reach the entire tu-
mor (Tortorice, 2011).
3. Rate of tumor growth: Tumor doubling time (time for the tumor to dou-
ble in mass) and growth fraction (proportion of proliferating cells in rela-
tion to the total number of tumor cells) are important factors affecting
Table 3. Performance Status Scales
The Karnofsky Performance Status scale has been used in oncology, hospice, case management, and other healthcare settings since
1949. It is a tool for classifying patients on a scale from 0 to 100 according to their level of functional impairment. The Karnofsky scale is
designed for patients age 16 and older.
Rating Description
100 Normal; no complaints; no evidence of disease
90 Able to carry on normal activity; minor signs or symptoms of disease
80 Able to carry on normal activity with effort; some signs or symptoms of disease
70 Cares for self; unable to carry on normal activity or do active work
60 Requires occasional assistance but able to care for most personal needs
50 Requires considerable assistance and frequent medical care
40 Disabled; requires special care and assistance
30 Severely disabled; hospital admission indicated although death not imminent
20 Very sick; hospital admission necessary; active supportive treatment necessary
10 Moribund; fatal processes progressing rapidly
0 Dead
The Eastern Cooperative Oncology Group, World Health Organization, and Zubrod Performance Status scales also are used to classify
patient responses to treatment. These scales are designed for patients age 16 and older.
Grade Description
0 Fully active; able to carry on all predisease performance without restriction
1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (e.g.,
light housework, office work)
2 Ambulatory and capable of all self-care but unable to carry out any work activities; up and about more than 50% of wak-
ing hours
3 Capable of only limited self-care; confined to bed or chair more than 50% of waking hours
4 Completely disabled; cannot carry on any self-care; totally confined to bed or chair
5 Dead
The Lansky Performance Scale is used to classify pediatric patients (younger than 16 years old) according to functionality.
Score Description
100 Fully active
90 Minor restriction in physically strenuous play
80 Restricted in strenuous play; tires more easily, otherwise active
70 Both greater restrictions of and less time spent in active play
60 Ambulatory up to 50% of time; limited active play with assistance/supervision
50 Considerable assistance required for any active play; fully able to engage in quiet play
40 Able to initiate quiet activities
30 Needs considerable assistance for quiet activity
20 Limited to very passive activity initiated by others (e.g., watching TV)
10 Completely disabled, not even passive play
Note. Based on information from National Marrow Donor Program & Medical College of Wisconsin, 2009; Skeel, 2011b.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
12 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
response. Cytotoxic chemotherapy agents are most effective if given dur-
ing the growth phase of the tumor, when a high percentage of cells are
susceptible to the effects of that agent (Skeel, 2011a; Tortorice, 2011).
4. Hormone receptor status
a) Presence of estrogen receptors (ERs) and/or progesterone receptors
(PRs) is prognostic for breast cancer. Patients who are ER/PR posi-
tive demonstrate better overall survival rates (Yackzan, 2011). Tumors
that grow more rapidly in the presence of a specific hormone may be
suppressed with an antihormonal agent.
b) Hormone receptor status has become increasingly important in can-
cer therapy.
5. Drug resistance: Many patients experience relapse because tumors be-
come resistant to the drugs used to treat them (McDermott, Downing,
& Stratton, 2011).
a) Genetic instability of tumor cells and the emergence of drug resis-
tance are currently considered the most significant determinants of
tumor response to treatment (Tortorice, 2011).
b) Complex biochemical pathways involving a multitude of receptors
and enzymes are implicated and depend upon the type of cell and
chemotherapy agent (Tortorice, 2011).
c) Research points to a complex interaction among cytotoxic agents,
chemical messengers (transporters that deliver drugs to the tumor),
and the genetic ability of malignant cells to avoid chemotherapy-
induced apoptosis because of their high rate of genetic instability
(Gaddis & Gullatte, in press; Tortorice, 2011).
d) Genomic changes, originally presenting in small subclones of can-
cer cells, often underlie acquired resistance, such as ABL mutation
in chronic myeloid leukemia and MET in non-small cell lung cancer.
Genomic differences have an important role in determining how a
given cancer will respond to treatment (McDermott et al., 2011).
e) Tumor cells may be inherently resistant to antineoplastic agents or de-
velop resistance after drug exposure because of the emergence of re-
sistant clones. Single-agent resistance or multidrug resistance (MDR)
can occur and may be caused by a number of factors.
(1) Insufficient dosing may lead to the development of resistant
cell clones arising from random mutations in cellular DNA.
(2) Chemotherapy may kill sensitive cells while sparing cells resis-
tant to treatment administered (Tortorice, 2011).
(3) MDR occurs when malignant cells are exposed to cytotoxic agents
possessing dissimilar mechanisms of action and appears to be
caused by mutations in the malignant cells’ regulatory system
(Tortorice, 2011). Several pathways are thought to be respon-
sible for MDR, including alterations in the metabolism of che-
motherapy within the tumor, the ability of tumor cells to repair
damaged DNA (thus bypassing apoptosis), and decreased up-
take by formerly susceptible cells (Tortorice, 2011). MDR path-
ways include the following.
(a) Overexpression of the MDR1 gene, which encodes for the
cell membrane efflux pump P-glycoprotein (P-gp), is be-
lieved to cause resistance by its ability to remove toxic mol-
ecules (e.g., chemotherapy) from inside the cell before the
drug can reach the DNA. The presence of P-gp is a poor
prognostic indicator (Gonzalez-Angulo et al., 2007; Tor-
torice, 2011).
(b) Resistance to topoisomerase drugs (e.g., doxorubicin) can oc-
cur when the tumor develops the ability to change the bind-
ing properties of topoisomerase enzymes (Tortorice, 2011).
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 1. Overview of Cancer and Cancer Treatment 13
(c) MDR can occur from increased levels of normally protec-
tive enzymes (e.g., glutathione S-transferase), which facil-
itate the elimination of platinum compounds and alkylat-
ing agents from malignant cells (Tortorice, 2011).
(4) Impaired metabolism may result in reduced drug activation or
increased drug deactivation.
(5) Other types of resistance
(a) Acquired resistance is the result of further mutations af-
ter exposure to additional drugs and nongenetic mech-
anisms (Lackner, Wilson, & Settleman, 2012). KRAS mu-
tations contribute to the acquired resistance of colorec-
tal cancers treated with agents targeted against epidermal
growth factor receptor (EGFR). KRAS mutations account
for 40%–50% of relapses among patients with colorectal
cancers (Azvolinsky, 2012).
(b) Emergent resistance occurs after the affected cells survive an
exposure to an environmental carcinogen (e.g., tobacco).
(c) Cells may be temporarily less responsive because of chang-
es in environment or stimuli or may have permanent resis-
tance (Freter & Goldie, 2012).
(d) Poor blood supply to the tumor may cause temporary re-
sistance, which prevents delivery of a therapeutic dose of
drug (Tortorice, 2011).
(6) Overcoming drug resistance remains a high priority. Recurrenc-
es are presumably attributed to the inability to assess which tu-
mors are resistant to treatment when administering in an ad-
juvant setting (Dawood et al., 2008). Researchers continue to
look for ways to deactivate P-gp in malignant cells and to iden-
tify new agents that alter the apoptotic pathways, increase the
effectiveness of current chemotherapy, and interact with spe-
cific characteristics associated with the DNA in malignant cells
(Barton-Burke & Wilkes, 2006).
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Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 2
Drug Development and
Clinical Trials
A. Development of new cytotoxic and other therapeutic agents: Although there
is a sense of urgency to develop new and better therapies, protection of the
public is paramount. Steps to develop new anticancer agents are complex,
as well as time and resource consuming. NCI, a division of the National In-
stitutes of Health (NIH), examines thousands of agents each year to discov-
er new ones for testing. Only a small percentage are selected for preclini-
cal testing, and even fewer are tested in phase I clinical trials (see Table 4).
1. Preclinical studies: Laboratory research using animal models often is
conducted collaboratively by NCI and pharmaceutical companies. The
NCI Cancer Therapy Evaluation Program (CTEP) seeks pharmaceuti-
cal sponsorship early once an agent is discovered because NCI does not
market new agents. Pharmaceutical companies may seek CTEP codevel-
opment (Humphrey et al., 2011).
2. Preclinical studies involve laboratory analysis and animal subjects; they
do not involve human subjects (Wong, Bales, & Hurtado, in press).
a) Scientists undertake empirical or rational research to develop a new
agent or a derivative of an existing agent that is more effective, has
fewer side effects, or is less toxic than existing agents.
b) The new agent is tested in vitro in various tumor cell lines. If the agent
is effective, scientists perform in vivo testing using mice or other re-
search animals.
c) The agent is tested for stability, solubility, and dose.
d) Scientists perform studies involving animals to predict the initial dose
for use in human studies.
B. Clinical trials involving humans: The purpose of a clinical trial is to study a
new agent, combination of agents, or device by involving human volunteers
in a scientific experiment. Scientists evaluate the safety, effectiveness, and
toxicities of a new drug or drug combination in humans. Clinical trials are
vital to improving patient care and reducing cancer morbidity and mortali-
ty. However, only about 3% of adults with cancer enroll in clinical trials (In-
stitute of Medicine, 2010). Nurses can have a positive impact on this num-
ber by being knowledgeable about clinical trials, assisting with patient edu-
cation, and recording careful documentation of patient symptoms and care
(Deininger, 2010).
1. Regulatory entities relevant to the protection of human research sub-
jects: In addition to strict federal regulation, multiple regulatory groups
oversee the participation of individuals in research (DeLaCruz &
McCabe, 2011).
a) The Office for Human Research Protections (OHRP) operates with-
in the DHHS and oversees the development of informed consent
(IC) documents, the formation and function of institutional review
boards (IRBs), and safeguarding the welfare of research participants. 17
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
18 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Table 4. Overview of Phases of Clinical Trials
Phase Description Goals Subjects Study Design
0 Exploratory study using • Provide human pharmacoki- • Limited number (~10– • Dose escalation
small doses of investiga- netic/pharmacodynamic 12) • Open-label
tional agent (i.e., micro- data prior to definitive phase • Nonrandomized
dosing for a drug or bio- 1–2 testing.
logic) • Determine whether mecha-
Very limited drug exposure nism of action defined in pre-
with limited duration of clinical models can be ob-
dosing (≤ 7 days) served in humans.
No therapeutic (or diagnos- • Refine biomarker assay us-
tic) intent ing human tumor tissue and/
Conducted prior to tradi- or surrogate tissue.
tional phase 1 study • Enhance efficiency of sub-
Conducted under an ex- sequent development of the
ploratory Investigational agent.
New Drug application • Increase chance of success
of subsequent development
of the agent.
I Traditional first-in-human • Evaluate the safety and tol- • Limited number (20– • Dose escalation
dose-finding study for sin- erability. 100) –– Traditional 3 + 3
gle agent • Determine the maximum tol- • Healthy volunteers –– Accelerated titration
Dose-finding study when erated dose. • Patient volunteers –– Adaptive
using multiple agents or –– Single agent • Usually includes many • Open-label
multiple interventions –– Combination of agents cancer types (e.g., sol- • Randomized (healthy
(e.g., drug plus radiation) –– Combination interventions id tumors) volunteers)
• Determine dose-limiting tox- • Refractory to standard • Nonrandomized (patient
icity. therapy or no remaining volunteers)
• Define optimal biologically standard therapy
active dose. • Adequate organ func-
• Evaluate pharmacokinetics/ tion, specifically bone
pharmacodynamics. marrow, liver, and kid-
• Observe preliminary re- ney
sponse (e.g., antitumor ac- • Pediatric studies con-
tivity). ducted after safety and
toxicity evaluation in
adults
II Phase IIA: Proof-of-concept • Phase IIA • Moderate number (80– • Open-label or blinded
study to provide initial in- –– Demonstrate activity of the 300) • Nonrandomized or ran-
formation on activity of in- intervention in the intend- • More homogenous pop- domized
tervention to justify con- ed patient condition/target- ulation that is deemed • One-stage, two-stage,
ducting a larger study ed population. likely to respond based or crossover
Phase IIB: Optimal dosing –– Establish proof of concept. on • Nonstratified or strat-
study to target population • Phase IIB: Establish optimal –– Phase I data ified
dosing for the intended pa- –– Preclinical models
tient condition/targeted pop- –– Mechanisms of ac-
ulation to be used in phase tion
III study. • Requires disease that
• Evaluate for safety. can be accurately mea-
sured and must be re-
producible
• May limit number of pri-
or treatments
III Randomized controlled • Compare efficacy of interven- • Large number (hun- • Open-label or blinded
study tion being studied to a con- dreds to thousands) • Randomized
trol group. • Homogenous popula- • Nonstratified or strat-
• Evaluate for safety. tion ified
• May be used for initial • Multi-institution/multisite
treatment
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 2. Drug Development and Clinical Trials 19
Table 4. Overview of Phases of Clinical Trials (Continued)
Phase Description Goals Subjects Study Design
IV Postmarketing • Evaluate safety during post- • Large number of sub- • Open-label
marketing period. jects with the labeled in- • Multi-institution/multisite
• May or may not be required dication of the newly
by the U.S. Food and Drug marketed drug/biologic
Administration.
• Compare the drug to another
similar product that is already
being marketed.
• Monitor for long-term effects
and additional safety, effica-
cy, and quality-of-life data.
• Assess drug-food interac-
tions.
• Assess effect in specific pop-
ulations (e.g., pregnant wom-
en, children), or determine
cost-effectiveness.
Note. Based on information from Doroshow & Kummar, 2009; Kummar et al., 2006; Lertora & Vanevski, 2012.
From “Types of Research: Experimental,” by E. Ness and G. Cusack in A.D. Klimaszewski, M.A. Bacon, J.A. Eggert, E. Ness, J.G. Westendorp, and K. Wil-
lenberg (Eds.), Manual for Clinical Trials Nursing (3rd ed.), in press, Pittsburgh, PA: Oncology Nursing Society. Copyright by the Oncology Nursing Society.
Reprinted with permission.
b) The U.S. Food and Drug Administration (FDA) regulates clinical tri-
als that involve the licensing of a drug or product regardless of the
source of research funding.
c) IRBs are institutionally based and assess clinical trials for risks, ben-
efits, and ethical status and monitor the overall conduct of the clin-
ical trial. NCI sponsors a Central IRB Initiative in consultation with
OHRP. This initiative was designed to decrease the administrative
burden on local IRBs and investigators. Information on the Central
IRB Initiative can be found at www.ncicirb.org.
d) A data monitoring committee is required for all phase III trials. The
purpose of this independent group of experts is to protect the safe-
ty of trial participants, the credibility of the study, and the validity of
study results. The committee may recommend termination of a study
if appropriate (Bales & Adams, in press).
2. Drug approval process
a) Research protocols are designed within an academic environment,
through NCI, by pharmaceutical companies, or by cooperative re-
search groups. Funding may originate from public or private sources.
b) If a trial involves a new agent, the FDA reviews and approves the agent
as an Investigational New Drug, or IND.
c) Table 4 presents an overview of the phases of clinical trials (Ness &
Cusack, in press).
d) The FDA approves a new drug for commercial use when studies have
documented its efficacy and safety.
e) The drug is marketed commercially.
f) Postmarketing studies are conducted to define new uses for approved
drugs and monitor for toxicities, long-term safety, and long-term ef-
fectiveness (Ness & Cusack, in press).
3. Pediatric patient involvement in clinical trials
a) More than 90% of pediatric patients with cancer receive treatment
at centers affiliated with a multi-institution collaborative research
group, such as the COG. Approximately 60% of children with can-
cer are treated in a COG protocol (COG, n.d.).
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
20 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
b) In general, new drugs are tested in adults before researchers under-
take studies involving children.
c) Because children’s size and metabolism differ significantly from those
of adults, drug data derived from adults may not apply to children.
4. Nurses’ roles in clinical trials: Nurses may
a) Help patients find clinical trials. Useful resources include (Deininger,
2010)
(1) NIH’s Clinical Trials website (http://clinicaltrials.gov), which
lists clinical trials and provides education about clinical trials
for consumers
(2) NCI’s Cancer Trials Support Unit (www.ctsu.org), which focus-
es on phase III clinical trials
(3) Coalition of National Cancer Cooperative Groups’ TrialCheck®
(www.trialcheck.org/services), which focuses on cooperative
group oncology trials
(4) Pharmaceutical company registry websites, such as GlaxoSmith-
Kline (www.gsk-clinicalstudyregister.com) and Eli Lilly (www
.lillytrials.com/initiated/initiated.html)
(5) Internationally, nationally, and locally developed and main-
tained registries.
b) Support prospective participants as they decide whether to enroll.
When patients are considering participation in a clinical trial, they
may be facing other stressors in addition to the enrollment decision,
including a new diagnosis of cancer, disease progression, financial
concerns, psychosocial distress, disruption of career, and role chang-
es at home. Nurses can help by screening for psychological distress at
every visit and referring patients to social work, pastoral care, or men-
tal health services as appropriate (Czaplicki, in press).
c) Ensure IC when patients decide to participate.
(1) IC is a heavily regulated process to protect human rights, of
which the IC document is only a part (Klimaszewski, in press).
Table 5 delineates the steps in the IC process. Nurses are in-
volved in this process by
(a) Ensuring that patients and/or family members understand
the purpose of participation in the clinical trial and allow-
ing adequate time for them to receive answers to all of their
questions. This involves arranging for time with the clini-
cal investigator and/or clinical trials nurse.
(b) Providing educational materials as required. All materials
presented to patients and families must be language spe-
cific, developmentally appropriate, and accurate.
(c) Documenting that patients understand the clinical trial,
follow-up and test schedules, and their right to withdraw
at any time (Klimaszewski, in press).
(2) The institution’s IRB reviews and revises the IC document for for-
mat and appropriateness of reading level for the patient and fam-
ily. NCI provides a consent form template for adult cancer trials
(see www.cancer.gov/clinicaltrials/conducting/simplification
-of-informed-consent-docs/page3). OHRP and FDA regulations
about the IC document are found in the Code of Federal Regula-
tions and may be viewed at www.hhs.gov/ohrp/humansubjects/
guidance/45cfr46.html#46.116. A basic consent document must
(U.S. DHHS, 2010)
(a) State that the study involves research, provide an explana-
tion of the purpose of the research, identify the possible
duration of the subject’s participation, and describe the
procedure(s).
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 2. Drug Development and Clinical Trials 21
Table 5. The Informed Consent Process
Step Key Elements
Initial meeting Provide subject and family/friends with the informed consent form (CF).
Discuss the CF logically with subject and one or more members of the research team.
Encourage subject and family to take notes.
Provide adequate time for subject and family members to consider participation and have all questions answered.
Provide subject with a video, audiotape, or interactive computer program to help him or her to understand the in-
formation in the CF.
Parents will represent subjects younger than age 18.
If subject is between age 7 and 18, ask for assent to participate, and provide an assent form for signature.
Time to read and Subject is afforded adequate time to review the CF at his or her leisure.
consider partici- Subject discusses the CF with family, friends, social workers, clergy, a subject representative, or other trusted ad-
pation visers.
Subject records questions and concerns for discussion at next meeting.
Assessment of Discuss subject’s questions and concerns that were recorded at home.
understanding Assess subject’s understanding with interactive questioning, a written questionnaire, or by having the patient ex-
plain specific parts of the CF in his or her own words.
Document assessment of subject’s understanding.
Answer subject’s questions until the patient states that he or she has enough information to make a decision.
Document subject’s statement regarding his or her decision.
Questions Encourage subject to ask questions until the participant is satisfied with his or her understanding of the CF.
Encourage subject to record questions while away from the clinic and either bring them to the next meeting or
schedule a visit to have the questions discussed.
Verification before Ask patient to verify that he or she still consents to the treatment he or she is about to receive immediately prior to
treatment administering the treatment.
New information Assure subject that any new information available will be shared.
Follow up on assurance.
Provide subject with an updated CF for signature (as required).
Document subject’s understanding of new information in the presence of family.
Document subject’s signing of the new CF, review of CF, and that all subject’s questions were answered.
Provide copy of CF to subject.
Communication Videotapes, audiotapes, interactive computer programs, discussions with qualified professional and lay individuals
techniques
Supplemental Videotapes, audiotapes, written materials, interactive computer programs
materials
Note. Based on information from National Cancer Institute, 2013.
From “Informed Consent,” by A. Klimaszewski in A. Klimaszewski, M. Bacon, J.A. Eggert, E. Ness, J.G. Westendorp, and K. Willenberg (Eds.), Manual for
Clinical Trials Nursing (3rd ed.), in press, Pittsburgh, PA: Oncology Nursing Society. Copyright by the Oncology Nursing Society. Reprinted with permission.
(b) Describe foreseeable risks or discomforts that the partici-
pant might encounter.
(c) Describe benefits to the participant or to any others.
(d) Disclose appropriate alternative treatments that may be ad-
vantageous to the participant, if applicable.
(e) Describe how confidentiality of records that identify the
participant will be managed.
(f) Explain whether any compensation or other medical
treatments will be made available if injury occurs. If in-
jury does occur, explain what medical treatments will
be available and where the participant can obtain fur-
ther information.
(g) Clearly document for the participant contact information
for a person who will answer questions about the research
and whom to contact if the participant sustains a research-
related illness or injury.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
22 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
(h) State that the participant may discontinue involvement
in the trial at any time without penalty or loss of further
treatment(s) and that participation is voluntary.
(3) The nurse should ensure that the parents or a legally autho-
rized representative of pediatric patients understand the con-
cepts of consent, assent, and dissent as they relate to a child’s
participation in research. While the parents/legally authorized
representative must provide consent, assent is a minor’s affir-
mative agreement to participate in research. Allowing assent
honors a minor’s autonomy to the extent that he or she has
developed the capacity to make informed choices. If a minor
does not object to participation, assent cannot be presumed
(Klimaszewski, in press). Dissent is a child’s active refusal to
participate in research. NCI provides information on the as-
sent process for care providers and parents and guardians (see
www.cancer.gov/clinicaltrials/learningabout/patientsafety/
childrensassent).
d) The Oncology Nursing Society (ONS) defined the role of oncology
clinical trials nurses through competencies (Daugherty, Schmieder,
Good, Leos, & Weiss, 2010) (see Table 6).
e) The oncology nurse caring for a patient on a study protocol has addi-
tional responsibilities depending upon the phase of the clinical trial,
such as performance and documentation of the following.
(1) Verify that the patient, parent, or legally authorized representa-
tive has given IC, that the original document is in the patient’s
Table 6. Oncology Clinical Trials Nurse Core Competencies
Competency Description
I. Protocol The oncology clinical trials nurse facilitates compliance with the requirements of the research protocol and
compliance good clinical research practice while remaining cognizant of the needs of diverse patient populations.
II. Clinical trials– The oncology clinical trials nurse utilizes multiple communication methods to facilitate the effective conduct of
related communi- clinical trials.
cation
III. Informed consent The oncology clinical trials nurse demonstrates leadership in ensuring patient comprehension and safety dur-
process ing initial and ongoing clinical trial informed consent discussions.
IV. Management of The oncology clinical trials nurse uses a variety of resources and strategies to manage the care of patients
clinical trial pa- participating in clinical trials, ensuring compliance with protocol procedures, assessments, and reporting re-
tients quirements, as well as management of symptoms.
V. Documentation The oncology clinical trials nurse provides leadership to the research team in ensuring collection of source
data and completion of documentation that validate the integrity of the conduct of the clinical trial.
VI. Patient The oncology clinical trials nurse utilizes a variety of strategies to enhance recruitment while being mindful of
recruitment the needs of diverse patient populations.
VII. Ethical issues The oncology clinical trials nurse demonstrates leadership in ensuring adherence to ethical practices during the
conduct of clinical trials in order to protect the rights and well-being of patients and the collection of quality data.
VIII. Financial The oncology clinical trials nurse identifies the financial variables that affect research and supports good fi-
implications nancial stewardship in clinical trials.
IX. Professional The oncology clinical trials nurse takes responsibility for identifying his or her ongoing professional develop-
development ment needs and seeks resources and opportunities to meet those needs, such as through membership in
nursing, oncology, or research organizations.
Note. From Oncology Clinical Trials Nurse Competencies (pp. 11–14), by P. Daugherty, L. Schmieder, M. Good, D. Leos, and P. Weiss, 2010, Pittsburgh, PA:
Oncology Nursing Society. Retrieved from http://www2.ons.org/media/ons/docs/publications/ctncompetencies.pdf. Copyright 2010 by the Oncology Nursing
Society. Reprinted with permission.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 2. Drug Development and Clinical Trials 23
medical record, and that the patient has received a copy be-
fore any study tests are performed or any study treatments are
administered.
(2) Clarify technical explanations of procedures and treatments.
(3) Obtain pretreatment assessment data.
(4) Measure height and weight, and check dose calculations with
a physician, pharmacist, or another qualified (i.e., chemother-
apy-biotherapy trained) nurse.
(5) Have emergency medications and equipment available as ap-
propriate.
(6) Instruct the patient to report changes or symptoms experienced
during and after drug administration.
(7) Assess the patient’s desire to continue by verbally affirming con-
sent prior to beginning drug infusion (Klimaszewski, in press).
Patients have the right to withdraw at any time.
(8) Administer the drug(s) according to the protocol.
(9) Assess and evaluate drug reactions. Use the NCI Common
Terminology Criteria for Adverse Events (CTCAE), available
online (see http://ctep.cancer.gov/protocolDevelopment/
electronic_applications/ctc.htm) to assess individual toxicities
and identify trends in the study population.
(10) Follow up with telephone calls to assess the patient for de-
layed or chronic side effects as appropriate (Klimaszewski,
in press).
C. Expedited approval: The FDA may hasten the approval of new drugs to ad-
dress an unmet medical need, provide a promising therapy to treat a seri-
ous condition, improve survival, or decrease toxicity of an accepted treat-
ment. Termed Fast Track, Breakthrough Therapy, Accelerated Approval, and Pri-
ority Review, these programs for expedited approval have potential benefits,
including (U.S. FDA, 2013)
1. Improved efficiency by promoting early communication between the
company submitting the drug and the FDA
2. Allowing submission of sections of the new drug application instead of
all components
3. Permitting the evaluation of various studies using surrogate end points
4. Providing priority review and accelerated approval of promising drugs.
References
Bales, C., & Adams, G. (in press). Data and safety monitoring plans. In A.D. Klimaszewski, M. Bacon,
J. Eggert, E. Ness, J.G. Westendorp, & K. Willenberg (Eds.), Manual for clinical trials nursing (3rd
ed.). Pittsburgh, PA: Oncology Nursing Society.
Children’s Oncology Group. (n.d.). What is a clinical trial? Retrieved from http://www
.childrensoncologygroup.org/index.php/what-is-a-clinical-trial
Czaplicki, K. (in press). Psychosocial distress. In A.D. Klimaszewski, M. Bacon, J. Eggert, E. Ness, J.G.
Westendorp, & K. Willenberg (Eds.), Manual for clinical trials nursing (3rd ed.). Pittsburgh, PA: On-
cology Nursing Society.
Daugherty, P., Schmieder, L., Good, M., Leos, D., & Weiss, P. (2010). Oncology clinical trials
nurse competencies. Retrieved from http://www2.ons.org/media/ons/docs/publications/
ctncompetencies.pdf
Deininger, H.E. (2010). Clinical trials. In J. Eggert (Ed.), Cancer basics (pp. 287–302). Pittsburgh, PA:
Oncology Nursing Society.
DeLaCruz, A., & McCabe, M.S. (2011). Principles of cancer clinical trials. In C.H. Yarbro, D. Wujcik,
& B.H. Gobel (Eds.), Cancer nursing: Principles and practice (7th ed., pp. 219–231). Burlington, MA:
Jones and Bartlett.
Doroshow, J.H., & Kummar, S. (2009). Role of phase 0 trials in drug development. Future Medicinal
Chemistry, 1, 1375–1380. doi:10.4155/fmc.09.117
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24 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Humphrey, R.W., Brockway-Lunardi, L.M., Bonk, D.T., Dohoney, K.M., Doroshow, J.H., Meech, S.J., …
Pardoll, D.M. (2011). Opportunities and challenges in the development of experimental drug com-
binations for cancer. Journal of the National Cancer Institute, 103, 1222–1226. doi:10.1093/jnci/djr246
Institute of Medicine. (2010). Transforming clinical research in the United States: Challenges and opportu-
nities: Workshop summary. Washington, DC: National Academies Press. Retrieved from http://www
.ncbi.nlm.nih.gov/books/NBK50892/pdf/TOC.pdf
Klimaszewski, A.D. (in press). Informed consent. In A.D. Klimaszewski, M. Bacon, J. Eggert, E. Ness,
J.G. Westendorp, & K. Willenberg (Eds.), Manual for clinical trials nursing (3rd ed.). Pittsburgh,
PA: Oncology Nursing Society.
Kummar, S., Gutierrez, M., Doroshow, J.H., & Murgo, A.J. (2006). Drug development in oncology:
Classical cytotoxics and molecularly targeted agents. British Journal of Clinical Pharmacology, 62, 15–
26. doi:10.1111/j.1365-2125.2006.02713.x
Lertora, J.J.L., & Vanevski, K.M. (2012). Clinical pharmacology and its role in pharmaceutical devel-
opment. In J.I. Gallin & F.P. Ognibene (Eds.), Principles and practice of clinical research (3rd ed., pp.
627–639). Boston, MA: Elsevier Academic Press. doi:10.1016/B978-0-12-382167-6.00043-6
National Cancer Institute. (2013). Simplification of informed consent documents: Appendix 4, communi-
cation methods. Retrieved from http://www.cancer.gov/clinicaltrials/conducting/simplification
-of-informed-consent-docs/page5#appendix4
Ness, E., & Cusack, G. (in press). Types of clinical research: Experimental. In A.D. Klimaszewski, M.
Bacon, J. Eggert, E. Ness, J.G. Westendorp, & K. Willenberg (Eds.), Manual for clinical trials nurs-
ing (3rd ed.). Pittsburgh, PA: Oncology Nursing Society.
U.S. Department of Health and Human Services. (2010). Title 45: Public welfare, Part 46: Protection
of human subjects, §46.116: General requirements for informed consent (45 C.F.R. §46.116). Re-
trieved from http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.116
U.S. Food and Drug Administration. (2013, June 26). Fast track, breakthrough therapy, accelerated ap-
proval and priority review: Expediting availability of new drugs for patients with serious conditions.
Retrieved from http://www.fda.gov/forconsumers/byaudience/forpatientadvocates/speeding
accesstoimportantnewtherapies/ucm128291.htm
Wong, S.F., Bales, C., & Hurtado, K. (in press). Investigational agents: Procurement, administration,
and accountability of research study drugs. In A.D. Klimaszewski, M. Bacon, J. Eggert, E. Ness, J.G.
Westendorp, & K. Willenberg (Eds.), Manual for clinical trials nursing (3rd ed.). Pittsburgh, PA: On-
cology Nursing Society.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 3
Principles of Antineoplastic
Therapy
A. Life cycle of cells: The cell life cycle is a five-stage reproductive process oc-
curring in both normal and malignant cells (see Figure 2) and propelled
by cyclin–cyclin-dependent kinase (CDK) complexes (Brown, in press; Ma-
lumbres, 2007; Otto, 2007; Williams & Stoeber, 2012).
1. Gap 0 (G0)
a) Resting or dormant phase
b) Cells are temporarily out of the cycle and not actively proliferating;
however, all other cellular activities occur.
c) Cells continue in G0 until there is a stimulus to enter the cell cycle.
d) Because they are not actively proliferating, cells in this phase have
some protection from exposure to cell cycle–specific chemothera-
py agents.
2. Gap 1 (G1)
a) Postmitotic phase
b) Cells begin the first phase of reproduction and growth by synthesiz-
ing proteins and RNA necessary for cell division.
3. Synthesis (S): DNA is replicated.
4. Gap 2 (G2)
a) Premitotic (or postsynthetic) phase
b) The second phase of protein and RNA synthesis occurs.
c) Preparation for mitotic spindle formation occurs.
d) The cell is now prepared for division.
5. Mitosis (M)
a) Cell division occurs.
b) Shortest phase of the cell life cycle
c) At the conclusion of mitosis, two daughter cells result with exact cop-
ies of the parent cell’s DNA. Cells either reenter the cell cycle to re-
produce or perform the specific functions of the tissue for which
they are programmed.
6. Cyclin–CDK complexes (Malumbres, 2007; Williams & Stoeber, 2012)
a) Cyclins are cell cycle kinase regulators (e.g., cyclin D).
b) CDKs are cell cycle kinase inhibitors (e.g., CDK4).
c) Cyclins and CDKs unite and create a complex that propels the cell
through each phase of the cell cycle (e.g., cyclin D-CDK4, cyclin D-
CDK6, and cyclin E-CDK2 drive G1).
d) CDK mutations have been linked to tumor formation (e.g., CDK6
is overexpressed in many hematologic malignancies, glioblastoma,
and lung cancer).
e) Anti-CDK/cyclin inhibitors are being developed and tested in clini-
cal trials as a method to inhibit tumor growth.
B. Chemotherapeutic agents: Drugs are classified according to pharmacologic
action or their effect on cell reproduction (see Table 7). 25
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
26 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
1. Cell cycle–specific drugs exert effect within a specific phase of the cell
cycle (Brown, in press; Hande, 2009).
a) These drugs have the greatest tumor cell kill when given in divid-
ed but frequent doses or as a continuous infusion with a short cy-
cle time. This allows the maximum number of cells to be exposed to
the drug at the specific time in their life cycle when they are vulner-
able to the drug.
b) Classifications include antimetabolites, plant alkaloids (camptothe-
cins, epipodophyllotoxins, taxanes, and vinca alkaloids), and miscel-
laneous agents.
2. Cell cycle–nonspecific drugs exert effect in all phases of the cell cycle,
including the G0 (resting) phase (Brown, in press; Hande, 2009).
Figure 2. Cell Cycle
R
?
Growth Factors
TGF-β DNA
damage
G0
CDK p53
Resting Stage
2,4,5,6 p27
Active pRb
protein
Cyclin D (master p21
brake)
Cell Division EARLY G1 Cyclin E CDK2
Cyclins A,B
CDK1
M LATE G1 Proteins
G2 S
Cyclin A
Cyclin B CDK2
CDK1 DNA Synthesis
Cyclin B
CDK1
The cell cycle consists of 4 phases (G1, S, G2, M) that are controlled by proteins called cyclins. The cyclins (D, E, A, B) are activat-
ed when complexed with enzymes called cyclin-dependent kinases (CDKs). Upon activation, the cyclin–CDK complex allows the cell
to progress through each specific cell cycle phase. Present throughout the cell cycle, the cyclin–CDK complexes serve as check-
points or monitors of the cell cycle. Inhibitory proteins prevent progression through the cell cycle if DNA damage is present or there
is a lack of nutrients or oxygen to support cellular proliferation. Examples of inhibitory proteins include p21, p27, p53. The inhibitory
proteins in turn are regulated by the presence of inhibitory growth factors and TGF-β. Once past R (the restriction point) the cell cy-
cle is turned “on” and progression through the cell cycle is inevitable. Cyclin–CDK complexes and pRB (the “master brake”) tightly
regulate the R point. The stability of the inhibitory proteins and cyclin–CDK complexes are altered in cancer, thereby altering control
of the cell cycle, and uncontrolled cellular proliferation prevails.
Note. From “Biology of Cancer” (p. 14), by C.J. Merkle in C.H. Yarbro, D. Wujcik, and B.H. Gobel (Eds.), Cancer Nursing: Principles and Practice (7th
ed.), 2011, Burlington, MA: Jones and Bartlett. Copyright 2011 by Jones and Bartlett Publishers. Reprinted with permission.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 7. Characteristics of Chemotherapeutic Agents
Mechanism Route of
Classification of Action Drug Administration Indications Side Effects Nursing Considerations
Alkylating Break DNA helix Altretamine PO Ovarian cancer Dose-limiting toxicities: Neurotoxici- Do not open capsules.
agents strand, thereby (Hexalen®) ty, peripheral neuropathy, myelosup- Monitor for progressive neurologic toxicity.
interfering with pression Instruct patients to take after meals and at bed-
DNA replication Nausea, vomiting, skin rash, hypersen- time.
sitivity, elevation of LFTs, abdominal (Eisai Inc., 2009)
cramps, diarrhea
Bendamustine IV CLL, indolent Dose-limiting toxicity: Myelosuppres- Infuse over 30–60 min.
(Treanda®) NHL sion Monitor closely for infusion reactions (especially
Pyrexia, nausea, vomiting, skin reac- in second or subsequent cycles).
tions Dose reduction or discontinuation may be neces-
sary for hematologic toxicities.
Take precautions for TLS in high-risk patients.
Concomitant use of allopurinol may increase risk
of severe skin toxicity.
(Cephalon, Inc., 2012)
Busulfan (IV: IV, PO CML, BMT prep- Dose-limiting toxicities: Myelosup- Monitor blood counts closely. If leukocyte count is
Busulfex®; aration pression, pulmonary fibrosis < 20,000/mm3, discontinue drug.
oral: Myleran®) Profound tachycardia, hypertension, Administer seizure prophylaxis.
chest pain, hyperpigmentation, alo- Instruct patients to take on an empty stomach to
pecia, sperm or ovarian suppression, decrease risk of nausea and vomiting.
confusion, seizures, mucositis, nausea, IV form should be administered through a central
vomiting, insomnia, hyperglycemia, line and has been associated with inflammation
Chapter 3. Principles of Antineoplastic Therapy
blurred vision, second malignancy and pain during infusion.
Hepatic sinusoidal obstruction syndrome (PDL BioPharma, Inc., 2007)
(previously known as veno-occlusive
disease) has been reported in patients
receiving doses > 16 mg/kg in conjunc-
tion with alkylating agents for stem cell
transplant (Solimando, 2008).
Carboplatin IV Ovarian cancer Dose-limiting toxicity: Thrombocyto- Drug is an irritant.
(Paraplatin®) penia Carboplatin exhibits much less renal toxicity than
Neutropenia (myelosuppression is cisplatin, so rigorous hydration is unnecessary
more pronounced with renal impair- unless renal dysfunction exists.
ment), nausea, vomiting, hypersen- Monitor blood counts closely, and reduce the
sitivity reaction, mild alopecia, skin dose per protocol. Specific dosing guidelines
rash are recommended for carboplatin. See Figures
15, 16, and 17.
Give after taxanes in sequential regimens to limit
myelosuppression and enhance efficacy.
(Continued on next page)
27
28
Table 7. Characteristics of Chemotherapeutic Agents (Continued)
Mechanism Route of
Classification of Action Drug Administration Indications Side Effects Nursing Considerations
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Alkylating Carboplatin Check creatinine level prior to each dose (for
agents (cont.) (Paraplatin®) AUC dosing).
(cont.) Have emergency medications available for hy-
persensitivity reaction, which usually occurs af-
ter the seventh dose.
(Bristol-Myers Squibb Co., 2010a)
Chlorambucil PO CLL, HL, NHL Dose-limiting toxicities: Myelosup- Use with caution in patients with seizure history
(Leukeran®) pression, skin reactions and within one month of radiation and/or cyto-
Ovarian or sperm suppression, nau- toxic therapy.
sea, vomiting, secondary malignan- (GlaxoSmithKline, 2004)
cy, hyperuricemia, pulmonary fibro-
sis, seizure (increased risk in children
with nephrotic syndrome)
Cisplatin IV Ovarian, testicu- Dose-limiting toxicities: Severe neph- Cisplatin is an irritant with vesicant potential if >
(Platinol®) lar, bladder, lung rotoxicity, myelosuppression 20 ml of 0.5 mg/ml concentrated solution is ex-
cancer Severe acute and delayed nausea, travasated.
vomiting, ototoxicity (tinnitus and/or Hold the drug if the patient’s SCr is > 1.5 mg/dl;
high-frequency hearing loss are most otherwise, irreversible renal tubular damage
common), hyperuricemia, hypersensi- may occur (Aronoff et al., 2007). Amifostine
tivity reaction, hypomagnesemia and may be used as a renal protectant. Rigorous
other electrolyte abnormalities, pe- hydration is necessary to prevent nephrotoxici-
ripheral neuropathy, SIADH ty. Use mannitol to achieve osmotic diuresis.
Potential exists for delayed nausea and vomiting
up to 6 days after administration.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Consider obtaining a baseline audiogram.
Monitor electrolytes and replace as needed.
(Bristol-Myers Squibb Co., 2010b)
Cyclophos- Intrapleural, IV, Breast and ovari- Dose-limiting toxicity: Hemorrhag- Give the dose, whether IV or PO, early in the day.
phamide PO an cancers, MM, ic cystitis Ensure adequate hydration. If given PO, have pa-
(Cytoxan®) leukemias, lym- Vomiting, myelosuppression, nausea, tients drink 2–3 L/day (Solimando, 2008).
phomas, neuro- alopecia, may cause a temporary Have patients empty their bladder frequently
blastoma, retino- maxillary burning if administered too and before bed to prevent hemorrhagic cystitis.
blastoma, myco- quickly, secondary malignancy, testic- Mesna may be considered in conjunction with
sis fungoides ular or ovarian failure IV fluids for prevention of hemorrhagic cystitis.
High-dose: acute cardiomyopathy, Pelvic irradiation potentiates hemorrhagic cystitis.
SIADH When used with radiation therapy, potential for
radiation recall exists with subsequent doses of
cyclophosphamide.
(Baxter Healthcare Corp., 2013)
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 7. Characteristics of Chemotherapeutic Agents (Continued)
Mechanism Route of
Classification of Action Drug Administration Indications Side Effects Nursing Considerations
Alkylating Dacarbazine IV Malignant mela- Dose-limiting toxicities: Severe neu- Dacarbazine is an irritant that may cause tis-
agents (cont.) (DTIC®) noma, HL tropenia and thrombocytopenia (with sue necrosis if extravasated. Administer by in-
nadir at 2–3 weeks or more) fusion over 30–60 min. May cause severe pain
Severe nausea and vomiting for up to and burning at the injection site and along the
12 hours, anorexia, alopecia, rash, course of the vein. To reduce these effects, in-
flu-like syndrome (fever, malaise, my- crease the diluent, reduce the infusion rate,
algias), hypotension, hypersensitivity and apply cold compresses to the needle inser-
reaction (uncommon), photosensitivi- tion site and along the vein.
ty, hepatic dysfunction Protect solution from light (pink solution indicates
decomposition).
Flu-like syndrome may occur up to 7 days after
drug administration; treat symptoms.
Reduce doses for patients with poor renal func-
tion.
(Teva Parenteral Medicines, Inc., 2007)
Ifosfamide IV Testicular cancer Dose-limiting toxicities: Hemorrhagic Administer the drug over 30 min or more.
(Ifex®) cystitis, myelosuppression To prevent hemorrhagic cystitis, always adminis-
Nausea, alopecia, vomiting, neurotoxic- ter with mesna. Mesna may be given PO, as a
ity (somnolence, confusion, hallucina- bolus dose, as a continuous infusion, or mixed
tions, depressive psychoses, and en- in the bag with the ifosfamide. Mesna dose
cephalopathy) should be 60%–100% of the ifosfamide dose
Methylene blue has been used to treat (based on weight). Refer to package insert for
ifosfamide-induced encephalopathy; specific dosing recommendations.
Chapter 3. Principles of Antineoplastic Therapy
reports have shown that the enceph- (Baxter Healthcare Corp., 2012)
alopathy may spontaneously resolve
(Patel, 2006).
Mechloreth- IV HL, NHL, CLL, Severe nausea, vomiting, alopecia, my- Drug is a vesicant.
amine (nitro- CML, mycosis elosuppression, pain or phlebitis at Administer the agent over several minutes
gen mustard, fungoides IV site, chills, fever, testicular or ovar- through the side arm of a free-flowing IV. Flush
Mustargen®) ian failure with 125–150 ml NS post infusion.
If extravasation occurs, antidote is sodium thio-
sulfate. Use mechlorethamine as soon after
preparation as possible (15–30 min); it is ex-
tremely unstable.
Do not mix mechlorethamine with any other drug.
(Baxter Oncology, 2012)
(Continued on next page)
29
30
Table 7. Characteristics of Chemotherapeutic Agents (Continued)
Mechanism Route of
Classification of Action Drug Administration Indications Side Effects Nursing Considerations
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Alkylating Melphalan IV, PO MM, ovarian can- Dose-limiting toxicity: Myelosuppres- Myelosuppression may be delayed and last 4–6
agents (cont.) (Alkeran®) cer sion weeks; monitor blood counts carefully. Hold or
Nausea, vomiting, mucositis, hypersen- reduce dose per institutional protocol.
sitivity reaction Instruct patients to take on an empty stomach.
Application of ice chips to oral cavity is recom-
mended during high-dose melphalan adminis-
tration to prevent oral mucositis (Lilleby et al.,
2006).
Drug must be administered within 1 hour of re-
constitution. Infuse over 15–30 minutes.
(GlaxoSmithKline, 2011a)
Oxaliplatin IV Colorectal cancer Dose-limiting toxicities: Peripheral Oxaliplatin has been described as an irritant and
(Eloxatin®) neuropathy, myelosuppression a vesicant.
Acute primary transient peripheral sen- Consider dose reduction in patients with renal
sory neuropathy that presents within dysfunction.
1–48 hours, resolves within 14 days, Monitor for acute, reversible effects and persis-
and manifests as paresthesia, dys- tent neurotoxicity.
esthesia, or hypoesthesia in hands, Avoid ice to oral cavity during oxaliplatin infusion.
feet, oral cavity, and throat; can be For 3–4 days after therapy, patients should avoid
aggravated by cold temperatures consuming cold drinks and foods and breathing
Anaphylactic reaction, nausea, vomit- cold air (cover mouth with scarf).
ing, diarrhea, pulmonary fibrosis, fa- Do not prepare or infuse in sodium chloride or
tigue, fever other chloride-containing solutions. D5W solu-
tion is recommended (Takimoto et al., 2007).
Flush after oxaliplatin with D5W before adminis-
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
tering other medications in the same line.
Infuse after taxanes in sequential regimens.
Calcium and magnesium infusions may be used
during oxaliplatin therapy to reduce neurotoxici-
ties (Wen, 2013).
However, in a trial that included 353 patients with
colon cancer undergoing adjuvant therapy with
FOLFOX (5-FU, oxaliplatin, and leucovorin),
patients were randomized to receive IV calci-
um and magnesium (1 g calcium gluconate, 1 g
magnesium sulfate) or placebo before and cal-
cium and magnesium after oxaliplatin. In a third
arm in the trial, patients received calcium and
magnesium before and placebo after the oxali-
platin. The results showed no differences be-
tween the groups in either acute neurotoxicity
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 7. Characteristics of Chemotherapeutic Agents (Continued)
Mechanism Route of
Classification of Action Drug Administration Indications Side Effects Nursing Considerations
Alkylating Oxaliplatin or cumulative sensory neurotoxicity, as as-
agents (cont.) (Eloxatin®) sessed both by patient and physician question-
(cont.) naires (Loprinzi et al., 2013).
(sanofi-aventis U.S. LLC, 2011)
Temozolo- PO, IV Refractory ana- Dose-limiting toxicity: Myelosuppres- Do not open capsules.
mide plastic astrocyto- sion Administer IV over 90 minutes.
(Temodar®) ma, newly diag- Nausea, vomiting, headache, fatigue, Instruct patients to take on an empty stomach to
nosed glioblasto- liver toxicity, rash, alopecia decrease risk of nausea and vomiting.
ma multiforme Do not administer if patients have had an allergic
reaction to dacarbazine.
Administer PCP prophylaxis with trimethoprim-
sulfamethoxazole in patients receiving with ra-
diation therapy for 42-day regimen.
Take oral dose with a full glass of water.
Consider bedtime administration for oral dos-
ing to decrease nausea and vomiting (Soliman-
do, 2008).
(Merck & Co., Inc., 2013)
Thiotepa IV, IT, intravesi- Bladder, breast, Dose-limiting toxicity: Myelosuppres- Thiotepa is primarily excreted in the urine; moni-
(Thioplex®) cal, intratumoral and ovarian can- sion tor renal function carefully.
cers, HL, NHL Hypersensitivity reaction, ovarian or Myelosuppression may be delayed (14–28 days).
Chapter 3. Principles of Antineoplastic Therapy
sperm suppression, nausea, vom- Thiotepa used in the transplant setting can
iting, pain at infusion site, rash, fe- cause severe skin irritation. Frequent shower-
ver, skin burn, mucositis, hemorrhag- ing immediately following and during the first
ic cystitis 24 hours after administration helps remove
the chemical from the skin. Additionally, avoid
tapes and skin adherents during and immedi-
ately following administration.
(Bedford Laboratories, 2001)
(Continued on next page)
31
32
Table 7. Characteristics of Chemotherapeutic Agents (Continued)
Mechanism Route of
Classification of Action Drug Administration Indications Side Effects Nursing Considerations
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Antimetabo- Azacitidine is be- Azacitidine SC, IV Patients with spe- Dose-limiting toxicities: Myelosup- IV: Mix in 50–100 ml NS or LR only. Infuse over
lites lieved to cause (Vidaza®) cific subtypes of pression, elevated SCr, renal failure 10–40 min. Administration should be completed
hypomethylation MDS Nausea, vomiting, diarrhea, fatigue, fe- within 1 hour of reconstitution.
of DNA and di- ver, erythema at injection site, hypo- SC: Vigorously shake or roll the vial to mix medi-
rect cytotoxicity kalemia, renal tubular acidosis, he- cation immediately prior to administration (solu-
on abnormal he- patic coma, constipation tion should be uniformly cloudy).
matopoietic cells Divide doses > 4 ml into two syringes and in-
in the bone mar- ject into two separate sites. Invert syringe 2–3
row. Abnormal times and roll vigorously between palms prior
cells, including to administration. To minimize skin irritation,
cancer cells, no ensure that the needle is empty of drug, and do
longer respond not expel air in needle before giving the
to normal growth injection. Do not use ice on injection site, as it
control mecha- may decrease drug absorption. Rotate sites for
nisms. The cy- administration among thigh, abdomen, and
totoxic effects of upper arm. Administer new injections at least
azacitidine cause one inch from old site. Avoid sites that are
these cells to die, tender, bruised, red, or hard.
whereas nonpro- Monitor CBC and liver and renal function during
liferating cells are therapy.
relatively insensi- Drug is contraindicated in patients with hyper-
tive to the medi- sensitivity to azacitidine or mannitol and those
cation. with advanced malignant hepatic tumors.
(Celgene Corp., 2012b)
Act in S phase; Capecitabine PO Breast and meta- Dose-limiting toxicities: Diarrhea, Patient education regarding importance of re-
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
inhibit enzyme (Xeloda®) static colon can- palmar-plantar erythrodysesthesia porting toxicity and dose reduction is critical.
production for cers (hand-foot syndrome) Drug is contraindicated in patients with known
DNA synthesis, Mucositis, nausea, vomiting, anemia, hypersensitivity to 5-FU.
leading to strand increased bilirubin, fatigue Monitor PT and INR closely, as capecitabine in-
breaks or prema- creases effect of warfarin.
ture chain termi- Administer with food and water.
nation (Genentech, Inc., 2010)
Cladribine IV Hairy cell leuke- Dose-limiting toxicities: Myelosup- Allopurinol and IV hydration are recommend-
(Leustatin®) mia pression, neurotoxicity ed for patients with high tumor burden to pre-
Fever, nausea, vomiting, hypersensitiv vent TLS.
ity reaction, TLS, nephrotoxicity (high- Use with caution in patients with liver and renal
dose therapy) dysfunction.
(Centocor Ortho Biotech Products, L.P., 2012)
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 7. Characteristics of Chemotherapeutic Agents (Continued)
Mechanism Route of
Classification of Action Drug Administration Indications Side Effects Nursing Considerations
Antimetabo- A purine nucleo- Clofarabine IV Patients ages Dose-limiting toxicities: Bone marrow Continuous IV fluid administration during the 5
lites (cont.) side antimetab- (Clolar®) 1–21 with re- suppression (including anemia, leu- days of chemotherapy administration is encour-
olite that incor- lapsed or refrac- kopenia, thrombocytopenia, neutro- aged to reduce risk of TLS and other adverse
porates into the tory ALL penia, and febrile neutropenia), infec- effects.
DNA chain inhib- tion, hepatobiliary toxicity, renal tox- Use prophylactic steroids to help prevent system-
iting DNA repair icity ic inflammatory response syndrome and capil-
Nausea, vomiting, diarrhea, rare cases lary leak syndrome.
of systemic inflammatory response Give allopurinol if hyperuricemia is expected.
syndrome/capillary leak syndrome Monitor respiratory status and blood pressure
and cardiac toxicity including tachy- during infusion.
cardia, pericardial effusion, and left Monitor renal and hepatic function during the
ventricular systolic dysfunction; TLS, days of administration.
headache, pruritus, rash Monitor hematologic status closely following
treatment.
(Genzyme Corp., 2013)
Cytarabine IV, SC, IT ALL, AML, CML, Dose-limiting toxicity: Myelosuppres- Determine if ordered dose is standard dose or
(cytosine ara- CNS leukemia sion high dose; administer according to institution-
binoside, Nausea, vomiting, anorexia, fever, mu- al guidelines.
ARA-C, cositis, diarrhea, hepatic dysfunction, Note: Toxicities vary depending upon rate of
Cytosar-U®) rash, pruritus, localized pain and/or high-dose cytarabine administration. Continu-
thrombophlebitis at IV site, photophobia ous-infusion cytarabine is associated with pul-
High-dose (1–3 g/m2): cerebellar tox- monary toxicity (fluid overload), and bolus ad-
icity, keratitis (treat with dexametha- ministration is associated with cerebellar toxici-
Chapter 3. Principles of Antineoplastic Therapy
sone ophthalmic drops), dermatolog- ties. Specific nursing interventions are warrant-
ic toxicities ed for each.
For IT administration: Use preservative-free saline.
Allopurinol and IV hydration are recommended
for newly diagnosed patients with AML or pa-
tients with high tumor burden to prevent TLS.
(APP Pharmaceuticals, LLC, 2008a)
Cytarabine IT only Lymphomatous High-dose: mucositis, diarrhea, chem- Do not use in pediatric patients.
liposomal meningitis ical arachnoiditis (nausea, vomiting, Administer IT only.
(DepoCyt®) headache, fever), neurotoxicity, sei- Patients should lie flat for 1 hour after lumbar
zure, nausea, vomiting, constipation, puncture.
weakness Monitor closely for immediate toxic reactions.
Administer dexamethasone 4 mg BID (PO or IV)
for 5 days (start day of cytarabine administra-
tion) to decrease symptoms of chemical arach-
noiditis.
(Sigma-Tau Pharmaceuticals, Inc., 2011a)
(Continued on next page)
33
34
Table 7. Characteristics of Chemotherapeutic Agents (Continued)
Mechanism Route of
Classification of Action Drug Administration Indications Side Effects Nursing Considerations
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Antimetabo- Decitabine IV MDS Myelosuppression, fever, fatigue, nau- Delay treatment if SCr ≥ 2 mg/dl or total bilirubin
lites (cont.) (Dacogen®) sea, cough, constipation, diarrhea, ≥ 2 × ULN until resolved.
hyperglycemia, petechiae, peripher- Use within 15 min of reconstitution. If this is not
al edema possible, return to pharmacy so solution can be
prepared in cold infusion fluid.
(Eisai Inc., 2010a)
Floxuridine Intra-arterial, IV Adenocarcinoma Myelosuppression, nausea, vomiting, Do not use in pediatric patients.
(FUDR®) of GI tract with diarrhea, mucositis, alopecia, photo- Recommendations about dose reduction apply to
metastasis to liv- sensitivity, darkening of the veins, ab- patients with compromised liver function. Adjust
er, gallbladder, or dominal pain, gastritis, enteritis, hep- dose per institutional protocol and monitor he-
bile duct atotoxicity, palmar-plantar erythro- patic function carefully.
dysesthesia (APP Pharmaceuticals, LLC, 2008b)
Fludarabine IV, PO CLL Dose-limiting toxicity: Myelosuppres- Administer as a 30-min infusion.
(Fludara®) sion Monitor PFTs.
Nausea, vomiting, diarrhea, rash, neu- Allopurinol and IV hydration are recommended
rotoxicity, interstitial pneumonitis, for newly diagnosed patients with CLL or pa-
weakness, hemolytic anemia, cough, tients with high tumor burden to prevent TLS.
infection Do not use in combination with pentostatin—may
cause severe pulmonary toxicity.
Use with caution in patients with renal impairment.
Tablets may be taken with or without food.
Do not chew, break, or crush tablets.
(Teva Parenteral Medicines, Inc., 2011)
Fluorouracil IV, topical Colorectal, Dose-limiting toxicities: Mucositis, Ensure that patients take year-round photosensi-
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
(5-FU, Adru- breast, pancreat- myelosuppression tivity precautions; encourage sunscreen use if
cil®) ic, and stomach Nausea, anorexia, vomiting, diarrhea, patients must be exposed.
cancers alopecia, ocular toxicities (e.g., in- Leucovorin often is given concurrently to en-
creased lacrimation, photosensitivity), hance 5-FU activity.
darkening of the veins, dry skin, car- Apply ice chips to the oral cavity 10–15 min
diac toxicity (rare), neurotoxicity pre- and post-IV bolus dose of 5-FU to reduce
oral mucositis in patients with GI malignan-
cies. Not recommended in patients receiving
capecitabine or oxaliplatin because of potential
discomfort with exposure to coldness.
(Teva Parenteral Medicines, Inc., 2012)
Gemcitabine IV Pancreatic, Dose-limiting toxicity: Myelosuppres- Do not use in pediatric patients.
(Gemzar®) breast, and ovar- sion (especially thrombocytopenia) Infuse over 30 min; infusion longer than 60 min or
ian cancers, Nausea, vomiting, fever, flu-like symp- more than weekly can increase pulmonary toxicity.
NSCLC toms, rash, peripheral edema, pulmo- Use with caution in patients with renal impairment.
nary toxicity with increased infusion time (Eli Lilly and Co., 2011)
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 7. Characteristics of Chemotherapeutic Agents (Continued)
Mechanism Route of
Classification of Action Drug Administration Indications Side Effects Nursing Considerations
Antimetabo- Mercaptopu- PO ALL Dose-limiting toxicity: Myelosuppres- Reduce oral dose by 75% when used concur-
lites (cont.) rine (6-MP, sion rently with allopurinol.
Purinethol®) Mucositis, nausea, hyperuricemia, alo- Patients should take drug on an empty stomach,
pecia, hyperpigmentation 1 hour before or 2 hours after meals.
(Gate Pharmaceuticals, 2011)
Methotrexate IM, IV, IT, PO, HD, NHL, leuke- Dose-limiting toxicities: Hepatotoxici- Drug is yellow in color.
SC mia; CNS metas- ty, renal toxicity High doses must be followed by timely admin-
tasis; lung, breast, Mucositis, nausea, myelosuppression, istration of leucovorin and vigorous hydration.
and head and neck oral or GI ulceration, pneumonitis, Follow dosing schedule carefully.
cancers; gestation- photosensitivity, neurotoxicity associ- Monitor serum methotrexate levels until ≤ 0.1
al trophoblastic tu- ated with high-dose therapy mmol. Monitor urine pH and maintain at ≥ 7 be-
mor; osteogenic fore treatment and until methotrexate levels are
sarcoma; rheuma- ≤ 0.1 mmol.
toid arthritis; pso- Instruct patients on strict mouth care.
riasis; gestational Patients must take photosensitivity precautions.
choriocarcinoma, Ensure that patients avoid taking multivitamins
chorioadenoma with folic acid.
destruens, and hy- Multiple drug interactions (e.g., NSAIDs, alcohol,
datidiform mole aspirin, warfarin, aminoglycosides) are possible.
Methotrexate is contraindicated in patients with
pleural or pericardial effusions and ascites be-
cause of severe toxicity from methotrexate ac-
cumulation.
Chapter 3. Principles of Antineoplastic Therapy
Glucarpidase (Voraxaze®) is FDA approved for
patients with delayed methotrexate clearance
due to renal impairment. This drug reduces
systemic methotrexate levels by rapidly con-
verting methotrexate to glutamate and 4-deoxy-
4-amino-N10-methylpteroic acid (DAMPA).
(BTG International Inc., 2013; Hospira, Inc., 2011b)
Nelarabine IV T-cell acute lym- Dose-limiting toxicity: Neurotoxicity Given as undiluted IV infusion over 2 hours for
(Arranon®) phoblastic leu- Myelosuppression, headache, nau- adults and 1 hour for pediatrics.
kemia and T-cell sea, vomiting, diarrhea, constipation, Administer with appropriate supportive care
lymphoblastic lym- cough, peripheral edema, fatigue, pe- medications to prevent hyperuricemia and TLS.
phoma ripheral neuropathy, dyspnea, neuro- Discontinue for ≥ grade 2 neurologic events
logic toxicities (somnolence, seizures, (severe somnolence, seizure, and peripheral
ataxia) neuropathy).
Use caution in patients with renal or hepatic dys-
function.
(GlaxoSmithKline, 2011b)
(Continued on next page)
35
36
Table 7. Characteristics of Chemotherapeutic Agents (Continued)
Mechanism Route of
Classification of Action Drug Administration Indications Side Effects Nursing Considerations
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Antimetabo- Disrupts folate- Pemetrexed IV Given in combi- Dose-limiting toxicity: Myelosuppres- Infuse over 10 minutes.
lites (cont.) dependent met- (Alimta®) nation with cis sion To reduce treatment-related hematologic and GI
abolic processes platin for the Side effects with pemetrexed plus cis- toxicity, administer folic acid 350–1,000 mcg
essential for cell treatment of ma- platin regimen include myelosuppres- PO daily starting 1 week prior to the first cycle
replication lignant pleu- sion, fatigue, nausea, vomiting, chest and daily for three weeks after final cycle. Give
ral mesothelio- pain, and dyspnea. Side effects are vitamin B12 injection 1,000 mcg IM 1 week be-
ma; nonsqua- reduced with vitamin supplementa- fore first cycle and repeat every 9 weeks until
mous NSCLC ini- tion. treatment is completed.
tial treatment in Renal and liver toxicity Dexamethasone 4 mg BID for 3 days starting the
combination with day before treatment decreases incidence of
cisplatin or as a skin rash.
single-agent af- Monitor CBC on days 8 and 15. Hold treatment
ter prior chemo- if absolute neutrophil count < 1,500 cells/mm3,
therapy platelet count < 100,000 cells/mm3, or creati-
nine clearance < 45 ml/min.
Monitor renal and hepatic function.
The concurrent use of NSAIDs may increase the
risk of renal damage.
(Eli Lilly and Co., 2013)
Pentostatin IV Hairy cell leuke- Dose-limiting toxicity: Myelosuppres- Administer with 500–1,000 ml 5% dextrose in ½
(Nipent®) mia sion NS solution prior to the infusion and an addi-
Fever, chills, nausea, vomiting, rash, tional 500 ml after infusion.
renal failure, confusion, hepatic en- Do not administer with fludarabine, carmus-
zyme elevation, lymphocytopenia, tine, etoposide, or high-dose cyclophospha-
heightened infection risk, cough mide.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
(Bedford Laboratories, 2010c)
Pralatrexate IV Peripheral T-cell Dose-limiting toxicity: Myelosuppres- Must give prophylactic folic acid and vitamin B12
(Folotyn®) lymphoma sion supplements. Supplement patients with vitamin
Mucositis, dermatologic reactions, TLS, B12 1 mg IM every 8–10 weeks and folic acid
edema, fatigue, nausea 1–1.25 mg PO daily.
Monitor liver and renal function.
Concurrent use with drugs with extensive re-
nal clearance may delay pralatrexate clear-
ance.
(Allos Therapeutics, 2011)
Thioguanine PO AML Dose-limiting toxicity: Myelosuppres- Monitor hepatic function.
(Tabloid®, sion (GlaxoSmithKline, 2008)
6-TG) Hyperuricemia, nausea, hepatotoxici-
ty, diarrhea
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 7. Characteristics of Chemotherapeutic Agents (Continued)
Mechanism Route of
Classification of Action Drug Administration Indications Side Effects Nursing Considerations
Antitumor Bind with DNA, Bleomycin IV, SC, IM, in- Malignant pleu- Dose-limiting toxicities: Hypersensi- Patients with lymphoma have a higher incidence
antibiotics thereby inhibiting (Blenoxane®) trapleural ral effusion; squa- tivity or anaphylactic reaction (rare), of anaphylaxis after receiving bleomycin than
DNA and RNA mous cell cancer pulmonary toxicity do other patients who receive the drug. There-
synthesis of head and neck; Hyperpigmentation, alopecia, photo- fore (per institutional protocol), a test dose of
cervical, vulvar, sensitivity, renal toxicity, hepatotoxic- 1–2 units IV, IM, or SC may be administered
penile, and testic- ity, fever, chills, erythema, rash, mu- before the first dose of bleomycin in patients
ular cancers; HL; cositis with lymphoma.
NHL Patients who have received prior bleomycin are
at risk for pulmonary toxicity when exposed to
oxygen during surgery. Ensure that patients
and family members understand the lifelong
necessity of disclosing previous use of bleo-
mycin when future needs for anesthesia oc-
cur to prevent a fatal episode of pulmonary
failure.
Because of the dose-related incidence of pul-
monary fibrosis, the cumulative lifetime dose
should not exceed 400 units.
PFTs are recommended at initiation of bleomy-
cin and every 1–2 months thereafter. Consid-
er stopping drug if a 30%–35% decrease from
pretreatment values occurs. Acetaminophen
and an antihistamine may decrease fever and
chills in first 24 hours after administration.
Chapter 3. Principles of Antineoplastic Therapy
(Bedford Laboratories, 2009)
Dactinomycin IV Ewing sarcoma, Dose-limiting toxicity: Myelosuppres- Dactinomycin is a vesicant.
(actinomycin D, Wilms tumor, tes- sion This drug may be ordered in micrograms, so
Cosmegen®) ticular cancer, Nausea, vomiting, alopecia, mucositis, check the dose carefully.
gestational tro- diarrhea, ovarian or sperm suppres- Contraindicated in patients with concurrent or re-
phoblastic dis- sion, radiation recall (hyperpigmenta- cent chickenpox or herpes zoster.
ease, rhabdo- tion of previously irradiated areas), si- Avoid within 2 months of radiation therapy for
myosarcoma nusoidal obstruction syndrome, he- right-sided Wilms tumor.
patic and renal toxicity (Ovation Pharmaceuticals, 2008)
Mitomycin IV Pancreatic, stom- Dose-limiting toxicities: Myelosup- Drug is purple/blue in color.
(Mutamycin®) Intravesicular ach, and bladder pression, CHF (doses > 30 mg/m2) Mitomycin is a vesicant.
cancers Nausea, vomiting, anorexia, alopecia, Nadir occurs 4–6 weeks after treatment begins.
mucositis, renal toxicity, pulmonary Acute shortness of breath and bronchospasm
toxicity, fatigue can occur very suddenly when this drug is giv-
en with a vinca alkaloid.
(Continued on next page)
37
38
Table 7. Characteristics of Chemotherapeutic Agents (Continued)
Mechanism Route of
Classification of Action Drug Administration Indications Side Effects Nursing Considerations
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Antitumor Mitomycin Contraindicated in patients with coagulation dis-
antibiotics (Mutamycin®) orders.
(cont.) (cont.) Hemolytic-uremic syndrome has been seen with
single dose ≥ 60 mg or cumulative doses ≥ 50
mg/m2.
(Bristol-Myers Squibb Co., 2006c)
Mitoxantrone IV Breast and pros- Dose-limiting toxicities: Myelosup- Fatal if given intrathecally.
(Novantrone®) tate cancers, pression, cardiotoxicity Mitoxantrone is an irritant with vesicant potential.
AML, multiple Arrhythmia (if patient was treated with Drug is blue in color.
sclerosis doxorubicin), nausea, vomiting, mu- Risk of cardiotoxicity with mitoxantrone is less
cositis, alopecia, edema, fever, weak- than that with doxorubicin, but prior anthracy-
ness, cardiotoxicity; drug may turn cline use, chest irradiation, or cardiac disease
the urine blue-green and can cause increases risk.
sclera to turn bluish. Prior to beginning therapy, evaluate patients for
cardiac signs/symptoms including obtaining
MUGA scan and baseline LVEF.
(EMD Serono, Inc., 2010)
Antitumor Bind with DNA, Daunorubi- IV ALL in children, Dose-limiting toxicities: Myelosup- Daunorubicin is a vesicant.
antibiotics thereby inhibiting cin (Cerubi- AML pression, cardiotoxicity Drug is red in color.
(anthracy- DNA and RNA dine®, Dauno- Nausea, vomiting, alopecia, hyperuri- Test patients’ cardiac ejection fraction scan be-
clines) synthesis mycin®) cemia, radiation recall, ovarian or fore starting therapy.
sperm suppression; drug may turn Use in caution in patients with renal or hepatic
the urine red. dysfunction.
Total lifetime dose in adults is 550 mg/m2 without
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
cardiovascular risk factors and 400 mg/m2 in
adults receiving chest irradiation.
(Bedford Laboratories, 2010a)
Daunorubicin IV AIDS-related Ka- Dose-limiting toxicities: Myelosup- Drug is red in color.
citrate lipo- posi sarcoma pression, cardiotoxicity Daunorubicin citrate liposomal is not a vesicant
somal (Dau- Nausea, vomiting, alopecia, fatigue, fe- but should be considered an irritant; take cau-
noXome®) ver, diarrhea, hyperuricemia, radia- tion to avoid extravasation.
tion recall, ovarian or sperm suppres- Consider dose reduction in patients with renal or
sion; drug may turn the urine red. hepatic dysfunction.
Test patients’ cardiac ejection fraction before
starting daunorubicin liposomal therapy.
This drug must be mixed in D5W only. Do not use
in-line filters.
(Gilead Sciences, 2011)
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 7. Characteristics of Chemotherapeutic Agents (Continued)
Mechanism Route of
Classification of Action Drug Administration Indications Side Effects Nursing Considerations
Antitumor Doxorubicin IV Breast, prostate, Dose-limiting toxicities: Myelosup- Doxorubicin is a vesicant.
antibiotics (Adriamycin®) ovarian, stom- pression, cardiotoxicity, hepatotoxicity Drug is red in color.
(anthracy- ach, bladder, thy- Nausea, vomiting, alopecia, mucosi- Doxorubicin may cause a flare reaction.
clines) (cont.) roid, and small tis, radiation recall, arrhythmia, hyper- Test patients’ cardiac ejection fraction before
cell lung cancers; uricemia, photosensitivity; drug may starting therapy.
MM, HL, NHL, turn the urine red. Do not exceed a lifetime cumulative dose of 550
ALL, AML; Wilms mg/m2 (450 mg/m2 if the patient has had prior
tumor, lymphoma, chest irradiation or concomitant cyclophospha-
sarcoma, neuro- mide treatment).
blastoma Consider initiating dexrazoxane (Zinecard®) for
patients who have received a cumulative dose
of 300 mg/m2 and are continuing doxorubicin
treatment. In pediatrics, dexrazoxane may be
used concurrently.
(Pfizer Inc., 2010)
Doxorubi- IV AIDS-related Ka- Dose-limiting toxicities: Myelosup- Drug is red in color.
cin liposomal posi sarcoma, pression, cardiotoxicity Doxorubicin liposomal is not a vesicant but
(Doxil®) ovarian cancer, Nausea, vomiting, alopecia, mucositis, should be considered an irritant; take caution to
MM arrhythmia, hyperuricemia, radiation avoid extravasation.
recall, palmar-plantar erythrodyses- The same warnings as with conventional doxo-
thesia, photosensitivity, hypersensi- rubicin apply regarding cardiovascular compli-
tivity reaction, electrolyte imbalance; cations.
drug may turn the urine red. Use only with D5W.
Chapter 3. Principles of Antineoplastic Therapy
Do not substitute for Adriamycin.
Start infusion at 1 mg/min over at least 30 min to
minimize infusion-related reactions. Do not use
in-line filter.
(Janssen Products, LP, 2013)
Epirubicin IV Breast cancer Dose-limiting toxicities: Myelosup- Epirubicin is a vesicant.
(Ellence®) pression, cardiotoxicity Drug is red in color.
Nausea, vomiting, mucositis, diarrhea, Consider dose reduction in patients with liver
alopecia, amenorrhea, infection, radi- dysfunction.
ation recall; drug may turn the urine Not recommended in patients with severe hepat-
red. ic dysfunction.
Reduce dose in patients with SCr > 5 mg/dl.
Cumulative dosing should not exceed 900 mg/
m2.
Test patient’s cardiac ejection fraction before
starting epirubicin therapy.
(Pfizer Inc., 2011)
(Continued on next page)
39
40
Table 7. Characteristics of Chemotherapeutic Agents (Continued)
Mechanism Route of
Classification of Action Drug Administration Indications Side Effects Nursing Considerations
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Antitumor Idarubicin IV ANLL Dose-limiting toxicities: Myelosup- Idarubicin is a vesicant. Infuse slowly over 10–15
antibiotics (Idamycin®) pression, cardiomyopathy min into free-flowing side-arm infusion.
(anthracy- Nausea, vomiting, alopecia, vein itch- Drug is red-orange in color.
clines) (cont.) ing, radiation recall, rash, mucositis, Cardiotoxicity of idarubicin is less than that of
diarrhea, GI hemorrhage; drug may daunorubicin.
turn the urine red or darker yellow. Cumulative doses > 150 mg/m2 idarubicin are as-
sociated with decreased ejection fraction.
Local reactions (hives at injection site) may occur.
Consider dose reduction in patients with renal or
hepatic impairment.
Do not administer to patients with bilirubin > 5
mg/dl.
(Teva Parenteral Medicines, Inc., 2009a)
Valrubicin Intravesical Intravesical thera- Dysuria, bladder spasm and irritation, Do not use in pediatric patients.
(Valstar®) py of BCG-refrac- urinary incontinence, leukopenia, hy- Valrubicin is administered as an intravesicular
tory in situ blad- perglycemia; drug may turn the urine bladder lavage.
der cancer red. Administer through non-PVC tubing.
(Endo Pharmaceuticals Solutions Inc., 2012)
Miscellaneous Degrades the Arsenic IV APL Fatigue, prolonged QT interval, APL Use with caution with other agents that prolong
chimeric PML/ trioxide differentiation syndrome, leukocyto- QT/QTc interval. Obtain baseline ECG prior to
RAR-alpha pro- (Trisenox®) sis, headache, nausea, vomiting, di- therapy. Ensure QTc interval < 500 msec pri-
tein; degrades arrhea, musculoskeletal pain, periph- or to infusion. Periodic QTc intervals should be
the NB4 human eral neuropathy, tachycardia, edema, measured during therapy (e.g., weekly) per in-
promyelocytic fever, insomnia, dermatitis, cough, stitutional guidelines.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
leukemia cells dyspnea Use with caution in patients with renal impair-
to cause partial ment. Monitor electrolytes during therapy. Main-
maturation and tain serum potassium > 4 mEq/L and magne-
trigger apoptosis; sium > 1.8 mg/dl.
causes the re- (Cephalon, Inc., 2010)
lease of toxic free
radicals inside
the cell that trig-
gers apoptosis of
the APL cell
Inhibits protein Asparaginase IV, SC, IM ALL Dose-limiting toxicity: Pancreatitis Giving the drug IM greatly reduces the incidence
synthesis (Elspar®) Nausea, vomiting, hepatotoxicity, fever, of anaphylaxis.
hyperglycemia, anaphylaxis, coagulop- Keep medications to treat anaphylaxis at bed-
athy, hypoalbuminemia, hypersensitivi- side.
ty reaction, renal toxicity, thrombus (Lundbeck, 2013)
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 7. Characteristics of Chemotherapeutic Agents (Continued)
Mechanism Route of
Classification of Action Drug Administration Indications Side Effects Nursing Considerations
Miscellaneous Asparaginase IM ALL, for patients Nausea, vomiting, hepatotoxicity, fever, Keep medications to treat anaphylaxis at bedside.
(cont.) Erwinia chry- who have devel- hyperglycemia, anaphylaxis, pancre- Limit the volume of reconstituted Erwinaze at
santhemi (Er- oped sensitivity to atitis, coagulopathy, hypersensitivity a single injection site to 2 ml; if reconstituted
winaze®) E. coli-derived as- reaction, renal toxicity, thrombus dose to be administered is > 2 ml, use multiple
paraginase injection sites.
(EUSA Pharma [USA], Inc., 2011)
Pegaspargase IM, IV ALL (may be Hepatotoxicity, coagulopathy, anaphy- Longer half-life (5–6 days) than asparaginase (1–2
(Oncaspar®) used upfront or laxis, hyperglycemia days); therefore, is dosed every 14 days versus
for those who daily or every 3 days. Check dosing carefully.
have developed Risk of anaphylaxis is less than that of aspara-
hypersensitivity to ginase.
asparaginase) (Sigma-Tau Pharmaceuticals, Inc., 2011b)
Acts in S phase Hydroxyurea PO CML, malignant Dose-limiting toxicities: Myelosup- Do not open capsules.
as antimetabolite (Hydrea®, melanoma, squa- pression, nausea, vomiting, diarrhea, Adjust the dose according to WBC counts; mon-
Mylocel®) mous cell cancer renal failure, mucositis, fever, hyper- itor WBCs at least every 2 weeks, and stop
of the head and uricemia, rash, hepatotoxicity, second treatment until counts recover. Do not change
neck, metastat- malignancies the dose frequently in older patients because
ic ovarian cancer, they may be more sensitive to the medication.
sickle-cell anemia Instruct patients on strict mouth care.
Doses may be divided within the 24-hour period
to decrease nausea and vomiting.
(Bristol-Myers Squibb Co., 2011b)
Chapter 3. Principles of Antineoplastic Therapy
Inhibits adre- Mitotane PO Adrenocortical Nausea, vomiting, mucositis, adrenal Monitor patients on warfarin therapy closely with
nal steroid pro- (Lysodren®) cancer insufficiency, lethargy, rash PT/INR.
duction Adrenal steroid replacement is indicated.
Consider dose reduction in patients with renal or
hepatic impairment.
(Bristol-Myers Squibb Co., 2006b)
May inhibit pro- Procarbazine PO HL Dose-limiting toxicity: Myelosuppres- Patients should avoid foods high in tyramine,
tein, RNA, and (Matulane®) sion such as aged cheeses, air-dried or cured
DNA synthesis Nausea, vomiting, hepatic dysfunction meats, fava or broad bean pods, tap/draft beer,
wine (> 120 ml), vermouth, marmite concen-
trate, sauerkraut, and soy sauce and other soy-
bean condiments because procarbazine inhib-
its monoamine oxidase.
Patients should avoid alcohol for possible
Antabuse®-like reaction.
(Sigma-Tau Pharmaceuticals, Inc., 2012)
(Continued on next page)
41
42
Table 7. Characteristics of Chemotherapeutic Agents (Continued)
Mechanism Route of
Classification of Action Drug Administration Indications Side Effects Nursing Considerations
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Miscellaneous Inhibits growth Eribulin IV Breast cancer Dose-limiting toxicities: Neutropenia, Monitor electrolytes, ECG, and renal and liver
(cont.) phase of micro- (Halaven®) neurotoxicity function tests.
tubules, arresting Peripheral neuropathy, fatigue, alope- Not compatible with D5W.
cell cycle at G2/M cia, nausea, constipation, anemia, (Eisai Inc., 2010b)
phase QTc prolongation
Inhibits the en- Romidepsin IV Cutaneous and Dose-limiting toxicities: Myelosup- Obtain baseline and periodic ECG.
zymatic activity (Istodax®) peripheral T-cell pression, life-threatening infections Monitor and correct electrolytes.
of HDAC, which lymphoma QTc prolongation, fatigue, fever, pruri- (Celgene Corp., 2013)
allows for the tus, nausea, vomiting, anorexia, con-
accumulation of stipation, diarrhea, TLS
acetyl groups on
histone lysine
residue, which
results in cell cy-
cle arrest and/
or apoptosis
of some trans-
formed cells
Inhibits the enzy- Vorinostat PO Cutaneous T-cell Dose-limiting toxicities: Thrombocy- Instruct patients to take once daily with food.
matic activity of (Zolinza®) lymphoma topenia, diarrhea Monitor CBC, electrolytes, glucose, and SCr ev-
HDAC, which al- Anemia, fatigue, nausea, thromboem- ery 2 weeks during first 2 months and monthly
lows for the ac- bolism, anorexia, dysgeusia, protein- thereafter because of possible hyperglycemia
cumulation of uria, QTc prolongation and QT prolongation.
acetyl groups on Capsules should not be opened or crushed.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
the histone ly- Drug may interact with warfarin (Coumadin®) (in-
sine residue, creasing PT/INR) and other HDAC inhibitors
which results in (valproic acid) (severe thrombocytopenia and
cell cycle arrest GI bleeding).
and/or apoptosis (Merck & Co., Inc., 2009)
of some trans-
formed cells
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 7. Characteristics of Chemotherapeutic Agents (Continued)
Mechanism Route of
Classification of Action Drug Administration Indications Side Effects Nursing Considerations
Miscellaneous Semisynthet- Ixabepilone IV Metastatic or lo- Dose-limiting toxicities: Peripher- CYP3A4 inhibitors may increase ixabepilone
(cont.) ic analog of ep- (Ixempra®) cally advanced al sensory neuropathy, myelosup- concentration, and CYP3A4 inducers may de-
othilone B; binds breast cancer pression crease ixabepilone concentration. Avoid St.
to beta-tubulin Fatigue, myalgia, alopecia, nausea, John’s wort.
on microtubules, vomiting, mucositis, diarrhea, muscu- Premedicate with diphenhydramine and famoti-
leading to cell loskeletal pain dine or ranitidine 1 hour prior to dose to de-
death by block- crease risk of hypersensitivity reaction.
ing cells in mitot- Mix only in LR in non-PVC bag. Administer
ic phase of cell through 0.2–1.2 micron in-line filter.
division cycle (Bristol-Myers Squibb Co., 2011c)
Inhibits protein Omacetaxine SC CML in chron- Dose-limiting toxicity: Myelosuppres- Monitor patient for bleeding.
synthesis and (Synribo®) ic or accelerated sion Rotate injection sites.
is independent phase with resis- Thrombocytopenia with bleeding risk, (Teva Pharmaceuticals USA, Inc., 2012)
of direct Bcr-Abl tance and/or in- hyperglycemia, nausea, vomiting, di-
binding tolerance to 2 or arrhea, alopecia, skin rash, injection-
more TKIs site reactions
Nitrosoureas Break DNA helix, Carmustine IV, implantation HL, NHL, CNS tu- Dose-limiting toxicity: Myelosuppres- Nadir occurs 4–6 weeks after therapy starts.
interfering with (BiCNU®) (Gliadel® wafer) mors, MM sion Because of delayed toxicity, successive treat-
DNA replication; Nausea, vomiting, renal toxicity, hepa- ments usually are given no more frequently
cross the blood- totoxicity, pulmonary fibrosis, ovarian than once every 6–8 weeks.
Chapter 3. Principles of Antineoplastic Therapy
brain barrier or sperm suppression Rapid infusion may cause burning along the vein
and flushing of the skin (infuse over at least 2
hours).
Mix in D5W non-PVC bag.
Long-term therapy can result in irreversible pulmo-
nary fibrosis, which may present as an insidious
cough and dyspnea or sudden respiratory failure.
(Bristol-Myers Squibb Co., 2007)
Lomustine PO CNS and brain Dose-limiting toxicity: Myelosuppres- Because of delayed myelosuppression, do not
(CeeNU®) tumors; HL sion repeat the dose more than once every 6 weeks.
Nausea, vomiting, alopecia, renal toxic- Administer on an empty stomach.
ity, hepatic toxicity, mucositis, anorex- Monitor PFTs, LFTs, and renal function.
ia, pulmonary fibrosis (Bristol-Myers Squibb Co., 2006a)
(Continued on next page)
43
44
Table 7. Characteristics of Chemotherapeutic Agents (Continued)
Mechanism Route of
Classification of Action Drug Administration Indications Side Effects Nursing Considerations
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Nitrosoureas Streptozocin IV Metastatic islet- Dose-limiting toxicity: Renal toxicity Streptozocin is an irritant.
(cont.) (Zanosar®) cell pancreatic Myelosuppression, nausea, vomiting, Nephrotoxicity may be dose limiting.
carcinoma hypoglycemia, proteinuria, hepato- This drug may alter glucose metabolism in some
toxicity patients.
Rapid infusion may cause burning along the vein.
(Sicor Pharmaceuticals, 2006)
Camptothe- Act in S phase; Irinotecan IV Metastatic Dose-limiting toxicity: Diarrhea Do not use in pediatric patients.
cins inhibit topoisom- (Camptosar®) colorectal cancer Myelosuppression, alopecia, fever, This drug can cause early and late diarrhea,
erase I; cause nausea, vomiting, mucositis, in- which can be dose limiting. Early diarrhea can
double-strand creased bilirubin, weakness occur within 24 hours of administration and
DNA changes generally is cholinergic. Many institutions use
atropine to treat early diarrhea. Refer to institu-
tional protocol regarding dosing and adminis-
tration of atropine and other antidiarrheals.
(Hospira, Inc., 2011a)
Topotecan IV, PO Metastatic ovari- Dose-limiting toxicity: Diarrhea Consider dose reduction in patients with renal
(Hycamtin®) an cancer, cervi- Myelosuppression, alopecia, nausea, impairment.
cal cancer, SCLC vomiting, headache, fatigue, fever, in- Do not crush, chew, or break capsules.
terstitial lung disease (GlaxoSmithKline, 2009)
Plant Induce irrevers- Etoposide IV, PO Testicular cancer, Dose-limiting toxicity: Myelosuppres- Do not administer this drug by means of rapid
alkaloids ible blockade of (VP-16, SCLC sion IV infusion or IV push. Infuse over 30–60 min
(epipodophyl- cells in premi- Toposar®, Nausea, vomiting, alopecia, anorex- to avoid hypotension.
lotoxins) totic phases of VePesid®) ia, hypotension, hypersensitivity reac- Monitor patients’ blood pressure during infu-
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
cell cycle (late Etoposide tion, anaphylaxis sion.
G2 and S phas- phosphate High-dose: Mucositis, diarrhea, myo- Prior to use, dilute the drug to a final concen-
es); interfere with (Etopophos®) cardial infarction, angina tration of 0.2–0.4 mg/ml to prevent precipi-
topoisomerase II tation.
enzyme reaction Monitor for crystallization during infusion.
If a patient has an allergic reaction to etopo-
side, premedicate with diphenhydramine.
Do not administer to patients with bilirubin > 5
mg/dl.
Consider dose reduction in patients with renal
or hepatic impairment.
(Bedford Laboratories, 2010b; Bristol-Myers
Squibb Co., 2011a)
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 7. Characteristics of Chemotherapeutic Agents (Continued)
Mechanism Route of
Classification of Action Drug Administration Indications Side Effects Nursing Considerations
Plant Teniposide IV Childhood ALL Dose-limiting toxicity: Myelosuppres- Drug may cause an allergic reaction.
alkaloids (VM-26, sion Do not administer via rapid infusion; infuse over
(epipodo- Vumon®) Hypotension, anaphylaxis, nausea, 30–60 min; monitor patients’ blood pressure
phyllotoxins) vomiting, mucositis, alopecia during the infusion.
(cont.) Administer through non-PVC tubing.
Consider dose reduction in patients with renal or
hepatic impairment.
(Bristol-Myers Squibb Co., 2011e)
Plant Stabilize microtu- Cabazitaxel IV Prostate cancer Hypersensitivity reaction, fatigue, di- Premedicate as follows to prevent hypersensitiv-
alkaloids bules, inhibiting (Jevtana®) arrhea, nausea, vomiting, myelosup- ity reaction, including anaphylaxis, at least 30
(taxanes) cell division; ef- pression, peripheral neuropathy, ab- min before treatment: IV antihistamine, cortico-
fective in G2 and dominal pain, back pain, arthralgia, steroid, and an H2 antagonist.
M phases asthenia Administer over 1-hour infusion.
Use with caution in patients with renal impair-
ment.
Not recommended in patients with severe hepat-
ic impairment.
(sanofi-aventis U.S. LLC, 2012)
Docetaxel IV NSCLC; breast, Myelosuppression, hypersensitivity re- Do not use in pediatric patients.
(Taxotere®) head and neck, action, fluid retention, alopecia, skin Docetaxel is an irritant. Extravasation may lead
prostate, and and nail changes, mucositis, nausea, to edema, erythema, and occasional pain
gastric cancers vomiting, paresthesia, neurotoxicity and blister formation.
Chapter 3. Principles of Antineoplastic Therapy
Premedicate as follows to reduce the severi-
ty of hypersensitivity reaction and fluid reten-
tion: dexamethasone 8 mg PO BID, beginning
1 day prior to docetaxel treatment and con-
tinuing for the day of treatment and 1 day af-
ter.
Do not use PVC tubing or bags to administer
docetaxel.
Consider dose reduction in patients with hepat-
ic impairment.
(sanofi-aventis U.S. LLC, 2010)
(Continued on next page)
45
46
Table 7. Characteristics of Chemotherapeutic Agents (Continued)
Mechanism Route of
Classification of Action Drug Administration Indications Side Effects Nursing Considerations
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Plant Paclitaxel IV Metastatic breast, Dose-limiting toxicities: Peripheral Do not use in pediatric patients.
alkaloids (Taxol®) and ovarian, can- neuropathy, hypersensitivity reaction Paclitaxel is an irritant and potential vesicant. Ex-
(taxanes) cers, NSCLC, Myelosuppression, alopecia, facial travasation may lead to local pain, edema, and
(cont.) AIDS-related Ka- flushing, myalgia, fatigue, cardiac ar- erythema at the infusion site. There are reports
posi sarcoma rhythmias, mucositis, diarrhea, nau- of necrosis.
sea, vomiting Drug is mixed in a mineral oil–like solvent that
can cause infusion-related hypersensitivity re-
actions.
Premedicate as follows to help to prevent hyper-
sensitivity reaction, including anaphylaxis, 30–
60 min before treatment: cimetidine 300 mg or
famotidine 20 mg IV, diphenhydramine 50 mg
IV, and (unless contraindicated) dexametha-
sone 20 mg IV (Solimando, 2008).
Filter paclitaxel with a 0.2 micron in-line filter.
Use glass bottles or non-PVC (polyolefin or poly-
propylene) bags to administer paclitaxel; do not
use PVC tubing or bags.
Consider dose reduction in patients with renal or
hepatic impairment.
To prevent severe myelosuppression, give pacli-
taxel before platinum-containing drugs.
(Bristol-Myers Squibb Co., 2011d)
Paclitaxel pro- IV Treatment of met- Dose-limiting toxicity: Myelosuppres- Drug is free of solvents; therefore, no premedica-
tein-bound astatic breast sion tion is required to prevent hypersensitivity reac-
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
particles; al- cancer after fail- Sensory neuropathy, myalgia, arthral- tions.
bumin-bound ure of combina- gia, nausea, vomiting, diarrhea, mu- Consider dose reduction by about 20% for se-
(Abraxane®) tion chemother- cositis, alopecia vere sensory neuropathy; resume treatment
apy or relapse with reduced dose when neuropathy improves
within 6 months to grade 1 or 2 (Solimando, 2008).
of adjuvant thera- Do not use in patients with baseline neutrophil
py and NSCLC count < 1,500 cells/mm3.
(Celgene Corp., 2012a)
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 7. Characteristics of Chemotherapeutic Agents (Continued)
Mechanism Route of
Classification of Action Drug Administration Indications Side Effects Nursing Considerations
Plant alka- Act in late G2 Vinblastine IV Testicular cancer, Dose-limiting toxicities: Myelosup- Vinblastine is a vesicant.
loids (vinca phase, blocking (Velban®) HL, Kaposi sar- pression, neurotoxicity Drug is fatal if given intrathecally.
alkaloids) DNA production, coma, histiocyto- Alopecia, anorexia, jaw pain, peripher- Generally, neurotoxicity occurs less frequently
and in M phase, sis, NHL, breast al neuropathy, constipation, paralyt- with vinblastine than with vincristine; however, it
preventing cell cancer ic ileus is rare and usually reversible.
division (Bedford Laboratories, 2010d)
Vincristine IV ALL, HL, NHL, Dose-limiting toxicity: Neurotoxicity Vincristine is a vesicant.
(Oncovin®) neuroblastoma, Alopecia, peripheral neuropathy, con- Drug is fatal if given intrathecally.
Wilms tumor, stipation, paralytic ileus, jaw pain, foot Neurotoxicity is cumulative, but often revers-
rhabdomyosar- drop, renal and hepatotoxicity ible; conduct a neurologic evaluation before
coma each dose. Withhold dose if severe paresthe-
sia, motor weakness, or other abnormality de-
velops.
Reduce dose in the presence of significant liv-
er disease.
Stool softeners and/or a stimulant laxative may
help to prevent severe constipation.
(Hospira, Inc., 2011c)
Vinorelbine IV NSCLC Dose-limiting toxicity: Myelosuppres- Do not use in pediatric patients.
(Navelbine®) sion Vinorelbine is a vesicant.
Nausea, vomiting, neurotoxicity, pe- Flush with 75–125 ml solution after completion of
ripheral neuropathy, alopecia, hepa- vinorelbine administration.
Chapter 3. Principles of Antineoplastic Therapy
totoxicity Drug is fatal if given intrathecally.
(Teva Parenteral Medicines, Inc., 2009b)
AIDS—acquired immunodeficiency syndrome; ALL—acute lymphocytic leukemia; AML—acute myeloid leukemia; ANLL—acute nonlymphocytic leukemia; APL—acute promyelocytic leukemia; AUC—area under the
plasma concentration versus time curve; BCG—bacillus Calmette-Guérin; BID—twice daily; BMT—bone marrow transplantation; CBC—complete blood count; CLL—chronic lymphocytic leukemia; CML—chronic my-
eloid leukemia; CNS—central nervous system; D5W—5% dextrose in water; dl—deciliter; DNA—deoxyribonucleic acid; ECG—electrocardiogram; FDA—U.S. Food and Drug Administration; 5-FU—5-fluorouracil; G2—
gap 2; GI—gastrointestinal; HDAC—histone deacetylases; HL—Hodgkin lymphoma; IM—intramuscular; INR—international normalized ratio; IT—intrathecal; IV—intravenous; kg—kilogram; LFT—liver function test;
LR—lactated Ringer’s solution; LVEF—left ventricular ejection fraction; M—mitosis; mcg—microgram; MDS—myelodysplastic syndrome; mEq—milliequivalent; mg—milligram; min—minute; ml—milliliter; MM—multi-
ple myeloma; mmol—millimole; msec—millisecond; MUGA—multigated acquisition; NHL—non-Hodgkin lymphoma; NS—normal saline; NSAID—nonsteroidal anti-inflammatory drug; NSCLC—non-small cell lung can-
cer; PCP—Pneumocystis jiroveci pneumonia; PFT—pulmonary function test; PO—by mouth; PT—prothrombin time; PVC—polyvinyl chloride; QTc—QT interval corrected; RNA—ribonucleic acid; S—synthesis; SC—
subcutaneous; SCLC—small cell lung cancer; SCr—serum creatinine; SIADH—syndrome of inappropriate antidiuretic hormone; TKI—tyrosine kinase inhibitor; TLS—tumor lysis syndrome; ULN—upper limit of normal;
WBC—white blood cell
Note. Based on information from Aronoff et al., 2007; Ascherman et al., 2000; Bragalone, 2012; Chu & DeVita, 2010; Elsevier/Gold Standard, 2013; Micromedex, 2013; Solimando, 2008; and manufacturers’ prescribing
information.
47
48 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
a) Cell cycle–nonspecific drugs are effective in treating tumors with
more slowly dividing cells.
b) If the cancer is sensitive to the agent used, the drug is incorporated
into the cell. The cell kill may not be instantaneous but may occur
when the cell attempts to divide.
(1) Destruction of tumor cells is directly proportional to the amount
of drug administered.
(2) These drugs are given intermittently, allowing the individual to
recover from dose-limiting toxicities before the drug is repeated.
(3) The most frequent dose-limiting toxicity is bone marrow sup-
pression.
c) Classifications include alkylating agents, antitumor antibiotics, hor-
monal therapies, and nitrosoureas.
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50 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
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Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 4
Principles of Biotherapy
A. Immunology: It is essential to understand the immune system in order to un-
derstand how biotherapy works. The immune system (see Figure 3) is a high-
ly specialized and adaptive system that protects an individual by providing
1. Defense against foreign organisms
2. Homeostasis: Destruction of aging or damaged cells
3. Surveillance: Identification of foreign, or nonself, substances.
B. Types of immune response (Medzhitov, 2008; Muehlbauer, 2011; Paul, 2008):
An immune response is the reaction of the immune system against a for-
eign substance, or antigen (e.g., bacteria). Two types of immune respons-
es exist (see Table 8).
1. Innate, or nonspecific, immunity (see Figure 4): Essential for induc-
ing a generic immune response to antigens (Janeway, Travers, Walport,
& Shlomchik, 2005). Innate immunity does not generate immunologic
memory and involves the following (Medzhitov, 2008).
Figure 3. Primary and Secondary Lymphoid Organs
Tonsils and
adenoids
Thymus
Lymph
nodes
Spleen
Peyer’s
Appendix
patches
Lymph
nodes
Lymphatic
vessels
Bone
marrow
51
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
52 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
a) Physical barriers (skin and mucous membranes)
b) Mechanical barriers (coughing, sneezing, and blinking)
c) Chemical barriers (tears and sweat)
d) Inflammatory responses (production of monocytes, macrophages,
and polymorphonuclear cells)
e) Complement activation
f) Acute-phase protein production (e.g., interleukin [IL]-2)
g) Production of large granular lymphocytes (natural killer [NK] or NK
and natural killer T [NKT] cells)
2. Adaptive, or specific, immunity: Secondary line of defense and involves
immunologic memory, specificity, and collaboration of B cells and T
cells (McHeyzer-Williams, 2008). The three types of adaptive immuni-
ty are the following.
Table 8. Innate and Adaptive Immune Responses
Immune
Response Mechanism of Action Cells Primarily Involved
Innate • Primary line of defense • Neutrophils
• Nonspecific • Monocytes, macrophages
• No memory • Large granular lymphocytes (natural killer
cells)
Adaptive • Secondary line of defense • Lymphocytes
• Specific memory • T cells (in cell-mediated immunity)
• B cells (in humoral immunity)
Note. Based on information from Paul, 2008.
Figure 4. Innate (Nonspecific) Immune Response
Natural killer cells
Lyse
Phagocytes
lf
gu
Tumor cells
En
Monocytes
Polymorphonuclear
leukocytes
Macrophages
Eng
ulf
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 4. Principles of Biotherapy 53
a) Humoral immunity (see Figure 5): B lymphocytes, memory B cells,
and plasma cells mediate humoral immunity. The result is the pro-
duction of immunoglobulins (Igs).
b) Cell-mediated immunity (see Figure 6): This type of immunity is me-
diated by T cells and their cytokine products. It does not involve an
antibody but rather cytotoxic T cells (TC) and helper T cells (TH1 or
TH2) (Reiner, 2008).
c) Regulatory T cells (Treg), also known as suppressor T cells (TS)
(1) Limit the activity of other immune effector cells.
Figure 5. Adaptive (Specific) Immune Response: B Cells and Humoral Immunity
Figure 6. Adaptive (Specific) Immune Response: Cell-Mediated Immunity
T-cell activation
Activated cytotoxic T cell kills foreign Activated helper T cell produces
cells, virally infected cells, or cells cytokines.
with new surface antigens.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
54 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
(2) Their major role is thought to be to prevent the onset of im-
munity to normal tissues of the body and limit the inflamma-
tory response that can occur with infections.
(3) Animals and people without Treg cells develop a variety of inflam-
matory disorders primarily involving the bowel, skin, and liver.
C. Cells of the immune system (see Figure 7): The immune response in-
volves the intricate interaction of a number of cells and proteins (Post-
White & Bauer-Wu, 2011). Many cells of the immune system express clus-
ter of differentiation (CD) markers on their surfaces. These CD markers
(e.g., CD4, CD20) are associated with certain immune functions. The sci-
ence behind biotherapy has capitalized on the use of CD markers to cre-
ate cell-specific therapy.
1. Antigen-presenting cells: Cells (e.g., macrophages, B cells, dendritic
cells) that efficiently present antigen to T cells; only dendritic cells are
capable of initiating a primary immune response.
2. T cells (Lesterhuis, Haanen, & Punt, 2011; Pardoll, 2012; Paul, 2008;
Reiner, 2008; Restifo, Robbins, & Rosenberg, 2008)
a) TH cells: Cells that coordinate the immune response and cell-mediat-
ed immunity; they are required to maintain cytotoxic T cell respons-
es and express CD4.
(1) TH1 cells are necessary for activating macrophages and are in-
volved in production of certain antibody isotypes.
(2) TH2 cells are effective activators of B cells, particularly in pri-
mary responses.
b) TC cells: Cells that kill foreign cells, virally infected cells, or cells with
new surface antigens. TC cells express CD8.
c) Treg/TS cells: Cells that interfere with development of immune reac-
tion when recognizing antigen. Their primary role is to modulate the
severity of inflammation produced by infection and prevent autoim-
munity; they may be involved in malignancy.
d) Memory T cells (TM cells): Cells that recognize specific antigens and
induce recall responses
e) Cytotoxic T-lymphocyte antigen 4 (CTLA-4): Part of a group of mole-
cules that contribute to activation or inhibition of T-cell immune re-
Figure 7. Cells of the Immune System
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 4. Principles of Biotherapy 55
sponses (i.e., it is an immune checkpoint). The consequence of CTLA-
4 ligands binding on antigen-presenting cells is a negative regulation
of T-cell activity. CTLA-4 expression decreases the activation of T cells
as well as sending inhibitory signals to the T cell. CTLA-4 is expressed
by activated CD8+ cells, but the primary role of CTLA-4 is diminishing
TH activity and enhancing Treg immunosuppressive activity.
3. NK cells: Cells that are cytotoxic to tumor cells and virally infected au-
tologous cells by producing substances that can bind to and destroy for-
eign invaders without having to identify a specific antigen. NK cells iden-
tify foreign substances by their lack of identifying surface molecules.
4. NKT cells: Cells that have markers both of NK cells and T cells
5. B lymphocytes: Plasma cell precursors; plasma cells manufacture Ig (an
antibody) specific to an initiating antigen.
6. Antibodies: Protein products of plasma cells; also known as immunoglob-
ulins, they enhance effector cell functions.
a) The majority of peripheral blood antibodies are IgG, which enhanc-
es phagocytosis of antigen by macrophages, monocytes, polymorpho-
nuclear cells, and some lymphocytes.
b) IgM is the first antibody produced in response to an antigen.
c) IgA is present in bodily secretions and helps to prevent infections
at sites where the environment interacts with the body, such as the
nose and lungs.
d) IgD is present in small amounts in normal serum. The exact biologic
function is unclear; however, IgD may have some antibody function
for penicillin, diphtheria, and insulin.
e) IgE exists in trace amounts in normal serum and is associated with
immediate hypersensitivity reactions. IgE antibodies are generated
when combined with certain antigens, thus activating the release of
histamine from mast cells.
7. Cytokines: Glycoprotein products of immune cells such as lymphocytes
and macrophages. Cytokines are produced in response to T-cell activa-
tion. Cytokines mediate effector defense functions. Cytokines themselves
usually are not cytotoxic (e.g., ILs, interferon [IFN]).
8. Chemokines: Known as chemotactic cytokines, these protein molecules reg-
ulate leukocyte migration and are key organizers of cell distribution in
both immune and inflammatory responses.
D. Tumor escape mechanisms: When immune surveillance fails, tumor forma-
tion occurs. The theories to explain this process include the following (Agar-
wal & Busse, 2010; Demaria et al., 2010; Liu, 2011; Muehlbauer, 2011; Topa-
lian, Weiner, & Pardoll, 2011).
1. Altered immunogenicity: Tumors are targeted by the immune system
through cell surface molecules that function as targets for antibody re-
sponses or by intracellular molecules that are presented within the con-
text of the major histocompatibility complex (MHC) molecules.
a) Altered antigen expression on the tumor cell surface allows the anti-
gen to go unrecognized by the humoral immune system.
b) Cell-mediated immune response is blunted through loss or alteration
of MHC molecules or loss or mutation of the peptide epitope that
binds to the MHC molecule and is recognized by T cells.
2. Antigen modulation: Antibodies produced as part of the immune re-
sponse cause antigens to enter the tumor cell or leave it completely.
This further limits the ability of the immune cells to recognize the tu-
mor cell as nonself.
3. Immune suppression: The tumor itself produces substances that alter
or inhibit the body’s immune response. One example is transforming
growth factor-beta, which inhibits T-cell activity.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
56 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
4. Acquired deficiencies to immune sensitivity: These include age- and dis-
ease-associated alterations such as decreased or increased apoptosis and
signaling defects of T cells.
5. Immunologic aging or immunosenescence: Causes decline in numbers of
naïve T cells, generation of TC cells, hematopoietic stem cells, phagocytes,
and NK cells, production of IL-2, signal transduction of lymphocytes, and
humoral immunity. There is also decreased antigen response and prolif-
eration, increased TM cells, and potentially decreased functional Treg cells.
6. Tumors fail to give off inflammatory warning signals to stimulate an im-
mune response.
E. Overview of biologic therapies
1. NCI defines biotherapy as treatment to boost or restore the ability of the
immune system to fight cancer, infections, and other diseases. It also is
used to lessen certain side effects that may be caused by some cancer
treatments. Agents used in biotherapy include mAbs, growth factors, and
vaccines (“Biotherapy,” n.d.).
2. Theory of immune surveillance
a) The transformation of a cell from normal to malignant involves a
number of genetic mutations over a span of years.
b) As cells differentiate, they produce proteins (antigens) on their surface
that the immune system recognizes as nonself; an immune response
can be mounted in defense. However, cells may not always recognize
cancer cells as foreign (Koon & McDermott, 2011; Restifo et al., 2008).
3. Methods of action: Biotherapeutic agents work by doing one or more of
the following (Koon & McDermott, 2011).
a) Enhancing the patient’s own immune response
b) Altering the milieu in which cancer cells grow by modifying the ac-
tions of normal cells in the area of the tumor
c) Increasing the vulnerability of cancer cells to the body’s own im-
mune system
d) Altering the pathway by which normal cells transform into malignant
cells, which may be more preventive than therapeutic
e) Preventing the metastasis of cancer cells
f) Enhancing the repair of normal cells damaged by treatment
g) Changing cancer cells so they behave like healthy cells
F. Categories of biotherapy (Koon & McDermott, 2011; Muehlbauer, 2011)
1. Cytokines
a) Cytokines are small protein molecules released by diverse cells through-
out the body, providing communication between the cells of the im-
mune system.
b) Cytokines generally are activated by a stimulus and induce responses
by binding to specific receptors. Cells expressing receptors for specif-
ic cytokines can be activated or inhibited, either of which alters the
immune effector function.
c) Cytokines affect the growth and differentiation of WBCs and regu-
late immune and inflammatory responses.
d) Cytokines may enhance cytotoxic activity and secrete additional cyto-
kines, resulting in amplification of immune response. This enhanced
immune response stimulates proliferation or activation and recruit-
ment of additional immune effector cells.
e) Cytokines are multifunctional substances having proinflammatory,
anti-inflammatory, and regulatory functions in the immune system.
f) Cytokines include a variety of ILs, IFNs, tumor necrosis factors (TNFs),
and transforming growth factor. Examples include IL-1, -2, -3, -4, -6,
-8, -10, and -15 and IFN-α and IFN-ß.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 4. Principles of Biotherapy 57
g) Cytokines regulate antibody production and the functions of B and
T cells, as well as interact with antigen-presenting cells and NK cells.
h) Examples of cytokines used for therapeutic purposes
(1) Hematopoietic growth factors
(2) IFNs
(3) ILs
2. mAbs (see Figure 8 for nomenclature) (Muehlbauer, Cusack, & Morris,
2006; Scheinberg, Rosenblat, Jurcic, Sgouros, & Junghans, 2011; Wu-
jcik, 2011)
a) General
(1) A type of targeted biotherapy derived from human antibodies,
mouse antibodies, or combinations thereof
(a) Murine: Derived from mouse antibody; less effective be-
cause they lack the ability to bind to the Fc receptor
(b) Chimeric: Combination of mouse and human antibodies
(c) Humanized: Small part mouse antibodies fused with hu-
man antibodies
(d) Human: Only human antibodies
(2) Cell surface proteins can function as targets for binding mAbs.
(3) mAbs target host tissues or proteins that support tumor growth,
such as growth factors and growth factor receptors, or they may
identify targets that are relatively unique to the tumor cell pop-
ulation.
Figure 8. Types of Monoclonal Antibodies
Comparison of monoclonal antibodies (brown: human, gray: nonhuman):
• Top row: mouse, chimeric
• Bottom row: humanized, chimeric/humanized, human
The substems according to the nomenclature of monoclonal antibodies are shown below each
antibody.
Note. Public domain image from Wikimedia Commons. Retrieved from http://en.wikipedia.org/wiki/
File:Chimeric_and_humanized_antibodies.svg.
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58 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
(4) mAbs may inhibit the binding of growth factors to their respec-
tive receptors on the cell surface and shut off downstream sig-
naling that stimulates tumor cell growth.
(5) Antibodies recognize and bind to specific antigens.
(a) Depending on its particular class and subtype, an antibody
can interact with other serum proteins, such as the com-
plement system or Fc receptors on cells, to activate normal
immune functions that selectively eliminate the antigen or
the target cell expressing that antigen.
(b) Antibody-dependent cellular cytotoxicity is thought to be
the major mechanism for response to most mAbs. It is be-
lieved to involve a three-step process:
i. The antibody binds to the antigen of the tumor cell.
An example is rituximab, which is anti-CD20 and binds
to CD20 receptors on lymphocytes.
ii. NK cells recognize the antibody-covered tumor cells.
iii. Cytotoxic proteins are released to destroy tumor cells.
(c) Alternatively, mAbs can act directly on the tumor cell to in-
duce cell death.
b) Unconjugated antibodies: Antitumor activity results solely from the
actions of the mAb on its targets. These mAbs do not have cytotoxic
agents or radioisotopes attached to them (Muehlbauer et al., 2006;
Scheinberg et al., 2011). Examples include
(1) Rituximab (targets CD20)
(2) Trastuzumab (targets human epidermal growth factor recep-
tor 2 [HER2])
(3) Cetuximab (targets EGFR)
(4) Bevacizumab (targets vascular endothelial growth factor [VEGF])
(5) Ipilimumab (targets anti-CTLA-4)
c) Conjugated antibodies: Antibodies are physically attached to anti-
tumor agents such as radioisotopes (through RIT), chemotherapy
drugs, toxins, or other biologic agents.
(1) After targeting specific antigens, conjugated mAbs release the
attached antitumor agent into the cells or deliver high lev-
els of local radioactive emissions to the site. An example of a
conjugated mAb is brentuximab vedotin, currently FDA ap-
proved for the treatment of HL and systemic anaplastic large-
cell lymphoma.
(2) An advantage of RIT is its ability to kill cells at a distance with
no need to bind to tumor cells directly to have beneficial effects.
(3) Examples of radioisotope conjugates (antibodies labeled with
a radioisotope)
(a) Ibritumomab tiuxetan (Zevalin®) (Spectrum Pharmaceu-
ticals, Inc., 2011)
(b) Iodine-131 tositumomab (Bexxar®) (GlaxoSmithKline, 2012a)
G. RIT (Iwamoto, Haas, & Gosselin, 2012; Sharkey & Goldenberg, 2011)
1. RIT is a radiopharmaceutical cancer treatment that employs radionu-
clide-labeled, or radiolabeled, mAbs. These antibodies, which are admin-
istered systemically by intravenous (IV) injection, recognize tumor-asso-
ciated antigens to deliver radioactivity to tumor cells selectively.
2. The goal of RIT is to destroy or inactivate cancer cells while preserving
the integrity of normal tissues.
3. Each radionuclide emits radiation particles and/or rays with energies
that are characteristic of that specific radionuclide. Depending on its
type, a radionuclide can emit one, two, or three types of emissions (Iwa-
moto et al., 2012; Sharkey & Goldenberg, 2011).
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 4. Principles of Biotherapy 59
a) Alpha particles
(1) Consist of two protons and two neutrons (the nucleus of a he-
lium atom)
(2) These particles have poor penetrating ability. Alpha particles
cannot penetrate the outermost layers of skin, and they travel
a maximum distance of 5 cm.
(3) A sheet of paper is sufficient to block the radiation source, or
a distance of 5 cm between the radiation source and the point
will shield the radiation.
(4) The skin of an alpha-irradiated patient is adequate to protect
others from radiation exposure; in other words, alpha particles
are not external hazards, but ingestion or inhalation can be le-
thal or produce secondary malignancies.
(5) Contact with an irradiated patient’s excreted body fluids may
be hazardous. The use of universal precautions is sufficient.
b) Beta particles
(1) Are electrons
(2) Have greater penetration abilities than do alpha particles and thus
have great potential to cause severe myelosuppression in a patient
(3) Like alpha particles, beta particles are not external hazards.
The patient’s skin or thick plastic shielding usually is adequate
protection from beta particles.
(4) Yttrium-90 (such as Zevalin) emits beta particles (Spectrum
Pharmaceuticals, Inc., 2011).
(5) After RIT
(a) The patient’s body fluids are temporarily radioactive.
(b) The patient should receive specific discharge instructions
to limit family exposure.
c) Gamma rays
(1) Are high-energy gamma-emitting radionuclides
(2) Protection from these rays is achieved by maintaining a specif-
ic distance from the radioactive source (the distance is specif-
ic to the radioisotope used) and using appropriate shielding.
(3) Patients receiving this type of radionuclide may have to be in ra-
diation isolation and behind lead shields (Iwamoto et al., 2012).
(4) Iodine-131 emits high-energy beta particles and gamma rays.
The thyroid gland concentrates iodine and is at risk of damage
if radioactive iodine is ingested.
4. Toxin-conjugated molecules
a) Toxins such as diphtheria or Pseudomonas exotoxin are potent inhibitors
of cell viability. One molecule of diphtheria toxin delivered intracellu-
larly is capable of inhibiting protein synthesis that results in cell death.
b) Antibodies and cytokines deliver these toxic molecules to cancer cells,
and cell death depends upon their uptake of them.
c) The strategy of delivering toxins intracellularly has resulted in FDA
approval of agents for the treatment of malignancy, for example, de-
nileukin diftitox for the treatment of persistent or recurrent CD25+
cutaneous T-cell lymphoma (NCI, 2013).
5. Vaccines
a) The goal of cancer vaccines is to harness the immune system to fight or
destroy the tumor. Theoretically, this can be achieved by the following
methods (Hammerstrom, Cauley, Atkinson, & Sharma, 2011; Liu, 2011).
(1) Protection against pathogens that can cause cancer
(2) Via immunosurveillance, where the body recognizes and de-
stroys cancer cells prior to their multiplying and giving rise to
clinically observable cancer
(3) Immunostimulation
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
60 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
b) Two vaccines for cancer prevention are FDA approved.
(1) Hepatitis B vaccine: Hepatitis B viral infection can lead to he-
patocellular carcinoma. This vaccine prevents hepatitis as well
as hepatocellular carcinoma.
(2) HPV vaccine (Cervarix® and Gardasil®): Infection with certain
strains of HPV has been associated with development of sever-
al cancers including cervical, anal, penile, and head and neck.
Gardasil protects against HPV types 6, 11, 16, and 18 (Merck &
Co., Inc., 2011). Cervarix protects against HPV types 16 and 18
(GlaxoSmithKline, 2011b).
(3) Most vaccines for cancer treatment are experimental, and results
have been disappointing. One vaccine is FDA approved for can-
cer treatment: sipuleucel-T (Provenge®) for advanced prostate
cancer. It is an autologous cellular immunotherapy containing
CD54+ cells designed to induce an immune response against
a common prostate cancer antigen (Dendreon Corp., 2011).
H. Therapeutic uses for biotherapeutic agents (see Table 9): Biotherapeutic
agents have been shown to
1. Cure, when used as a primary or adjuvant therapy
2. Improve overall response or increase disease-free survival when used in
conjunction with conventional therapies (Koon & McDermott, 2011;
Oldham, 2009)
3. Control or stabilize disease
4. Maintain or enhance QOL.
I. Supportive uses for biotherapeutic agents: Biotherapeutic agents can de-
crease the severity of toxicities associated with other therapeutic modali-
ties (e.g., hematopoietic growth factors can lessen the side effects of che-
motherapy).
J. Biotherapeutic strategies: Advances in the knowledge of molecular biology
have led to the development of agents referred to as targeted therapies. These
agents are divided into those that target the extracellular, such as receptors
on the cell surface (e.g., mAbs), and those that target intracellular process-
es. A growing number of unique molecular targets have been identified with-
in cancer cells, resulting in the discovery of novel agents, many of which are
oral. See Table 10 for a list of targeted therapies.
1. Signal transduction and targeted therapies (Bafico, Grumolato, & Aar-
onson, 2008; Clark, 2011; Pawson & Jorgensen, 2008; Wilkes, 2006;
Wilkes, Esper, & Muehlbauer, 2006; Wujcik, 2011) (See Figure 9 for com-
mon terminology.)
a) Cellular growth, function, and apoptosis are regulated by a complex
network of biochemical and molecular messengers. This process is
referred to as cell signaling.
b) Signal transduction is the generation of a signal from either outside
the cell (growth factors and growth factor receptors) or inside the
cell (tyrosine kinase receptors) that produces a signaling cascade to
the cell nucleus and delivers a signal for the cell to divide.
(1) The nucleus then directs the cell activities. This could include
cell proliferation, induction of angiogenesis, increased growth
factor production, or inhibition of apoptosis.
(2) Receptor tyrosine kinases contain several domains, including an
extracellular ligand-binding domain, a transmembrane domain,
and an intracellular domain containing protein tyrosine kinase.
(3) Activation of receptor tyrosine kinases triggers a biochemical
cascade of cell-signaling events. This signal transduction can
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 9. Characteristics of Biologic Agents
Mechanism Route of
Classification of Action Drug Administration Indications Side Effects Nursing Considerations
Colony- Stimulates erythro- Darbepoetin SC Treatment of anemia associated with Hypertension, skin Risk of death, stroke, thrombosis, and serious
stimulating poiesis via the same (Aranesp®) chronic renal failure, whether or not rash, urticaria, pure cardiovascular events is increased if Hgb >
factors mechanism as en- the patient is receiving dialysis red cell aplasia, my- 11 g/dl when administered.
dogenous erythro- Treatment of anemia in patients with algia, infection, fa- Ensure adequate iron stores in patients pri-
poietin nonmyeloid malignancies where ane- tigue, edema, di- or to and during use.
mia is caused by concomitantly ad- arrhea, thrombotic Drug may be administered every 1, 2, or
ministered chemotherapy and at least events 3 weeks, but maintain consistent dosing
two additional months of chemothera- schedule.
py is planned Use lowest effective dose to avoid blood
transfusions.
Do not shake vials or syringes containing drug.
Store in refrigerator.
Do not freeze.
Prescribers and hospitals must enroll in the
ESA APPRISE Oncology Program.
Use is not indicated in patients in whom
cure is the anticipated outcome of chemo-
therapy treatment.
Discontinue use when treatment with che-
motherapy is completed.
(Amgen, Inc., 2012a)
Stimulates erythro- Epoetin alfa SC Treatment of anemia associated with Hypertension, skin Risk of death, stroke, thrombosis, and serious
poiesis via the same (Procrit®) chronic renal failure, whether or not rash, urticaria, pure cardiovascular events is increased if Hgb >
mechanism as en- the patient is receiving dialysis red cell aplasia, my- 11 g/dl when administered.
dogenous erythro- Treatment of zidovudine-associated algia, infection, fa- Ensure adequate iron stores in patients pri-
poietin anemia in HIV-infected patients tigue, edema, di- or to and during use.
Treatment of anemia in patients with arrhea, thrombotic May be given 3 times weekly or as a single
Chapter 4. Principles of Biotherapy
nonmyeloid malignancies where ane- events weekly dose.
mia is caused by concomitant use of Use lowest effective dose to avoid blood
chemotherapy and at least two ad- transfusions.
ditional months of chemotherapy is Do not shake vials or syringes containing drug.
planned Store in refrigerator.
To reduce the need for allogeneic red Do not freeze.
blood cell transfusions in patients Prescribers and hospitals must enroll in the
scheduled to undergo elective non- ESA APPRISE Oncology Program.
cardiac, nonvascular surgery Use is not indicated in patients in whom
cure is the anticipated outcome of chemo-
therapy treatment.
Discontinue use when treatment with che-
motherapy is completed.
(Janssen Products, LP, 2013)
(Continued on next page)
61
62
Table 9. Characteristics of Biologic Agents (Continued)
Mechanism Route of
Classification of Action Drug Administration Indications Side Effects Nursing Considerations
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Colony- Regulates the pro- Filgrastim (G- SC, IV To decrease the incidence of infection Allergic reactions in- Store in refrigerator.
stimulating duction of neutro- CSF, Neupo- in patients with neutropenic fever as- cluding urticar- Do not freeze.
factors (cont.) phils within the bone gen®) sociated with myelosuppressive anti- ia, rash, and fa- Drug may be diluted with D5W.
marrow cancer treatments for nonmyeloid ma- cial edema; rare Do not dilute with saline solutions.
lignancies risk of splenic rup- Do not shake vials or syringes containing
To reduce the time to neutrophil recov- ture; ARDS, alveo- drug.
ery and duration of fever following in- lar hemorrhage and Avoid use 24 hours before through 24 hours
duction or consolidation chemothera- hemoptysis, nausea, after administration of chemotherapy; first
py in patients with AML vomiting, bone pain, dose should be administered at least 24
To reduce the duration of neutropenia fever hours after chemotherapy is administered.
and associated sequelae in patients (Amgen, Inc., 2013)
receiving myeloablative chemothera-
py prior to BMT
To mobilize hematopoietic progenitor
cells into peripheral blood for collec-
tion via leukapheresis
For chronic administration to reduce the
incidence and duration of sequelae of
neutropenia in patients with congeni-
tal, cyclic, or idiopathic neutropenia
Human G-CSF; Tbo-filgrastim SC Reduction in the duration of severe Allergic reactions, risk Administer with safety needle guard device.
binds to G-CSF re- (Granix™) neutropenia in patients with nonmy- of splenic rupture, Inject the entire dose in the prefilled sy-
ceptors and stimu- eloid malignancies receiving myelo- ARDS, bone pain, ringe in order to activate the safety nee-
lates proliferation of suppressive anticancer drugs asso- may induce severe dle guard.
neutrophils ciated with a clinically significant inci- sickle-cell crisis in Store in refrigerator at 36°F–46°F.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
dence of febrile neutropenia patients with sickle- Avoid shaking.
cell disease Tbo-filgrastim should be clear without parti-
cles; inspect prior to administration.
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 9. Characteristics of Biologic Agents (Continued)
Mechanism Route of
Classification of Action Drug Administration Indications Side Effects Nursing Considerations
Colony- Regulates the pro- Pegfilgrastim SC To decrease the incidence of infection Allergic reactions in- Pegfilgrastim reduces renal clearance and
stimulating duction of neutro- (PEG-G-CSF; related to neutropenia in patients with cluding urticaria, prolongs persistence compared to filgras-
factors (cont.) phils within the bone Neulasta®) nonmyeloid malignancies receiving rash, facial edema; tim.
marrow myelosuppressive chemotherapy rare risk of splenic Do not administer in the period beginning
rupture; ARDS, nau- 14 days before until 24 hours after ad-
sea, vomiting, bone ministration of myelosuppressive chemo-
pain, fever therapy.
Administer as a single 6 mg injection once
per chemotherapy cycle.
Do not administer the 6 mg fixed dose to
children or adolescents weighing less
than 45 kg.
Store in refrigerator.
Do not freeze.
Do not shake vials or syringes containing
drug.
(Amgen, Inc., 2012b)
Stimulates keratino- Palifermin IV To decrease the incidence and duration Skin rash, skin erythe- Do not use within 24 hours before, during,
cyte GFR to result (rHuKGF, of severe oral mucositis in patients ma, pruritus, fever, or after administration of myelosuppres-
in proliferation, dif- Kepivance®) with hematologic malignancies receiv- dysesthesia, tongue sive chemotherapy.
ferentiation, and mi- ing myelosuppressive chemotherapy discoloration, tongue Administer for 3 days before and then 3
gration of epitheli- prior to BMT thickening, taste al- days after myelosuppressive chemother-
al cells terations, pain, ar- apy.
thralgias, elevated The third dose should occur 24–48 hours
serum amylase, ele- prior to starting chemotherapy; the fourth
vated serum lipase dose should be given on the day of he-
matopoietic stem cell infusion, after the
Chapter 4. Principles of Biotherapy
infusion is complete.
Do not shake reconstituted solution.
Protect reconstituted product from light
and do not use if stored at room temper-
ature for longer than 1 hour.
Do not filter reconstituted solution.
(Amgen, Inc., 2009)
(Continued on next page)
63
64
Table 9. Characteristics of Biologic Agents (Continued)
Mechanism Route of
Classification of Action Drug Administration Indications Side Effects Nursing Considerations
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Colony- Induces commit- Sargramostim SC, IV Following induction chemotherapy in Edema, capillary leak Dilute in NS solution for IV use.
stimulating ted progenitor cells (GM-CSF, Leu- patients with AML to shorten neutro- syndrome, pleural or Store in refrigerator.
factors (cont.) to divide and differ- kine®) phil recovery and reduce incidence of pericardial effusions, Do not freeze.
entiate in the GM infection. dyspnea, fever, ab- Do not shake vials or syringes contain-
pathways, including For mobilization of hematopoietic pro- dominal pain, head- ing drug.
neutrophils, mono- genitor cells for collection via leuka- ache, chills, diar- Do not administer through in-line filter.
cytes/macrophages, pheresis and to speed engraftment rhea, bone pain (sanofi-aventis U.S. LLC, 2012)
and myeloid-derived following autologous transplantation
dendritic cells of progenitor cells
To accelerate myeloid recovery follow-
ing allogeneic BMT
In patients with failure of engraftment
following BMT
Interferons Mechanisms of ac- IFN alfa-2b SC, IM, IV Treatment of hairy cell leukemia, malig- Fever, chills, malaise, Counsel patients on potential for side ef-
(IFNs) tivity are not clear- (Intron® A) nant melanoma, follicular lymphoma, myalgia, headache, fects, including but not limited to flu-like
ly understood but in- condylomata acuminata, AIDS-relat- anorexia, fatigue, syndrome.
clude inhibition of vi- ed Kaposi sarcoma, chronic hepati- depression, suicid- Store in refrigerator.
ral replication, di- tis B and C al ideation, nau- Do not freeze.
rect antiproliferation sea, vomiting, diar- Do not shake product.
of tumor cells, and rhea, nephrotic syn- Protect from light.
modulation of host drome, pancreati- Product in multidose vial is stable for 30
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
immune response. tis, psychosis, hallu- days after reconstitution when stored in
cinations, renal fail- refrigerator.
ure, renal insufficien- Drug is contraindicated in patients with au-
cy, leukopenia, ane- toimmune hepatitis or decompensated
mia, thrombocytope- liver disease.
nia, retinopathy, thy- Use with caution in patients with a history
roid abnormalities, of debilitating medical disease such as
hepatotoxicity pulmonary disease, cardiovascular dis-
ease, diabetes mellitus, coagulation dis-
orders, or severe myelosuppression.
Monitor triglycerides.
(Merck & Co., Inc., 2012)
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 9. Characteristics of Biologic Agents (Continued)
Mechanism Route of
Classification of Action Drug Administration Indications Side Effects Nursing Considerations
Interferons Immunomodulato- IFN-gamma SC To reduce frequency and severity of in- Fever, headache, Hold therapy or reduce dose by 50% in
(IFNs) (cont.) ry effects including (Actimmune®) fections related to chronic granuloma- rash, chills, injection- cases of severe reactions.
enhancement of ox- tous disease site tenderness, fa- Flu-like syndrome may exacerbate preex-
idative metabolism To delay progression of severe malig- tigue, diarrhea, vom- isting cardiac conditions, such as CHF.
of macrophages, nant osteoporosis iting, nausea, myal- (InterMune, Inc., 2009)
ADCC, activation gia, arthralgia, my-
of NK cells, and ex- elosuppression, ele-
pression of Fc re- vated hepatic trans-
ceptors and cell sur- aminases, altered
face antigens mental status, gait
disturbance, dizzi-
ness
Interleukins Promotes prolifera- Aldesleukin (IL- SC, IV Treatment of renal cell carcinoma and Fever, rigors, malaise, Do not use with an in-line filter.
(ILs) tion, differentiation, 2, Proleukin®) metastatic melanoma headache, myalgia, Do not mix with NS or bacteriostatic water.
and recruitment of arthralgia, tachycar- Store in refrigerator.
T and B cells, NK dia, hypotension, Do not freeze.
cells, LAK cells, cardiomyopathy, ar- Protect from light.
and tumor-infiltrat- rhythmias, capillary Do not mix with other medications.
ing lymphocytes leak syndrome, dys- Monitor fluid status, vital signs, mental sta-
that enhance tumor- pnea, nausea, vomit- tus, and urine output. Hypotension is
fighting capabilities; ing, diarrhea, stoma- dose limiting and mimics septic shock;
increases produc- titis, dizziness, ane- use IV boluses carefully; treatment may
tion of IFN-gamma, mia, thrombocytope- require vasopressor support.
IL-1, and TNF nia, leukopenia, ele- Drug is contraindicated in patients with
vated transaminas- cardiac disease, abnormal pulmonary
es, elevated serum function, or organ allografts.
creatinine and BUN, Assess fall risk during treatment.
Chapter 4. Principles of Biotherapy
neurologic toxicities, May exacerbate or lead to initial presenta-
skin rash, pruritus, tion of autoimmune diseases or inflam-
hyperbilirubinemia matory disorders such as Crohn dis-
ease, scleroderma, thyroiditis, inflamma-
tory arthritis, diabetes mellitus, and cho-
lecystitis.
(Prometheus Laboratories Inc., 2012)
(Continued on next page)
65
66
Table 9. Characteristics of Biologic Agents (Continued)
Mechanism Route of
Classification of Action Drug Administration Indications Side Effects Nursing Considerations
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Interleukins Stimulates mega- Oprelvekin (IL- SC To prevent severe thrombocytope- Anaphylaxis, dilution- Store in refrigerator.
(ILs) (cont.) karyocytopoiesis 11, Neumega®) nia and reduce the need for platelet al anemia, diarrhea, Do not freeze.
and thrombopoiesis transfusions in patients with nonmy- dizziness, fever, flu- Reconstitute with sterile water and use
eloid malignancies receiving chemo- id retention resulting within 3 hours of reconstitution.
therapy in peripheral edema, Do not shake or freeze following reconsti-
pulmonary edema, tution.
dyspnea, capillary Protect from light.
leak syndrome, atrial Use with caution in patients with preexist-
arrhythmias and ex- ing CHF or other conditions that may be
acerbation of preex- exacerbated by fluid retention.
isting pulmonary ef- Dosing should be initiated 6–24 hours after
fusions, headache, completion of chemotherapy and discon-
nausea, vomiting, in- tinued at least 2 days before the start of
somnia, rhinitis the next cycle of chemotherapy.
(Wyeth Pharmaceuticals, 2006)
Hematopoi- Inhibits the CXCR4 Plerixafor SC In combination with filgrastim to mobi- Diarrhea, nausea, fa- Use actual body weight to calculate dose;
etic stem cell receptor, which (Mozobil®) lize hematopoietic stem cells for col- tigue, injection-site daily dose should not exceed 40 mg.
mobilizers competitively blocks lection from peripheral blood of pa- reactions, headache, Store single-use vials at room temperature.
binding of SDF1-α tients with multiple myeloma or non- dizziness, arthralgia, Use reduced dose in patients with creati-
ligand that anchors Hodgkin lymphoma who are candi- vomiting nine clearance < 50 ml/min.
developing hema- dates for autologous stem cell trans- Four daily morning doses of filgrastim
topoietic stem cells plantation should be given prior to the first dose of
in the bone marrow, plerixafor.
resulting in release Plerixafor may be repeated for up to 4 con-
into the peripher- secutive days.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
al blood Each daily dose of plerixafor should be giv-
en approximately 11 hours before any
planned apheresis session.
(Genzyme Corp., 2010)
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 9. Characteristics of Biologic Agents (Continued)
Mechanism Route of
Classification of Action Drug Administration Indications Side Effects Nursing Considerations
Autologous Autologous CD54+ Sipuleucel-T IV Treatment of asymptomatic or minimally Infusion reactions Each dose is cellularly unique and for use
cellular immu- mononuclear cells (Provenge®) symptomatic metastatic castrate- such as fever, chills, only in one individual patient.
notherapy are collected from resistant prostate cancer dyspnea, hypoxia, The patient’s mononuclear cells are col-
the patient and acti- bronchospasm, nau- lected via apheresis 3 days prior to
vated in culture with sea, vomiting, fa- planned infusion, shipped to the manu-
PAP-GM-CSF for tigue, hypertension, facturer for preparation of the infusion,
subsequent infusion. tachycardia, joint and then returned to the administration
The activated cells ache, headache site.
are designed to in- Confirmation of product release using pa-
duce an immune tient-specific product disposition forms
response against must be performed prior to infusion.
prostatic acid phos- Do not administer through a cell filter.
phatase antigen ex- Premedicate patients with acetaminophen
pressed in patients and a histamine antagonist.
with prostate cancer. Employ universal precautions when han-
dling sipuleucel-T.
Prepared infusion bag must remain with-
in the insulated container until time of in-
fusion.
Do not administer infusion if the storage
bag leaks or clumps remain after gen-
tle mixing.
Once infusion product is removed from in-
sulated storage, it should not remain
at room temperature for longer than 3
hours.
The 60-minute infusion must be completed
prior to expiration date and time.
Chapter 4. Principles of Biotherapy
(Dendreon Corp., 2011)
ADCC—antibody-dependent cell-mediated cytotoxicity; AIDS—acquired immunodeficiency syndrome; AML—acute myeloid leukemia; ARDS—adult respiratory distress syndrome; BMT—bone marrow transplantation;
BUN—blood urea nitrogen; CD54+—cluster of differentiation 54 positive; CHF—congestive heart failure; CXCR4—chemokine receptor 4; D5W—5% dextrose in water; ESA—erythropoiesis-stimulating agent; G-CSF—
granulocyte–colony-stimulating factor; GFR—glomerular filtration rate; GM—granulocyte macrophage; GM-CSF—granulocyte macrophage–colony-stimulating factor; Hgb—hemoglobin; HIV—human immunodeficiency
virus; IM—intramuscular; IV—intravenous; LAK—lymphokine-activated killer; NK—natural killer; NS—normal saline; PAP-GM-CSF—prostatic acid phosphatase granulocyte macrophage–colony-stimulating factor; rHuK-
GF—recombinant human keratinocyte growth factor; SC—subcutaneous; SDF1-α—stromal cell–derived factor 1-alpha; TNF—tumor necrosis factor
67
68
Table 10. Characteristics of Targeted Therapies
Mechanism Route of
Classification of Action Drug Administration Indications Side Effects Nursing Considerations
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Immunotoxin Directs cytotox- Denileu- IV Treatment of patients Hypersensitivity, vascu- Confirm that patient’s malignant cells express CD25 prior to
ic action of diph- kin diftitox with persistent or re- lar leak syndrome, hypo- use of agent.
theria toxin to (Ontak®) current cutaneous T- tension, edema, hypoal- Discontinue use of agent if patient’s serum albumin is < 3 g/
cells that ex- cell lymphoma whose buminemia, fever, chills, dl because of risk of capillary leak syndrome.
press the IL-2 malignant cells ex- headache, rash, anorex- Premedicate with acetaminophen and an antihistamine.
receptor, result- press the CD25 com- ia, reduced lymphocytes, Incidence of adverse effects diminishes after first two treat-
ing in inhibition ponent of the IL-2 re- increased transaminases, ment courses.
of cellular pro- ceptor asthenia, infection, pain, Store at or below –10°C (14°F).
tein synthesis nausea, vomiting, dys- Thaw vials in refrigerator for < 24 hours or at room temper-
leading to cell pnea, cough, loss of visu- ature for 1–2 hours. Agent cannot be refrozen after thaw-
death al acuity ing and must be brought to room temperature before pre-
paring dose.
Concentration of agent must be ≥ 15 mcg/ml during all
steps of product preparation.
Vials should not be heated.
Avoid vigorous agitation.
Use prepared solution within 6 hours.
Do not infuse through a filter.
Protect from light.
(Eisai Inc., 2010)
Miscellaneous Exact antineo- Lenalido- PO Treatment of patients Risk of fetal harm, neu- Women should avoid becoming pregnant during treatment
biologic plastic mecha- mide (Rev- with transfusion-de- tropenia, thrombocyto- and within 4 weeks of discontinuing treatment because of
response nism is unclear limid®) pendent anemia sec- penia, deep vein throm- risk of fetal harm. A pregnancy test should be performed
modifiers but may be re- ondary to low- or inter- bosis, pulmonary embo- prior to initiating therapy and repeated every 4 weeks in
lated to immuno- mediate-risk MDS as- lism, pruritus, rash, dry women of child-bearing age or with regular menses, and
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
modulatory, an- sociated with the 5q skin, diarrhea, constipa- every 2 weeks in women with irregular menses.
tiangiogenic, or chromosomal deletion tion, nausea, nasophar- Discontinue lenalidomide immediately if pregnancy occurs
antineoplastic In combination with yngitis, cough, dyspnea, during treatment.
properties. dexamethasone in pa- pharyngitis, fatigue, pyrex- Male patients must adhere to strict methods of contracep-
tients with multiple my- ia, peripheral edema, as- tion and be informed of the teratogenic risks of lenalido-
eloma who have re- thenia, arthralgia, dizzi- mide.
ceived at least one pri- ness, headache, muscle Revlimid is only available under the RevAssist® program to
or therapy cramps, upper respiratory ensure patients are properly informed of fetal risks.
tract infections Concomitant use with dexamethasone increases the risk of
developing thrombosis; prophylactic anticoagulation may
be warranted.
Capsules should be taken with water.
Capsules should be swallowed whole and not chewed,
crushed, or broken.
Dosage adjustments are recommended in patients with a
creatinine clearance < 60 ml/min.
(Celgene Corp., 2011)
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 10. Characteristics of Targeted Therapies (Continued)
Mechanism Route of
Classification of Action Drug Administration Indications Side Effects Nursing Considerations
Miscellaneous Exact antineo- Pomalid- PO Treatment of patients Risk of fetal harm, venous Women should avoid becoming pregnant during treatment
biologic plastic mecha- omide with multiple myelo- thromboembolism, neu- and within 4 weeks of discontinuing treatment because of
response nism is unclear (Poma- ma who have received tropenia, anemia, dizzi- risk of fetal harm. A pregnancy test should be performed
modifiers but may be re- lyst®) at least two prior ther- ness, confusion, neuropa- prior to initiating therapy and repeated every 4 weeks in
(cont.) lated to immuno- apies, including le- thy, second malignancies, women of child-bearing age or with regular menses, and
modulatory, anti- nalidomide and bort- fatigue, asthenia, periph- every 2 weeks in women with irregular menses.
angiogenic, and ezomib, and have evi- eral edema, constipation, Male patients must adhere to strict methods of contracep-
anti-inflammato- dence of disease pro- diarrhea, nausea, vomit- tion and be informed of the teratogenic risks of pomalid-
ry properties. gression within 60 ing, pneumonia, upper re- omide.
days of completion of spiratory tract infections, Discontinue pomalidomide immediately if pregnancy occurs
the last therapy back pain during treatment.
Pomalyst® is only available under the Pomalyst® REMS
program to ensure patients are properly informed of fe-
tal risks.
Dose adjustments are recommended for patients with neu-
tropenia or thrombocytopenia.
(Celgene Corp., 2013)
Exact antineo- Thalido- PO In combination with Deep vein thrombosis, pul- Women should avoid becoming pregnant beginning 4
plastic mecha- mide (Tha- dexamethasone for monary embolism, drowsi- weeks before treatment, during treatment, and within 4
nism is unclear lomid®) treatment in patients ness, somnolence, periph- weeks of discontinuing treatment because of risk of fe-
but may be re- with newly diagnosed eral neuropathy, dizziness, tal harm.
lated to immuno- multiple myeloma orthostatic hypotension, A pregnancy test should be performed prior to initiating
modulatory, anti- Treatment of erythema neutropenia, confusion, therapy and repeated every 4 weeks in women of child-
angiogenic, and nodosum leprosum anxiety, tremor, insomnia, bearing age or with regular menses, and every 2 weeks in
anti-inflammato- depression, fatigue, fever, women with irregular menses.
ry properties. anemia, thrombocytope- Thalomid must be dispensed and administered in compli-
nia, constipation, anorex- ance with the Thalomid REMSTM program.
Chapter 4. Principles of Biotherapy
ia, nausea, edema, bone Male patients must adhere to strict methods of contracep-
pain, dyspnea, rash, dry tion and be informed of the teratogenic risks of thalido-
skin, increased hepatic mide.
enzymes, increased SCr, Discontinue thalidomide immediately if pregnancy occurs
muscle weakness during treatment.
Concomitant use with dexamethasone increases the risk of
developing thrombosis; prophylactic anticoagulation may
be warranted.
Because of the potential for significant drowsiness, instruct
patients to avoid situations where impaired mental and/
or physical functioning could put themselves or others at
risk of harm.
(Celgene Corp., 2012)
(Continued on next page)
69
70
Table 10. Characteristics of Targeted Therapies (Continued)
Mechanism Route of
Classification of Action Drug Administration Indications Side Effects Nursing Considerations
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Monoclonal Binds to and in- Bevaci- IV In combination with Hemorrhage, hypertension, Avoid use for at least 28 days after major surgery; surgical
antibodies hibits the activity zumab 5-fluorouracil–contain- proteinuria, CHF, asthe- incision should be fully healed.
of human VEGF (anti-VEGF ing regimens as first- nia, diarrhea, abdominal Suspend treatment with bevacizumab at least 28 days be-
to its receptors antibody, or second-line treat- pain, headache, neutrope- fore elective surgery.
(FLT and KDR), Avastin®) ment for patients with nia, hyponatremia, protein- Store agent in refrigerator. Diluted solution may be stored
blocking prolifer- metastatic carcinoma uria, arterial thromboem- for up to 8 hours under refrigeration.
ation and forma- of the colon or rectum bolic events, GI perfora- Do not freeze.
tion of new blood In combination with car- tion, wound healing com- Do not shake.
vessels boplatin and paclitaxel plications, fistula formation Protect from light.
for first-line treatment in the GI tract, and/or in- Do not mix or administer with dextrose-containing solutions.
of patients with unre- tra-abdominal abscesses, Monitor blood pressure during treatment.
sectable, locally ad- infusion reactions Permanently discontinue medication if patients develop GI
vanced, recurrent, or perforation, wound dehiscence requiring medical inter-
metastatic nonsqua- vention, serious bleeding, nephrotic syndrome, or hyper-
mous NSCLC tensive crisis.
Treatment of glioblas- Temporarily suspend if evidence of moderate to severe pro-
toma in patients with teinuria or severe hypertension until evaluation and treat-
progressive disease ment are provided.
following previous Risk of CHF exists in patients who have previously received
therapy anthracyclines.
In combination with IFN (Genentech, Inc., 2011a)
alfa for treatment of
metastatic renal cell
carcinoma
Drug-antibody Brentux- IV Treatment of Hodgkin Peripheral neuropathy, neu- Reconstitute vials with 10.5 ml of sterile water. Do not
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
conjugate; binds imab ve- lymphoma in patients tropenia, anaphylaxis, in- shake.
to CD30+ cells dotin (anti- after failure of autolo- fusion reactions, JCV in- Dilute reconstituted solution immediately to a concentra-
allowing for in- CD30 an- gous stem cell trans- fection resulting in pro- tion of between 0.4–1.8 mg/ml and infuse immediately or
ternalization of tibody, Ad- plantation or after fail- gressive multifocal leuko- store in refrigerator and use within 24 hours.
the antibody cetris®) ure of ≥ 2 multiagent encephalopathy, Stevens- Concomitant use with bleomycin is contraindicated be-
complex and re- chemotherapy regi- Johnson syndrome, fa- cause of risk of pulmonary toxicity.
lease of MMEA mens in patients who tigue, upper respiratory Patients can be premedicated with acetaminophen, a hista-
component that are not candidates for tract infection, nausea, di- mine antagonist, and a corticosteroid.
binds to tubulin autologous stem cell arrhea, vomiting, anemia, Coadministration with CYP3A4 inhibitors, including grape-
and causes dis- transplantation pyrexia, thrombocytope- fruit juice, or inducers may increase or decrease concen-
ruption of cell di- Treatment of system- nia, rash, abdominal pain, trations of MMEA component.
vision leading to ic anaplastic large cell cough (Seattle Genetics, 2012)
apoptosis lymphoma after failure
of ≥ 1 multiagent che-
motherapy regimen
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 10. Characteristics of Targeted Therapies (Continued)
Mechanism Route of
Classification of Action Drug Administration Indications Side Effects Nursing Considerations
Monoclonal Binds to extra- Cetuximab IV In patients with EGFR- Infusion-related reactions Serious, potentially fatal infusion reactions may occur.
antibodies cellular domain (anti- expressing metastatic including bronchospasm, Cardiopulmonary arrest has occurred in patients when
(cont.) of EGFR, result- EGFR colorectal cancer after fever, chills, rigors, angio- used in combination with radiation therapy.
ing in inhibition antibody, failure of irinotecan- edema, urticaria, hypo- Dose modification is recommended following development
of cell growth Erbitux®) and oxaliplatin-based tension, and stridor; pul- of acneform rash.
and induction of regimens monary toxicity, acneform Instruct patients to wear sunscreen and hats and limit sun
apoptosis, and With irinotecan or in pa- rash, dry skin and fissur- exposure.
decreased ma- tients with metastatic ing, malaise, asthenia, fe- Premedicate with an H1 antagonist.
trix metallo- colorectal cancer who ver, diarrhea, fatigue, nau- Administer through 0.22-micron in-line filter.
proteinase and are intolerant of irino- sea, vomiting, anorexia, Flush line with NS after infusion.
VEGF produc- tecan leukopenia, hypomagne- Store agent in refrigerator.
tion In combination with ra- semia, weight loss, phar- Do not dilute.
diation therapy to treat yngitis, cardiopulmonary Do not shake.
local or regionally ad- arrest Do not freeze.
vanced squamous cell Protect from light.
carcinoma of the head Discard unused portion after 8 hours at room temperature
and neck or 12 hours under refrigeration.
In recurrent or metastat- (Eli Lilly & Co., 2012)
ic squamous cell car-
cinoma of the head
and neck progressing
after platinum-based
therapy
In combination with plat-
inum-based therapy
with 5-fluorouracil for
first-line treatment of
patients with recurrent
Chapter 4. Principles of Biotherapy
locoregional or meta-
static squamous cell
carcinoma of the head
and neck
(Continued on next page)
71
72
Table 10. Characteristics of Targeted Therapies (Continued)
Mechanism Route of
Classification of Action Drug Administration Indications Side Effects Nursing Considerations
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Monoclonal Binds to the Denosum- SC Prevention of skeletal Hypocalcemia, osteonecro- Store in refrigerator. Allow 15–30 min to warm to room tem-
antibodies transmembrane ab (anti- events due to bone sis of jaw, fatigue, asthe- perature before administration. A 27-gauge needle should
(cont.) protein RANKL RANKL metastases of solid tu- nia, hypophosphatemia, be used to withdraw entire contents from vial for dosing.
that inhibits os- antibody, mors nausea Correct and monitor serum calcium, vitamin D, and magne-
teoclast activi- Prolia®, Treatment to increase sium before and during treatment.
ty and bone re- Xgeva®) bone mass in men An oral examination and preventive dentistry should be
sorption with nonmetastat- performed prior to starting treatment and during therapy.
ic prostate cancer re- Good oral hygiene should be practiced during therapy. In-
ceiving androgen de- vasive dental procedures should be avoided while taking
privation therapy, and denosumab.
women with breast (Amgen, Inc., 2012b)
cancer receiving adju-
vant aromatase inhibi-
tor therapy at high risk
for bone fractures
Binds to the Eculizum- IV Treatment to reduce he- Headache, nasopharyngi- Store in refrigerator.
complement pro- ab (anti-C5 molysis in patients tis, back pain, nausea; in- Do not freeze.
tein C5, which antibody, with paroxysmal noc- creased risk of meningo- Protect from light.
inhibits its cleav- Soliris®) turnal hemoglobinuria coccal infections Do not shake.
age to C5a and Treatment of patients Do not administer as an IV push or bolus.
C5b; this inhibits with atypical hemolytic Dilute to a final concentration of 5 mg/ml prior to adminis-
formation of the uremic syndrome tration.
terminal com- Allow product to warm to room temperature prior to admin-
ponents C5b-9, istration.
thus mediating Diluted solutions are stable for 24 hours.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
intravascular he- Administer by IV infusion over 35 min.
molysis. Do not use in patients with unresolved serious Neisseria
meningitides infection or those who are not currently vac-
cinated against Neisseria meningitides. Vaccinate pa-
tients at least 2 weeks prior to the first dose of eculizum-
ab. Revaccinate according to medical guidelines for vac-
cine use.
Because of the risk of meningococcal infections, eculizum-
ab is only available through a restricted program requiring
enrollment of prescribers and counseling of patients.
(Alexion Pharmaceuticals, Inc., 2011)
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 10. Characteristics of Targeted Therapies (Continued)
Mechanism Route of
Classification of Action Drug Administration Indications Side Effects Nursing Considerations
Monoclonal Binds to CD20 Ibritumomab IV Treatment of relapsed or Severe and potentially life- Drug is combined with rituximab.
antibodies on B cells result- tiuxetan refractory low-grade, threatening allergic reac- Premedicate with acetaminophen and diphenhydramine.
(cont.) ing in direct de- (anti-CD20 follicular, or trans- tions during infusion; fe- Patients with a platelet count < 100,000/mm3 should not be
livery of the ra- antibody, formed B-cell NHL ver, chills, rigors, head- treated with ibritumomab.
dioactive isotope Zevalin®) ache, nausea, broncho- Administer ibritumomab through a 0.22 micron in-line filter.
indium-111 or yt- spasm, dyspnea, myalgia, Administered dose cannot exceed 32 mCi regardless of pa-
trium-90 that in- arthralgia, asthenia, pro- tient’s weight.
duces cell dam- longed B-cell lymphocyto- Drug is not transported with radioisotope; radiolabeling must
age through the penia, leukopenia, throm- be done by appropriate personnel in a specialized facility.
formation of free bocytopenia, neutropenia, Drug is intended as single-course treatment.
radicals anemia, severe cutaneous Monitor closely for extravasation.
and mucocutaneous reac- Store in refrigerator.
tions, secondary leukemia Do not freeze.
or MDS Use of antiplatelet or anticoagulant drugs should be avoid-
ed following recent use of ibritumomab.
(Spectrum Pharmaceuticals, Inc., 2011)
Binds CTLA-4 Ipilimumab IV Treatment of unresect- Immune-mediated adverse Store in refrigerator.
and blocks its (anti-CTLA-4 able or metastatic mel- reactions resulting in en- Do not shake.
negative regula- antibody, anoma terocolitis, hepatitis, derma- Diluted product may be stored at room temperature or un-
tion of T-cell acti- Yervoy®) titis, neuropathy, or endocri- der refrigeration for up to 24 hours.
vation and prolif- nopathy Protect from light.
eration, increas- Prior to each dose, evaluate patients for signs and symp-
ing T-cell antitu- toms of enterocolitis, dermatitis, neuropathy, and endo-
mor immune re- crinopathy and perform laboratory assessment of blood
sponse chemistries, liver function, and thyroid function.
(Bristol-Myers Squibb Co., 2012)
Binds to CD20 Ofatumumab IV Treatment of CLL in pa- Infusion reactions including Do not shake.
Chapter 4. Principles of Biotherapy
on B cells and (anti-CD20 tients refractory to bronchospasm, dyspnea, Do not freeze.
B-cell CLL re- antibody, fludarabine and alem- laryngeal edema, pulmo- Protect from light.
sulting in ADCC Arzerra®) tuzumab nary edema, flushing, hy- Administer through in-line filter.
and comple- pertension, hypotension, Premedicate with acetaminophen, H1 antagonist, and a
ment-dependent syncope, myocardial in- corticosteroid.
cytotoxicity farction, back or abdomi- Prepare doses in NS.
nal pain, fever, rash, urti- Store diluted solution under refrigeration.
caria, or angioedema; se- Infusion should be started within 12 hours of preparation
vere neutropenia or throm- and discarded after 24 hours.
bocytopenia, progressive (GlaxoSmithKline, 2011a)
multifocal leukoencepha-
lopathy, hepatitis B infec-
tion/reactivation, intestinal
obstruction, infections
(Continued on next page)
73
74
Table 10. Characteristics of Targeted Therapies (Continued)
Mechanism Route of
Classification of Action Drug Administration Indications Side Effects Nursing Considerations
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Monoclonal Binds to EGFR Panitu- IV Single-agent treatment Dermatologic toxicity includ- Advise patients to wear sunscreen and a hat to limit sun
antibodies and competitive- mumab for EGFR-express- ing dermatitis acneform, exposure.
(cont.) ly inhibits bind- (anti- ing metastatic colorec- pruritus, erythema, rash, Dose modification is recommended following infusion-relat-
ing of ligands to EGFR tal carcinoma with dis- skin exfoliation, paronych- ed reactions or dermatologic toxicity.
this receptor; this antibody, ease progression on ia, dry skin, and skin fis- Drug must be given by IV infusion pump via a 0.22 micron
prevents receptor Vectibix®) or following fluoropy- sures, which may be com- in-line filter.
autophosphory- rimidine-, oxaliplatin-, plicated by abscesses and Dilute dose with NS.
lation and activa- or irinotecan-contain- sepsis; fatigue, abdominal Do not shake diluted product.
tion of receptor- ing regimens pain, hypomagnesemia, Do not exceed a final concentration of 10 mg/ml.
associated kinas- infusion reactions, keratitis Store in refrigerator.
es that results in Do not freeze.
inhibition of cell Protect from light.
growth, induction Use diluted solution within 6 hours at room temperature or
of apoptosis, de- within 24 hours if under refrigeration.
creased produc- Combination of panitumumab with oxaliplatin-containing
tion of proinflam- regimens is contraindicated in patients with mutant KRAS
matory cytokines metastatic colorectal cancer or in whom KRAS status is
and VGFs, and unknown.
internalization of (Amgen, Inc., 2012a)
EGFR
Targets the ex- Pertuzumab IV In combination with Left ventricular dysfunction, Monitor LVEF during treatments and hold doses if ejection
tracellular dimer- (Perjeta®) trastuzumab and infusion-related reactions, fraction decreases to < 40% or ≥ 10% from baseline lev-
ization domain docetaxel for treat- fatigue, asthenia, peripher- els to between 40%–45%.
of HER2 protein ment of patients with al edema, mucosal inflam- Do not administer mixed with other IV medications.
that blocks HER2+ metastatic mation, alopecia, rash, Store in refrigerator. Keep vials in original container until
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
ligand-dependent breast cancer nail changes, diarrhea, time of use to protect from light.
heterodimeriza- nausea, vomiting, neutro- Dilute in 250 ml 0.9% saline only and mix with gentle inver-
tion of HER2 with penia, anemia, peripher- sion. Do not shake.
other similar pro- al neuropathy, headache, If not used immediately, diluted solutions can be stored un-
teins. This inhibits myalgia, anorexia der refrigeration for up to 24 hours.
intracellular sig- May cause fetal harm when administered to pregnant wom-
naling that results en. Determine pregnancy status of patients prior to start-
in slowing cell ing treatment with pertuzumab.
growth and trig- Patients must be tested for HER2 status before initiation of
gering apoptosis. treatment because use has only been studied in patients
Also triggers an- who overexpress HER2 protein.
tibody-dependent (Genentech, Inc., 2012b)
cell-mediated cy-
totoxicity.
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 10. Characteristics of Targeted Therapies (Continued)
Mechanism Route of
Classification of Action Drug Administration Indications Side Effects Nursing Considerations
Monoclonal Binds to CD20 Rituximab IV Treatment of relapsed Severe infusion-related re- Administer only by IV infusion.
antibodies on B cells result- (anti-CD20 or refractory low-grade actions including urticar- Store in refrigerator.
(cont.) ing in activation antibody, follicular CD20+ B-cell ia, hypotension, angioede- Do not freeze.
of complement- Rituxan®) NHL ma, hypoxia, or broncho- Do not shake product.
dependent cyto- First-line treatment of spasm; fever, chills, rigors, Protect vials from direct sunlight.
toxicity as well follicular CD20+ B-cell headache, dyspnea, myal- Agent is stable for 24 hours under refrigeration.
as ADCC NHL in combination gia, arthralgia, prolonged Consider premedication with acetaminophen and diphen-
with chemotherapy B-cell lymphopenia, leu- hydramine.
and as monotherapy in kopenia, infection, asthe- Infusion-related side effects may resolve with slowing or
patients who have had nia, nausea, rash, hepati- suspending infusion.
a complete or partial tis B reactivation, progres- Incidence of infusion-related side effects is reduced with
response to rituximab sive multifocal leukoen- subsequent infusions.
plus chemotherapy cephalopathy, cardiac ar- Potential exists for development of TLS within 12–24 hours
Treatment of low-grade rhythmias, bowel obstruc- after infusion.
CD20+ B-cell NHL in tion and/or perforation, re- Prophylaxis against Pneumocystis jiroveci pneumonia and
patients with stable nal toxicity herpesvirus infections in patients with CLL for up to 12
disease or who have months after treatment.
achieved a partial or (Genentech, Inc., 2012c)
complete response with
CVP chemotherapy
First-line treatment of dif-
fuse large B-cell CD20+
NHL in combination
with CHOP or other an-
thracycline-based che-
motherapy regimen
First-line treatment
in combination with
fludarabine and cyclo-
Chapter 4. Principles of Biotherapy
phosphamide in pa-
tients with CD20+ CLL
In combination with meth-
otrexate to treat moder-
ate to severe rheuma-
toid arthritis in patients
who have not respond-
ed to one or more TNF-
antagonist therapies
In combination with glu-
cocorticoids in pa-
tients with Wegener
granulomatosis or mi-
croscopic polyangiitis
(Continued on next page)
75
76
Table 10. Characteristics of Targeted Therapies (Continued)
Mechanism Route of
Classification of Action Drug Administration Indications Side Effects Nursing Considerations
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Monoclonal Binds to CD20 Tositu- IV Treatment of patients Anaphylaxis, hypothyroid- Agent is not indicated for initial treatment of CD20+ NHL.
antibodies on pre-B and momab 131I with CD20+ relapsed ism, severe and prolonged Agent should not be administered to patients with platelet
(cont.) mature lympho- (anti-CD20 or refractory, low- thrombocytopenia, ane- count < 100,000/mm3 or neutrophil count < 1,500/mm3.
cytes and B-cell antibody, grade, follicular, or mia, neutropenia, aller- Treatment involves two separate steps (dosimetric dose
NHL resulting in Bexxar®) transformed NHL in- gic reactions, asthenia, fe- and therapeutic dose) separated by 7–14 days.
apoptosis, com- cluding patients refrac- ver, infection, chills, rigors, Thyroid-blocking agents should be given beginning 24
plement-depen- tory to rituximab sweating, nausea, vomit- hours prior to tositumomab 131I therapy and continued for
dent cytotoxic- ing, hypotension, dyspnea, at least 14 days.
ity, and ADCC; bronchospasm, abdominal Premedicate with acetaminophen and diphenhydramine.
ionizing radia- pain, rash, secondary leu- The same IV tubing set must be used throughout the entire
tion caused by kemia/MDS or nonhema- dosimetric or therapeutic steps to prevent loss of drug.
iodine-131 (131I) tologic malignancies Administer both doses through a 0.22 micron in-line filter.
results in addi- Instruct patients on how to minimize exposure of other peo-
tional cell death. ple to radioactivity that will remain in their system for sev-
eral days.
Only personnel trained in handling radioactive agents
should prepare and administer this agent.
Store in refrigerator.
Do not freeze.
Protect from light.
Do not shake.
(GlaxoSmithKline, 2012a)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 10. Characteristics of Targeted Therapies (Continued)
Mechanism Route of
Classification of Action Drug Administration Indications Side Effects Nursing Considerations
Monoclonal Binds to the ex- Trastuzum- IV In combination with Infusion reactions of chills, Administer only by IV infusion.
antibodies tracellular do- ab (anti- treatment regimens fever, headache, dizzi- Store in refrigerator.
(cont.) main of HER2, HER2 anti- of doxorubicin, cyclo- ness, dyspnea, hypoten- Do not freeze.
resulting in me- body, Her- phosphamide, and pa- sion, rash, and asthenia; Solution reconstituted with bacteriostatic water is stable for
diation of ADCC ceptin®) clitaxel or docetax- pulmonary toxicity related 28 days under refrigeration.
against cells that el and carboplatin or to infusion; cardiomyopa- Solution reconstituted with sterile water must be used im-
overproduce as monotherapy after thy, hypersensitivity reac- mediately and not saved.
HER2 anthracycline-based tions, diarrhea, leukope- Dilute dose only with NS. Do not use D5W.
regimens for adju- nia, anemia, neutropenia, Do not shake product.
vant treatment of pa- infection, thrombosis HER2 protein overexpression is seen in 25%–30% of pri-
tients with HER2-over- mary breast cancers.
expressing node-pos- Do not administer concurrently with doxorubicin and cyclo-
itive or node-negative phosphamide; intended to be administered following com-
breast cancer pletion of doxorubicin and cyclophosphamide.
As single-agent thera- LVEF must be determined prior to initiation and during
py for treatment of pa- treatment. Cardiomyopathy is increased in patients also
tients with metastatic receiving an anthracycline-containing regimen.
breast cancer whose (Genentech, Inc., 2010)
tumors overexpress
HER2 and who have
received one or more
chemotherapy regi-
mens for their disease,
or in combination with
paclitaxel for treatment
of patients with met-
astatic breast cancer
whose tumors overex-
Chapter 4. Principles of Biotherapy
press HER2 and who
have not previously re-
ceived chemotherapy
for their disease
As first-line therapy in
combination with cispl-
atin and capecitabine
or 5-fluorouracil for
treatment of HER2-
overexpressing met-
astatic gastric cancer
or gastroesophage-
al junction adenocar-
cinoma
(Continued on next page)
77
78
Table 10. Characteristics of Targeted Therapies (Continued)
Mechanism Route of
Classification of Action Drug Administration Indications Side Effects Nursing Considerations
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Monoclonal Binds to the ex- Ado-trastu- IV Treatment of patients Hepatotoxicity, cardiotoxici- First infusion is administered over 90 min. Patients should
antibodies tracellular do- zumab em- with HER2+ metastat- ty, thrombocytopenia, pul- be monitored for infusion-related reactions during and for
(cont.) main of HER2, tansine ic breast cancer who monary toxicity, peripheral at least 90 min following completion of the infusion. If in-
resulting in re- (anti-HER2 have previously been neuropathy, infusion- fusion is tolerated, subsequent infusions can be infused
ceptor-mediated antibody treated with trastu- related reactions, hyper- over 30 min with monitoring continuing for at least an ad-
internalization conjugated zumab and a taxane sensitivity, diarrhea, con- ditional 30 min.
and intracellular with em- either alone or in com- stipation, nausea, fatigue, Dose reductions based on the manufacturer’s recommenda-
release of em- tansine, bination musculoskeletal pain, ep- tions should occur in the event of certain adverse effects.
tansine (DM1), Kadcyla™) istaxis Ado-trastuzumab emtansine should be infused using a 0.22
which disrupts micron inline nonprotein-absorptive polyethersulfone filter.
the cell’s micro- Do not mix or infuse ado-trastuzumab emtansine with oth-
tubule network, er medications.
leading to cell Caution should be made not to confuse ado-trastuzumab
cycle arrest and emtansine with trastuzumab (Herceptin).
apoptosis Ado-trastuzumab emtansine should only be diluted with
0.9% saline solution. Do not dilute with D5W.
Prepared diluted solutions can be stored under refrigera-
tion for up to 4 hours.
Do not freeze or shake prepared solutions.
Ado-trastuzumab emtansine can cause fetal harm when
administered to pregnant women. Determine pregnancy
status of patients prior to initiating ado-trastuzumab em-
tansine and inform patients of fetal risks and the need for
effective contraception during treatment with ado-trastu-
zumab emtansine.
Concomitant use with CYP3A4 inhibitors should be avoided
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
because of the risk of increased toxicity. If use of CYP3A4
inhibitors cannot be avoided, use of ado-trastuzumab em-
tansine may be delayed until the CYP3A4 inhibitor has
cleared from the patient’s system or if the patient is moni-
tored closely for adverse effects.
(Genentech, Inc., 2013)
Small Inhibits VEGF Axitinib PO Treatment of advanced Hypertension, thromboem- Administer doses every 12 hours.
molecule receptors with (Inlyta®) renal cell carcinoma bolism, hemorrhage, GI May be taken with or without food.
inhibitors tyrosine kinase after failure of previous perforation, GI fistula for- Concomitant use with CYP3A4/5 inhibitors, including
activity that in- therapy mation, hypothyroidism, grapefruit juice, or inducers may alter exposure to axitinib
terferes with tu- PRES, proteinuria, elevat- and should be avoided. If concomitant use cannot be
mor angiogene- ed LFTs avoided, dose adjustment of axitinib should be made.
sis, growth, and Dosing should be held beginning at least 24 hours before
progression surgery because of risk of impaired wound healing. Time
to restart therapy is based on clinical judgment.
(Pfizer Inc., 2012b)
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 10. Characteristics of Targeted Therapies (Continued)
Mechanism Route of
Classification of Action Drug Administration Indications Side Effects Nursing Considerations
Small Inhibits chymo- Bortezo- IV, SC Treatment of patients Peripheral neuropathy, hy- Use with caution in patients with severe renal or hepatic
molecule trypsin-like ac- mib (Vel- with multiple myelo- potension, cardiomyopa- disease.
inhibitors tivity of 26S pro- cade®) ma or mantle cell lym- thy, pulmonary infiltrates, Monitor hydration status and treat as necessary.
(cont.) teasome result- phoma who have re- nausea, vomiting, diar- Platelet count should be > 70,000/mm3 and neutrophil
ing in disruption ceived at least one pri- rhea, constipation, blurred count > 1,000/mm3 when bortezomib is combined with
of cellular ho- or therapy vision, fatigue, myelosup- melphalan and prednisone.
meostatic mech- pression, PRES, hyperbili- Reconstitute only with NS.
anisms that rubinemia, hepatitis Use reconstituted solutions within 8 hours.
can lead to cell Concentrations of SC (2.5 mg/ml) or IV (1 mg/ml) dos-
death es are different, and final volume depends on calculat-
ed dose.
SC injection site should be rotated in thigh or abdomen. Se-
lect new site at least 1 inch from old site, and avoid ten-
der or bruised areas.
Concomitant use with CYP3A4 inhibitors, including grape-
fruit juice, or inducers may alter exposure to bortezomib.
Do not use in pediatric patients.
Fatal if given intrathecally.
(Millennium Pharmaceuticals, Inc., 2012)
Inhibits BCR- Bosutinib PO Treatment of adult pa- Diarrhea, nausea, vomiting, Take with food.
ABL tyrosine ki- (Bosulif®) tients with chronic, ac- abdominal pain, thrombo- Monitor liver transaminases and hold dose if elevations > 5
nase created by celerated, or blast cytopenia, anemia, neu- × ULN occur. Discontinue if bilirubin elevations > 2 × ULN
the Ph+ genetic phase Ph+ CML that is tropenia, hepatic toxicity, or alkaline phosphatase elevations occur.
abnormality, in- resistant or intolerant fluid retention resulting in Hold dosing and adjust dose if severe or persistent throm-
hibiting prolifera- to other therapies pericardial effusion, pleu- bocytopenia or neutropenia occur. Hold dosing if other
tion, and induc- ral effusion, pulmonary or clinically significant moderate or severe nonhematologic
es apoptosis in peripheral edema, fever, or toxicities occur, then restart once symptoms abate.
Chapter 4. Principles of Biotherapy
BCR-ABL+ cell rash, headache Concomitant use with CYP3A4 inhibitors, including grape-
lines fruit juice, or inducers may alter exposure to bosutinib.
Concomitant use with P-glycoprotein inhibitors such as
verapamil or diltiazem may alter exposure to bosutinib.
Avoid use in pregnant women because of risk of fetal harm.
Use of proton pump inhibitors may reduce bosutinib con-
centration and is not recommended. Use of antacids or H2
blockers should be separated from bosutinib administra-
tion by ≥ 2 hours.
(Pfizer Inc., 2012a)
(Continued on next page)
79
80
Table 10. Characteristics of Targeted Therapies (Continued)
Mechanism Route of
Classification of Action Drug Administration Indications Side Effects Nursing Considerations
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Small Inhibits tyrosine Cabo- PO Treatment of patients GI perforations and fistu- Do not administer with food. Patients should not eat at least
molecule kinase activity of zantinib with progressive, met- las, hemorrhage, thrombo- 2 hours before and 1 hour after taking cabozantinib.
inhibitors multiple receptor (Come- astatic, medullary thy- embolism, wound compli- Capsules should be swallowed whole and not opened.
(cont.) kinases involved triq™) roid cancer cations, hypertension, os- Missed doses should not be taken within 12 hours of the
with oncogene- teonecrosis of the jaw, pal- next dose.
sis, metastasis, mar-plantar erythrodyses- Concomitant use with CYP3A4 inhibitors, including grape-
tumor angiogen- thesia, proteinuria, PRES, fruit juice, or inducers may alter exposure to cabozantinib.
esis, and main- diarrhea, stomatitis, nau- Dose should be adjusted or discontinued permanently in
tenance of the sea, oral pain, constipa- the event of certain adverse effects. See manufacturer’s
tumor microenvi- tion, abdominal pain, vom- prescribing information for full details.
ronment iting, fatigue, weight loss, Treatment with cabozantinib should be held at least 28
loss of appetite, dysgeu- days prior to elective surgery and resumed based on clin-
sia, hypocalcemia, hypo- ical assessment of wound healing.
phosphatemia, hepatotox- (Exelixis, Inc., 2012)
icity, lymphopenia, neutro-
penia, thrombocytopenia
Binds to and in- Carfilzomib IV Treatment of patients Cardiac arrest, CHF, myo- Administer over 2–10 min on two consecutive days.
hibits the 20S (Kyprolis®) with multiple myelo- cardial ischemia, pulmo- Premedicate with dexamethasone 4 mg PO/IV prior to each
proteasome, re- ma who have received nary hypertension, dys- dose during the first cycle and in subsequent cycles if in-
sulting in anti at least two previous pnea, infusion reactions fusion reactions occur.
proliferative and therapies and whose including fever, chills, ar- Hold and modify dose if patients develop hematologic, car-
antiapoptotic ac- disease has pro- thralgia, myalgia, flushing, diac, renal, or hepatic toxicities, pulmonary hypertension,
tivities gressed on or with- hypotension, syncope, or pulmonary complications, peripheral neuropathy, or other
in 60 days of the last angina, TLS, thrombocy- grade 3–4 toxicities.
treatment topenia, anemia, leukope- Do not administer mixed with other IV medications. Infusion
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
nia, hepatic toxicity, renal line should be flushed with NS or D5W before and after
toxicity, fatigue, diarrhea, administration of carfilzomib.
headache, peripheral ede- Store unopened vials in refrigerator. Reconstituted prod-
ma, back pain, peripher- uct is stable for 24 hours under refrigeration or 4 hours at
al neuropathy, herpesvirus room temperature.
infection Antiviral prophylaxis should be considered in patients with
a history of herpes zoster infection.
Because of the risk of fatigue, dizziness, fainting, or hypo-
tension, advise patients not to drive or operate heavy ma-
chinery if they experience these symptoms.
(Onyx Pharmaceuticals, Inc., 2012)
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 10. Characteristics of Targeted Therapies (Continued)
Mechanism Route of
Classification of Action Drug Administration Indications Side Effects Nursing Considerations
Small Inhibits multiple Crizotinib PO Treatment of locally ad- Hepatotoxicity, pneumoni- Determination of ALK+ NSCLC is required for treatment.
molecule tyrosine kinases, (Xalkori®) vanced or metastatic tis, QT prolongation, vi- May be taken with or without food.
inhibitors including ALK, ALK+ NSCLC sion changes, nausea, di- Capsules should be swallowed whole and not crushed,
(cont.) which reduces arrhea, vomiting, edema, chewed, or opened.
tumor cell prolif- constipation, neutropenia, Monitor and correct for hypomagnesemia and hypokalemia to
eration and sur- fatigue, anorexia, dizzi- reduce risk of QT prolongation. Do not use in patients with
vival ness, dyspnea hypokalemia, hypomagnesemia, or long QT syndrome.
Concomitant use with CYP3A4 inhibitors, including grape-
fruit juice, or inducers may alter exposure to crizotinib.
(Pfizer Inc., 2013)
Inhibits multi- Dasatinib PO Treatment of newly diag- Myelosuppression, fluid re- Do not crush or cut tablets.
ple tyrosine ki- (Sprycel®) nosed Ph+ CML tention including pleural Tablets may be taken with or without food and either in the
nases, includ- Treatment of chron- and pericardial effusion, morning or evening.
ing BCR-ABL, ic, accelerated, or prolonged QT interval by Use with caution if patients are taking anticoagulants.
SRC family, c- myeloid or lymphoid ECG, diarrhea, nausea, Concomitant use with CYP3A4 inhibitors, including grape-
KIT, EPHA2, and blast-phase CML with abdominal pain, vomiting, fruit juice, or inducers may alter exposure to dasatinib and
PDGFR-beta resistance or intoler- bleeding, cardiomyopathy, should be avoided. If concomitant use cannot be avoided,
ance to prior therapy pulmonary arterial hyper- dose adjustment of dasatinib should be made.
including imatinib tension Use of proton pump inhibitors or H2 antagonists may re-
Treatment of Ph+ ALL duce dasatinib concentration and is not recommended.
with resistance or in- Use of antacids should be separated from administration
tolerance to prior ther- of dasatinib by ≥ 2 hours.
apy Elevation of transaminases or bilirubin, hypocalcemia, and
hypophosphatemia may occur. Hypocalcemia may require
oral calcium supplements.
(Bristol-Myers Squibb Co., 2011)
Inhibits the in- Erlotinib PO Treatment of locally ad- Rash, diarrhea, anorexia, fa- Patients should take on an empty stomach at least 1 hour
Chapter 4. Principles of Biotherapy
tracellular phos- (Tarceva®) vanced or metastatic tigue, dyspnea, GI bleed- before or 2 hours after food.
phorylation NSCLC after failure of ing or perforation, conjunc- Concomitant use with CYP3A4 inhibitors or inducers may
of tyrosine ki- at least one prior che- tivitis, nephrotoxicity, hep- alter exposure to erlotinib.
nase associated motherapy regimen atotoxicity, myocardial in- Monitor LFTs and consider dose reductions.
with EGFR, ex- As monotherapy for farction, cerebrovascular Monitor INR in patients receiving warfarin.
pressed on the maintenance treat- accident, ocular disorders, Monitor for GI bleeding and elevated INR.
surfaces of nor- ment in patients with elevated INR Diarrhea can be managed with loperamide. Both diarrhea
mal and cancer locally advanced or Rare reports of serious ILD and skin reactions may require dose reduction or tempo-
cells metastatic NSCLC (acute onset of new or rary interruption of therapy.
who have not pro- progressive pulmonary (Genentech, Inc., 2012d)
gressed after 4 cy- symptoms [e.g., dyspnea,
cles of platinum-based cough, fever]); interrupt
therapy therapy for evaluation if
these symptoms develop.
(Continued on next page)
81
82
Table 10. Characteristics of Targeted Therapies (Continued)
Mechanism Route of
Classification of Action Drug Administration Indications Side Effects Nursing Considerations
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Small Erlotinib In combination with
molecule (Tarceva®) gemcitabine for treat-
inhibitors (cont.) ment of locally ad-
(cont.) vanced, unresectable,
or metastatic pancre-
atic cancer
Binds to Everolimus PO Treatment of postmeno- Noninfectious pneumonitis, Patients should take drug at the same time each day and
FKBP12 intracel- (Afinitor®; pausal women with infections, oral ulceration, consistently either with or without food.
lular protein and Afinitor advanced hormone renal failure, diarrhea, fa- Tablets should be swallowed whole with a full glass of wa-
inhibits mTOR, Disperz® receptor–positive, tigue, nausea, vomiting, ter.
which is a ser- tablets for HER2-negative breast edema, nasopharyngi- Dose adjustment is required in hepatic insufficiency.
ine-threonine oral sus- cancer in combination tis, epistaxis, rash, weight Concomitant use with CYP3A4 inhibitors, including grape-
kinase down- pension) with exemestane af- loss, decreased appe- fruit juice, or inducers may alter exposure to everolimus.
stream of the ter patients have failed tite, dysgeusia, headache, Concomitant use with P-glycoprotein inhibitors such as
PI3K/AKT path- treatment with letro- cough, dyspnea, anemia, verapamil or diltiazem may alter exposure to everolimus.
way, resulting in zole or anastrozole leukopenia, thrombocyto- Everolimus whole blood trough levels should be monitored
reduced cell pro- Treatment of adults with penia, hyperglycemia, hy- routinely using the same assay and laboratory through-
liferation and an- unresectable, local- percholesterolemia, ele- out treatment. Measure trough concentrations 2 weeks af-
giogenesis ly advanced or meta- vated hepatic transami- ter starting treatment and with changes in dose, interact-
static progressive neu- nases, hypertriglyceride- ing drugs, hepatic function, or dosage form (oral tablets or
roendocrine tumors of mia, hypoalbuminemia, tablets for oral suspension).
pancreatic origin hypokalemia Titrate dosage to achieve trough levels of 5–15 ng/ml.
Treatment of adult pa- Prepare oral suspension in 25 ml of water only, immediately
tients with advanced prior to use, and discard if not administered within 60 min.
renal cell carcino- Prepared doses should not exceed 10 mg. If higher dos-
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
ma after failed treat- es are required, prepare a second dose. Once tablets are
ment with sunitinib or added to water, allow 3 min for suspension to form, stir
sorafenib gently, and have patients drink. After administration, add
Treatment of subepen- 25 ml additional water to the same glass and stir with the
dymal giant cell as- same spoon to resuspend any remaining particles and
trocytoma in patients administer to patient.
with tuberous sclerosis Oral suspension may be administered using an oral syringe
complex in doses not to exceed 10 mg per syringe. After dosing
via an oral syringe, rinse the syringe with 5 ml of water
to capture remaining drug particles and administer to pa-
tient.
(Novartis Pharmaceuticals Corp., 2012a)
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 10. Characteristics of Targeted Therapies (Continued)
Mechanism Route of
Classification of Action Drug Administration Indications Side Effects Nursing Considerations
Small Inhibits BCR- Imatinib PO Treatment of patients Edema and fluid retention, Weigh patients frequently, and monitor for signs and symp-
molecule ABL tyrosine ki- mesylate with newly diagnosed GI irritation, nausea, vom- toms of fluid retention.
inhibitors nase created by (Gleevec®) Ph+ CML in chron- iting, anemia, neutropenia, Ensure that patients take imatinib with food and a large
(cont.) the Ph+ genetic ic phase thrombocytopenia, hepa- glass of water.
abnormality, in- Treatment of patients totoxicity, cardiomyopathy, For patients who are unable to swallow tablets, the tablets
hibiting prolifer- with Ph+ CML in hemorrhage, dermatologic may be dispersed in a glass of water or apple juice imme-
ation and induc- blast crisis, acceler- toxicity, hypothyroidism diately before administration.
ing apoptosis in ated phase, or chron- Monitor CBC, differential, and LFTs.
BCR-ABL+ cell ic phase after failure of CYP3A4 inducers may decrease levels of imatinib and
lines IFN alfa therapy should be avoided or a 50% dose increase should be
Treatment of patients considered.
with relapsed or re- CYP3A4 inhibitors, including grapefruit juice, may increase
fractory Ph+ ALL exposure to imatinib and should be avoided.
Treatment of patients Imatinib may increase activity of warfarin, and concomitant
with myelodysplastic/ use should be avoided.
myeloproliferative dis- Advise women of childbearing age not to become pregnant
orders associated with while taking imatinib.
PDGFR gene rear- (Novartis Pharmaceuticals Corp., 2012b)
rangements
Treatment of patients
with systemic masto-
cytosis without certain
c-KIT mutations
Treatment of patients
with hypereosinophil-
ic syndrome and/or
chronic eosinophilic
leukemia in the pres-
Chapter 4. Principles of Biotherapy
ence of certain mu-
tations
Treatment of patients
with unresectable, re-
current, and/or meta-
static dermatofibrosar-
coma protuberans
Treatment of patients
with unresectable and/
or metastatic GIST
Adjuvant treatment of
resected GIST
(Continued on next page)
83
84
Table 10. Characteristics of Targeted Therapies (Continued)
Mechanism Route of
Classification of Action Drug Administration Indications Side Effects Nursing Considerations
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Small 4-Anilinoquinaz- Lapatinib PO In combination with Diarrhea, palmar-plantar Instruct patients to take lapatinib at least 1 hour before or 1
molecule oline kinase in- (Tykerb®) capecitabine for treat- erythrodysesthesia, nau- hour after a meal. However, capecitabine should be taken
inhibitors hibitor of the in- ment of patients with sea, rash, vomiting, diar- with food or within 30 min after food.
(cont.) tracellular tyro- advanced or meta- rhea, fatigue, decreased Lapatinib dose should be taken once daily; do not divide
sine kinase do- static breast cancer LVEF, hepatotoxicity, pul- the daily dose.
mains of both whose tumors overex- monary toxicity, QT pro- Modify the dose in patients with severe hepatic impairment.
EGFR and press HER2 and who longation Concomitant use with CYP3A4 inhibitors, including grape-
HER2 receptors have received prior fruit juice, or inducers may alter exposure to lapatinib and
therapy including an should be avoided or the dose adjusted if concomitant
anthracycline, a tax- use is required.
ane, and trastuzumab Confirm normal ejection fraction before beginning drug.
In combination with le- Lapatinib should be discontinued in patients if LVEF
trozole in postmeno- drops below lower limits of normal.
pausal women with Diarrhea may be managed with antidiarrheal agents; re-
hormone receptor– place fluids and electrolytes if severe.
positive breast can- Lapatinib may cause fetal harm when administered to preg-
cer that overexpress- nant women.
es HER2 Monitor and correct for hypomagnesemia and hypokalemia
to reduce risk of QT prolongation.
(GlaxoSmithKline, 2012b)
Binds to and sta- Nilotinib PO Treatment of patients Rash, pruritus, nausea, fa- Instruct patients to swallow capsules whole with water. For
bilizes the in- (Tasigna®) newly diagnosed with tigue, headache, consti- patients unable to swallow capsules, the contents may
active confor- Ph+ CML in chronic pation, diarrhea, vomiting, be mixed in one teaspoon of applesauce and taken with-
mation of BCR- phase thrombocytopenia, neutro- in 15 min.
ABL, the kinase Treatment of chronic- penia, anemia, elevated li- Twice-daily doses should be taken at 12-hour intervals.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
produced by the and accelerated-phase pase, hepatotoxicity, elec- No food should be consumed for at least 2 hours before the
Ph chromosome Ph+ CML in adult pa- trolyte abnormalities, pro- dose and 1 hour after.
tients resistant or intol- longed QT interval Check CBC every 2 weeks for the first 2 months, then
erant to prior therapy Sudden deaths have been monthly.
including imatinib reported. Monitor and correct for hypomagnesemia and hypokalemia to
reduce risk of QT prolongation. Do not use in patients with
hypokalemia, hypomagnesemia, or long QT syndrome.
Obtain ECG at baseline, 7 days after initiation, and periodi-
cally to monitor QTc.
Avoid concomitant use of drugs known to prolong QT in-
terval.
Concomitant use of CYP3A4 inhibitors, such as grape-
fruit juice, or inducers may alter exposure to nilotinib and
should be avoided. Dose reduction may be necessary if
inhibitors must be given, and the QTc should be moni-
tored closely.
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 10. Characteristics of Targeted Therapies (Continued)
Mechanism Route of
Classification of Action Drug Administration Indications Side Effects Nursing Considerations
Small Nilotinib Do not use in patients who are pregnant or breast-feeding.
molecule (Tasigna®) Women of childbearing age should use effective contra-
inhibitors (cont.) ception during treatment.
(cont.) Concomitant use of proton pump inhibitors may reduce ab-
sorption of nilotinib.
(Novartis Pharmaceuticals Corp., 2011)
Inhibits VEGF Pazopanib PO Treatment of advanced Hepatotoxicity, LVEF dys- Doses should be taken once daily at least 1 hour before or
receptors with (Votrient®) renal cell carcinoma function, hemorrhage, 2 hours after a meal.
tyrosine kinase thromboembolism, GI per- Do not crush tablets.
activity, which in- foration, GI fistula forma- Concomitant use of CYP3A4 inhibitors, including grapefruit
terferes with tu- tion, PRES, hypertension, juice, and inducers may alter exposure to pazopanib and
mor angiogene- hypothyroidism, protein- should be avoided.
sis, growth, and uria, infection, diarrhea, Measure LFTs before start of pazopanib use, and monitor
progression hair color changes, nau- at least monthly during the first 4 months of treatment and
sea, anorexia, vomiting, then periodically thereafter.
fatigue, leukopenia, neu- Discontinue the drug permanently in patients in whom ALT
tropenia, thrombocytope- > 3 × ULN and bilirubin levels increase > 2 × ULN while
nia, lymphocytopenia, hy- on pazopanib.
pophosphatemia, hyper- Use with caution in patients with a history of QT prolonga-
glycemia, hypomagnese- tion or concomitantly using other drugs that prolong QT
mia, headache, myalgia interval.
Stop use of drug at least 7 days prior to planned surgery,
and restart based on clinical judgment.
Concomitant use with simvastatin may increase risk of ALT
elevations.
(GlaxoSmithKline, 2012c)
Chapter 4. Principles of Biotherapy
(Continued on next page)
85
86
Table 10. Characteristics of Targeted Therapies (Continued)
Mechanism Route of
Classification of Action Drug Administration Indications Side Effects Nursing Considerations
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Small Inhibits multi- Rego- PO Treatment of patients Hepatotoxicity, hemorrhage, Patients should take drug at the same time each day.
molecule ple membrane- rafenib with metastatic hand-foot skin reactions, Tablets should be swallowed whole with a low-fat breakfast.
inhibitors bound and intra- (Stivarga®) colorectal cancer who rash, hypertension, cardi- Reduce dose for grade 2 hand-foot skin reactions, and hold
(cont.) cellular kinases have previously been ac ischemia, myocardial dose for grade 2 hand-foot skin reactions that recur or do
involved in on- treated with other ther- infarction, PRES, GI perfo- not improve within 7 days despite dose reduction.
cogenesis, tu- apies including a fluo- ration or fistula, complica- Hold dose for grade 2 hypertension.
mor angiogene- ropyrimidine, oxaliplat- tions with wound healing, Hold dose for any other grade 3–4 adverse reaction and
sis, and mainte- in, irinotecan, anti- asthenia, fatigue, pain, fe- then restart at a reduced dose after patient recovers from
nance of tumor VEGF therapy, and ver, anorexia, diarrhea, the reaction. Restart dosing following grade 4 reactions
microenviron- anti-EGFR therapy (if mucositis, weight loss, in- only if the potential benefit outweighs the risks.
ment KRAS wild type) fection, dysphonia, ane- Hold dose if elevations in hepatic transaminases, and re-
Treatment of patients mia, thrombocytopenia, start only if the potential for benefit outweighs the risk of
with locally advanced, lymphopenia, hypocalce- hepatotoxicity. Discontinue dosing if transaminase (AST
unresectable or met- mia, hypokalemia, hypo- or ALT) levels are > 20 × ULN or > 3 × ULN with a biliru-
astatic GIST follow- natremia, hypophosphate- bin > 2 × ULN or recurrent elevated transaminases > 5 ×
ing previous treatment mia, proteinuria ULN despite dose reduction.
with imatinib and suni- May cause fetal harm when administered to pregnant women.
tinib Concomitant use with CYP3A4 inhibitors, including grape-
fruit juice, or inducers may alter exposure to regorafenib.
(Bayer Healthcare, 2013)
Inhibits JAK 1 Ruxolitinib PO Treatment of patients Thrombocytopenia, anemia, Store at room temperature.
and 2, which (Jakafi®) with intermediate- or neutropenia, infections May be taken with or without food.
mediate cyto- high-risk myelofibrosis, If patients are unable to swallow the tablets, ruxolitinib may
kines and growth including primary my- be mixed to a suspension by adding the tablet to 40 ml of
factors responsi- elofibrosis, post-poly- water and stirring for 10 min before administration via na-
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
ble for hemato- cythemia vera myelo- sogastric tube, followed by a flush with 75 ml of water. Ad-
poiesis and im- fibrosis, and post-es- minister the suspension within 6 hours of preparation.
mune function sential thrombocytope- The starting dose is based on a patient’s current platelet
nia myelofibrosis count, and CBC should be monitored every 2–4 weeks
until the dose is stabilized, and then as needed.
Hold dose if platelet count is < 50,000 × 106/L; may restart,
possibly at a reduced dose, after platelet recovery.
Dose may be increased incrementally after at least 4 weeks
of therapy and no more frequently than every 2 weeks
to a maximum of 25 mg twice daily if an inadequate re-
sponse has been achieved.
When used concomitantly with strong CYP3A4 inhibitors,
the recommended starting dose is 10 mg twice daily in
patients with a platelet count > 100,000 × 106/L. Avoid use
with strong CYP3A4 inhibitors in patients with a platelet
count < 100,000 × 106/L.
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 10. Characteristics of Targeted Therapies (Continued)
Mechanism Route of
Classification of Action Drug Administration Indications Side Effects Nursing Considerations
Small Ruxolitinib Dose adjustment is recommended in patients with creati-
molecule (Jakafi®) nine clearance < 60 ml/min or hepatic impairment.
inhibitors (cont.) When discontinuing therapy for reasons other than throm-
(cont.) bocytopenia, a gradual taper by 5 mg twice daily each
week should occur.
Patients are at an increased risk for herpes zoster infec-
tions and should be advised to seek treatment if symp-
toms present.
(Incyte Corp., 2012)
Multikinase in- Sorafenib PO Treatment of unresect- Palmar-plantar erythro- Doses should be taken at least 1 hour before or 2 hours af-
hibitor that is (Nexavar®) able hepatocellular dysesthesia, rash, hyper- ter a meal.
believed to de- carcinoma and ad- tension, myocardial infarc- Continue treatment until patients no longer benefit from
crease tumor vanced renal cell car- tion, mucositis, dyspep- therapy or until unacceptable toxicity occurs.
cell signaling, cinoma sia, increased lipase, in- Caution patients to avoid becoming pregnant during treat-
angiogenesis, creased amylase, diar- ment and for 2 weeks after treatment has stopped.
and apoptosis rhea, nausea, vomiting, Sorafenib has been shown to cause birth defects or fe-
decreased appetite, in- tal loss.
creased risk of bleeding, Use with carboplatin and paclitaxel is contraindicated in
peripheral neuropathy, GI patients with squamous cell lung cancer because of in-
perforation, prolongation creased risk of mortality.
of QT interval, hypophos- Sorafenib may increase activity of warfarin if taken concom-
phatemia, lymphopenia, itantly.
neutropenia, anemia (Bayer Healthcare, 2011)
Decreases tu- Sunitinib PO Treatment of GIST after Myelosuppression, hep- Medication may be taken with or without food.
mor cell prolifer- (Sutent®) disease progression atotoxicity, left ventricu- Obtain baseline ejection fraction prior to initiation of suni-
ation and reduc- while on imatinib or in- lar dysfunction, hypothy- tinib.
es tumor angio- tolerance to imatinib roidism, diarrhea, consti- Concomitant use with CYP3A4 inhibitors, such as grape-
Chapter 4. Principles of Biotherapy
genesis through Treatment of advanced pation, nausea, vomiting, fruit juice, or inducers may alter exposure to sunitinib.
tyrosine kinase renal cell carcinoma mucositis, stomatitis, dys- Monitor and correct for hypomagnesemia and hypokalemia
inhibition Treatment of progres- pepsia, skin discoloration, to reduce risk of QT prolongation.
sive, well-differentiat- rash, depigmentation of (Pfizer Inc., 2011)
ed, unresectable, lo- hair, palmar-plantar eryth-
cally advanced or met- rodysesthesia, fatigue, hy-
astatic pancreatic neu- pertension, bleeding, ede-
roendocrine tumors ma, QT prolongation, im-
paired wound healing, ve-
nous thromboembolism,
pancreatitis
(Continued on next page)
87
88
Table 10. Characteristics of Targeted Therapies (Continued)
Mechanism Route of
Classification of Action Drug Administration Indications Side Effects Nursing Considerations
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Small Binds to the in- Temsiroli- IV Treatment of advanced Rash, asthenia, mucositis, Preparation requires use of manufacturer-provided diluent
molecule tracellular pro- mus (To- renal cell carcinoma nausea, edema, hypersen- and then additional dilution with NS.
inhibitors tein FKBP12, re- risel®) sitivity reactions, anorexia, Premedicate with prophylactic IV diphenhydramine 25–50
(cont.) sulting in inhibi- myelosuppression, hyper- mg (or similar antihistamine) approximately 30 min before
tion of mTOR, glycemia, hyperlipidemia, the start of each dose.
causing an inter- hypercholesterolemia, hy- Hold dosing if platelet count < 75,000/mm3 or neutrophil
ruption of cell di- pertriglyceridemia, elevat- count < 1,000/mm3.
vision ed alkaline phosphatase, Dose reductions are required in patients with even mild he-
elevated SCr, lymphope- patic impairment, and drug is contraindicated in patients
nia, hypophosphatemia, with bilirubin > 1.5 × ULN.
elevated AST, ILD, oppor- Use with CYP3A4 inhibitors, including grapefruit juice, or
tunistic infections, bowel inducers may alter exposure to temsirolimus and should
perforation be avoided or the dose adjusted if concomitant use is re-
quired.
Store in refrigerator.
Protect from light.
Prepare temsirolimus in PVC-free, non-DEHP glass bottles
or infusion bags and tubing.
Protect prepared product from light and administer through
an in-line filter of < 5 microns within 6 hours after dilution
in NS.
Hyperglycemia and hyperlipidemia are likely and may re-
quire treatment. Monitor lipid profiles.
Patients receiving additional anticoagulation may be at in-
creased risk for bleeding.
Monitor for symptoms of radiographic changes of ILD.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Because of abnormal wound healing, use with caution in
the perioperative period.
Patients should avoid receiving live vaccines and having
close contact with those who have received live vaccines.
Bowel perforations may occur; promptly evaluate for fever,
abdominal pain, bloody stools, and acute abdomen.
Women of childbearing potential should be advised of the
potential hazard to the fetus and to avoid becoming preg-
nant during treatment.
Monitor renal function at baseline and throughout treat-
ment.
(Wyeth Pharmaceuticals, 2011)
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 10. Characteristics of Targeted Therapies (Continued)
Mechanism Route of
Classification of Action Drug Administration Indications Side Effects Nursing Considerations
Small Inhibits VEGF Vandetanib PO Treatment of symptom- QT prolongation, skin reac- Caprelsa is available only through a restricted distribution
molecule and EGFR tyro- (Caprel- atic or progressive, un- tions, skin photosensitivity, program requiring certification of prescribers and phar-
inhibitors sine kinase ac- sa®) resectable, locally ad- ILD, pneumonitis, ischemic macies.
(cont.) tivity that inter- vanced or metastat- cardiovascular events, Do not crush tablets.
feres with endo- ic multifocal medullary hemorrhage, heart failure, If patients are unable to swallow tablets, the tablets can be
thelial cell mi- thyroid cancer diarrhea, hypothyroidism, dispersed in 2 oz of noncarbonated water, stirred for ap-
gration, prolifer- hypertension, PRES, rash, proximately 10 min, and then swallowed immediately. Any
ation, and new acne, nausea, headache, residue in the glass should be mixed with 4 oz of addition-
blood vessel fatigue, anorexia, abdom- al water and swallowed by patient.
survival inal pain Avoid skin exposure to crushed tablets.
Concomitant use with CYP3A4 inducers may increase ex-
posure to vandetanib and should be avoided.
Use is contraindicated in patients with congenital QT pro-
longation.
Monitor and correct for hypocalcemia, hypomagnesemia,
and hypokalemia to reduce risk of QT prolongation.
Obtain ECG at baseline and recheck 2–4 weeks and 8–12
weeks after starting vandetanib, and then every 3 months
thereafter.
Avoid concomitant use of drugs that prolong QT interval, or
perform more frequent ECG monitoring if use is unavoid-
able.
Instruct patients to wear sunscreen and protective clothing
when exposed to sun.
(AstraZeneca Pharmaceuticals, 2011)
Chapter 4. Principles of Biotherapy
(Continued on next page)
89
90
Table 10. Characteristics of Targeted Therapies (Continued)
Mechanism Route of
Classification of Action Drug Administration Indications Side Effects Nursing Considerations
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Small Inhibits the mu- Vemura PO Treatment of unresect- Hypersensitivity, cutaneous Doses should be taken approximately every 12 hours.
molecule tated form of fenib able melanoma or squamous cell carcinoma, Drug may be taken with or without food.
inhibitors BRAF serine/ (Zelboraf®) melanoma containing skin reactions, QT prolon- Tablets should be swallowed whole with a glassful of water.
(cont.) threonine kinase the BRAF V600E mu- gation, hepatotoxicity, pho- Do not crush or chew tablets.
tation tosensitivity, eye irritation, Because of the risk of developing cutaneous squamous
new malignant melanoma cell carcinoma, patients should receive a dermatologic
lesions, alopecia, pruritus, evaluation prior to starting vemurafenib and then every 2
hyperkeratosis, arthralgia, months thereafter.
fatigue, nausea, diarrhea, Monitor and correct for hypocalcemia, hypomagnesemia,
headache and hypokalemia to reduce risk of QT prolongation.
ECG should be obtained at baseline, 15 days after the start
of treatment, monthly during the first three months of
treatment, and then at least every 3 months thereafter.
Avoid use in patients with a QTc > 500 ms, and hold thera-
py if QTc exceeds this time during treatment.
Instruct patients to avoid sun exposure and wear protective
clothing, sunscreen, and lip balm when outdoors.
Vemurafenib is a CYP1A2 and CYP2D6 inhibitor and CYP
3A4 inducer; avoid concomitant use with other medica-
tions metabolized by these enzymes because of the po-
tential for altered metabolism.
Concomitant use with CYP3A4 inhibitors, including grape-
fruit juice, and inducers may alter exposure to vemu-
rafenib.
(Genentech, Inc., 2011b)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Inhibits trans- Vismo- PO Treatment of metastat- Muscle spasm, alopecia, Drug may be taken with or without food.
membrane sig- degib (Eri- ic basal cell carcinoma dysgeusia, weight loss, fa- Patients should swallow capsules whole. Do not crush or
nal transduction vedge®) or locally advanced tigue, diarrhea, anorex- chew.
in the Hedgehog basal cell carcinoma ia, constipation, arthralgia, Because of teratogenicity, determine pregnancy status of
pathway respon- that has advanced fol- vomiting women of childbearing age prior to starting therapy. In-
sible for cell de- lowing surgery or in form male patients of fetal risk, and instruct on use of
velopment patients who are not contraception during treatment.
candidates for surgery Patients may not donate blood during treatment or for at
or radiation therapy least 7 months after completing treatment.
Concomitant use with agents that reduce stomach acid,
such as a proton pump inhibitor or H2 antagonist, may re-
duce absorption of vismodegib.
(Genentech, Inc., 2012a)
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 10. Characteristics of Targeted Therapies (Continued)
Mechanism Route of
Classification of Action Drug Administration Indications Side Effects Nursing Considerations
Small Acts as a solu- Ziv-afliber- IV In combination with Hemorrhage, GI perfora- Store in refrigerator, and keep vials in original container un-
molecule ble receptor and cept (Zal- 5-fluorouracil, leucov- tion, impaired wound heal- til time of use to protect from light.
inhibitors binds to VEGF- trap®) orin, and irinotecan ing, fistula formation, hy- Administer infusions over 1 hour through a 0.2 micron poly-
(cont.) A, VEGF-B, and in patients with meta- pertension, arterial throm- ethersulfone filter prior to any of the other drugs used in
placental growth static colorectal can- boembolic events includ- the chemotherapy regimen. Do not use with filters made
factor (known cer that is resistant or ing transient ischemic at- from polyvinylidene fluoride or nylon.
as PIGF), lead- progressing following tack, cerebrovascular acci- Do not use product if solution is anything other than clear,
ing to inhibition treatment with oxalipl- dent, and angina, protein- colorless to pale yellow in color.
of neovascular- atin-based therapy uria, nephrotic syndrome, Discard unused product following initial one-time access
ization and de- thrombotic microangiopa- into vial.
creased vascular thy, neutropenia, infection, Dilute in NS or D5W to a concentration of 0.6–8 mg/ml.
permeability thrombocytopenia, diar- Do not administer mixed with other IV medications.
rhea, dehydration, PRES, Diluted solution may be stored under refrigeration for up to
anorexia, stomatitis, ab- 4 hours.
dominal pain, fatigue, el- Hold dosing at least 4 weeks prior to elective surgery.
evated hepatic transam- Hold dosing if recurrent or severe hypertension occurs, and
inases restart once blood pressure is controlled.
Monitor urine protein, and hold dosing if proteinuria > 2
g/24 hours; restart once proteinuria < 2 g/24 hours. Dose
reduction is recommended for recurrent proteinuria > 2
g/24 hours.
(Regeneron Pharmaceuticals, Inc., 2012)
Chapter 4. Principles of Biotherapy
ADCC—antibody-dependent cellular cytotoxicity; ALK—anaplastic lymphoma kinase; ALL—acute lymphoblastic leukemia; ALT—alanine aminotransferase; AST—aspartate transferase; BCR-ABL—breakpoint cluster re-
gion-Abelson; BRAF—v-raf murine sarcoma viral oncogene homolog B; CBC—complete blood count; CD—cluster of differentiation; CHF—congestive heart failure; CHOP—cyclophosphamide, doxorubicin, vincristine,
prednisone; CLL—chronic lymphocytic leukemia; CML—chronic myeloid leukemia; CTLA-4—cytotoxic T-lymphocyte antigen 4; CVP—cyclophosphamide, vincristine, prednisone; DEHP—di-2-ethylhexyl phthalate; D5W—
5% dextrose in water; ECG—electrocardiogram; EGFR—epidermal growth factor receptor; EPHA2—ephrin A2; FLT—Fms-related tyrosine kinase; GI—gastrointestinal; GIST—gastrointestinal stromal tumor; H—his-
tamine; HER2—human epidermal growth factor receptor 2; IFN—interferon; IL—interleukin; ILD—interstitial lung disease; INR—international normalized ratio; IV—intravenous; JAK—Janus-associated kinases; JCV—
John Cunningham virus; KDR—kinase insert domain receptor; KRAS—Kirsten rat sarcoma viral oncogene homolog; LFT—liver function test; LVEF—left ventricular ejection fraction; mCi—millicurie; MDS—myelodysplas-
tic syndrome; min—minutes; MMEA—monomethyl auristatin E; ms—millisecond; mTOR—mammalian target of rapamycin; NHL—non-Hodgkin lymphoma; NS—normal saline; NSCLC—non-small cell lung cancer; oz—
ounces; PDGFR—platelet-derived growth factor receptor; Ph+—Philadelphia chromosome–positive; PO—by mouth; PRES—posterior reversible encephalopathy syndrome; PVC—polyvinyl chloride; QTc—QT interval
corrected; RANKL—receptor activator of nuclear factor κB ligand; REMS—risk evaluation and mitigation strategy; SC—subcutaneous; SCr—serum creatinine; TLS—tumor lysis syndrome; TNF—tumor necrosis factor;
ULN—upper limit of normal; VEGF—vascular endothelial growth factor; VGF—Vaccinia virus growth factor
91
92 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Figure 9. Common Terminology in Cell Signaling
• Ligands: Molecules, such as growth factors, that activate receptors, such as growth factor
receptors, on the surface of the cell
• Ligand binding: The process by which the ligand attaches to a specific receptor site and
activates the receptor, thereby activating the signaling pathway. This is similar to antigen-an-
tibody binding.
• Monomer: Single receptor, inactivated state
• Dimerization: Activation of receptor through monomer pairing. Dimerization occurs between
two adjacent receptors that have bound ligands. That is, two monomers that are side by side
on the surface of the cell are paired and activated by the ligand. The joining activates a series
of signals.
• Phosphorylation: Activation of a chemical process to initiate signaling, such as with tyro-
sine kinase
• Heterodimerization: The pairing of two different ligand-bound receptors together, such as
Erb1 and Erb2
• Homodimerization: The joining of two receptors of the same subtype, such as two Erb1
(HER1) receptors or two Erb2 (HER2), Erb3 (HER3), or Erb4 (HER4) receptors
Note. Based on information from Paul, 2008.
initiate on the ligands of the extracellular domain, sending a
signal through the transmembrane to intracellular tyrosine ki-
nase and on to the nucleus of the cell.
(4) Tyrosine kinases modify themselves as well as other cellular pro-
teins by putting phosphate molecules on the amino acid tyrosine.
(a) This activity is necessary for receptor signaling.
(b) Targeted therapies are directed toward specific molecules
(targets) along a cellular signaling pathway that is involved
in tumor growth, proliferation, and invasion.
(5) Targeted therapies moderate, control, and/or kill cancer cells
and work differently than either chemotherapy or radiation
therapy (see Figure 10).
(6) Therapies targeting intracellular pathways, or tyrosine kinase
receptors, are small molecules and, to date, mostly oral thera-
pies. Because of the need for long-term inhibition of signaling,
chronic oral therapy represents the most rational approach to
dosing. Patients may develop drug resistance with kinase-target-
ed therapies. Examples:
(a) Erlotinib
(b) Sorafenib
(c) Sunitinib
(d) Imatinib
(7) Mammalian target of rapamycin (mTOR) kinase inhibition:
Temsirolimus
(8) BRAF V600E mutations: Vemurafenib
(9) Anaplastic lymphoma kinase–positive: Crizotinib
(10) Therapies targeting growth factor receptors in the extracellular
pathways are generally mAbs (see previous section).
2. Growth factors
a) Growth factors are produced by cells in all body tissues.
b) They are primarily responsible for initiating the complex cell signal-
ing that is required to maintain cell viability and division.
c) These factors can influence cells in either a positive or negative way
that affects cell survival, apoptosis, and differentiation.
d) Growth factors bind with their specific receptors and initiate a cas-
cade of intracellular signaling.
e) Examples of growth factors
(1) Epidermal growth factor (EGF), which binds to EGFR
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 4. Principles of Biotherapy 93
(2) VEGF, which binds to the vascular endothelial growth factor
receptor (VEGFR)
f) Redundancies exist in cell signaling. Several extracellular signals may
lead to the activation of the same pathway.
(1) The final response of the cell may differ depending on the re-
sponse from the nucleus.
(2) Despite this redundancy with stimuli, the kinetics and extent of
activation may vary, leading to vastly different outcomes.
K. Angiogenesis and antiangiogenic agents (Keith & Simon, 2008; Oklu, Walk-
er, Wicky, & Hesketh, 2010; Viale, 2007; Wilkes, 2007; Wisinski & Gradishar,
2011; Wujcik, 2011)
1. Angiogenesis is the development of new blood vessels. It is a complex,
multistep process that is required for a host of normal functions, includ-
ing wound healing, tissue repair, reproduction, growth, and development.
2. Under normal circumstances, angiogenesis is tightly controlled by a bal-
ance of stimulators and inhibitors.
3. In malignant angiogenesis, that balance is upset, leading to irregular mo-
lecular and cellular events that contribute to tumor neovascularization.
Figure 10. Cancer Treatments: Mechanisms of Action
Note. Figure courtesy of the Institute for Medical Education & Research, Inc., June 22, 2012. Used with permission.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
94 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
4. In the context of tumors, angiogenesis refers to the growth of new vessels
within a tumor. The new vessels develop from the existing vascular net-
work and provide a blood supply for the tumor.
5. Tumors are initially antiangiogenic, so there must be a factor, known as
an angiogenic switch, that makes them proangiogenic. This switch is what
turns on tumor angiogenesis.
a) Hypoxia activates intracellular molecules including the hypoxia-
inducible factor-1 (HIF-1) complex. HIF-1 activation causes upreg-
ulation of proangiogenic factors including VEGF, platelet-derived
growth factor, and nitric oxide synthase. HIF-1 is essential in induc-
ing the angiogenic switch, changing the microenvironment from an-
tiangiogenic to proangiogenic.
b) VEGF and basic fibroblast growth factor are circulating growth fac-
tors known to induce angiogenesis. Their presence has been report-
ed to correlate with extent of disease, clinical status, and survival.
c) Endothelial cells line the vasculature of normal tissues. In a resting
state, they provide a homeostatic barrier that prevents the uncontrolled
extravasation of intravascular components and inhibits coagulation.
d) When a tumor begins to grow in normal tissue, tumor cells release
factors that elicit responses from the surrounding endothelium. The
result is vascular growth from normal tissue into the tumor.
e) Neovascularization contributes to tumor invasion and metastasis.
(1) Tumor vasculature is permeable and disorganized with a weak
basement membrane. These conditions facilitate the migration
of endothelial cells.
(2) VEGF can cause accumulation of endothelial cells and stimu-
late further tumor angiogenesis.
(3) Blood flow in tumors is sluggish, thus inducing hypoxia and
acidosis. Tumor hypoxia further induces tumor angiogenesis.
(4) Hypoxia and acidosis may contribute to chemotherapy and ra-
diotherapy resistance because of lack of oxygen.
6. Other molecular pathways involved in tumor angiogenesis
a) Matrix metalloproteinases (MMPs) are involved in degrading the ex-
tracellular matrix components (ECM). In angiogenesis, MMPs invade
the ECM via new vessel formation and lead to proliferation and mi-
gration of tumor cells.
b) Tumor angiogenesis also affects the Notch receptor pathway. Notch sur-
face cell receptors are involved in cell fate, cell differentiation, and cell
proliferation. Vascular endothelial cells express certain Notch receptors.
One type is needed for the vascular development of embryos but also is
upregulated in tumor vasculature. This process may be VEGF mediated.
7. Antiangiogenic agents
a) Mechanism of action: Antiangiogenic agents target the neovascula-
ture of tumors to halt their growth, prevent tumor invasion, and pre-
clude metastatic diffusion. Potentially, antiangiogenic agents are ide-
al for use with other cancer therapy modalities because they maxi-
mize the efficacy of the other therapies.
b) Side effects: Table 10 lists some of the side effects of antiangiogen-
ic agents.
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Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 5
Nursing Considerations in
Cancer Treatment
A. Ethical issues: The rapidly changing healthcare environment necessitates
that nurses be sensitive to ethical and legal issues. Issues arise in the care
of all patients, but the intensity is often greater in the cancer population
when patients, families, and healthcare professionals face potentially diffi-
cult moral choices.
1. Ethical issues related to cancer therapy
a) Healthcare realities that present potential ethical issues
(1) Major advances: Medical technology, increased expectations,
and changing moral attitudes combine to generate complex
ethical and legal problems related to cancer and palliative care
(Butts & Rich, 2012; Pavlish, Brown-Saltzman, Hersh, Shirk, &
Nudelman, 2011; Pendry, 2007; Smith et al., 2011). In particu-
lar, the use of life-sustaining measures may raise ethical ques-
tions when healthcare professionals
(a) Fail to discuss a patient’s wishes before a crisis developed
(b) Are reluctant or fail to communicate medical treatment
options with a grief-stricken family
(c) Fail to consider supportive care measures
(d) Experience moral distress related to personal values or bi-
ases.
(2) Changing healthcare environment: Staffing shortages, realloca-
tion of resources, consolidation, and corporatization have result-
ed in growing administrative dominance over clinical practice
(Agency for Healthcare Research and Quality [AHRQ], 2013;
Centers for Medicare and Medicaid Services [CMS], 2013; In-
stitute of Medicine, 2004; Pendry, 2007).
(3) Increasing numbers of underinsured and undocumented in-
dividuals: Even for people with health insurance, the need to
make copayments can lead to debt. Children and the working
poor are most affected by poor coverage. Also, some people
with insurance are unable to obtain reimbursement for certain
treatments, such as BMT or off-label use of medications (Brock,
2010; CMS, 2013).
(4) Increases in cultural diversity: Cultural and communication dif-
ferences present a range of challenges, from discussion of diag-
nosis and prognosis to decisions about who will provide long-
term care (AHRQ, 2013; Butts & Rich, 2012).
(5) Use of alternative therapies: Increasing use of complementa-
ry and alternative medicine, either in conjunction with or as a
substitute for conventional treatment, is the result of many fac-
tors, including the unpredictable nature of individual response
to cancer and its treatment, the individual’s need for a sense
of control, belief in individual rights and determination, and 97
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
98 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
cultural and spiritual beliefs (Butts & Rich, 2012; Cooley, 2010;
Fouladbakhsh, 2013).
(6) Expanded use of targeted therapies, discovery of genetic mu-
tations, and increase in molecular testing: As personalized
therapies become more common, healthcare professionals
are expected to apply this knowledge to practice. Reimburse-
ment for testing and services, extensive family history collec-
tion, and costs of targeted and biologic therapies offer more
challenges to patients, the healthcare system, and profession-
als (Bronchud, Foote, Giaccone, Olopade, & Workman, 2008;
Calzone, Masny, & Jenkins, 2010).
b) Ethical issues that oncology nurses face in daily practice (Pendry, 2007)
(1) End-of-life decisions
(2) Informed consent
(3) Patient autonomy and decision-making capacity
(4) The right to refuse treatment
(5) Undertreatment of pain
(6) The healthcare environment and reform
(7) Access to care
(8) Confidentiality
(9) Scientific integrity
(10) Intra-family conflicts
(11) Nurse-family conflicts
(12) Nurse-physician conflicts
(13) Physician-family conflicts
(14) Participation in clinical research
2. The Joint Commission (2011) requires accredited institutions to provide
access to an ethics consultation to assist in evaluating the decision-mak-
ing capacity of an individual as well as to assist with problem resolution.
3. The ethical principles guiding decision making are summarized in Ta-
ble 11.
Table 11. Ethical Principles
Principle Description Clinical Examples
Autonomy Independent decision making by an in- Respecting an individual’s choice even when different from one’s
dividual in accordance with his or her own
own best interest Providing supportive services
Nonmaleficence The duty to do no harm Providing complete information
Providing survivorship services
Recognizing professional limitations and seeking consultation/col-
laboration
Adhering to professional standards of care
Beneficence The duty to act in the best interest of Personalizing care based on individual desires, culture, disease,
the involved person and other factors
Providing evidence-based care
Justice Equitable distribution of available re- Offering/providing treatment regardless of ability to pay, culture, or
sources socioeconomic status
Assisting with or referring for financial support
Veracity Truth telling Explaining treatment in understandable terms before it is initiated
Providing accurate information and educational materials
Fidelity Faithfulness to promises made Following up as promised
Providing survivorship care planning
Fostering collegiality
Note. Based on information from Beauchamp & Childress, 2009.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 5. Nursing Considerations in Cancer Treatment 99
B. Legal issues related to cancer therapy: Adhering to national, state, and in-
stitutional standards is a fundamental responsibility of all nurses (American
Nurses Association, 2010; Brown, Marcus, & Bales, in press; Sabatino, 2010).
1. The acts and standards guiding nursing practice
a) Nurse practice acts: State laws that define nursing performance in
fundamental terms for each state
b) ONS’s Statement on the Scope and Standards of Oncology Nursing Practice:
Generalist and Advanced Practice (Brant & Wickham, 2013) describes the
minimum standard of care to which a patient with cancer is entitled.
c) Infusion Nursing Standards of Practice (Infusion Nurses Society, 2011)
describes the current standards of nursing practice for IV therapy.
d) Sources of institution-specific standards
(1) Standards of practice
(2) Nursing policy and procedure manuals
(3) Job descriptions
(4) IRB decisions
2. Common legal issues
a) Medication errors (see Section D: Patient Safety)
b) Documentation issues: The duty to keep accurate records is a funda-
mental nursing responsibility. The medical record is scrutinized in the
event of litigious action and is believed to reflect the care rendered
(American Society of Health-System Pharmacists [ASHP], 2011; An-
derson & Townsend, 2010; Brock, 2010).
(1) Common documentation errors
(a) Omitting significant observations
(b) Failing to document the patient’s response to an intervention
(c) Failing to document patient teaching and understanding
(d) Failing to document what was taught and to whom
(2) Nursing actions to include in documentation
(a) Telephone conversations, particularly those in which the
nurse gives the patient instructions or advice
(b) Pertinent conversations with the patient, family, or other
caregivers
(c) Interagency referrals
(d) Cytotoxic drug administration: See Appendices 1 and 2.
(e) Treatment-related documentation including the following,
when applicable
i. Two unique patient identifiers (such as name, medi-
cal record number, or date of birth)
ii. Patient-specific measurements used to calculate dos-
es (e.g., body surface area [BSA])
iii. Pertinent laboratory and diagnostic test results
iv. Date and time of therapy
v. Drug name, dose, route of administration, and infu-
sion duration
vi. Volume and type of IV fluids administered
vii. Assessment of the IV site before, during, and after in-
fusion
viii. Information about the infusion device (e.g., vein se-
lection, needle size, type of device, infusion pump)
ix. Verification of IV access device patency, including pres-
ence of a blood return before, during, and after IV therapy
(f) Patient assessment and evaluation of the patient response
to and tolerance of treatment
(g) Patient and family education related to drugs received, tox-
icities, toxicity management, and follow-up care
(h) Post-treatment or discharge instructions
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
100 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
c) Informed consent
(1) Process: Patients must give IC for treatment, enrollment in a
clinical trial, or participation in nursing research (Beauchamp
& Childress, 2009; Butts & Rich, 2012; Klimaszewski, in press;
Pojman, 2010). With the exception of research, each institu-
tion determines its own practice related to how and if a patient
must provide written IC before receiving antineoplastic medi-
cations (Jacobson et al., 2012). It is important to maintain con-
sistency between policy and practice throughout the institution.
The following approaches have been used.
(a) The general hospital “consent to treat” document serves as
the signed permission to provide antineoplastic medications.
(b) The patient signs a consent form designed specifically for
the administration of antineoplastic medications and that
is part of the medical record.
(c) Some centers use a general procedure consent form for
antineoplastic medications.
(d) A specific form is not signed, but consent is documented
within the medical record.
(2) Requirements
(a) The IC document must state the right of the patient to re-
fuse or discontinue treatment at any time.
(b) The IC document and, subsequently, physicians and nurs-
es, must guarantee patients that ongoing support and care
will be provided if they decline or discontinue treatment
connected with the trial or research.
(c) Nurses and physicians have different but complementary
roles in the IC process.
(d) See Chapter 2 for additional information on the IC pro-
cess and the nurse’s role.
C. Safety standards for antineoplastic administration
1. ASCO/ONS Chemotherapy Administration Safety Standards: In 2008, ASCO
and ONS began a collaboration to outline safety standards for the ad-
ministration of chemotherapy (Jacobson et al., 2009).
a) Professionals from disciplines across health care were included in the
development process of this consensus document, which applies to
all practice settings and focuses on patient safety.
b) Standards address staffing-related issues, chemotherapy planning,
documentation, orders, preparation, education, administration, and
monitoring.
c) The standards are included in ASCO’s Quality Oncology Practice Ini-
tiative (QOPI®) program, which certifies hematology/oncology prac-
tices based on quality indicators.
d) The original standards and later revisions were published in the
Journal of Clinical Oncology, the Journal of Oncology Practice, and the
Oncology Nursing Forum (Jacobson et al., 2009, 2012; Neuss et al.,
2013).
e) For more information, visit www.ons.org/practice-resources/clinical
-practice/ascoons-chemotherapy-administration-safety-standards.
D. Patient safety: The nurse is the final checkpoint in the medication admin-
istration process. Strategies should be implemented to minimize the occur-
rence of medication errors.
1. Prevalence of medication errors
a) As reported by the Institute of Medicine (2004), 3.7% of inpatients
experienced an adverse event related to a medication error.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 5. Nursing Considerations in Cancer Treatment 101
b) Preventable adverse drug events have been found to cause one out
of five injuries or deaths to patients in hospitals (AHRQ, 2000; Leape
et al., 1991).
c) Weingart et al. (2010) studied errors related to oral chemotherapy us-
ing incident reports from seven comprehensive cancer centers, a lit-
erature and Internet search, U.S. Pharmacopeial Convention [USP]
reports, and pharmacy and incident reports from the authors’ own
center. The majority of errors resulted in a near-miss of a dose; 39.3%
involved inaccurate supply, which resulted in adverse drug events. In-
cidents derived from the literature and Internet search and the au-
thors’ hospital incident reporting system showed a greater percent-
age of adverse drug events (73.1% and 58.8%, respectively) compared
with the other sources (Weingart et al., 2010).
2. Risks associated with the administration of cytotoxic agents (Schwap-
pach & Wernli, 2010)
a) Toxicity
b) Low margin for dosing error (e.g., use of high-dose ablative therapy
leaves essentially no margin for error)
c) Widely varying dosages and administration schedules (doses and
schedules may be patient-specific)
d) Doses often are modified based on patients’ clinical status and response.
e) Complicated and varying medications, schedules, and regimens
3. Types of chemotherapy medication errors (ASHP, 2011; Schwappach &
Wernli, 2010; Sheridan-Leos, 2007; Weingart et al., 2010)
a) Administration of the wrong dose (under- or overdosing)
b) Schedule and timing errors
c) Use of the wrong drug
d) Infusion rate errors
e) Omission of drugs or hydration
f) Improper drug preparation
g) Route errors (e.g., intrathecal [IT] versus IV)
h) Administration to the wrong patient
i) Administration when laboratory values not appropriate
4. Factors contributing to medication errors in chemotherapy: Most medi-
cation errors are system-related and not attributable to individual negli-
gence or misconduct (Schwappach & Wernli, 2010; Sheridan-Leos, 2007;
Weingart et al., 2010).
a) Stress
b) Understaffing
c) Lack of experience in administering chemotherapy
d) Unclear or ambiguous chemotherapy orders
e) Lack of experience in administering the specific chemotherapy drug
with which the error occurred
f) Fatigue
g) Illegible handwriting
h) Inaccessibility of information about chemotherapy drugs
i) Chemotherapy drug packaging or vial difficult to read or understand
j) Increasing number of complicated schedules and new drug combi-
nations
5. Strategies for preventing medication errors (ASHP, 2011; Jacobson et
al., 2012)
a) Verify all pertinent clinical patient information, including patient’s
measured height and weight, laboratory results, and BSA.
b) Ensure that up-to-date drug information and other resources are read-
ily available to clinicians.
c) Support institutional policy that prohibits verbal orders for chemo-
therapy.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
102 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
d) Use preprinted, standardized forms or computerized physician or-
der entry to order cytotoxic drugs when possible.
e) Avoid the use of abbreviations, acronyms, coined names, and other
ambiguous methods of communicating drug information.
f) Provide ongoing education to patients about their medications, and
encourage them to ask questions and seek clarification before their
drugs are administered.
g) Ensure adherence to institutional policies and procedures.
h) Verify all chemotherapy doses, scheduling, and dosing calculations
(see Chapter 7). Support institutional policy for a systematic meth-
od of dose verification.
i) Review orders in an environment with minimal distractions.
j) Limit chemotherapy administration to RNs who are qualified by ed-
ucation and training.
k) Use standardized processes to verify and document the accuracy and
appropriateness of all chemotherapy doses.
6. Inadvertent IT administration: The inadvertent administration of vin-
cristine and other drugs into the subarachnoid space (IT administra-
tion) has resulted in a number of tragic deaths around the world (Gil-
bar & Seger, 2012). Publications from the Joint Commission (2005),
WHO (2007), and the Institute for Safe Medication Practices (2006)
prompted institutions to reevaluate their preparation and delivery of
vinca alkaloids and of IT medications in general. A multidisciplinary
review of the process of drug preparation and administration is advised
in each practice setting.
a) The ASCO/ONS Chemotherapy Administration Safety Standards
(Jacobson et al., 2012) call for organizational policies related to
IT medications. These drugs should not be prepared with any oth-
er agents. Once prepared, they should be marked with a uniquely
identifiable medication label and stored in a separate container or
location from other drugs. All IT medications are to be delivered
to the patient only with other medications intended for adminis-
tration into the CNS.
b) Special procedures should be followed for the administration of IT
medications. See Figure 11 for recommendations.
c) Both the Joint Commission and WHO recommended that vincristine
and other vinca alkaloids be diluted and administered IV via a mini-
bag. Opponents to this approach have cited the risk of extravasation,
as many institutions have policies against the infusion of vesicant che-
motherapy into a peripheral vein. Gilbar and Carrington (2006) re-
ported that vinca alkaloids can be safely administered as low-volume,
short-term infusions with minibags. (See recommendations for ad-
ministration of short-term IV infusions in Chapter 6.)
d) Bortezomib is another drug that is fatal when administered by the IT
route. Bortezomib is administered either by rapid IV push or by sub-
cutaneous (SC) injection. The stability of bortezomib when diluted
in a minibag has not been established (Gilbar & Seger, 2012). There-
fore, other processes to prevent the inadvertent IT administration of
bortezomib should be used.
E. Safe handling and disposal of hazardous drugs (HDs): Many drugs used in
the treatment of cancer are hazardous to healthcare workers. The term haz-
ardous describes drugs that require special handling because occupational
exposure may cause adverse health effects. These effects occur because of
the inherent toxicities of the drugs (ASHP, 2006; NIOSH, 2004). Accord-
ing to the Occupational Safety and Health Administration (OSHA, 1999),
a safe level of occupational exposure to HDs is unknown, and no reliable
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 5. Nursing Considerations in Cancer Treatment 103
Figure 11. Recommendations to Prevent Errors With Intrathecal Chemotherapy Administration
• Administer vincristine and other vinca alkaloids IV via a minibag (i.e., IV piggyback). The stability of bortezomib when diluted in a
minibag has not been established.
• Vinca alkaloids and bortezomib should include a clear warning label: “FOR INTRAVENOUS USE ONLY—FATAL IF GIVEN BY OTH-
ER ROUTES.”
• Vinca alkaloids and bortezomib should never be given in the same treatment room as intrathecal medications. For patients receiving
antineoplastic medications by multiple routes, it is highly recommended that they either receive them in different practice areas or on
different days.
• Only healthcare providers who have received specialized educational programs should prescribe, prepare, transport, or administer
intrathecal chemotherapy.
• Different connectors should be used, whenever possible, for medicines to be administered via the intrathecal and other parenteral
routes.
• Institutions should establish a list of drugs that can and cannot be given intrathecally.
• Orders for intrathecal chemotherapy should be written on a separate form than IV chemotherapy. Consider using an intrathecal che-
motherapy order form.
• Intrathecal chemotherapy should be prepared and delivered as close as possible to the time of administration.
• Intrathecal chemotherapy should be packaged, transported, and stored in specifically designated containers separately from IV or
other drugs. Intrathecal drugs should be clearly labeled both on the syringe and outer container “For Intrathecal Use.”
• Intrathecal chemotherapy should not be stored in patient care areas.
• Conduct a time-out immediately preceding intrathecal chemotherapy administration, including a formal two-person checking proce-
dure by a chemotherapy-competent nurse and at least one other chemotherapy-trained healthcare professional. Document verifica-
tion of the right drug, dose, route, patient, and time.
Note. Based on information from Gilbar & Seger, 2012; Institute for Safe Medication Practices, 2006, 2012; Joint Commission, 2005; World Health Organi-
zation, 2007.
From “Preventing Intrathecal Chemotherapy Errors: One Institution’s Experience,” by L.H. Smith, 2009, Clinical Journal of Oncology Nursing, 13, p. 345.
doi:10.1188/09.CJON.344-346. Copyright 2009 by the Oncology Nursing Society. Adapted with permission.
method of monitoring work-related exposure exists. Therefore, it is imper-
ative that those who work with HDs adhere to practices designed to mini-
mize occupational exposure.
1. Definition: ASHP (1990) provided the first definition of HDs [a)–e)];
NIOSH (2004, 2010, 2012) subsequently refined the definition [f)]. Drugs
are considered hazardous if they demonstrate one or more of the follow-
ing characteristics in humans or animals.
a) Carcinogenicity
b) Teratogenicity or developmental toxicity
c) Reproductive toxicity
d) Organ toxicity at low doses
e) Genotoxicity
f) New drugs similar in structure or toxicity to drugs classified as haz-
ardous using the above criteria
2. Potential adverse health effects associated with occupational exposure:
Published evidence indicating the increased occurrence of cancer among
occupationally exposed nurses and other healthcare workers (Blair et
al., 2001; Gunnarsdottir, Aspelund, Karlsson, & Rafnsson, 1997; Hansen
& Olsen, 1994; Levin, Holly, & Seward, 1993; Martin, 2005) is limited
because of the failure to connect exposure to health outcomes. IARC
publishes independent assessments of the carcinogenic risks of chem-
icals and has identified 11 drugs and two combination chemotherapy
regimens used in cancer treatment as known human carcinogens. Oth-
er antineoplastic agents are classified as probable or possible carcino-
gens (see Table 12) (IARC, 2013).
a) Structural defects in a fetus because of occupational exposure dur-
ing pregnancy (Hemminki, Kyyronen, & Lindbohm, 1985; Peelen,
Roeleveld, Heederik, Kromhout, & de Kort, 1999)
b) Adverse reproductive outcomes, including miscarriage (Lawson et al.,
2012), infertility (Fransman, Roeleveld, et al., 2007; Martin, 2005),
preterm births, and learning disabilities in offspring of nurses ex-
posed to HDs during pregnancy (Martin, 2005)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
104 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Table 12. Antineoplastic Agents Classified as Carcinogens
Exposure Risk Agents
Group 1: Carcinogenic to humans • Arsenic trioxide
• Azathioprine
• Busulfan
• Chlorambucil
• Cyclophosphamide
• ECB (etoposide, cisplatin, and bleomycin)
• Etoposide
• Melphalan
• MOPP (mechlorethamine hydrochloride, vincristine,
procarbazine, and prednisone)
• Semustine
• Tamoxifen
• Thiotepa
• Treosulfan
Group 2A: Probably carcinogenic • Azacitidine
to humans • Carmustine
• Cisplatin
• Doxorubicin
• Lomustine
• Mechlorethamine hydrochloride
• Procarbazine
• Teniposide
Group 2B: Possibly carcinogenic to • Amsacrine
humans • Bleomycin
• Dacarbazine
• Daunorubicin
• Mitomycin
• Mitoxantrone
• Streptozocin
Note. Based on information from International Agency for Research on Cancer, 2013.
c) Chromosomal damage in healthcare workers following exposure to
HDs (Bouraoui et al., 2011; El-Ebiary, Abuelfadl, & Sarhan, 2013; Mc-
Diarmid, Oliver, Roth, Rogers, & Escalante, 2010; Yoshida, Kosaka,
Tomika, & Kumagai, 2006)
d) Acute symptoms such as hair loss, abdominal pain, fatigue, nausea,
nasal irritation or sores, contact dermatitis, allergic reactions, skin in-
jury, and eye injury (Baykal, Seren, & Sokmen, 2009; Constantinidis
et al., 2011)
3. Potential adverse health outcomes associated with occupational expo-
sure to biotherapy agents: Limited data are available regarding the ef-
fects of occupational exposure to biologic agents. It is unclear wheth-
er the criteria in the definition of HDs are adequate for protein-based
drugs (Halsen & Krämer, 2011).
a) Most biologic agents do not affect DNA and do not cause genetic
changes.
b) Antiangiogenic agents pose a risk to a fetus (e.g., thalidomide, le-
nalidomide) (Celgene Corp., 2012).
c) Several targeted agents meet one or more of the criteria in the NIOSH
definition of HDs and should be handled as hazardous (e.g., handled
with personal protective equipment [PPE] and not crushed). These
include dasatinib, imatinib mesylate, nilotinib, pazopanib hydro-
chloride, sorafenib, sunitinib malate, and vorinostat (NIOSH, 2012).
d) mAbs: Based on mechanism of action, some mAbs may cause devel-
opmental toxicity, including alemtuzumab, bevacizumab, cetuximab,
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 5. Nursing Considerations in Cancer Treatment 105
panitumumab, rituximab, and trastuzumab (Halsen & Krämer, 2011);
however, NIOSH does not classify these agents as HDs.
e) Conjugated mAbs are hazardous because of the attached radioactive
isotopes (e.g., tositumomab) or toxins (e.g., brentuximab vedotin).
f) Many drugs used for non-oncology indications meet one or more of
the criteria for HDs and should be handled as HDs. These include
immunosuppressant agents, antivirals, several anticonvulsants, estro-
gens, progestins, and androgens.
g) A list of HDs is found in NIOSH’s List of Antineoplastic and Other Haz-
ardous Drugs in Healthcare Settings 2012, with periodic updates on the
NIOSH website at www.cdc.gov/niosh/topics/hazdrug.
4. Routes of exposure
a) Absorption through skin or mucous membranes following direct
drug contact or contact with surfaces or objects that are contaminat-
ed with HDs
(1) Many studies reported measurable levels of cytotoxic agents in
the urine of healthcare workers (Connor et al., 2010; Fransman,
Peelen, et al., 2007; Sottani, Porro, Comelli, Imbriani, & Mi-
noia, 2010; Sugiura, Asano, Kinoshita, Tanimura, & Nabeshima,
2011; Yoshida et al., 2011), most likely from dermal absorption.
(2) Multiple studies have documented contamination of the envi-
ronment with HDs in drug preparation areas, drug administra-
tion areas, and patient care areas (Konate et al., 2011; Kopp,
Schierl, & Nowak, 2013; Matsumoto et al., 2010; Siderov, Kirsa,
& McLauchlan, 2010; Sottani et al., 2010; Sottani, Porro, Im-
briani, & Minoia, 2012; Sugiura et al., 2011; Touzin, Bussieres,
Langlois, & Lefebvre, 2009).
(3) Several researchers have reported drug contamination on the
outside of drug vials when delivered by the manufacturers (Con-
nor et al., 2005; Favier, Gilles, Ardiet, & Latour, 2003; Fischer,
Groebmair, Herwig, Pfaller, & Schierl, 2010; Touzin, Bussières,
Langlois, Lefebvre, & Gallant, 2008; Zock, Soefje, & Ricka-
baugh, 2011). Cyclophosphamide, 5-FU, ifosfamide, and plati-
num have all been detected on vial exteriors using various sam-
pling techniques. These findings indicate that nurses are at risk
for skin exposure if they do not wear PPE while handling un-
opened drug vials.
b) Injection from needlesticks or contaminated sharps (ASHP, 2006;
NIOSH, 2004)
c) Inhalation of drug aerosols, dust, or droplets (Harrison & Schultz,
2000; Kiffmeyer et al., 2002; Mason et al., 2005)
d) Ingestion of contaminated food, beverages, tobacco products, or oth-
er hand-to-mouth behavior (NIOSH, 2004)
5. Hierarchy of hazard controls aimed at reducing worker exposure (Con-
nor, 2006)
a) Eliminate the hazard: The best way to protect workers from a haz-
ardous exposure is to eliminate the hazard or substitute a less tox-
ic substance for the hazardous material, but this is not feasible with
drug therapy.
b) Engineering controls: These are machines or equipment used to iso-
late or contain the hazard to reduce worker exposure.
c) Administrative controls: This third level of protection includes safe
handling policies, procedures, work practices, and education and
training of those responsible for HD handling.
d) PPE: The final level of protection, consisting of protective equipment
and garments designed for worker protection from HDs, places the
primary responsibility for protection on the worker.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
106 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
6. Guidelines regarding PPE
a) Apparel
(1) Gloves: Wear two pairs of disposable gloves that are powder free
and have been tested for use with HDs. The FDA requires per-
meation testing for gloves to be labeled as appropriate for use
with chemotherapy. The ASTM International (2013) standard
involves permeation testing with chemotherapy drugs from sev-
eral chemical classes. Gloves must prevent HD permeation for
a minimum of 30 minutes. Results are printed on the glove box
or are available from the manufacturer. Several types of materi-
als, such as latex, neoprene, nitrile, and polyurethane, are used
to make chemotherapy gloves. Tested latex gloves provide pro-
tection but should be used with caution because of the poten-
tial for latex sensitivity. Inspect gloves for physical defects be-
fore use. Remove and discard gloves immediately after use, if
a tear, puncture, or drug contact occurs, or after 30 minutes
of wear (ASHP, 2006; NIOSH, 2004; Wallemacq et al., 2006).
Wearing double gloves and removing them carefully reduces
the opportunity for exposure (NIOSH, 2008). Remove outer
gloves first, turning them inside out to prevent the contaminat-
ed outer surfaces from touching the inner gloves. Remove the
inner gloves last after discarding all contaminated items and
PPE. Do not reuse gloves.
(2) Gowns: Wear a disposable, lint-free gown made of a low-perme-
ability fabric, such as polyethylene-coated materials (Connor,
2006). The gown should have a solid front, long sleeves, tight
cuffs, and back closure. The inner glove cuff is worn under the
gown cuff; the outer glove cuff extends over the gown cuff to
fully protect the skin. Discard the gown if it is knowingly con-
taminated, before leaving HD-handling areas, and when fin-
ished with HD handling. Gowns are meant for single use. Used
gowns should not be hung up or reapplied after removal. This
prevents transfer of drug contamination to the environment
and the worker’s clothing (NIOSH, 2008).
(3) Respirators: Wear a NIOSH-approved respirator (such as a non-
powered, air-purifying, particulate-filter respirator) when inha-
lation exposure is possible. Two examples are when adminis-
tering an aerosolized HD or cleaning an HD spill. Consult the
safety data sheet (SDS) for the respirator appropriate to the sit-
uation (NIOSH, 2005). Surgical masks do not provide respira-
tory protection from HD aerosols.
(4) Eye and face protection: Wear a face shield or a combination
of mask and face shield that provides splash protection when-
ever HD splashing is possible.
b) Situations requiring PPE: Wear PPE whenever HDs might be released
into the environment, such as in the following situations (NIOSH,
2004).
(1) Handling any HD vials, ampules, or packaging materials
(2) Introducing or withdrawing needles or dispensing pins from
HD vials
(3) Transferring drugs from HD vials to other containers using nee-
dles or dispensing pins and syringes
(4) Opening ampules of HDs
(5) Expelling air from an HD-filled syringe
(6) Administering HDs by any route
(7) Spiking IV bags containing HDs and changing IV tubing
(8) Priming IV tubing with HDs
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 5. Nursing Considerations in Cancer Treatment 107
(9) Handling HD leakage from tubing, syringe, and connection sites
(10) Discontinuing infusions of HDs
(11) Disposing of HDs and items contaminated by HDs
(12) Handling the body fluids of a patient who had received HDs
in the past 48 hours
(13) Cleaning HD spills
(14) Touching any surface that is potentially contaminated with HD
residue
7. Storage and labeling
a) In clinical areas
(1) Store chemotherapy drug containers in a designated location
that limits exposure of healthcare workers and provides appro-
priate storage conditions (e.g., temperature and light).
(2) Use a distinct label on all HD containers to indicate the hazard-
ous nature of the contents (OSHA, 1999).
(3) Have access to instructions (e.g., SDS) regarding what to do in
the event of accidental HD exposure.
(4) Check HD containers before taking them from the storage area
to ensure that the packaging is intact and to detect any leak-
age or breakage.
b) In the home (Polovich, 2011) (see Appendix 1)
(1) Keep HDs out of reach of children and pets.
(2) Store HDs in containers that provide protection from punc-
ture or breakage.
(3) Label HD containers to indicate the hazardous nature of their
contents.
(4) Provide instructions listing the procedure for handling a dam-
aged HD container.
(5) Store HDs in an area free of moisture and temperature extremes.
(6) Provide HD spill kits and instructions for their use.
(7) Give verbal and written instructions about handling and stor-
ing HDs and HD waste.
8. During compounding: Maintain sterile technique during the preparation
of parenteral drugs. USP (2008) issued standards for sterile products,
including HDs. The environment in which sterile HD preparation takes
place must meet all standards for ventilation, including air exchanges
per hour, particle counts, and negative pressure. For a full explanation
of the standards, refer to the USP document.
a) Chemotherapy drugs
(1) Prepare sterile cytotoxic drugs in a primary engineering control
(PEC) that protects parenteral doses from microbial contami-
nation and the environment from HD contamination (ASHP,
2006; NIOSH, 2004; USP, 2008). The two main types of PECs
are biologic safety cabinets (BSCs) and compounding aseptic
containment isolators (CACIs). A BSC has an open front, in-
ward airflow that creates an air barrier to prevent HD contam-
ination from escaping, and downward high-efficiency particu-
late air (HEPA)-filtered airflow to minimize bacterial contam-
ination of sterile preparations. A CACI is an enclosed cabinet
that does not allow air exchange with the environment except
through a HEPA filter, with attached sleeves and gloves through
which the operator performs drug manipulations. A PEC must
(a) Be located in an area that is physically separate from oth-
er preparation areas and be at negative pressure to an ad-
jacent ante area (USP, 2008)
(b) Eliminate exhaust through a HEPA filter and ideally be vent-
ed to the outside (ASHP, 2006; NIOSH, 2004; USP, 2008)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
108 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
(c) Be used by individuals trained to employ techniques that
reduce contamination
(d) Be decontaminated at the end of drug preparation or im-
mediately if a spill occurs
(e) Be serviced according to the manufacturer’s recommen-
dations
(f) Be recertified after relocation, repair, filter replacement,
and/or every six months (National Sanitation Foundation,
2007; OSHA, 1999).
(g) The exhaust fan of a BSC should operate continuously ex-
cept when the BSC is being repaired or moved. After the fan
has been off, the BSC should be decontaminated before use.
(2) When preparing unsterile HDs, such as oral drugs that require
compounding or crushing, an isolator intended for contain-
ment may be used (NIOSH, 2004). Decontaminate the PEC
following use.
(3) Wash hands before donning PPE.
(4) Wear chemotherapy-designated PPE.
(5) If desired, place a sterile, plastic-backed absorbent pad on the
work surface.
(6) Limit items placed in the PEC to avoid interfering with airflow
(ASHP, 2006).
(7) Use safe technique when opening ampules (ASHP, 2006).
(a) Clear fluid from the ampule neck.
(b) Tilt the ampule away from yourself.
(c) Wrap gauze or an alcohol pad around the neck of the ampule.
(d) Break the ampule in the direction away from yourself.
(e) Use a filtered needle to withdraw fluid.
(8) When reconstituting drugs from vials, avoid pressure buildup,
which can result in the release of drug aerosols. Use a closed-
system transfer device (CSTD) if available (NIOSH, 2004). Ac-
cording to NIOSH (2004), a CSTD is “a drug transfer device
that mechanically prohibits the transfer of environmental con-
taminants into the system and the escape of hazardous drug or
vapor concentrations outside the system” (p. 44). CSTDs are
supplemental engineering controls and do not eliminate the
need for a PEC or PPE (NIOSH, 2004).
(9) Use tubing and syringes with Luer-lock fittings.
(10) Avoid overfilling syringes. An overfilled syringe may separate
from the plunger end (OSHA, 1999).
(11) Spike IV bags and prime tubing with compatible fluid before
adding cytotoxic drugs (ASHP, 2006; OSHA, 1999) or use a
CSTD to minimize leakage and exposure (Harrison, Peters, &
Bing, 2006; Sessink, Connor, Jorgenson, & Tyler, 2011; Siderov
et al., 2010; Yoshida et al., 2009). Glass IV bottles are discour-
aged for HDs because of the need for venting and the potential
for breakage, both of which can result in exposure.
(12) Place a label on each HD container that says “Cytotoxic Drug”
or a similar distinct warning.
(13) Wipe the outside of the HD container (e.g., syringe or IV bag)
with moist gauze before placing it in a sealable bag for trans-
port. Avoid transferring HD contaminants to the outside of the
transport bag.
(14) Dispose of all material that has come into contact with an HD
in a waste container designated for cytotoxic waste.
(15) Remove and discard outer gloves and gown. Then remove in-
ner gloves.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 5. Nursing Considerations in Cancer Treatment 109
(16) Wash hands with soap and water before touching anything or
leaving the work area.
b) Biotherapy drugs
(1) Use safe handling precautions (e.g., PEC and PPE) for bio-
therapy agents that are considered hazardous (NIOSH, 2004).
(2) A nuclear pharmacist prepares radiolabeled mAbs for infusion.
Note: Federal and state laws require that radiation safety warn-
ing signs designate the areas in which radioisotopes are stored
or used (Iwamoto, Haas, & Gosselin, 2012).
9. Transporting HDs (OSHA, 1999)
a) Transport syringes containing HDs in a sealed container with the Lu-
er-lock end of the syringe capped. Do not transport syringes with at-
tached needles.
b) Select a transport receptacle that can contain HD spillage if dropped
(e.g., a leakproof, zipper-lock bag), and add impervious packing ma-
terial as necessary to avoid damage during transport.
c) Label the outermost HD receptacle with a distinct label to indicate
that its contents are hazardous.
d) Ensure that whoever transports HDs has access to a spill kit and is
trained in HD spill cleanup.
10. Safe handling precautions during administration (ASHP, 2006; OSHA,
1999; Polovich, 2011)
a) Always wear chemotherapy-designated PPE.
b) Work below eye level.
c) Ensure that a spill kit and chemotherapy waste container are available.
d) Use a CSTD or place a disposable, absorbent, plastic-backed pad on
the work area to absorb droplets of the drug that may spill.
e) Use a CSTD or place a gauze pad under the syringe at injection ports
to catch droplets during administration.
f) Use a CSTD or needles, syringes, and tubing with Luer-lock con-
nectors.
g) If priming occurs at the administration site, prime IV tubing with
a fluid that does not contain the HD or by using the backflow
method.
h) After drug administration, remove the IV container with the tubing
attached (NIOSH, 2004; Polovich, 2011). Do not remove the spike
from IV containers or reuse tubing.
i) Use detergent and water or cleansing wipes to clean surfaces that
come into contact with HDs (Polovich, 2011).
j) Discard all HD-contaminated material and PPE in a designated che-
motherapy waste container.
11. Special precautions for RIT: Special precautions are necessary to pro-
tect healthcare workers from exposure while caring for patients receiving
RIT. Radiation protection standards and regulations are determined by
the U.S. Nuclear Regulatory Commission (NRC), the FDA (radiophar-
maceuticals), and state radiation regulatory agencies.
a) Occupational radiation exposure should be kept as low as reasonably
achievable. This requires close collaboration between the healthcare
team and the radiation safety officer (RSO). Three factors help pro-
vide protection (Iwamoto et al., 2012).
(1) Time: Limit the amount of time spent near the radioactive source.
Radiation exposure is directly proportional to the amount of
time spent near the source. After a patient receives RIT, the pa-
tient is considered the radioactive source.
(2) Distance: Maximize the amount of space between personnel and
the radioactive source. Radiation exposure decreases as the dis-
tance from the radioactive source increases.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
110 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
(3) Shielding: Add a protective barrier between the radioactive
source and personnel. The type of shielding used depends on
the type of radiation.
b) Radiation monitoring devices are used to measure occupational ex-
posure.
(1) Monitoring of personnel: Personnel monitoring is required by
law whether a patient is treated as an inpatient or outpatient.
A film badge is the most widely used monitoring device. Each
person caring for a patient receiving radiation therapy should
be assigned a film badge that is only worn within the work envi-
ronment, is changed according to institutional guidelines, and
is not shared with anyone else (Iwamoto et al., 2012). A dosim-
eter is another kind of radiation monitoring device. It can be a
personal device or one that is shared after being reset.
(2) Monitoring of the environment: Environmental monitoring is
done with a survey meter that reacts to the presence of ioniz-
ing particles. After a course of inpatient RIT is completed and
before the room is cleaned, the RSO surveys the room, linens,
and trash.
12. Handling a patient’s body fluids
a) After chemotherapy
(1) Wear double chemotherapy-tested gloves and a disposable
gown when handling the blood, emesis, or excreta of a patient
for at least 48 hours after the patient has received chemother-
apy. Wear a face shield if splashing is possible (NIOSH, 2004).
(2) For an incontinent patient, clean the patient’s skin well with
each diaper change. Apply a protective barrier ointment to the
skin of the patient’s diaper area to decrease the chance of skin
irritation from contact with drug metabolites (Polovich, 2011).
(3) Flush the toilet with the lid down after disposing of excreta from
a patient who has received HDs within the past 48 hours. When
a lid is not present, consider covering the open toilet with a plas-
tic-backed pad to prevent splashing while flushing. Although
there is no research to support the effectiveness of double flush-
ing in reducing contamination, it has been suggested in the past
(Brown et al., 2001; Welch & Silveira, 1997) and may be helpful
with low-volume-per-flush toilets (Polovich, 2011).
b) After RIT (Iwamoto et al., 2012)
(1) Institute standard precautions as previously described when
handling the patient’s body fluids (e.g., sweat, saliva, urine, fe-
ces, blood, semen, vaginal fluid). The duration of precautions
varies depending on the radionuclide’s half-life.
(2) Consult the RSO or nuclear pharmacist for precautions based
on the specific radioisotope.
13. Handling a patient’s linens
a) After chemotherapy (Polovich, 2011)
(1) To the extent possible, preclude the need for laundering lin-
ens and clothing by using disposable linens or leakproof pads
to contain HD-contaminated body fluids.
(2) If body fluids are present, use standard precautions when han-
dling the linens of a patient who had received chemotherapy
within 48 hours.
(3) Handle HD-contaminated bed linens and clothing as follows.
(a) In the hospital setting
i. Handle linens with PPE and place into a leakproof bag.
ii. In most institutions, all linens are handled as contam-
inated by laundry personnel before washing.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 5. Nursing Considerations in Cancer Treatment 111
(b) In the home setting (Polovich, 2011) (see Appendix 1)
i. Wearing gloves, place contaminated linens into a wash-
able pillowcase, separate from other items.
ii. Machine wash linens and cloth diapers twice in hot
water, with regular detergent, separately from other
household items.
iii. Discard disposable diapers in plastic bags to prevent
leakage.
iv. Discard used gloves in a chemotherapy waste contain-
er if available.
b) After RIT (Iwamoto et al., 2012)
(1) If body fluids are present, use standard precautions when han-
dling the linens of a patient who has received RIT.
(2) Keep linens in the hospital room until surveyed and cleared by
the RSO or nuclear pharmacist.
14. Disposal of HDs and materials contaminated with HDs
a) In the hospital setting (NIOSH, 2004)
(1) Place soft contaminated materials into a sealable, leakproof bag
or a rigid chemotherapy waste container marked with a brightly
colored label that indicates the hazardous nature of the contents.
(2) Use puncture-proof containers for sharp or breakable items.
Dispose of needles and syringes intact; do not break or recap
needles or crush syringes.
(3) Seal containers when full.
(4) Do not dispose of drug-contaminated items in infectious waste
(red) containers. Some facilities autoclave or microwave these
materials (NIOSH, 2004; Smith, 2002), which does not deac-
tivate HDs.
(5) Follow institutional policy regarding disposal of partial doses
of HDs when administration is interrupted.
(6) Only housekeeping personnel who have received instruction in
safe handling procedures should handle chemotherapy waste
containers. These personnel should wear gowns with cuffs and
a back closure and two pairs of disposable chemical-protective
gloves.
b) In the home setting (Polovich, 2011) (see Appendix 1)
(1) Some agencies that provide HDs arrange for proper disposal
of contaminated equipment.
(2) Follow all the instructions applicable to the hospital setting
except those related to handling the filled waste container (if
provided).
(3) Designate an area away from children and pets where filled con-
tainers are placed for pickup.
(4) Follow county and state regulations regarding the disposal of
chemotherapy wastes.
15. Procedures following acute HD exposure: Accidents, improper tech-
nique, faulty equipment, or negligence in PEC operation can lead to
exposure (OSHA, 1999).
a) Initial interventions
(1) In the event of skin exposure: Remove any contaminated gar-
ments and immediately wash contaminated skin with soap and
water. Refer to the SDS for agent-specific interventions.
(2) In case of eye exposure: Immediately flush the eye with saline
solution or water for at least 15 minutes (OSHA, 1999), then
seek emergency treatment. Ideally, each area where HDs are
handled should contain an eyewash station. An acceptable al-
ternative is a sterile saline IV container connected to IV tubing.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
112 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
(3) In the event of inhalation exposure, move away from the area
of exposure as quickly as possible. Depending on the severity of
symptoms, seek emergency treatment from an employee health
professional or emergency department. Refer to the SDS for
agent-specific interventions.
(4) For accidental ingestion, do not induce vomiting unless indi-
cated in the SDS. Depending on the severity of symptoms, seek
emergency treatment from an employee health professional or
emergency department. Refer to the SDS for agent-specific in-
terventions.
b) Reporting (Polovich, 2011)
(1) In case of employee exposure: Report HD exposure to the em-
ployee health department or as institutional policy requires.
(2) In case of patient exposure: Report the exposure as institution-
al policy requires. In addition, inform the patient’s healthcare
providers.
16. Spill management
a) Radioactive spills: In case of a spill of radiolabeled antibody or con-
tamination with the radioactive body fluid of a patient recently treat-
ed with RIT (Iwamoto et al., 2012)
(1) Restrict access to the area and contact the RSO immediate-
ly. Never try to clean the area or touch the radioactive source.
Adhere to the principles of time, distance, and shielding (dis-
cussed previously in paragraph 11).
(2) Follow other applicable NRC guidelines.
b) HD spills: Consider any leak of HDs that is greater than a few drops a
spill. Spill kits must be available wherever HDs are stored, transport-
ed, prepared, or administered (see Figure 12). Train everyone who
works with HDs in spill cleanup. Individuals trained in handling haz-
ardous materials (such as a Hazardous Materials Response Team)
should clean up large spills whenever possible (OSHA, 2004b). In
case of a spill involving an HD, follow these procedures.
(1) Assess the spill to determine the need for additional help with
cleanup.
(2) Immediately post signs warning others of the hazardous spill to
prevent them from exposure.
(3) Don two pairs of chemotherapy-designated gloves, a disposable
gown, and a face shield.
(4) Wear a NIOSH-approved respirator (OSHA, 2004c).
(5) Use appropriate items in the spill kit to contain the spill, such
as absorbent pads, cloths, or spill control pillows.
Figure 12. Contents of an Antineoplastic Spill Kit
• Two pairs of disposable chemical-protective gloves (optional: a pair of utility gloves)
• Low-permeability, disposable protective garments (coveralls or gown and shoe covers)
• Face shield
• Respirator
• Absorbent, plastic-backed sheets or spill pads
• Disposable towels (3–4)
• At least two sealable thick plastic hazardous waste disposal bags with an appropriate warn-
ing label
• A disposable scoop for collecting glass fragments and sharps
• A puncture-resistant container for glass fragments
Note. Based on information from American Society of Health-System Pharmacists, 2006.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 5. Nursing Considerations in Cancer Treatment 113
(6) Clean up the spill according to its location and type. Access the
SDS for the spilled agent to determine if any inactivators are
recommended (Gonzalez & Massoomi, 2010).
(a) To clean up a spill on a hard surface (ASHP, 2006)
i. Wipe up liquids using absorbent pads or spill con-
trol pillows. Wipe up solids using wet absorbent pads.
ii. Pick up glass fragments using a small scoop or utili-
ty gloves worn over chemotherapy gloves. Do not use
hands to pick up sharps. Place all sharps in a punc-
ture-proof container.
iii. Place puncture-proof container and contaminated ma-
terials into a leakproof waste bag. Seal the bag. Place
the sealed bag inside another bag, appropriately la-
beled as chemotherapy waste. For the moment, leave
the outer bag open.
iv. Clean the spill area thoroughly, from least contaminat-
ed to most contaminated areas, using detergent and
sodium hypochlorite solution (bleach) if appropri-
ate, based on the surface. If using bleach, allow con-
tact with the surface for at least 30 seconds and fol-
low with a neutralizer (e.g., 1% sodium thiosulfate).
Rinse twice with clean water.
v. Use fresh detergent solution to wash any reusable
items used to clean up the spill and items located in Chemotherapy Spill Cleanup
the spill area. Use water to rinse the washed items. Re- Video
peat the washing and rinsing.
vi. Remove PPE and place disposable items in the un- To view videos download
sealed chemotherapy waste disposal bag. ChemoBio4thInteractive.pdf
vii. Seal the outer disposal bag and place it in a puncture-
proof chemotherapy waste container.
viii. Follow institutional or manufacturer’s guidelines re-
garding cleaning or maintenance of equipment (e.g.,
an IV pump).
ix. Dispose of all material used in the cleanup process ac-
cording to institutional policy and federal, state, and
local laws (OSHA, 1999).
(b) To clean up a spill on a carpeted surface (note that carpet is
not recommended in HD administration areas) (ASHP, 2006)
i. Don PPE, including a NIOSH-approved respirator.
ii. Use absorbent powder, not absorbent towels, to ab-
sorb the spill.
iii. Use a small vacuum with a HEPA filter (Gonzalez &
Massoomi, 2010), reserved for HD cleanup only, to
remove the powder. Dispose of the collection bag as
chemotherapy waste. Clean the outside of the vacu-
um before storing.
iv. Clean the carpet as usual.
v. Follow guidelines for a spill on a hard surface to clean
and dispose of other contaminated items.
(c) To clean up a spill in a BSC or CACI (ASHP, 2006; OSHA,
1999)
i. Clean the spill according to the guidelines for a spill
on a hard surface. Complete cleanup by rinsing the
surface with sterile saline for irrigation.
ii. Include the drain spillage trough in washing efforts.
iii. If the spill contaminated the HEPA filter: Seal the
open front of a BSC in plastic. Label any type of PEC
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
114 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
as contaminated equipment. Schedule a PEC service
technician to change the HEPA filter. Ensure that the
PEC is not used before the filter is changed.
(d) To clean up a spill in the home setting: See Figure 13.
(7) Report and document the spill according to institutional pol-
icy: For any spill greater than a few drops, complete a report
about the spill and forward it to those specified by institution-
al policy (ASHP, 2006). Document the following.
(a) Name of the drug
(b) Approximate volume of spill
(c) How the spill occurred
(d) Spill management procedures followed
(e) The names of personnel, patients, and others exposed to
the spill
(f) A list of personnel notified of the spill
17. Requirements for policies regarding the handling of HDs: OSHA (2004a)
requires that employers provide a safe or healthful workplace. Employ-
ers must implement policies and procedures related to the safe handling
of HDs. Policies should address all aspects of handling these hazardous
chemicals to protect employees, patients, customers, and the environ-
ment from contamination. Such policies must (NIOSH, 2004)
a) Outline procedures to ensure the safe storage, transport, administra-
tion, and disposal of hazardous agents
b) Describe the procedure for identifying and updating the list of HDs
used in the facility
c) Require that all employees who handle HDs wear PPE
d) Mandate that HDs be prepared in a BSC, CACI, or containment iso-
lator (USP, 2008)
Figure 13. Spill Kit Procedure for Home Use
(Please review this procedure with your nurse.)
1. Do not touch the spill with unprotected hands.
2. Open the spill kit and put on both pairs of gloves. If the bag or syringe with chemotherapy drugs has been broken or is leaking and
you have a catheter or implanted port in place, before cleaning the spill, disconnect the catheter from the tubing and flush and cap
it.
3. Put on the gown (closes in back), face shield, and respirator.
4. Use spill pillows to contain spill—put around puddle to form a “V.”
5. Use the absorbent sheets to blot up as much of the drug as possible.
6. Put contaminated clean-up materials directly into the plastic bag contained in the kit. Do not lay them on unprotected surfaces.
7. Use the scoop and brush to collect any broken glass, sweeping toward the V’d spill pillows, and dispose of the glass in the box of
the kit.
8. While still wearing the protective gear, wash the area with dishwashing or laundry detergent and warm water, using disposable rags
or paper towels, and put them in the plastic bag with other waste. Rinse the area with clean water and dispose of the towels in the
same plastic bag.
9. Remove gloves, face shield, respirator, and gown and place them in the plastic bag. Put all contaminated materials, including the
spill kit box, into the second large plastic bag, and seal and label the bag with the hazardous waste label in the kit.
10. Wash your hands with soap and water.
11. Call the home health nurse, clinic, or doctor’s office promptly to report the spill. Plans need to be made to replace the spilled chemo-
therapy so that treatment can be completed. Arrangements will be made to have the waste material picked up or have you bring it to
the hospital for proper disposal.
12. If the spill occurs on sheets or clothing, wash the items in hot water, separate from other laundry. Wash clothing or bed linen con-
taminated with body wastes in the same manner.
13. Patients on 24-hour infusions should use a plastic-backed mattress pad to protect the mattress from contamination.
Following these procedures prevents undue exposure and ensures your safety. Call your nurse if you have any questions. Thank you.
Note. Based on information from National Institute for Occupational Safety and Health, 2004.
From “Home Chemotherapy Safety Procedures,” by C. Blecker, 1989, Oncology Nursing Forum, 16, p. 721. Copyright 1989 by the Oncology Nursing Soci-
ety. Adapted with permission.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 5. Nursing Considerations in Cancer Treatment 115
e) Prohibit staff from eating, drinking, smoking, chewing gum, using to-
bacco, storing food, and applying cosmetics in areas where HDs are
prepared or administered
f) Mandate training for all employees who prepare, transport, or ad-
minister HDs or care for patients receiving these drugs. This train-
ing must include the risks of exposure and appropriate procedures
for minimizing exposure. The policy should describe how training is
documented (OSHA, 2012).
g) Require that documents such as SDSs are available to healthcare work-
ers who handle HDs
h) State that spills should be managed according to the institution’s HD
spill policy and procedure
i) Set forth a plan for medical surveillance of personnel handling HDs
j) Address HD handling around pregnant workers. Even when recom-
mended precautions are used, the potential for accidental expo-
sure cannot be eliminated (Connor et al., 2010; Schierl, Böhlandt,
& Nowak, 2009; Siderov et al., 2010; Turci et al., 2011). Developing
fetuses and newborn infants may be more susceptible to harm from
certain HDs. Therefore, an additional level of protection is suggest-
ed for those most vulnerable to the reproductive and developmental
effects of HDs. Employers must allow employees who are actively try-
ing to conceive or are pregnant or breast-feeding to refrain from ac-
tivities that may expose them and their fetus to reproductive health
hazards such as chemical, physical, or biologic agents. Alternate duty
that does not include HD preparation or administration must be
made available upon request to both men and women in the afore-
mentioned situations or who have other medical reasons for avoid-
ing exposure to HDs. The employee has the responsibility of notify-
ing the employer of the specific situation (e.g., pregnancy, precon-
ception, breast-feeding). The American College of Occupational and
Environmental Medicine (2011) provides guidelines for reproduc-
tive hazard management.
k) Define quality improvement programs that monitor compliance with
safe handling policies and procedures.
References
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Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 6
Administration
Considerations
A. Routes of administration
1. Oral: The use of oral antineoplastic agents is more common than in the past
and is likely to double in the next several years (Moody & Jackowski, 2010).
a) Advantages
(1) Convenience of home treatment
(2) Decreased time spent in outpatient or inpatient oncology de-
partments
(3) Increased sense of control and independence for the patient
b) Disadvantages
(1) Can be expensive and may result in reimbursement- and insur-
ance-related issues
(2) Patient difficulty in adhering to treatment regimen due to
(a) Difficulty swallowing medication
(b) Complex dosing and schedules
(3) Inconsistent absorption of agents
c) Potential complications
(1) Food-drug interactions (e.g., grapefruit juice can interfere with
a liver isoenzyme needed to metabolize medications) (Good-
in, 2007)
(2) Drug-drug interactions resulting in excess toxicity or decreased
efficacy
(3) Incorrect dosing
(4) Patients continuing medications beyond the planned dura-
tion of treatment or despite side effects that necessitate hold-
ing treatment
d) Nursing implications (Moody & Jackowski, 2010)
(1) Verify the accurate dosing of oral anticancer therapy using the
same process as for IV chemotherapy.
(2) Wear PPE when administering hazardous oral agents.
(3) Do not crush hazardous oral agents outside of a BSC or oth-
er containment device. If a patient has difficulty swallowing or
has a feeding tube, ask the pharmacist to provide the drug in a
ready-to-administer form.
(4) Set up a schedule to monitor patients’ response to therapy, in-
cluding follow-up laboratory testing and office visits.
e) Patient education for self-administration of oral therapy
(1) Provide verbal and written information about the drug(s), dose,
schedule, storage, and safe handling.
(2) Explain the scheduled days and times the medication should
be taken and dates of office visits and laboratory tests. A calen-
dar is a useful tool for some patients.
(3) Emphasize side effects that should be reported immediately to
healthcare providers and any that require holding treatment. 121
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
122 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
(4) Establish a process to evaluate patient adherence to therapy, in-
cluding correct dose and schedule. For example,
(a) Make a scheduled phone call with the patient three to five
days after initiation of medication to assess compliance.
(b) Instruct the patient and family members to bring the med-
ication schedule, calendar, and any other tool developed
to all follow-up appointments.
2. Subcutaneous: SC injection allows agents to be administered into the
SC tissue by piercing the epidermal and dermal layers of skin (Joanna
Briggs Institute, 2012).
a) Advantages
(1) Ease of administration
(2) Well tolerated
(3) Decreased side effects for some agents
b) Disadvantages
(1) Inconsistent absorption
(2) Patients with decreased adipose tissue have increased risk of
drug misplacement.
c) Potential complications
(1) Pain at injection site
(2) Infection
(3) Bleeding/bruising
d) Nursing implications
(1) Wear PPE.
(2) Most common site for SC injection is the abdomen; however,
avoid the umbilicus and scars.
(3) Monitor platelet count.
(4) Use the smallest needle possible. Some medications are in pre-
packaged syringes; follow manufacturer’s instructions.
(5) Rotate injection sites if multiple injections are needed.
3. Intramuscular (IM): IM injections are used to administer medication
deep into the muscle. The ventrogluteal muscle (anterior gluteal site)
is considered the thickest gluteal muscle, and use of this site has fewer
complications (Joanna Briggs Institute, 2012).
a) Advantage: Rapid absorption of medication
b) Disadvantages and potential complications
(1) Pain
(2) Infection
(3) Peripheral nerve damage/neuropathy
(4) Hematoma
(5) Tissue necrosis
(6) Permanent damage to sciatic nerve
c) Nursing implications (Joanna Briggs Institute, 2012)
(1) Wear PPE.
(2) Use the proper size needle to ensure that medication is delivered
into the muscle and not SC tissue, especially with obese patients.
(3) Choose appropriate site.
(4) Insert at 90° angle and pull back on syringe to ensure injection
is not near a blood vessel.
(5) Avoid massaging the site.
4. Intraperitoneal (IP): IP chemotherapy can be used to treat ovarian can-
cer, as well as other cancers that cause peritoneal seeding such as low-
grade gastrointestinal (GI) and appendiceal carcinomas (Marin, Olesze-
wski, & Muehlbauer, 2007). Combining IP chemotherapy with IV ther-
apy may offer a survival benefit over IV therapy alone in select patients
with ovarian cancer (Potter & Held-Warmkessel, 2008). IP chemothera-
py may be administered using a catheter or implanted IP port.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 6. Administration Considerations 123
a) Advantages (Potter & Held-Warmkessel, 2008)
(1) Chemotherapy agents are delivered directly into the peritone-
al cavity, providing higher concentrations of drug to the tumor.
(2) Systemic absorption by diffusion causes prolonged exposure
to the tumor via capillary flow. Lower doses can potentially be
used, decreasing the systemic side effects and allowing for cy-
clic treatment over time.
(3) IP access devices can be used to remove excess fluid from the
peritoneal cavity, and family members can be taught how to do
this if needed (Camp-Sorrell, 2011).
b) Disadvantages (Potter & Held-Warmkessel, 2008)
(1) Only select patients with minimal disease are candidates for
IP therapy.
(2) Patients require a surgical procedure to place the peritoneal
catheter or IP port.
(3) Potential exists for catheter-related infection or complications
such as bowel obstruction, abdominal pain, or peritonitis.
(4) Frequent postural changes are required following infusion,
which may be difficult for patients with comorbid conditions
such as arthritis, musculoskeletal disorders, or previous surgeries.
c) Potential side effects (Almadrones, 2007; Camp-Sorrell, 2011)
(1) Abdominal pressure and distention related to large amounts of
fluids placed into the peritoneal space
(2) Increased bladder irritation due to abdominal fullness, which
results in increased urinary frequency
(3) Severe nausea and vomiting
(4) Decreased appetite related to the large fluid volume
(5) Dyspnea secondary to abdominal distention
(6) Bleeding
(7) Diarrhea
(8) Ileus
(9) Infection
(10) Intestinal perforation
(11) Anaphylaxis
d) Nursing implications
(1) Utilize PPE.
(2) Place the patient in semi-Fowler position (Camp-Sorrell, 2011;
Hydzik, 2007).
(3) Access the peritoneal port with a 19-gauge noncoring right-
angle needle. Depending on the patient’s size, use a needle
length of 1–1.5 inches (Hydzik, 2007).
(4) Flush the port according to institutional policy and procedure.
(5) Evidence is lacking to support the warming of IP fluid; therefore,
IP solution can be administered at room temperature (Camp-
Sorrell, 2011; Hydzik, 2007). However, if the patient reports be-
ing cold, provide warm blankets (Hydzik, 2007).
(6) Rotate the patient side to side every 15 minutes for one hour
after infusion (Hydzik, 2007).
(7) Drain fluid from the peritoneal cavity following dwell time, if
ordered.
5. Intrathecal: IT chemotherapy is used for patients with central nervous
system malignancies, including primary brain tumors, metastasis to the
brain or leptomeninges from solid tumors, lymphoma, and leukemia
(Aiello-Laws & Rutledge, 2008).
a) IT route delivers chemotherapy directly into the cerebrospinal fluid.
b) Cerebrospinal fluid can be accessed by a surgically implanted ventric-
ular reservoir (e.g., Ommaya) or by lumbar puncture.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
124 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
c) The most commonly used IT agents are methotrexate and cytarabine
(Aiello-Laws & Rutledge, 2008). Note: Vinca alkaloids, such as vincris-
tine, are lethal if administered via the IT route and should never be
given IT because of severe neurologic toxicity, including coma and
death (Schulmeister, 2006). The majority of chemotherapy agents do
not have IT indications.
d) Advantages
(1) Direct and consistent drug levels in the cerebrospinal fluid
(2) Ability to access the cerebrospinal fluid for testing as well as to
administer opiates and other medications
e) Disadvantages
(1) Requires surgical procedure to place intraventricular device
(2) Lumbar puncture is an invasive procedure.
(3) Requires a physician or specialty-trained RN to administer che-
motherapy.
f) Potential side effects
(1) Increased intracranial pressure
(2) Headaches
(3) Confusion
(4) Lethargy
(5) Nausea and vomiting
(6) Seizures
(7) Infection
g) Nursing implications
(1) Utilize PPE.
(2) Ensure that only preservative-free solutions are used for IT che-
motherapy (Camp-Sorrell, 2011).
(3) IT chemotherapy must be labeled “For Intrathecal Use Only.”
Wraps or packages should be removed immediately prior to ad-
ministration by the person administering the medication (Aiello-
Laws & Rutledge, 2008).
(4) Perform a “time-out” or other procedure designed to verify that
IT is the intended route for the medication.
(5) Monitor the patient for the potential complications listed pre-
viously.
6. Intrapleural: Intrapleural chemotherapy is used to treat malignant pleu-
ral effusions, which can be caused by mesothelioma, other solid tumors,
and hematologic disorders that metastasize to the pleura (Polovich, 2011;
Shuey & Payne, 2005). Other treatments include repeated thoracente-
sis, pleurodesis with sclerosing agent, insertion of pleural catheter, surgi-
cal procedures, radiation, and systemic chemotherapy (Shuey & Payne,
2005; Walker & Bryden, 2010).
a) Advantages
(1) May prevent recurrence of malignant pleural effusions
(2) Multiple agents can be used as sclerosing agents, such as chemo-
therapy agents, antibiotics, talc, and biotherapy agents (Shuey
& Payne, 2005).
b) Disadvantages
(1) Requires insertion of a thoracotomy tube
(2) Must be performed by a physician
c) Potential side effects
(1) Pain
(2) Infection
(3) Pneumothorax
d) Nursing implications
(1) Utilize PPE.
(2) Maintain aseptic technique.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 6. Administration Considerations 125
(3) Position the patient in a sitting position, leaning forward over
a sturdy locked tray table with a pillow as a headrest (Shuey &
Payne, 2005).
(4) The effusion fluid must be completely drained from the pleu-
ral cavity before instillation of the agent.
(5) Allow the agent to remain for the prescribed dwell time if ap-
plicable. If fluid is drained, handle as contaminated fluid (Po-
lovich, 2011).
(6) Observe for signs and symptoms of respiratory distress.
7. Intravesicular: Intravesicular chemotherapy is used to treat urinary blad-
der cancer (Washburn, 2007). The standard treatment for nonmuscle in-
vasive bladder cancer is transurethral resection followed by intravesical
chemotherapy using bacillus Calmette-Guérin, thiotepa, mitomycin C,
or gemcitabine (Shelley et al., 2012). The urinary bladder is a perfect or-
gan for regional therapy (Shen, Shen, Wientjes, O’Donnell, & Au, 2008).
a) Advantages
(1) Delivery of chemotherapy agents directly into the bladder to
eliminate residual disease and prevent recurrence
(2) Avoids side effects of systemic chemotherapy
b) Disadvantage: Requires bladder catheter insertion
c) Potential side effects
(1) Urinary tract infection
(2) Cystitis
(3) Bladder contracture
(4) Urinary urgency
(5) Extravasation with vesicant administration
d) Nursing implications
(1) Utilize PPE including face shield (Washburn, 2007).
(2) Maintain sterile technique during catheter insertion.
(3) Monitor for signs of extravasation, especially pain (Washburn,
2007). If the patient has uncontrolled pain following use of a
vesicant agent, suspect extravasation. Drain the agent and urine,
and notify physician immediately.
(4) Follow physician orders or protocol for schedule and position-
ing of the patient and drainage of agent after instillation.
8. Intra-arterial: Intra-arterial infusion allows chemotherapy to be delivered
in higher concentrations directly into a tumor site (Matthews, Snell, &
Coats, 2006). According to Camp-Sorrell (2011), several agents can be
delivered via the intra-arterial route: cisplatin, doxorubicin, 5-FU, flox-
uridine, irinotecan, mitomycin, oxaliplatin, paclitaxel, protein-bound
paclitaxel, tumor necrosis factor, and vinblastine.
a) Common sites (Camp-Sorrell, 2011)
(1) Liver
(2) Head and neck
(3) Bone
b) The three types of arterial access devices are short-term catheters, im-
planted arterial ports, and implanted arterial pumps (Camp-Sorrell,
2011).
(1) Short-term catheters: A nontunneled percutaneous arterial
catheter is placed during an angiographic procedure. This is
usually done in an interventional radiology department under
local anesthesia (Barber & Fabugais-Nazario, 2003). The most
common sites for insertion are the femoral and brachial artery
(Camp-Sorrell, 2011).
(2) Implanted arterial ports: These are similar to venous ports, with
the catheter surgically implanted into an artery. They are accessed
when needed, using a noncoring needle (Camp-Sorrell, 2011).
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
126 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
(3) Implanted arterial pumps: These are intended for long-term
use. The infusion rate of the pumps can be programmable or
set by the manufacturer (Camp-Sorrell, 2011).
c) Advantages (Camp-Sorrell, 2011)
(1) Higher exposure of the tumor site to the chemotherapy agent,
potentially resulting in greater tumor response and decreased
systemic side effects
(2) Avoidance of extensive surgical procedures and potential com-
plications related to surgery (e.g., liver resection)
(3) Patients with liver metastasis may be surgical candidates after
treatment with intra-arterial chemotherapy.
d) Disadvantages
(1) Requires an invasive procedure performed by physician
(2) Requires specialized nursing care and education
(3) Not all patients are candidates for intra-arterial chemotherapy.
e) Potential side effects (Camp-Sorrell, 2011)
(1) Infection
(2) Catheter migration or dislodgment
(3) Occlusion and thrombosis
(4) Bleeding at catheter insertion site
(5) Device failure
f) Nursing implications
(1) Obtain specialized training to assess and monitor arterial cath-
eters.
(2) Immediately following intra-arterial catheter insertion, assess
the involved limb for peripheral pulses, color, temperature,
numbness and tingling, and bleeding (Camp-Sorrell, 2011).
(3) Utilize PPE.
(4) Monitor for occlusions.
(5) Review and understand the different types of devices.
(6) Review and understand the flushing and dressing change pro-
tocols per institutional policy.
(7) Avoid using arterial access devices for routine blood sampling
(Camp-Sorrell, 2011).
9. IV: Most chemotherapy is currently administered by the IV route. IV drugs
are delivered by IV push, short-term infusion, or continuous infusion.
a) Advantages
(1) Consistent absorption
(2) Direct route into bloodstream
b) Disadvantages
(1) Increased patient and healthcare provider time, often in a
healthcare setting
(2) Damage to the peripheral veins may necessitate central venous
access.
c) Potential complications (Joanna Briggs Institute, 2012)
(1) Infiltration
(2) Pain
(3) Phlebitis/cellulitis
(4) Infection
(5) Thrombosis
d) Nursing implications—Peripheral venous access
(1) Avoid the ventral surface of the wrist when starting peripheral
IVs because of increased pain and potential damage to the ra-
dial nerve. Use the nondominant arm whenever possible (In-
fusion Nurses Society, 2011).
(2) Avoid areas of flexion.
(3) Avoid using lower extremities.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 6. Administration Considerations 127
(4) Choose veins that are large, smooth, and pliable.
(5) Avoid using the arm of patients who have had axillary lymph
node dissection.
(6) Avoid using an established IV site that is more than 24 hours
old whenever possible. CDC recommendations (O’Grady et al.,
2011) allow use of peripheral IVs for up to 96 hours, but that
recommendation is based on risk of catheter-related infection;
use of irritants or vesicants may shorten the useful life of a pe-
ripheral IV access device. Thoroughly assess any established IV
site prior to use.
(7) Perform hand hygiene, wear gloves, prepare site with antisep-
tic, allow skin to dry, and avoid touching the insertion site af-
ter applying antiseptic (O’Grady et al., 2011).
(8) Use the smallest catheter possible to deliver the planned ther-
apy. IV peripheral catheters range in gauges from 14–28 and
lengths from 5/8 to 2 inches (Camp-Sorrell, 2011).
(9) Use a catheter equipped with a safety mechanism to avoid sharps
injury (Infusion Nurses Society, 2011).
(10) Perform venipuncture according to institutional policy and pro-
cedure. If unsuccessful, restart IV using a different site on the op-
posite arm, if possible, or proximal to the previous puncture site.
(11) The chemotherapy agents may be connected directly to the IV Chemotherapy Administration
catheter or to a line of compatible maintenance solution. Se- Through an Implanted Port
cure all connections with Luer-lock devices. Administer agents Video
according to institutional policy.
(12) Check for blood return prior to initiating chemotherapy. Do To view videos download
not pinch the IV administration tubing to determine blood re- ChemoBio4thInteractive.pdf
turn because the vein can rupture. Aspirate with a syringe by
the lowest Y-site and clamp off fluid from the bag or use gravity
to check by lowering the IV bag below the patient’s IV site (Jo-
anna Briggs Institute, 2012).
(13) Observe for swelling, burning, tightness, cool skin, skin color
change, and flow rate (Joanna Briggs Institute, 2012). If infil-
tration occurs, immediately stop infusion and restart IV using
a different site on the opposite arm, if possible, or proximal to
the previous puncture site.
10. Central venous catheters (CVCs): CVCs include percutaneous subclavi-
an catheters, tunneled subclavian catheters, peripherally inserted cen-
tral catheters, and implanted ports. Assess for catheter function and
patency prior to use by aspirating for a blood return. Catheter occlu-
sion may occur as a result of extraluminal fibrin deposit or intralumi-
nal thrombosis. Drug precipitate may cause a blockage when the cath-
eter is not flushed adequately between agents (Cummings-Winfield &
Mushani-Kanji, 2008).
a) Implanted ports: Access with a noncoring needle following skin
preparation according to institutional policy. Select the appropri-
ate needle length (0.5–2 inches) based on the depth of the port
(Camp-Sorrell, 2011). Stabilize the needle as needed, and cover the
insertion site with a transparent semipermeable membrane dress-
ing (Infusion Nurses Society, 2011). Inspect the insertion site for
evidence of needle dislodgment, leakage of IV fluid, drainage, or
edema during infusions.
b) For all CVCs: Verify catheter placement and function either by x-ray
or fluoroscopic dye study prior to initial use per institutional guide-
lines. Check for blood return by aspiration. DO NOT administer cyto-
toxic agents in the absence of blood return. The following may help
to establish blood return (Camp-Sorrell, 2011).
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
128 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
(1) Attempt to flush with normal saline, and gently pull back. Re-
position the patient. Ask the patient to cough and take a deep
breath.
(2) Obtain physician order for declotting procedure, and follow
institutional protocol.
(3) Use x-ray or dye study to confirm proper placement of CVC and
to rule out catheter malfunction or migration in the absence of
blood return, according to institutional policy.
11. Special considerations for vesicant administration
a) When administering a vesicant through a peripheral IV site
(1) Avoid using an IV pump or syringe pump to minimize pressure
on the vein (Infusion Nurses Society, 2011).
(2) Remain with the patient during the entire infusion (Sauerland,
Engelking, Wickham, & Corbi, 2006).
(3) Limit administration to IV push or short infusion lasting no lon-
ger than 30–60 minutes (Sauerland et al., 2006).
(4) Verify blood return every 2–5 ml for IV push and every 5–10
minutes during a short infusion (Sauerland et al., 2006).
(5) Closely monitor for signs and symptoms of extravasation, such
as swelling, loss of blood return, and patient’s report of pain
or burning sensation. Confirming extravasation of vesicants
during chemotherapy administration can be difficult because
manifestations can vary from no immediate signs to pain, swell-
ing, and loss of blood return, as well as differentiating extrav-
asation from flare and recall reactions (Wickham, Engelking,
Sauerland, & Corbi, 2006).
(6) Discontinue vesicant administration at the first sign of extrav-
asation.
b) When administering a vesicant through a central vascular access
device (VAD)
(1) Administer via IV push, short infusion, or continuous infusion,
as ordered.
(2) Verify blood return prior to, during, and after drug administration.
(3) Monitor the IV site throughout the infusion according to in-
stitutional policy.
(4) Discontinue vesicant administration at the first sign of extrav-
asation.
c) Piggyback or short-term infusion
(1) Verify blood return and IV patency prior to hanging the infusion.
(2) Attach the secondary tubing to the injection port closest to the
patient using a needleless, Luer-lock connector (Infusion Nurs-
es Society, 2011).
(3) Initiate flow rate according to the physician order, and observe
the patient for any reactions.
(4) Once the short infusion is complete, check vein patency and
flush the line with a compatible solution.
d) Continuous infusions: Used when a constant plasma concentration over
an extended period of time is desired (Joanna Briggs Institute, 2012)
(1) Central VADs are preferred.
(2) Connect directly to the IV access device or by secondary IV set
to a compatible line of maintenance solution, according to in-
stitutional policy.
(3) Secure connections with Luer-locking devices.
(4) Monitor the IV site throughout the infusion according to policy.
(5) When patients are discharged with a portable pump for home
infusion, ensure they are instructed on how to manage prob-
lems with the pump and infusion and on how and when the
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 6. Administration Considerations 129
infusion will be discontinued (e.g., in the home or infusion
center).
(6) Flush line at the completion of the infusion.
e) IV push: Refer to physician order or institutional guidelines for sug-
gested IV push rates, diluents, and other drug-specific details.
(1) Free-flow method (side-arm technique) (Infusion Nurses So-
ciety, 2011)
(a) Attach the syringe with the drug at the injection port clos-
est to the patient.
(b) Aspirate for blood to verify IV patency.
(c) Allow compatible IV solution to flow freely.
(d) Slowly administer the chemotherapy agent, allowing the
flush solution to dilute the drug. Unless otherwise indicat-
ed, administer the agent at a rate of 1–2 ml/min.
(e) If multiple agents are administered, flush with a compati-
ble fluid between each agent and at the completion of the
infusion.
(2) Direct IV push method: Cytotoxic agents are administered IV
push directly into the IV device. Refer to institutional policy
and procedure.
(a) Establish venous access. Obtain a new access site when ad-
ministering a vesicant via a peripheral vein (Infusion Nurs-
es Society, 2011).
(b) Flush the line with sterile IV solution in a syringe, and ver-
ify blood return.
(c) Detach the flush syringe, and attach the syringe contain-
ing the chemotherapy agent.
(d) Slowly administer the agent, aspirating for blood return
every 2–5 ml.
(e) Upon completion, disconnect the syringe carefully, minimiz-
ing blood loss; the blood will contain the cytotoxic agent.
(f) Connect a syringe with sterile flush solution, and gently
flush the catheter.
(g) Cap or disconnect the IV access device, as indicated.
B. Adherence to therapy
1. With the increasing numbers of oral therapies available, adherence to
the prescribed medication regimen is a concern (Weingart et al., 2008).
2. Barriers to adherence (Barefoot, Blecher, & Emery, 2009; Jarvis, 2012;
Moody & Jackowski, 2010)
a) The individual’s culturally based health beliefs. Disease causation
may be viewed from a biomedical, naturalistic, or magico-religious
perspective.
b) Cost of the medication, copayment
c) Where to obtain the drug (e.g., local versus specialty pharmacy)
d) Complexity of regimen
e) Health literacy
f) Patient’s physical condition (e.g., ability to swallow medications)
g) Side effects
h) Poor understanding of the importance of adherence or poor patient-
provider relationship
i) Lack of acceptance of illness because of current state of feeling well
(asymptomatic)
j) Inadequate follow-up/missed appointments
3. Optimizing adherence (Anderson & Klemm, 2008; Barefoot et al., 2009;
Jacobson et al., 2012; Winkeljohn, 2010)
a) Provide patient education.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
130 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
b) Employ behavior modification for patient and family as necessary.
Engage the patient and family members in the treatment process.
c) Use reminder systems.
(1) Pill boxes
(2) Calendars
(3) Diaries
(4) Follow-up telephone calls
d) Discuss medications at each intervention.
e) Perform pill counts.
f) Include caregivers in all discussions.
C. Pretreatment nursing assessment: Assess and document the following in-
formation.
1. Patient history: Identify cancer diagnosis, past and present surgical pro-
cedures, radiation therapy, and hormonal agents.
a) Use of complementary and alternative medicine (CAM): Question-
ing in a nonthreatening manner may encourage patients to dis-
close the use of these therapies. CAM includes the following (Na-
tional Center for Complementary and Alternative Medicine, 2013).
(1) Natural products such as vitamins and supplements
(2) Manipulative body-based practices such as chiropractic care
(3) Mind and body medicine such as meditation, yoga, and acu-
puncture
b) Allergies: Identify food, drug, and environmental allergies, includ-
ing latex (Infusion Nurses Society, 2011). Document all allergies in
the medical record.
c) Past medical history: Identify underlying health issues, such as hyper-
tension, diabetes, and cardiac and pulmonary disorders. Include any
psychiatric illness. Identify alcohol and substance abuse.
d) Medication review: Obtain an up-to-date list of medications. Include
all prescription, recreational, and over-the-counter medications and
herbal and vitamin supplements. This information is essential to ad-
dress possible drug-drug and drug-herb interactions (Shelley, Suss-
man, Williams, Segal, & Crabtree, 2009).
e) Symptom review: Assess symptoms related to the cancer diagnosis,
treatment regimen, comorbidities, and psychological issues (Jako-
bsson, Ekman, & Ahlberg, 2008).
(1) Poorly controlled symptoms affect QOL (Roiland & Heidrich,
2011) and adherence to the treatment protocol. Use standard-
ized forms or checklists to ensure thorough symptom assess-
ment (Brem & Kumar, 2011; Williams, Williams, LaFaver-Rol-
ing, Johnson, & Williams, 2011).
(2) Review nutritional status. Diet affects treatment tolerance (Ralph,
Von Ah, Scheett, Hoverson, & Anderson, 2011). Make the ap-
propriate recommendations and referrals.
f) Distress: Establish the need for interdisciplinary referrals such as so-
cial workers, counselors, or religious or spiritual providers.
(1) Assess family structure and dynamics, living conditions, and
caregivers.
(2) Determine practical concerns such as transportation, financial,
or insurance issues.
(3) Assess cultural issues that may influence the treatment plan.
(4) Identify religious beliefs or spiritual concerns that may affect
dietary and other requirements and restrictions.
(5) Screening tools
(a) Assess performance status by using an appropriate scale
(see Table 3).
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 6. Administration Considerations 131
(b) Assess and document pain using an age-appropriate pain
scale (e.g., FACES Pain Rating Scale, 0–10 numeric pain
rating scale, McGill Pain Questionnaire [National Initia-
tive on Pain Control, n.d.]).
(c) Assess fatigue using the Brief Fatigue Inventory (Mendoza
et al., 1999), the Piper Fatigue Scale (Piper et al., 1998),
or the Schwartz Cancer Fatigue Scale (Schwartz, 1998).
2. Patient data
a) Measure and document height and weight. Compare to previous
weight, and address significant changes.
b) Obtain, review, and document current laboratory values that are per-
tinent to the specific antineoplastic agents (e.g., assessment of kidney
function prior to cisplatin) (Jacobson et al., 2012).
c) Review and document diagnostic tests that are pertinent to the specif-
ic antineoplastic agent (e.g., cardiac ejection fraction prior to doxo-
rubicin).
d) Review diagnosis, tumor type, grade, and stage of current disease.
3. Cancer treatment during pregnancy: The most common malignancies
diagnosed during pregnancy are breast, cervical, thyroid, leukemia, lym-
phoma, and ovarian (Brewer, Kueck, & Runowicz, 2011).
a) Collaborate with a maternal-fetal medicine team prior to initiation
of treatment.
b) Assist the patient in evaluating the risks and benefits to mother and
unborn child (Rimes, Gano, Hahn, Ramirez, & Milbourne, 2006).
c) Establish accurate gestational age. Cytotoxic chemotherapy is harm-
ful to the fetus during the first trimester. Chemotherapy is not rec-
ommended after 35 weeks to avoid delivery during a period of bone
marrow suppression and the lack of drug excretion from immature
fetal organs (Giacalone, Laffargue, & Bénos, 1999; Visco, Meyer, Xi,
& Brown, 2009).
d) Inform the patient that breast-feeding is contraindicated during che-
motherapy.
4. Practices that promote safety during antineoplastic therapy: Using stan-
dardized orders, computerized physician order entry, and electronic med-
ication administration records can reduce medication errors.
a) Advantages of electronic systems (Levy et al., 2011; Rogers, 2009)
(1) Provide improved legibility
(2) Provide alerts for missing orders, incorrect doses, and wrong
route, time, and schedule
(3) Promote continuity of care between inpatient and outpatient
departments
(4) Increase communication among healthcare providers
(5) Provide easy access to pertinent patient data related to chemo-
therapy administration (e.g., laboratory and diagnostic tests)
b) Directly involving the patient and family members in the adminis-
tration of chemotherapy can serve as a safety mechanism. Future re-
search may identify the best methods for patients and families to be
involved in safe chemotherapy administration (Schwappach, Ho-
chreutener, & Wernli, 2010).
5. Treatment plan (Jacobson et al., 2012)
a) Review the prescribed treatment plan/protocol. Verify that orders are
written and signed by a qualified licensed independent practitioner.
b) Identify patients participating in a clinical trial, and confirm presence
of a signed IC form. Notify clinical trials nurse for additional infor-
mation if needed (if applicable).
c) Confirm that IC was obtained for the chemotherapy treatment. Fol-
low institutional policy related to the IC process.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
132 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
d) Read and scrutinize the entire chemotherapy order to ensure it is
complete. Complete chemotherapy orders include the following el-
ements (Neuss et al., 2013).
(1) Two patient identifiers
(2) Date(s) of administration (schedule, treatment interval)
(3) Diagnosis
(4) Regimen name
(5) Planned duration of treatment
(6) Current cycle number
(7) Criteria to administer the chemotherapy/biotherapy (e.g., lab-
oratory values, toxicity)
(8) Allergies
(9) Method of dose calculation
(10) Height, weight, and other variables used to calculate doses
(11) Name of chemotherapy and biotherapy agents using generic
names rather than brand names
(12) Drug dose
(13) Route and rate of administration
(14) Length of infusion (if applicable)
(15) Supportive care (e.g., premedications, hydration, growth factors)
(16) Sequence of administration, if applicable
Pretreatment Preparation for e) Confirm the patient’s current, measured height and weight.
Chemotherapy Administration f) Have two individuals recalculate the BSA (or other method of dose
Video calculation) and dose, and compare with the prescribed dose. Follow
institutional policy regarding which personnel are considered quali-
To view videos download fied to participate in the double-check process (e.g., two chemother-
apy-competent RNs, RN and pharmacist).
ChemoBio4thInteractive.pdf
g) Determine if the chemotherapy agents have irritant or vesicant po-
tential.
6. Treatment: Patient preparation
a) Inform the patient and family who will be administering the chemo-
therapy.
b) Verbally review the treatment plan with the patient and/or family
members.
c) Provide a detailed explanation to the patient, family, and/or caregiv-
ers of the prescribed chemotherapy agent or protocol, the route of
administration, and short- and long-term side effects and respond to
any questions or concerns.
d) Confirm the patient’s full name and second identifier, such as date
of birth or medical record number.
e) Notify the prescribing healthcare provider of any symptoms that may
require a change in the treatment plan.
f) Obtain baseline vital signs.
7. Treatment: Staff preparation
a) Assemble the appropriate PPE.
b) Obtain the necessary equipment based on route of administration
(e.g., infusion pump).
c) Ensure that a spill kit and emergency medications and equipment
are available.
d) Ensure that delivered products match the ordered drugs and are la-
beled appropriately with the following information (Neuss et al., 2013).
(1) Patient’s full name and second identifier (e.g., date of birth,
medical record number)
(2) Date of administration
(3) Full generic name of the agent
(4) Route of administration
(5) Total dose
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 6. Administration Considerations 133
(6) Total volume required to administer dose
(7) Date and time the drug was prepared and the expiration date
if not for immediate use. Some agents are unstable and must
be administered within a specific period of time.
8. Chemotherapy administration (Neuss et al., 2013)
a) Confirm the treatment plan with the patient prior to each treat-
ment.
b) Wear PPE.
c) Double-check the drug(s), and document the verification process by
two designated approved healthcare providers.
(1) Confirm two patient identifiers.
(2) Confirm drug name, dose, volume, rate, route, and cycle number.
(3) Obtain two signatures.
(4) Confirm rate setting on infusion pump (when used).
d) Obtain consent from patient to begin treatment as per institutional
policy (Klimaszewski, 2008).
e) Initiate chemotherapy via the appropriate route.
f) Monitor patient during administration for immediate complications.
g) Document the drug administration and the patient’s response.
h) Provide education and written discharge instructions.
i) Confirm the follow-up plan with patient and/or family member.
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Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 6. Administration Considerations 135
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Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 7
Pretreatment Care
A. Patient education
1. Definitions
a) Patient education, as defined by the journal Patient Education and
Counseling, is “a planned learning experience using a combination
of methods such as teaching, counseling, and behavior modification
techniques, which influence patients’ knowledge and health and ill-
ness behavior. Patient counseling is an individualized process involv-
ing guidance and collaborative problem-solving to help the patient
to better manage the health problem. Patient education and coun-
seling involve an interactive process [that] assists patients to partici-
pate actively in their health care” (Elsevier, n.d., “Definitions” para.).
b) Bastable, Gramet, Jacobs, and Sopczyk (2011) defined patient educa-
tion as “the process of helping patients learn healthcare behaviors to
incorporate into their lives with the ultimate goal of optimal health
and independence in self-care activities” (pp. 12–13).
c) Falvo (2011) stated that “by definition, one cannot be a teacher un-
less there is a learner. Therefore, merely giving information to pa-
tients does not mean that learning has occurred. To be effective, in-
formation must be presented in a way that makes it relevant” (p. 38).
2. Factors that affect patient teaching (Bastable et al., 2011; Blecher, 2004;
Rigdon, 2010)
a) The educator’s expertise regarding the information provided
b) The learners’ health literacy
c) The educator’s understanding of differences in individuals’ learn-
ing styles
d) The strategies available to the educator for patient education
e) The educator matching appropriate strategies to specific content
and learners
f) The educator’s ability to involve the individual in the learning process
3. Short-term outcomes of patient education (Blecher, 2004; Jacobson et
al., 2012)
a) Empowering active participation in health care
b) Explanation of diagnosis and treatment options
c) Verbalization of an understanding of the goals and duration of therapy
d) Identification of both short- and long-term signs and symptoms that
need to be reported
e) Demonstration of the ability to perform self-care and/or adapt to
potential limitations
f) Promotion of adaptive coping skills in a life-threatening condition
g) Autonomous decision making regarding treatment or no treatment
h) Identification and appropriate use of community resources
4. Long-term outcomes of patient education (Joint Commission, 2012a, 2012b)
a) Improved self-care behaviors
b) Improved health-related QOL
c) Decreased healthcare costs
d) Increased customer satisfaction 137
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
138 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
e) Better-informed patients, thus lessening the chance of malpractice
claims
5. Methods of patient education (e.g., auditory, visual, return demonstra-
tion) should be selected based on patients’ preferences and abilities.
6. Barriers to patient education
a) Barriers to learning should be assessed on an individual basis. The
following are some common barriers to comprehension (Joint Com-
mission, 2012a, 2012b; Mann, 2011).
(1) Lack of knowledge of diagnosis and treatment plan
(2) Differences in the expectations regarding the purpose of treatment
between the patient/significant other and the healthcare team
(3) Concerns or misconceptions about therapy due to prior expe-
rience or the experience of a friend or relative, which may dis-
suade the patient from undergoing treatment
(4) Language barriers
(5) Educational barriers
(6) Health literacy barriers
(7) Physical barriers: Pain; visual, hearing, and cognitive impair-
ments; and inability to speak can interfere with patients’ com-
prehension.
(8) Psychosocial or emotional issues may create barriers to learning.
b) Methods of overcoming barriers
(1) Allow patients to express concerns, and attempt to manage
their anxiety.
(2) Manage physical barriers, such as pain, and ensure that learn-
ers have glasses, hearing aids, etc., as needed.
(3) Provide access to translators, either in person or through tele-
communications. Note: Significant others are not recommend-
ed as translators because of role conflicts or inability to com-
municate complex medical terminology.
(4) Correct any misconceptions concerning diagnosis, treatment,
and follow-up care.
(5) Tailor teaching to the patient’s level of understanding.
(6) Assess patients individually, and present information at an ap-
propriate level.
(7) Cancer-related Spanish-language educational literature is avail-
able through NCI at www.cancer.gov.
(8) Cancer-related literature for patients with low literacy is avail-
able through NCI at www.cancer.gov.
7. Scope of information:
a) Provide verbal information and written material that is easy to read. En-
courage patients and family members to ask questions and actively listen.
b) Education should encompass the following (Castiglia, Drummond,
& Purden, 2011; Wilson, Mood, & Nordstrom, 2010).
(1) Names of the prescribed antineoplastic agents and the ratio-
nale for the use of each agent.
(2) Potential short- and long-term side effects of therapy
(3) Medications that will be used to alleviate some of the side effects
(4) When to call the physician or nurse
(5) How to contact the multidisciplinary team, including physi-
cians, nurses, emergency department, scheduling office, and
support services
(6) Schedule for laboratory and follow-up visits
8. Documentation: Nurses need to assess and document patients’ under-
standing of content after education takes place to meet regulatory (i.e.,
Joint Commission) standards, manage risk, and enhance staff commu-
nication (Joint Commission, 2012a, 2012b; Negley, Ness, Fee-Schroeder,
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 7. Pretreatment Care 139
Kokal, & Voll, 2009). Documentation of understanding should include
patients’ ability to verbalize or demonstrate learning. It also should iden-
tify future needs for reinforcement of information. If patients cannot
comprehend the information or they refuse education, this also must
be documented, along with alternative plans. Methods to assess patient
understanding include the following.
a) Patient/significant other is able to verbalize an understanding of the
information presented, including the name(s) of the medication(s)
and the purpose of the therapy.
b) Patient/significant other can identify and verbalize key instructions
for self-care.
c) Patient/significant other can identify and verbalize symptoms/side
effects to report and whom to call.
d) Patient brings new prescriptions on a follow-up visit and correctly ver-
balizes the instructions for use.
e) Patient is able to perform a return demonstration on items such as
temperature monitoring and hand washing.
f) Patient/significant other is able to accurately verbalize dates and times
of the next follow-up visit.
g) For oral agents, the patient/significant other is able to verbalize the
name of the medication, correct procedure for administration (e.g.,
with or without food), and safe handling and disposal procedures.
B. Verification and maintenance of treatment as planned
1. The treatment plan
a) Maintaining the planned treatment schedule is important because
systemic cancer treatments often have a narrow margin of therapeu-
tic benefit (Levine, 2010).
(1) Minor adjustments below therapeutic doses can result in de-
creased tumor response, whereas minor adjustments above ther-
apeutic doses can result in increased toxicity without increased
benefit (Levine, 2010).
(2) To ensure optimal patient outcomes, the oncology nurse must
(a) Evaluate the appropriateness of the treatment plan for the
disease being treated. The pathology and stage of cancer
should be clear in the patient record.
i. Goals of therapy should be stated.
ii. The plan should include what cancer drugs are to be
given, at what frequency, and for what duration.
(b) Perform safety checks to ensure that the agents are given
as intended with appropriate premedications and support-
ive care measures (Jacobson et al., 2012).
(c) Verify that regimen-specific laboratory and other diagnos-
tic measures are performed and evaluated as applicable
(Jacobson et al., 2012).
b) Maintaining a treatment plan’s dose intensity (total planned dose
over total planned period of time) is associated with improved pa-
tient survival, and higher dose intensity may improve tumor re-
sponse and cure rates (Crivellari, Monfardini, Stragliotto, Marino,
& Aversa, 2007).
(1) Dose reductions and treatment delays often occur because of
toxicities such as febrile neutropenia (Weycker, Barron, Edels-
berg, Kartashov, & Lyman, 2012).
(2) Appropriate use of growth factor support (e.g., filgrastim) can
reduce the occurrence of complications related to febrile neutro-
penia in patients on myelosuppressive chemotherapy (Quirion,
2009).
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
140 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
(3) When potential toxicities are proactively addressed, dose reduc-
tions and delays may be prevented or minimized (Kawashima
et al., 2012).
c) Verification of cancer treatment orders is not as simple as knowing a
single recommended dose or maximum safe dose, as is true for many
non-oncology medications.
(1) Appropriate doses for a given chemotherapy may vary widely
depending on the indication and route.
(2) For example, depending on the condition being treated, dos-
es of methotrexate may range from 2.5 mg orally to 8 g/m2 IV
with a requirement for leucovorin rescue and other support-
ive measures (Kalb, Strober, Weinstein, & Lebwohl, 2009; War-
nick & Auger, 2009).
d) Institutional policies and procedures should detail the process for
regimen and dose verification for cancer treatment orders.
(1) Policies and procedures should clearly define the steps to take
when discrepancies, potentially inappropriate orders, or other
concerns arise (Jacobson et al., 2012).
(2) The oncology nurse evaluates the appropriateness of the treat-
ment regimen considering the indication, route of adminis-
tration, concomitant treatments, and other factors, including
any premedications and supportive care medications (Jacob-
son et al., 2012).
e) The oncology nurse works with the patient and the care team to en-
sure that treatments remain on schedule at planned doses.
(1) Assessment and teaching before, during, and after treatment with
appropriate follow-up regarding identified needs is important.
(2) Developing an education checklist for nurses can ensure standard-
ized approach to patient education (Mueller & Glennon, 2007).
(3) Teaching should include information regarding symptom man-
agement strategies.
(4) Education regarding symptom management enables prompt
evaluation and treatment of potentially serious toxicities, such
as neutropenic fever (Hawley, Loney, & Wiece, 2011).
2. Concepts of dose intensity and dose-dense therapy
a) Dose intensity: Dose intensity refers to the amount of drug given over
a period of time (e.g., mg/m2/week) (NCI, n.d.). Maintaining dose
intensity ensures optimal exposure of the tumor to chemotherapy
agents. Treatment delays or dosage reductions decrease dose intensity.
b) Dose-dense therapy: A standard regimen that is given with less time be-
tween cycles is referred to as a dose-dense regimen (NCI, n.d.). Dose-
dense regimens increase dose intensity. The rationale for dose-dense
therapy is to minimize tumor regrowth between cycles (Bayraktar &
Arun, 2012). Myeloid growth factors reduce the severity and dura-
tion of neutropenia from myelosuppressive treatments, allowing for
reduced time between treatment cycles (Quirion, 2009).
c) Relative dose intensity (RDI) is a way of expressing the actual dose
intensity compared to the planned dose intensity. It is expressed as a
percentage derived by dividing the actual dose of chemotherapy giv-
en over a period of time by the planned dose of chemotherapy over
the planned period of time (Loibl et al., 2011).
(1) Example: The plan calls for 100 mg/m2 of an agent weekly for
four weeks.
(a) The patient receives 100 mg/m2 on weeks 1, 2, and 3, and
75 mg/m2 on week 4.
(b) The planned dose intensity was 400 mg/m2/4 weeks, or
100 mg/m2/week.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 7. Pretreatment Care 141
(c) The actual dose intensity was 375 mg/m2/4 weeks, or 94
mg/m2/week.
(d) Therefore, the RDI was 94% (375 divided by 400).
(2) A study of patients with metastatic breast cancer (N = 933) found
that an RDI of 85% or greater was an important factor in ex-
tending time to disease progression and increasing overall sur-
vival in patients receiving first-line anthracycline/taxane-based
therapy (Loibl et al., 2011).
(a) In the same study, dose reductions were primarily related
to toxicity. Dose delays were due to logistics and patient
desires (Loibl et al., 2011). This highlights the necessity of
patient education regarding the importance of maintain-
ing the treatment plan.
(b) Providing supportive care measures as needed to maintain
dose intensity is extremely important to improving long-
term survival.
(3) A 20-year study of patients with breast cancer (N = 386) treat-
ed with adjuvant chemotherapy found that when RDI fell be-
low 65%, survival rates were similar to not having received che-
motherapy at all (Lenhart, 2005).
3. Role of the nurse in verifying the treatment plan and schedule
a) Prior to initiating a cancer treatment regimen, the oncology nurse should
(1) Review the regimen and anticipated side effects.
(2) Verify that the ordered regimen is appropriate for the indication.
(3) If a nonstandard regimen or research protocol is used, en-
sure that a copy of the nonstandard regimen or research
protocol is available to verify the ordered regimen (Jacob-
son et al., 2012).
(4) Always verify orders against the known regimen or protocol.
Do not verify doses against a previous treatment that may have
been based on different clinical factors (e.g., renal function).
(5) Obtain clarification orders prior to initiating the cancer treat-
ment regimen if there are aspects of the orders that are unclear
or can be interpreted in more than one way.
b) Verification includes
(1) Checking that prescribed doses are within the normal range
for the indication
(2) Ensuring appropriate time intervals between scheduled treat-
ments
(3) Ensuring that the route, volume, and rate of infusion (as appli-
cable) are clearly stated and appropriate
(4) Reviewing and documenting laboratory values and other fac-
tors that may require changes in treatment
(5) Ensuring that all questions regarding orders are addressed pri-
or to preparation of chemotherapy.
c) Institutions must ensure that processes, tools, and technologies (i.e.,
calculators) are in place to enable appropriate verification of treat-
ment regimens by the nurse (Jacobson et al., 2012).
d) The oncology nurse serves a critical role in preventing harm to pa-
tients by appropriately ensuring the verification process is completed.
(1) Errors that result in harm to patients may occur during the
ordering process. Factors independently associated with dos-
ing errors include the use of carboplatin (requires complex
AUC [area under time-versus-concentration curve] calcula-
tions), regimens with three or more agents, and regimens
requiring modifications (e.g., for renal function) (Ranchon
et al., 2012).
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
142 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
(2) Use of electronic ordering systems in which prescribers direct-
ly enter orders for chemotherapy regimens has the potential
to reduce transcription errors. However, it does not preclude
the need for two independent verifications of dose calculations.
e) Verbal and/or telephone orders for chemotherapy or modifications
to existing orders are not acceptable.
(1) An exception to this rule is an order to hold or stop chemother-
apy (Jacobson et al., 2012).
(2) Faxed or electronically signed orders sent via email are accept-
able as written orders (Jacobson et al., 2012). This is a safe meth-
od for addressing the home medications of a patient hospital-
ized during off-hours.
4. Verification of patient understanding of the treatment plan
a) See also Patient Education.
(1) Verify patient understanding of and IC for therapy prior to ini-
tiating treatment.
(a) IC must be documented in the patient’s record.
(b) The process for obtaining IC, including who is responsi-
ble and allowed to obtain IC, should be specified in insti-
tutional policies and procedures (Jacobson et al., 2012).
(2) Provide written information regarding plan of care in language
appropriate for the patient.
(3) Allow opportunities for questions and assessment of under-
standing.
(4) Ensure patient understanding of therapies to continue at home,
symptom management strategies, follow-up appointments, and
importance of compliance with the treatment plan and schedule.
b) Involving the patient in the plan of care and providing appropriate
education may reduce medication administration errors (Schwap-
pach, Hochreutener, & Wernli, 2010).
(1) Include the patient in the verification process prior to each cy-
cle of chemotherapy (Jacobson et al., 2012).
(2) Verify the prepared drug including the correct drug, dose, vol-
ume (as applicable), route, rate (as applicable), and appear-
ance of medication.
(3) Verify the correct patient using two identifiers (e.g., full name
and date of birth) against both the orders and the prepared
drug at the point of administration.
5. Promoting continuity of care: Systems must be in place to ensure accu-
rate and complete reporting of the treatment plan and history when the
patient moves from one healthcare setting to another (Jacobson et al.,
2012). A change of healthcare setting (e.g., if the patient is hospitalized
following a clinic visit) is not in itself a reason to stop or delay treatments,
as this may result in reduced RDI or suboptimal care. Incomplete or inac-
curate communication during transition between care settings can lead
to treatment errors. Communication should include
a) Medication reconciliation: Communicating a list of all current med-
ications, which can then be evaluated regarding whether to contin-
ue in the new care setting
b) A summary of prior cancer treatments and the current treatment plan
including, as applicable, the cycle number, day of treatment, etc. (Ja-
cobson et al., 2012).
6. Verification of the chemotherapy and biotherapy orders: The nurse
must become familiar with the planned regimen and evaluate the need
for clarification or additional information before initiating treatment.
a) Treating facilities must provide the resources to meet this responsi-
bility (Jacobson et al., 2012). This may be in the form of
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 7. Pretreatment Care 143
(1) Printed drug and regimen references that are updated regularly
(2) Online access to current evidence-based guidelines (e.g., Nation-
al Comprehensive Cancer Network [NCCN] guidelines, www.
nccn.org) and drug-specific information (e.g., FDA, www.fda
.gov)
b) Use of step-by-step checklists may be helpful in designing double-
check systems to prevent errors (White et al., 2010).
c) Institutions should consider standardized order sets for commonly
used regimens to reduce the chance of errors during the ordering
process (Jacobson et al., 2012).
d) Order sets should use generic drug names unless there are multiple
brands of the generic drug and a specific brand formulation is de-
sired (Jacobson et al., 2012).
e) Unapproved abbreviations should not be used in order sets (Jacobson
et al., 2012). An example of unapproved abbreviations can be found
at the Joint Commission’s “Facts About the Official ‘Do Not Use’ List”
at www.jointcommission.org/assets/1/18/Do_Not_Use_List.pdf.
f) Complexity of treatment regimens increases the risk for mistakes and
ambiguity when orders are handwritten. Use of preprinted order sets
and computer ordering systems potentially can decrease the occur-
rence of ambiguous or incomplete orders (Jacobson et al., 2012).
g) Mechanisms must exist for the reporting, tracking, and analysis of
errors that occur related to cancer treatments. Although individual
practitioner competencies are important, many errors occur related
to system weaknesses (e.g., tolerance of unacceptable abbreviations).
h) Efforts should focus on identifying areas of high risk and designing
systems to reduce human error (Ashley et al., 2011).
7. Standard treatment regimens, research protocols, and tailored pro-
tocols
a) Standard treatment regimens: These are treatment regimens deter-
mined to be efficacious for a given cancer and patient condition. Spe-
cific agents with specified doses, routes, rates, and sequence are iden-
tified within the regimen. All of the agents in a regimen constitute
one cycle of treatment. The timing of cycles and planned number of
cycles is included within the standard treatment plan.
b) Investigational regimens: Researchers continue to investigate new
agents and new ways of giving and combining older agents with the
goal of improving tumor response to therapy or reducing the toxic-
ity of therapy.
(1) When a research protocol is used, communication among team
members is imperative to ensure the protocol is followed ex-
actly as written.
(2) Failure to follow the protocol exactly can lead to difficulty in
interpreting the research findings and possibly reduce the va-
lidity of findings (Ermete, 2012).
(3) If a research protocol is used at multiple centers, the same ver-
sion of the protocol must be used at all sites (Mitchell & Smith,
in press).
c) Tailored or individualized protocols: With better understanding of
the interplay of tumor molecular biology, the role of genetics, and
other factors, some regimens are individualized for patients. Patient-
specific and tumor-specific data guide the use of agents that are more
likely to have a positive effect while eliminating toxic agents not like-
ly to be of benefit. Some examples include
(1) Testing breast cancer tumors for overexpression of HER2, which
predicts benefit from treatment with anti-HER2 drugs in addi-
tion to traditional chemotherapy (Viale & Yamamoto, 2008)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
144 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
(2) Testing colon cancer tumors for KRAS mutation, which predicts
benefit from use of anti-EGFR therapy
(3) Using the patient’s immune system to specifically target the tu-
mor. Sipuleucel-T is prepared by taking a patient’s own white
cells via apheresis, “priming” these cells by exposure to a mole-
cule commonly found in prostate cancer, and then reinfusing
the cells (Smart, 2010).
8. High-dose chemotherapy: Some chemotherapy regimens call for very
high doses of chemotherapy to achieve cure or enduring response.
a) Patients receiving these regimens require more supportive care (e.g.,
transfusions, growth factor support) because of severe myelosuppres-
sion and other toxicities.
b) Oncology nurses must be familiar with the assessment and support-
ive care required when giving high doses of chemotherapy (Brown
& Faltus, 2011).
(1) The risk of cardiac toxicity with cyclophosphamide increases sig-
nificantly when given at high doses (Viale & Yamamoto, 2008).
(2) With administration of high doses of cytarabine, routine neu-
rologic assessments are performed to detect early signs of cer-
ebellar toxicity (Brown, 2010).
(3) High doses of methotrexate can be fatal if leucovorin is not giv-
en to help the body to eliminate the methotrexate. This is re-
ferred to as a leucovorin rescue.
(4) High-dose chemotherapy sometimes is used with the goal of my-
eloablation in preparation for hematopoietic progenitor stem
cell transplantation. Administration of myeloablative chemo-
therapy is highly complex and can be lethal. Nurses should be
prepared with the specialized knowledge and skills required in
caring for these patients before, during, and following trans-
plantation (Brown & Faltus, 2011).
9. Verification of dose modifications: If standard doses are modified, the
rationale should be documented (Jacobson et al., 2012). This allows the
nurse to assess the appropriateness of dosing. Some reasons for dose
modification include comorbid conditions (e.g., renal failure), toxicities
from prior treatment, and other factors such as age and polypharmacy.
a) Older age: Chemotherapy regimens are sometimes modified or re-
duced in older adults because of presumed inability to tolerate stan-
dard doses as renal function declines with age.
(1) Age alone should not exclude consideration of chemotherapy.
(2) Actual comorbid conditions and functional status may be bet-
ter indicators than age to determine the need for dosage mod-
ifications.
(a) Standard doses and combination regimens in older adult
patients with good performance status and without signifi-
cant comorbidities may be appropriate (Aggarwal & Langer,
2012). Dose reductions, while reducing potential toxici-
ties, may increase the risk for poor response to treatment.
(b) Adjuvant chemotherapy in patients age 70–79 with non-
small cell lung cancer has been well tolerated compared
to younger populations and in associated with improved
survival (Cuffe et al., 2012).
(c) Appropriate myeloid growth factor support may improve the
ability to maintain standard-dose regimens (Quirion, 2009).
b) Children and infants: In pediatric oncology, agents sometimes are
converted from standard BSA dosing (mg/m2) to weight-based dos-
ing (mg/kg) (Levine, 2010).
(1) This may be done using the “rule of 30” (30 kg = 1 m2).
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 7. Pretreatment Care 145
(2) The rationale is that BSA dosing may not be accurate or optimal
because of organ development in very young (younger than three
years) and small (less than 10 kg to less than 30 kg) children.
(a) High rates of ototoxicity (15%) with subsequent need for
hearing aids have occurred in infants treated with carbo-
platin and vincristine (N = 60) for retinoblastoma when
dosing was based on BSA. Previous studies in which mg/
kg dosing strategies were used did not result in significant
hearing loss (Leahey, 2012).
(b) BSA may be preferred at times. A study using weight-based
dosing of busulfan for allogeneic stem cell transplantation
in young children found inadequate tumor responses due
to underdosing. The children’s immune systems had recov-
ered and rejected the transplants (Trigg, 2004).
(3) Safe administration of chemotherapy in a pediatric setting re-
quires a specialized knowledge set. The Association of Pediat-
ric Hematology/Oncology Nurses (APHON) provides resourc-
es for pediatric oncology nurses. APHON has developed a Pedi-
atric Chemotherapy and Biotherapy Provider Program, which
standardizes nurses’ education regarding the administration of
chemotherapy and biotherapy to the pediatric population. For
more information, visit APHON’s website at www.aphon.org.
c) Polypharmacy: Sometimes interactions between medications neces-
sitate dosage adjustments or additional monitoring. This can occur
with primary treatment agents as well as supportive care medications.
(1) One example is aprepitant, a supportive care agent given
in combination with other drugs to prevent chemotherapy-
induced nausea and vomiting (CINV) (Dunphy & Walker, 2010).
Because of the way aprepitant is metabolized, usage may affect
coadministered medications.
(a) Aprepitant increases the effect of corticosteroids, especial-
ly when they are administered orally. It may be advisable to
reduce corticosteroids when they are not part of the can-
cer treatment itself (Aapro & Walko, 2010).
(b) Aprepitant may affect warfarin sodium several days after
the last dose of aprepitant is given, and international nor-
malized ratio (INR) should be closely monitored (Aapro
& Walko, 2010).
(c) Cisplatin, a highly emetogenic agent that typically calls for
aprepitant use, has been independently associated with el-
evations in INR (Yano et al., 2011).
(d) Aprepitant may increase the effect of some chemotherapy
agents (Bubalo et al., 2007).
(2) Drug interactions are common and often unavoidable. Nurses
must be cognizant of the possibility of drug interactions that
may alter the efficacy of drugs.
(a) Assess all medications for potential interactions, including
over-the-counter medications and CAM therapies (Jacob-
son et al., 2012).
(b) Evaluate allergies and prior hypersensitivity reactions (Ja-
cobson et al., 2012).
(c) Consult with an oncology pharmacist if a patient is receiv-
ing multiple drugs for cancer therapy or has comorbid con-
ditions such as diabetes or heart failure.
(d) Be aware of common antineoplastic drug-drug interactions
and have access to resources that enable safe nursing prac-
tice in medication administration (Daouphars et al., 2012).
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
146 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
10. Verification of dose calculations
a) Institutional policies and procedures should specify the minimum
components required for order sets to be considered complete and
acceptable. Missing components should be addressed during the veri-
fication process and prior to drug preparation (Jacobson et al., 2012).
b) Errors in dose calculations may cause significant patient harm (Levine,
2010).
c) Two chemotherapy-competent individuals (e.g., nurses, pharmacists),
in addition to the ordering prescriber, should perform independent
double checks of dosage calculations and ensure that required com-
ponents of chemotherapy orders are present (Jacobson et al., 2012).
(1) Independent calculations help to prevent bias errors. Each
person performs calculations independently, and the results
are compared.
(2) If the independent results are not consistent with the ordered
dose, the nurse needs to obtain clarification before preparing
the chemotherapy.
(3) Institutions must ensure that nurses verifying and administer-
ing cancer treatments are adequately trained in performing
calculations and other aspects of the verification process. Sys-
tems should be in place to confirm that verifications are done
and documented prior to preparation of chemotherapy (Ja-
cobson et al., 2012).
(a) After initial competence (knowledge) and proficiency (abil-
ity to use the knowledge) of the nurse has been determined,
institutions must have processes to evaluate and document
continuing competence and proficiency at regular inter-
vals (e.g., annually) (Jacobson et al., 2012).
(b) Development of proficiency checklists may be helpful in
this process (Crannell, 2012).
d) Weights and heights used for dose calculations must be measured
(not stated) values. Institutions may choose to state in policies and
procedures an acceptable time frame for measured values (e.g., up
to 24 hours prior to administration time).
11. How doses are calculated
a) Several methods of dosing may be used depending on the prescribed
agent. Some medications are prescribed with fixed initial doses (mg),
whereas others are dosed based on weight (mg/kg), BSA (mg/m2),
or AUC calculations that account for renal function (Levine, 2010).
b) Fixed doses: This means the prescribed dose does not require calcula-
tion based on patient size. Many oral agents are dosed in this manner.
(1) Verification entails ensuring that the ordered dose is appropri-
ate for the condition being treated. The diagnosis and stage of
disease and prior treatments should be clearly documented in
the patient record (Jacobson et al., 2012).
(2) A standard starting dose (typical for the average patient) may
require modification based on comorbid conditions. Package
inserts often describe known conditions requiring dose mod-
ifications.
(3) The rationale for any dose modifications should be clearly stat-
ed in the patient’s record (Jacobson et al., 2012).
c) Weight-based dosing: Dosing is expressed as dose of drug per unit of
body weight (e.g., mg/kg). Doses are calculated using an accurate-
ly measured weight.
d) BSA-based dosing: Most cytotoxic chemotherapy drugs are dosed based
on BSA, or the estimated total area of a person’s skin expressed in
square meters (m2). BSA should be calculated using a current mea-
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 7. Pretreatment Care 147
sured height and weight, not a height and weight stated by the pa-
tient (Griggs et al., 2012).
(1) Advantages: The underlying assumption is that by incorporat-
ing both height and weight, BSA is a more reliable indicator
than weight alone for predicting pharmacokinetics.
(2) Disadvantages
(a) Increased complexity of dose calculations increases the
chance for medication errors.
(b) BSA dosing does not account for factors other than height
and weight that might influence pharmacokinetics, such
as age and gender (Jäger et al., 2012). For example, a man
and woman who both have a BSA of 2.0 m2 may have vast-
ly different renal and hepatic functions.
(c) In addition to the current use of clinical factors in modi-
fying BSA-based doses, future strategies may incorporate
genotype and phenotype markers as well as therapeutic
drug monitoring to achieve optimal doses (Gao, Klumpen,
& Gurney, 2008).
(3) Despite the issues with BSA-based dosing, it remains the most
common method for dosing many chemotherapy agents. Nurs-
es should be aware of drug-specific recommendations for dos-
age adjustments that account for patient variability such as re-
nal and liver function.
(4) Several different formulas can be used for calculating BSA, each
yielding slightly different results. For this reason, it should be
clear which formula the prescriber used when calculating drug
doses (Jacobson et al., 2012).
(a) In the United States, the most commonly used formu-
la is the Mosteller equation (see Figure 14) (Gaguski &
Karcheski, 2011). However, no evidence has shown that
one BSA formula is more advantageous than another
(Griggs et al., 2012).
(b) An advantage of the Mosteller equation is that it can be car-
ried out with any calculator that has a square root function.
(5) Intentional modifications made to the BSA to obtain adjust-
ed doses should be clearly stated. If an ideal or adjusted body
weight is used instead of actual weight to calculate BSA, this
should be indicated in the order and the rationale should be
clearly documented.
(6) Evidence no longer supports routinely adjusting doses down-
ward for obesity with most chemotherapy agents.
(a) Dose reductions may result in reduced clinical benefit,
while dosing based on actual weight does not typically in-
crease myelotoxicity.
Figure 14. Formulas for Determining Body Surface Area
Mosteller equation (most commonly used in the United States):
√ height in cm × weight in kg
3,600
This formula is converted to inches and pounds as
√ height in inches × weight in pounds
3,131
Note. Based on information from Kouno et al., 2003.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
148 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
(b) Obese patients have been observed to experience less pro-
found myelosuppression compared to non-obese patients us-
ing actual weight for BSA-based dosing (Griggs et al., 2012).
(7) Institutional policies and procedures should specify acceptable
methods for calculating BSA (e.g., specifying that Mosteller
equation is to be used).
(a) Online calculators, handheld BSA calculators, or any oth-
er tools used to obtain BSA should be validated for accu-
racy prior to use.
(b) The tools used should be based on the same formula used
by the ordering provider.
(8) The nurse should be aware of medication-specific circumstanc-
es that affect dosing based on BSA.
(a) For example, vincristine is dosed based on BSA, but pre-
scribers often cap the dose at a maximum of 2 mg regard-
less of BSA to reduce potential neurologic toxicities.
(b) This capped dose may be further reduced when coadmin-
istered with azole antifungal therapies (Harnicar, Adel, &
Jurcic, 2009).
e) Carboplatin and AUC-based dosing: AUC calculations are common-
ly used to determine carboplatin doses. AUC refers to the amount of
drug exposure over time or the total drug concentration in plasma
over a period of time (Gaguski & Karcheski, 2011).
(1) AUC dosing of carboplatin accounts for age, gender, weight,
and renal function. Carboplatin drug clearance is strongly cor-
related with renal function (Hiraike et al., 2011).
(2) The Calvert formula is typically used to determine the total dose
of carboplatin in milligrams (see Figure 15). The target AUC is
specified in the order.
(3) In practice, an estimated creatinine clearance (estCrCl) is used
with the Calvert formula rather than an actual glomerular fil-
tration rate (GFR), which requires a 24-hour urine collection.
(4) The estCrCl is related to GFR and is used in calculating carbo-
platin doses.
(a) Example: The order calls for “Carboplatin AUC 6.”
(b) The calculated estCrCl is 50 ml/min.
(c) GFR + 25 (estCrCl + 25) = 50 + 25 = 75
(d) Target AUC × 75 = 6 × 75 = 450 mg
(e) Carboplatin dose = 450 mg
(5) Several formulas, each yielding significantly different results,
exist for obtaining the value for estCrCl. Dosing errors can oc-
cur when a different formula is used than that intended by the
prescriber.
(6) The Cockcroft-Gault formula (see Figure 16) is the most com-
monly used in the United States to obtain estCrCl (Gaguski &
Karcheski, 2011).
(7) Generally, the formulas for estCrCl are reliable.
(a) Exceptions include emaciated and/or immobile patients
in whom actual GFR is typically lower than estCrCl.
Figure 15. Calvert Formula
Dose of carboplatin (mg) = (target AUC) × (GFR + 25)
Total dose calculated is in mg, not mg/m2.
Note. Based on information from Calvert et al., 1989.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 7. Pretreatment Care 149
(b) Estimations may be inaccurate in patients with rapidly chang-
ing serum creatinine levels (Gaguski & Karcheski, 2011).
(c) For obese patients, evidence shows that use of actual GFR
may be preferred over an estimated value. If an estCrCl is
used in this population, the prescriber may choose to use
an adjusted weight or alternative formula to Cockcroft-Gault
to determine estCrCl (Nelson, Formica, Cooper, Schwartz,
& Rutherford, 2012).
(8) Importantly, changes in how laboratories determine serum
creatinine may result in underestimation of serum creatinine
when it is low.
(a) Use of these values may result in overestimated CrCl and
subsequent overdosing of carboplatin with risk of increased
toxicity without added clinical benefit (Smart, 2011).
(b) For this reason, the FDA has recommended capping est-
CrCl at 125 ml/min in patients with normal renal function.
See Figure 17 for examples of dose capping. Dose capping
is not required when an actual GFR is used in calculating
the carboplatin dose (Smart, 2011).
(9) Patients with high GFR (measured, not estimated) may require
dose adjustments to minimize toxicity. However, this is an area
where a standardized approach is still controversial (Roy et al.,
2011).
(10) The rationale and choice of any calculation modifications should
always be clearly documented to enable the verification process
(Jacobson et al., 2012).
12. When calculations do not agree
a) Several factors can result in verification calculations yielding results
different from the ordered doses.
(1) A change in the patient’s weight: Minor weight changes typi-
cally are not significant. However, patients should be weighed
Figure 16. Calculation of Glomerular Filtration Rate: Cockcroft-Gault Method
Males:
estCrCl (ml/min) = (140 – age) × (weight in kg)
72 × serum creatinine (mg/dl)
Females:
estCrCl (ml/min) = (140 – age) × (weight in kg) × (0.85)
72 × serum creatinine (mg/dl)
estCrCl—estimated creatinine clearance
Note. Based on information from Cockcroft & Gault, 1976.
Figure 17. Carboplatin Dose Capping Using Estimated Creatinine Clearance
Dose of carboplatin (mg) = (target AUC) × (estCrCl + 25)
estCrCl capped at 125 ml/min
Maximum doses for sample target AUCs:
• Target AUC 6: Maximum carboplatin dose = 6 × (125 + 25) = 900 mg
• Target AUC 5: Maximum carboplatin dose = 5 × (125 + 25) = 750 mg
• Target AUC 4: Maximum carboplatin dose = 4 × (125 + 25) = 600 mg
AUC—area under the concentration-versus-time curve; estCrCl—estimated creatinine clearance
Note. Based on information from Calvert et al., 1989; Smart, 2011.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
150 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
before each treatment cycle and the doses calculated based on
the current weight.
(2) Using different formulas for verifying calculations
(3) An error in calculations during the ordering process
(4) An error in the calculations during the verification process.
The first step when noting discrepancies in doses is to recheck
the calculations.
b) Policy should indicate if rounding of doses is acceptable or expected.
c) Policies and procedures should dictate the acceptable variance be-
tween the ordered dose and the recalculated or rounded dose. For
example, a 5% variance rule is common practice (Levine, 2010). With
this, as long as the recalculated or rounded dose is within 5% of the
actual ordered dose, it is acceptable to proceed. Some facilities ac-
cept a variance up to 10% (Gaguski & Karcheski, 2011).
(1) When the ordered dose is 100 mg, a 5% variance rule allows
administration of the drug when recalculations fall between
95 mg and 105 mg. With a 10% variance rule and a 100 mg or-
dered dose, administration is allowed when recalculations fall
between 90 mg and 110 mg.
(2) Without a policy that states an acceptable variance, the nurse
must clarify any dose discrepancy with the prescriber before ad-
ministering treatment.
(3) It is not in the oncology nurse’s scope of practice to determine
acceptable variance without policies and procedures guiding
the process.
13. Verification of medication sequence
a) The order in which chemotherapy and biotherapy agents are giv-
en may affect the pharmacokinetics and pharmacodynamics of the
agents. However, it is not always known if specific sequences of treat-
ments result in better outcomes.
b) A review of published studies evaluating 35 different chemother-
apy combination sequences found only 14 combinations in which
sequence did not seem to have an impact relative to toxicity or
clinical benefit. For the remaining 21 combination regimens, im-
proper sequencing of the chemotherapy agents demonstrated the
potential for increasing toxicity or decreasing the effectiveness of
the regimen (Mancini & Modlin, 2011). The following are some
examples.
(1) Paclitaxel should be given before cisplatin, as the reverse is
known to cause more severe neutropenia without increasing
the effectiveness of the regimen (Mancini & Modlin, 2011).
(2) For the treatment of non-small cell lung cancer, cisplatin should
be given before irinotecan because this sequence has demon-
strated more favorable tumor response rates without increased
toxicity (Han et al., 2006).
c) The sequence of administration should be stated in the chemother-
apy orders (Jacobson et al., 2012).
d) Some institutions develop algorithms or charts to assist staff in deter-
mining administration sequence when no specific direction is given
in the chemotherapy orders.
(1) As new research and medications become available, these tools
should be updated to reflect the most current evidence.
(2) In the absence of specific policy-driven direction, the nurse
should seek clarification of sequence from the ordering pro-
vider when the orders are not clear.
14. Verification of oral agents
a) See also Appendix 3.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 7. Pretreatment Care 151
b) Oral formulations of chemotherapy and biologic agents require the
same processes of verification as other types of systemic cancer treat-
ments. ASCO/ONS have published specific safety standards to ad-
dress the growing use of oral agents (Neuss et al., 2013).
c) Many oral agents are based on fixed dosing regimens, but some re-
quire dose calculations.
d) Ensuring patient/caregiver understanding of the oral treatment reg-
imen is critical when the agents are administered at home.
e) Some patients do not adhere to treatment regimens because of a
lack of understanding or inadequate preparation (Simchowitz et
al., 2010).
f) Retail pharmacists are not always familiar with oral cancer medica-
tions and may not have the background to provide adequate patient
education (Simchowitz et al., 2010).
g) Complex treatment schedules may make it difficult for some patients
to maintain adherence. Continuing follow-up (e.g., phone calls) and
providing treatment calendars may be helpful.
h) Failure to adhere to the treatment regimen may result in worse out-
comes.
(1) For example, rapid tumor progression and resistance can occur
after only short periods of abstaining from kinase inhibitors such
as imatinib. Patient education should include the importance of
maintaining the regimen as ordered (Barnes & Reinke, 2011).
(2) This highlights the importance of ensuring communication of
the treatment plan between healthcare settings. Cancer thera-
pies should not be stopped solely because of a change in health-
care setting.
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Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 8
Infusion-Related
Complications
A. Types of infusion complications: The oncology nurse must be alert for im-
mediate complications of cytotoxic therapy. This section covers complica-
tions that patients may experience during or shortly after chemotherapy ad-
ministration. Terms used include
1. Extravasation: A passage or escape into the tissues; passage or escape of
antineoplastic chemotherapeutic drugs into tissue (Mosby’s Dictionary of
Medicine, Nursing and Health Professions, 2009)
2. Vesicants (also referred to as blistering agents): A drug or agent capable
of causing tissue necrosis when extravasated (Mosby’s, 2009)
3. Flare reaction: “Erythema, pruritus, and localized urticaria at or adjacent
to the site of drug administration” (Castells & Matulonis, 2012)
4. Irritant: An agent that produces inflammation or irritation (Mosby’s, 2009)
B. Extravasation
1. Pathophysiology: Tissue damage secondary to vesicant infiltration or
leakage outside of the vessel that occurs as a result of one of two major
mechanisms
a) The vesicant binds to nucleic acids in the DNA of healthy cells in
the tissue, causing cell death. The dead cells release complexes,
which are taken up by adjacent healthy cells. This process of cellu-
lar uptake of extracellular substances sets up a continuing cycle of
tissue damage as the DNA-binding vesicant is retained and recircu-
lated in the tissue for a long period of time (Luedke, Kennedy, &
Rietschel, 1979). Examples of DNA-binding vesicants include an-
thracyclines (daunorubicin, doxorubicin, epirubicin, idarubicin),
dactinomycin, mechlorethamine (nitrogen mustard), mitomycin,
and mitoxantrone.
b) The vesicant does not bind to cellular DNA. The vesicant has an indi-
rect rather than direct effect on the cells in healthy tissue. It is even-
tually metabolized in the tissue and is more easily neutralized than
DNA-binding vesicants (Ener, Meglathery, & Styler, 2004). Examples
of non-DNA-binding vesicants include plant alkaloids (vinblastine,
vincristine, vindesine, vinorelbine) and taxanes (docetaxel, pacli-
taxel, paclitaxel protein-bound particles for injectable suspension),
which are mild vesicants.
2. Factors affecting tissue damage severity
a) Type of vesicant extravasated (DNA-binding or nonbinding)
b) Concentration and amount of vesicant in the tissue
c) Location of extravasation
d) Patient factors, such as older age, comorbidity (e.g., diabetes), and
impaired immunocompetence (Ener et al., 2004; Schulmeister, 2011)
3. Risk factors for peripheral extravasation (Goolsby & Lombardo, 2006;
Sauerland, Engelking, Wickham, & Corbi, 2006) 155
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
156 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
a) Small, fragile veins
b) Previous multiple venipunctures
c) Prior treatment with irritating or sclerosing drugs, such as chemo-
therapy
d) Sensory deficits
e) Limited vein selection because of lymph node dissection, lymphede-
ma, or limb removal
f) Impaired cognition, altered mental status (impairs ability to detect
administration site sensation changes), or somnolence
g) Probing during IV catheter insertion
h) Inadequately secured IV catheter
i) Administration site in areas with minimal overlying tissue (e.g., dor-
sum of the hand, wrist, or antecubital area)
j) Use of rigid IV devices (e.g., steel-winged “butterfly” needles)
4. Possible etiologies of peripheral extravasations (Sauerland et al., 2006)
a) Vein wall puncture, piercing, or trauma
b) Dislodgment of the catheter from the vein
c) Administration of a vesicant in a vein below a recent (less than 24
hours) venipuncture site
d) Administration of a vesicant in a vein below a recent or nonhealed
vesicant extravasation site
e) Inadvertent IM or SC vesicant administration
5. Risk factors for extravasation from central VADs (Sauerland et al., 2006)
a) Difficulty encountered during device insertion (e.g., probing during
venipuncture, inability to advance guidewire or catheter)
b) Inadvertent slicing, piercing, or nicking of catheter prior to or dur-
ing insertion
c) Device misplacement with catheter tip outside of the venous system
d) Inadequately secured noncoring needles (implanted ports)
e) Deeply implanted ports
f) Presence of a fibrin sheath or thrombus at the catheter tip
g) Catheter migration
h) Long dwell time of catheters inserted using a subclavian approach (in-
creases risk of catheter fracture secondary to compression or “pinch-
off” between the clavicle and first rib)
6. Possible etiologies of extravasations from central VADs (Goossens, Stas,
Jérôme, & Moons, 2011; Sauerland et al., 2006)
a) Vein perforation
b) Catheter leakage, rupture, or fracture
c) Separation of the catheter from a portal body (implanted ports)
d) Incomplete insertion of a noncoring needle into an implanted port
e) Noncoring needle dislodgment from an implanted port
f) Backflow of vesicant along the catheter to the venotomy site second-
ary to fibrin sheath or thrombus at the catheter tip
7. Signs and symptoms of vesicant extravasation: Irritation of the vein
and flare reactions may mimic some of the signs and symptoms of
vesicant extravasation (see Table 13 and Appendix 2). Irritation of
the vein and flare reactions are unique to peripheral chemothera-
py administration; they do not occur when chemotherapy is admin-
istered via central VADs because the chemotherapy is rapidly dilut-
ed in large veins (Wickham, Engelking, Sauerland, & Corbi, 2006).
Signs and symptoms of vesicant extravasation are found in Table 13.
Additional signs and symptoms include the following (Ener et al.,
2004).
a) IV flow rate that slows or stops
b) Resistance during IV bolus (push) vesicant administration
c) Leaking around the IV catheter or implanted port needle
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 8. Infusion-Related Complications 157
Table 13. Signs and Symptoms Associated With Vesicant Extravasation, Venous Irritation, and Flare Reaction
Signs and
Symptoms Vesicant Extravasation Venous Irritation Flare Reaction
Pain Immediate: Pain typically occurs and is described Aching and tightness along a No pain; the skin overlying the
as burning, stinging, or a sensation of coolness at peripheral vein, above the ad- vein may itch.
and around the vesicant administration site. How- ministration site, occurs as
ever, some patients do not experience pain when the drug infuses.
a vesicant extravasates.
Delayed: Pain usually increases in intensity over
time.
Redness Immediate: Redness in the area of the vesicant ad- The vein may appear red- Immediate blotches or streaks
ministration site commonly occurs but is not al- dened or darkened. develop along the vein, which
ways present or may be difficult to detect if the ex- usually subside within a few
travasation is occurring deeper in the tissue (e.g., minutes. Wheals may appear
as a result of needle dislodgment from implant- along the vein.
ed port).
Delayed: Redness generally intensifies over time.
Swelling Immediate: Swelling commonly is observed and is Swelling does not occur. Swelling does not occur.
easier to detect when extravasation is superficial
(e.g., from a peripheral vein) rather than deep in
the tissue (e.g., implanted ports).
Delayed: Swelling typically increases over time.
Blood return Immediate: Loss of blood return from IV device oc- Blood return should be pres- Blood return is present.
curs. ent. If loss of blood return oc-
curs, suspect infiltration of ir-
ritant.
Ulceration Immediate: Skin integrity is intact Ulceration does not occur. Ulceration does not occur.
Delayed: If vesicant extravasation is not treated,
blistering and sloughing begin within 1–2 weeks,
followed by tissue necrosis that may require sur-
gical debridement and skin grafting or flap place-
ment.
Note. Based on information from Goolsby & Lombardo, 2006; Sauerland et al., 2006; Schulmeister, 2011.
8. Possible consequences of untreated vesicant extravasation (Ener et al.,
2004; Goolsby & Lombardo, 2006)
a) Blistering (usually begins within three to five days)
b) Peeling and sloughing of skin (usually begins within two weeks af-
ter extravasation)
c) Tissue necrosis (usually evident two to three weeks after extravasation)
(1) DNA-binding vesicants remain in the tissue for long periods of
time. The area of tissue necrosis becomes progressively larger
and deeper over time.
(2) Non-DNA-binding vesicants are more easily metabolized in the tis-
sue. Tissue necrosis is generally localized and improves over time.
d) Damage to tendons, nerves, and joints
e) Functional and sensory impairment of the affected area
f) Disfigurement
g) Loss of limb
9. Vesicant extravasation management: A suspected vesicant extravasation
is best assessed and managed using a systematic and collaborative ap-
proach that involves the patient, the nurse administering the vesicant,
and the oncologist treating the patient.
a) Initial management of extravasation: Steps to take when a vesicant
extravasation occurs or is suspected (Goolsby & Lombardo, 2006;
Schulmeister, 2011)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
158 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
(1) Immediately STOP administering the vesicant and IV fluids.
(2) Disconnect the IV tubing from the IV device. Do not remove
the IV device or noncoring port needle.
(3) Attempt to aspirate residual vesicant from the IV device or port
needle using a small (1–3 ml) syringe.
(4) Remove the peripheral IV device or port needle.
(5) Assess the site of the suspected extravasation.
(6) Assess symptoms experienced by the patient (e.g., pain, impair-
ment in range of motion of extremity).
(7) Notify the physician or advanced practice nurse.
(8) Initiate appropriate management measures in accordance with
Table 14 and institutional policies.
b) Vesicant extravasation antidotes and treatments
(1) Efficacy: The efficacy of extravasation antidotes and treatments
is unknown, with the exception of dexrazoxane for injection,
which has a 98.2% overall efficacy for treating anthracycline
extravasation (Mouridsen et al., 2006). In two European stud-
ies, 53 of 54 patients with biopsy-confirmed anthracycline ex-
travasation did not require surgical intervention after receiving
dexrazoxane administered IV daily for three days. The median
baseline extravasation area was 25 cm2 (range 1–253 cm2), and
11 patients had extravasation areas exceeding 75 cm2. Thirteen
patients had late sequelae at the extravasation site such as pain,
Table 14. Vesicant Extravasation Management Guidelines
Immediate Antidote or Treatment Administration,
Classification/Drug Topical Therapy Antidote or Treatment Patient Monitoring, and Follow-Up
Alkylating agent Apply ice for Antidote: Sodium thiosulfate Inject 2 ml of the sodium thiosulfate so-
• Mechlorethamine 6–12 hours fol- Mechanism of action: Neutralizes mechlor- lution for each milligram of mechloreth-
hydrochloride lowing sodium ethamine to form nontoxic thioesters that amine suspected to have extravasat-
(nitrogen mustard, thiosulfate an- are excreted in the urine ed. Inject the solution SC into the extrav-
Mustargen®) tidote injection Preparation: Prepare 1/6 molar solution. asation site using a 25-gauge or small-
(Lundbeck, • If 10% sodium thiosulfate solution: Mix 4 er needle (change needle with each in-
2012). ml with 6 ml sterile water for injection. jection).
• If 25% sodium thiosulfate solution: Mix Assess the extravasation area for pain,
1.6 ml with 8.4 ml sterile water. blister formation, and skin sloughing peri-
Storage: Store at room temperature be- odically as needed or in accordance with
tween 15°C–30°C (59°F–86°F). institutional policy.
Instruct the patient to monitor the extrava-
sation site and report fever, chills, blister-
ing, skin sloughing, and worsening pain.
Instruct the patient with peripheral extrav-
asations to report arm or hand swelling
and stiffness.
Anthracenedione Apply ice pack No known antidotes or treatments Extravasation typically causes blue discol-
• Mitoxantrone for 15–20 min- oration of the infusion site area and may
(Novantrone®) utes at least require debridement and skin grafting
four times a (EMD Serono, Inc., 2008).
day for the first Assess the extravasation area for pain,
24 hours. blister formation, and skin sloughing peri-
odically as needed or in accordance with
institutional policy.
In collaboration with the physician or ad-
vanced practice nurse, refer the patient
for specialized care when indicated or
needed (e.g., plastic or hand surgery
consult, physical therapy, pain manage-
ment, rehabilitation services).
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 8. Infusion-Related Complications 159
Table 14. Vesicant Extravasation Management Guidelines (Continued)
Immediate Antidote or Treatment Administration,
Classification/Drug Topical Therapy Antidote or Treatment Patient Monitoring, and Follow-Up
Anthracyclines Apply ice pack Treatment: Dexrazoxane for injection (To- The first dexrazoxane infusion should be
• Daunorubicin (but remove at tect® Kit, Biocodex, Inc., 2011) initiated as soon as possible and within 6
(Cerubidine®) least 15 min- Note: Totect is the U.S. Food and Drug Ad- hours of the anthracycline extravasation.
• Doxorubicin utes prior to ministration (FDA)-approved treatment Dexrazoxane should be infused over 1–2
(Adriamycin®) dexrazoxane for anthracycline extravasation, and its hours in a large vein in an area other
• Epirubicin treatment). manufacturer maintains a patent for use than the extravasation area (e.g., op-
(Ellence®) on the product. Although Zinecard® and posite arm). The same arm should be
• Idarubicin generic dexrazoxane are neither indicat- used only when the patient’s clinical sta-
(Idamycin®) ed nor FDA-approved for anthracycline tus (e.g., lymphedema, loss of limb) pre-
extravasation treatment, their clinical ef- cludes use of the unaffected arm, and a
ficacy in treating anthracycline extrava- large vein distal to the extravasation site
sations has been documented in the lit- should be used for dexrazoxane admin-
erature (Arroyo et al., 2010; Conde- istration.
Estévez et al., 2010; Langer, 2007, 2008; Dimethyl sulfoxide should not be applied to
Uges et al., 2006). the extravasation area.
Mechanism of action: Unknown Assess the extravasation area for pain,
Dose: The recommended dose of dexrazox- blister formation, and skin sloughing peri-
ane is based on the patient’s body sur- odically as needed or in accordance with
face area: institutional policy.
• Day 1: 1,000 mg/m2 Instruct the patient to monitor the extrava-
• Day 2: 1,000 mg/m2 sation site and report fever, chills, blister-
• Day 3: 500 mg/m2 ing, skin sloughing, and worsening pain.
The maximum recommended dose is 2,000 Instruct patients with peripheral extravasa-
mg on days 1 and 2 and 1,000 mg on day tions to report arm or hand swelling and
3. The dose should be reduced 50% in pa- stiffness.
tients with creatinine clearance values < Instruct the patient about treatment side
40 ml/min. effects (e.g., nausea/vomiting, diarrhea,
Preparation: Each 500 mg vial of dexrazox- stomatitis, bone marrow suppression, el-
ane must be mixed with 50 ml diluent. The evated liver enzyme levels, infusion-site
patient’s dose is then added to a 1,000 burning).
ml normal saline infusion bag for admin- Monitor the patient’s complete blood count
istration. and liver enzyme levels.
Storage: Store at room temperature be-
tween 15°C–30°C (59°F–86°F).
Antitumor antibiotics Apply ice pack No known antidotes or treatments Assess the extravasation area for pain,
• Mitomycin for 15–20 min- blister formation, and skin sloughing peri-
(Mutamycin®) utes at least odically as needed or in accordance with
• Dactinomycin four times a institutional policy.
(actinomycin D, day for the first In collaboration with the physician or ad-
Cosmegen®) 24 hours. vanced practice nurse, refer the patient
for specialized care when indicated or
needed (e.g., plastic or hand surgery
consult, physical therapy, pain manage-
ment, rehabilitation services).
Plant alkaloids and Apply warm Antidote: Hyaluronidase Administer 150 units of the hyaluroni-
microtubule inhib- pack for 15– Mechanism of action: Degrades hyaluron- dase solution as five separate injections,
itors 20 minutes at ic acid and promotes drug dispersion and each containing 0.2 ml of hyaluronidase,
• Vinblastine least 4 times absorption SC into the extravasation site using a
(Velban®) per day for Preparation: Available hyaluronidase prepa- 25-gauge or smaller needle (change
• Vincristine the first 24–48 rations are needle with each injection).
(Oncovin®) hours. • Amphadase™ (bovine, hyaluronidase in- Assess the extravasation area for pain,
• Vinorelbine Elevate extrem- jection) (Amphastar Pharmaceuticals, blister formation, and skin sloughing peri-
(Navelbine®) ity (peripher- 2005): Vial contains 150 units per 1 ml; odically as needed or in accordance with
al extravasa- use 1 ml of solution. Do not dilute. Use institutional policy.
tions). solution as provided. Store in refrigerator Instruct the patient to monitor the extrava-
at 2°C–8°C (36°F–46°F). sation site and report fever, chills, blister-
ing, skin sloughing, and worsening pain.
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
160 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Table 14. Vesicant Extravasation Management Guidelines (Continued)
Immediate Antidote or Treatment Administration,
Classification/Drug Topical Therapy Antidote or Treatment Patient Monitoring, and Follow-Up
Plant alkaloids and • Hylenex® (recombinant, hyaluronidase Instruct patients with peripheral extravasa-
microtubule inhibi- human injection) (Halozyme Therapeu- tions to report arm or hand swelling and
tors (cont.) tics, Inc., 2012): Vial contains 150 units stiffness.
per 1 ml. Do not dilute. Use solution as
provided. Store in refrigerator at 2°C–8°C
(36°F–46°F).
Taxanes Apply ice pack No known antidote or treatment Docetaxel extravasation may cause hyper-
• Docetaxel for 15–20 min- pigmentation, redness, and tenderness
(Taxotere®) utes at least (sanofi-aventis U.S. LLC, 2007).
• Paclitaxel 4 times a day Paclitaxel is a mild vesicant; extravasa-
(Taxol®) for the first 24 tion may cause induration, blistering,
• Paclitaxel protein- hours. and rarely tissue necrosis (Bristol-Myers
bound particles Squibb Co., 2011; Stanford & Hardwicke,
for injectable 2003).
suspension Protein-bound paclitaxel extravasation
(Abraxane®) has been identified during post-approv-
al use and reported to the manufactur-
er. It is advisable to monitor the infu-
sion site closely for possible infiltration
during administration (Celgene Corp.,
2012).
Assess the extravasation area for pain,
blister formation, and skin sloughing peri-
odically as needed or in accordance with
institutional policy.
Instruct the patient to monitor the extrav-
asation site and to report fever, chills,
blistering, skin sloughing, and worsen-
ing pain.
Instruct patients with peripheral extravasa-
tions to report arm or hand swelling and
stiffness.
fibrosis, atrophy, and local sensory disturbance; all were judged
as mild (Mouridsen et al., 2006).
(2) Anecdotal reports: No clinical trials have been conducted to de-
termine the efficacy of dimethyl sulfoxide, sodium thiosulfate,
hyaluronidase, growth factors, early surgical intervention, saline
washout or flush-out, or hyperbaric oxygen in treating biopsy-con-
firmed vesicant extravasations. Information about these antidotes
and treatments is anecdotal and based on case reports (Dough-
erty & Oakley, 2011; Goolsby & Lombardo, 2006; Schrijvers,
2003; Wickham et al., 2006).
10. Documentation of vesicant extravasation and treatment: Key elements
that may be included in vesicant extravasation documentation are list-
ed in Figure 18. Extravasation treatments/antidotes used should also
be documented.
11. Patient follow-up: Dependent upon individual patient needs and insti-
tutional policies
a) Periodically assess the patient’s response to extravasation treatment.
b) Assessment may include inspection and measurement of the extrava-
sation area, skin integrity, presence of pain or other symptoms, arm/
hand mobility (for peripheral extravasations), and sensation.
c) Obtain follow-up photographs that include the date and time in the
photograph per institutional policy.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 8. Infusion-Related Complications 161
d) In collaboration with the physician or advanced practice nurse, re-
fer the patient for specialized care when indicated (e.g., plastic or
hand surgery consultation, physical therapy, pain management, re-
habilitation services).
e) Instruct the patient to protect the extravasation area from sunlight,
monitor the site, and report fever, chills, blistering, skin sloughing,
and worsening pain.
C. Irritation
1. Irritants: Chemotherapy agents that may inflame and irritate the periph-
eral veins include bleomycin, carboplatin, carmustine, dacarbazine, eto-
poside, floxuridine, gemcitabine, ifosfamide, liposomal daunorubicin,
liposomal doxorubicin, streptozocin, and topotecan (Ener et al., 2004;
Sauerland et al., 2006).
2. Irritants with vesicant properties
a) Oxaliplatin (Eloxatin®)
(1) Has been described as both an irritant (de Lemos & Waliss-
er, 2005; Kennedy, Donahue, Hoang, & Boland, 2003) and
a vesicant (Baur, Kienzer, Rath, & Dittrich, 2000). Case re-
ports describe induration, edema, red-brown skin discolor-
ation, hyperpigmentation, and rare instances of tissue necro-
sis. Kretzschmar et al. (2003) retrospectively reviewed 11 cas-
es of peripheral oxaliplatin extravasation and found that even
with large-volume (≥ 40 mg) extravasations of oxaliplatin, tis-
sue necrosis did not occur.
(2) Pericay et al. (2009) published a case report of a 165 mg dose
of oxaliplatin that extravasated when a noncoring needle dis-
lodged from an implanted port, resulting in edema and skin
discoloration. They concluded that the effect was that of an ir-
ritant rather than a vesicant.
(3) The manufacturer of oxaliplatin states that extravasation
has, in some cases, included necrosis and injection-site re-
actions such as redness, swelling, and pain (sanofi-aventis
U.S. LLC, 2011).
(4) Because cold packs cause local vasoconstriction, they may precip-
itate or worsen the cold neuropathy associated with oxaliplatin.
Figure 18. Key Elements of Vesicant Extravasation Documentation
• Date and time that extravasation occurred or was suspected
• Type and size of peripheral venous access device or type of central venous access device
and gauge/length of noncoring needle (implanted ports)
• Location and patency of peripheral or central venous access device
• Number and location(s) of venipuncture attempts (for peripheral vesicant administration)
• Description and quality of a blood return before and during vesicant administration
• Vesicant administration technique (e.g., bolus, infusion)
• Concentration and estimated amount of extravasated vesicant
• Symptoms reported by patient (e.g., burning, pain)
• Description of administration site appearance including measurement of edema and/or red-
ness if present
• Photographs of administration site that include date and time in the photograph field
• Assessment of extremity (if applicable) for range of motion and discomfort with movement
• Immediate nursing interventions (e.g., topical cooling or heating, physician notification)
• Follow-up recommendations (e.g., referral to plastic surgery, return appointments)
• Patient teaching (e.g., skin assessment, temperature monitoring, reporting pain)
Note. From “Extravasation Management: Clinical Update,” by L. Schulmeister, 2011, Seminars in Oncology
Nursing, 27, p. 85. doi:10.1016/j.soncn.2010.11.010. Copyright 2011 by Elsevier Inc. Reprinted with permis-
sion.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
162 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
(5) A warm pack applied to an oxaliplatin extravasation site is
preferable and may reduce local pain and inflammation (Foo,
Michael, Toner, & Zalcberg, 2003).
(6) High-dose dexamethasone (8 mg twice daily for up to 14 days)
has been reported to reduce oxaliplatin extravasation-related
inflammation (Kretzschmar et al., 2003).
b) Vinorelbine (Navelbine®)
(1) Has been described as both an irritant (de Lemos, 2005;
Rittenberg, Gralla, & Rehmeyer, 1995) and a vesicant (Ener
et al., 2004; Goolsby & Lombardo, 2006; Hadaway, 2007; Sau-
erland et al., 2006). Case reports describe skin discoloration,
chemical phlebitis, localized rash, urticaria, blistering, and rare-
ly, skin sloughing.
(2) The manufacturer of vinorelbine states that it is an irritant, and
extravasation may cause local tissue necrosis or thrombophle-
bitis (Bedford Laboratories, 2005).
(3) Data suggest that rapid IV infusion over 6–10 minutes followed
by a flush of more than 75–124 ml of IV fluid may reduce vinorel-
bine-induced irritation (de Lemos, 2005).
c) Melphalan (Alkeran®)
(1) Information in the literature is conflicting about the risk of extrav-
asation injury associated with melphalan. The drug is listed as nei-
ther an irritant nor a vesicant by Dorr, Alberts, and Soble (1986),
as a possible irritant by Schwartz, Rockey, Surati, and Gullatte
(in press), as an irritant by Ener et al. (2004) and Goolsby and
Lombardo (2006), and as a vesicant by Sauerland et al. (2006).
(2) The manufacturer of IV melphalan states that care should be
taken to avoid possible extravasation, and in cases of poor pe-
ripheral venous access, use of a central venous line should be
considered (GlaxoSmithKline, 2010).
d) Bendamustine hydrochloride (Treanda®): The manufacturer of
bendamustine states that it has received postmarketing reports of
bendamustine extravasation requiring hospitalization for erythe-
ma, marked swelling, and pain, and that precautions should be
taken to avoid extravasation (Cephalon, Inc., 2010). Dilution in
500 ml normal saline, which is recommended by the manufactur-
er, and an infusion time of one to two hours reduced bendamus-
tine-induced venous irritation in a study of 21 patients in Japan
(Watanabe et al., 2013).
e) Irinotecan (Camptosar®): The manufacturer of irinotecan states that
care should be taken to avoid extravasation of irinotecan, and should
extravasation occur, topical flushing of the skin with sterile water and
application of ice are recommended (Pfizer Inc., 2010).
3. Risk factors for irritation
a) Small veins
b) Prior treatment with irritating or sclerosing drugs, such as chemo-
therapy
4. Possible etiologies of venous irritation (Doellman et al., 2009)
a) pH (< 5 or > 9) of infused drugs
b) Hypertonic solutions (e.g., osmolarity > 350 mOsm/L)
c) Concentrated drugs or infusion solutions
5. Signs and symptoms of venous irritation: See Table 13.
6. Management of venous irritation
a) Application of warm pack may reduce local discomfort.
b) Restarting the peripheral IV in a larger vein in another location may
be indicated.
c) Consult a pharmacist to explore diluting irritating medications.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 8. Infusion-Related Complications 163
d) Instruct patients to report the development of a hard cord along the
vein, pain, and temperature elevation.
D. Flare reaction: A flare reaction occurs during peripheral administration of
doxorubicin and is thought to be due to local release of histamine from mast
cells or basophils (Curran, Luce, & Page, 1990). It is characterized by tran-
sient erythema along the vein proximal to the IV site and may be accompa-
nied by pruritus and urticaria. Flare reactions are distinguishable from ex-
travasation by the lack of pain or swelling and the presence of blood return
(Castells & Matulonis, 2012). In the event of a flare reaction,
1. Verify presence of blood return. If absent, assess for signs and symptoms
of extravasation.
2. Flush the vein slowly with saline and observe for resolution of flare, usu-
ally within 45 minutes.
3. If resolution does not occur, obtain an order from an authorized pre-
scriber to administer hydrocortisone or diphenhydramine. For adults,
the diphenhydramine dose is 25–50 mg IV followed by a saline flush.
4. Do not resume the infusion through the IV site until the flare reaction
resolves completely. Consider restarting the IV in another site.
5. If the drug is administered again at a later date, premedication with an
antihistamine and/or corticosteroids may prevent flare reaction (Cas-
tells & Matulonis, 2012).
6. Document the episode, including all treatment(s) and the patient’s re-
sponse, according to institutional policy.
E. Acute infusion reactions: Hypersensitivity, anaphylaxis, and cytokine-release
syndrome
1. Pathophysiology
a) Hypersensitivity and anaphylaxis are mediated by the immune system
and usually are allergic in nature. These reactions may be triggered
by an allergen to which the patient is sensitized. The allergen may be
a chemotherapy or biotherapy agent, its metabolites, or the drug di-
luent (Lee, Gianos, & Klaustermeyer, 2009). The agents cause direct
or immunoglobulin E (IgE)-mediated mast cell degranulation with
release of histamine. Some reactions may be related to complement
activation. Symptoms range from itching at the injection site to sys-
temic shock caused by smooth muscle contraction, increased vascular
permeability, and vasodilation (Soar, 2009). Reactions usually occur
within 5–30 minutes of initiating the dose of chemotherapy but may
occur hours later with some agents (Gobel, 2005; Lee et al., 2009).
b) Cytokine-release syndrome, which is commonly referred to as infusion
reaction, is a symptom complex that occurs in association with mAb
infusions. This type of reaction is related to the release of cytokines
such as IL-2, IFN, and TNF from the targeted cells and other recruit-
ed immune cells, such as lymphocytes (Breslin, 2007).
2. Risk factors for hypersensitivity and anaphylaxis (Gobel, 2005)
a) Administration of a chemotherapy agent known to cause hypersen-
sitivity reactions (see Figure 19)
b) Preexisting allergies, such as to foods, drugs, bee stings (Grosen, Sii-
tari, Larrison, Tiggelaar, & Roecker, 2000), blood products, or radio-
graphic contrast media
c) Previous exposure to the agent
d) Failure to administer known effective prophylactic premedications
3. Risk factors for cytokine-release syndrome: See Figure 20 (Breslin, 2007;
Gobel, 2007; Lenz, 2007).
a) First infusion of mAbs
b) Chemotherapy-naïve patients receiving mAbs
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
164 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Figure 19. Immediate Hypersensitivity Reactions:
Predicted Risk of Chemotherapy
High Potential Occasional Potential Rare Potential
• L-Asparaginase • Anthracyclines • Bleomycin
• Taxanes –– Doxorubicin • Chlorambucil and mel-
–– Paclitaxel –– Daunorubicin phalan
–– Docetaxel –– Idarubicin • Cyclophosphamide and
• Platinum compounds –– Epirubicin ifosfamide
–– Cisplatin • Mercaptopurine • Cytarabine and fludarabine
–– Carboplatin • Azathioprine • Dacarbazine
–– Oxaliplatin • Dactinomycin
• Epipodophyllotoxins • 5-Fluorouracil
–– Etoposide • Hydroxyurea
–– Teniposide • Methotrexate
• Polyethylene glycol-modi-
fied E. coli asparaginase
• Vincristine and vinblastine
Note. From “Chemotherapy-Induced Hypersensitivity Reactions,” by B.H. Gobel, 2005, Oncology Nursing Fo-
rum, 32, p. 1028. doi:10.1188/05.ONF.1027-1035. Copyright 2005 by Oncology Nursing Society. Reprinted
with permission.
Figure 20. Biotherapy Drugs Associated With Hypersensitivity Reactions
and Cytokine-Release Syndromes
Interferon Monoclonal Antibodies
• Interferon alfa • Murine
• Interferon beta (1A and 1B) –– Ibritumomab tiuxetan
• Interferon gamma –– Tositumomab
• Chimeric
Interleukin –– Brentuximab
• Aldesleukin –– Cetuximab
• Denileukin diftitox –– Rituximab
• Humanized
Kinase Inhibitor –– Alemtuzumab
• Temsirolimus –– Bevacizumab
–– Gemtuzumab ozogamicin
–– Trastuzumab
• Fully human
–– Ipilimumab
–– Ofatumumab
–– Panitumumab
Note. Based on information from Bristol-Myers Squibb Co., 2013; GlaxoSmithKline, 2011; Gobel, 2007;
Lenz, 2007; Seattle Genetics, Inc., 2012; Wyeth Pharmaceuticals, 2012.
c) Patients with leukemia or lymphoma, especially those having high
circulating lymphocyte counts (> 25,000/mm3)
4. Preadministration guidelines: Implement the following steps to prevent
and manage hypersensitivity reactions, anaphylaxis, and infusion reactions.
a) Obtain and record baseline vital signs.
b) Review the patient’s allergy history (e.g., food, medication, environ-
ment).
c) Administer premedications as ordered. Common premedications in-
clude histamine (H) blockers (e.g., H1 blocker [diphenhydramine], H2
blocker [ranitidine], acetaminophen (for mAbs), and dexamethasone.
d) Ensure emergency equipment and medications are readily available.
e) Obtain physician orders for emergency treatment before drug ad-
ministration. Written standing orders for management of hypersen-
sitivity and infusion reactions are recommended (Gobel, 2005; Lenz,
2007; Viale, 2009).
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 8. Infusion-Related Complications 165
f) Instruct the patient to report symptoms of hypersensitivity and infu-
sion reaction.
g) Monitor for reactions with each treatment; hypersensitivity reactions
can occur with a patient’s repeated exposure to a drug and at any
time during the infusion or the treatment cycle. For example, the in-
cidence of hypersensitivity reactions with platinum-containing agents
increases with multiple doses and can occur after the drug has been
infused (Gobel, 2005; Lee et al., 2009; Winkeljohn & Polovich, 2006).
h) Perform an intradermal skin test or administer a test dose before
the initial dose of the drug to a patient who has a high likelihood
of a hypersensitivity reaction. For a patient receiving repeated doses
of carboplatin, a valid method of predicting a reaction is a skin test
performed after the sixth dose. False-positive and false-negative skin
tests are possible with oxaliplatin and asparaginase (Lee et al., 2009).
(1) Observe the patient for any local or systemic reaction for a min-
imum of 30 minutes. If no sign of reaction is evident, proceed
with the initial dosing.
(2) When administering an IV drug that is associated with hyper-
sensitivity, observe the patient for signs and symptoms of reac-
tion and be prepared to intervene.
(a) Any patient who has had a severe anaphylactic reaction ac-
companied by hypotension should not be treated again with
that agent except in special circumstances (Viale, 2009).
(b) Avoid administering subsequent doses if a patient is con-
sidered to be sensitized to the drug. If the drug is critical
to the treatment plan, premedication with antihistamines
or corticosteroids (Gobel, 2005; Lenz, 2007) or a desen-
sitization protocol (Cortijo-Cascajares et al., 2013; Lee et
al., 2009; Viale, 2009) may prevent a recurrent hypersensi-
tivity reaction. Discontinuation and drug substitution may
be necessary.
5. Clinical manifestations of anaphylaxis (Soar, 2009) and hypersensitivity
a) Airway compromise, such as tongue or throat swelling, stridor, hoarse-
ness
b) Breathing difficulties, such as shortness of breath, wheezing, cyano-
sis, or respiratory arrest
c) Circulatory compromise, such as tachycardia, hypotension, myocar-
dial ischemia, or cardiac arrest
d) Neurologic changes, such as confusion, agitation, or loss of con-
sciousness
e) Skin and mucosal changes, such as erythema, urticaria, or periorbit-
al or facial edema
f) Abdominal cramping, diarrhea, nausea, and vomiting (less common)
6. Clinical manifestations of cytokine-release syndrome (severe reactions are
characterized by rapid onset and more severe symptoms) (Breslin, 2007)
a) Fever or chills
b) Nausea
c) Hypotension
d) Tachycardia
e) Asthenia
f) Headache
g) Rash
h) Tongue and throat swelling
i) Dyspnea
7. Emergency management of anaphylaxis: Symptoms of reaction usually
arise within 30 minutes of initial administration or increase in infusion
rate (Gobel, 2005). Immediate action is imperative.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
166 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
a) STOP drug infusion immediately.
b) Maintain an IV line with normal saline or another appropriate solution.
c) Stay with the patient. Have another staff member notify the physician
and emergency team, or, if outside the hospital setting, call the local
emergency medical service.
d) Place the patient in a comfortable position: sitting if short of breath
or vomiting, lying flat if hypotensive with elevated legs for shock (sys-
tolic blood pressure < 60 mm Hg).
e) Monitor vital signs (pulse, respirations, blood pressure, oxygen satu-
ration) every 2 minutes until the patient is stable, then every 5 min-
utes for 30 minutes, then every 15 minutes. Monitor electrocardio-
gram (ECG) for serious reactions.
f) Maintain airway, assessing the patient for increasing edema of the re-
spiratory tract. Administer oxygen if needed. Anticipate the need for
cardiopulmonary resuscitation.
g) Administer emergency medications based on symptoms (Sampson et
al., 2006; Soar, 2009) (see Table 15).
h) Provide emotional support to the patient and family.
i) Document all treatments and the patient’s response in the medical
record.
Table 15. Emergency Drugs for Use in Case of Hypersensitivity or Anaphylactic Reactions*
Indication Drug Dose Comments
Bronchial constriction Epinephrine 0.1–0.5 mg IM into thigh (0.1–0.5 IM administration is preferred over IV to min-
(dyspnea, wheezing, ml of 1:1,000 solution or EpiPen® imize adverse cardiac effects. Anterior-lateral
stridor) 0.3 mg automatic device) thigh is preferable to deltoid (may also be ad-
ministered by inhalation or subcutaneously).
May repeat every 5–10 minutes if needed.
Shortness of breath, Oxygen 6–10 L/min by face mask Patients who are hemodynamically unstable
tachypnea (rate > 20 may also benefit from oxygen.
breaths per minute), or
decreased oxygen sat- Albuterol 2.5 mg by inhalation (3 ml of Hold if heart rate is > 110 beats per minute.
uration 0.083% inhalation solution) by neb-
ulizer
Hypotension (> 30% Epinephrine 0.1–0.5 mg IM into thigh (0.1–0.5 IM administration is preferred over IV to min-
decrease in systolic ml of 1:1,000 solution or EpiPen® imize adverse cardiac effects, except in the
blood pressure from 0.3 mg automatic device) or 50– presence of cardiovascular collapse. Cardiac
baseline) 100 mcg IV bolus (0.2 mcg/kg) for monitoring is recommended.
hypotension (0.5–1 ml of 1:10,000
solution)
Normal saline IV 500 ml fluid bolus Over 10 minutes × 1, then as ordered. Mul-
tiple fluid boluses may be required if patient
remains hypotensive despite epinephrine.
Hives, itching, flushing, Diphenhydramine 25–50 mg IVP To counteract the multiple effects of hista-
swollen lips or tongue Famotidine 20 mg IV mine release, both H1 and H2 blockers should
OR be administered.
Ranitidine 50 mg IV
To prevent delayed Methylprednisolone 30–50 mg IV Limited evidence is available to support this
reaction Hydrocortisone 100–500 mg IV recommendation, although steroids have
injection been used frequently.
Dexamethasone 10–20 mg IV
* Additional emergency medications (e.g., sodium bicarbonate, furosemide, lidocaine, naloxone hydrochloride, sublingual nitroglycerine) and emergency
supplies (e.g., oxygen, suction machine with catheters, Ambu® bag) should be available in case of medical emergency.
IM—intramuscular; IV—intravenous; IVP—intravenous push
Note. Based on information from Sampson et al., 2006; Soar, 2009.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 8. Infusion-Related Complications 167
j) Symptoms of anaphylaxis may recur hours after initial interven-
tion; therefore, patients who have experienced a grade 3 or 4 re-
action (NCI CTEP, 2010) should be hospitalized and monitored
closely for 24 hours (Sampson et al., 2006). See Table 16 for grad-
ing criteria.
8. Clinical management of cytokine-release syndrome (Gobel, 2007; Lenz,
2007)
a) Stop infusion, and observe the patient until symptoms resolve, which
usually occurs within 30 minutes.
b) Administer additional H blockers as ordered.
c) Resume infusion at a slower rate (50%) after resolution of symptoms,
and titrate the rate slowly.
d) For severe reactions (Table 16), administer emergency medications
based on symptoms (see Table 15).
9. Clinical management of localized hypersensitivity (Wilkes, 2010)
a) Observe for and evaluate symptoms (e.g., urticaria).
b) Administer diphenhydramine, ranitidine, or corticosteroids per phy-
sician order or according to protocol.
c) Monitor vital signs at least every 15 minutes for 1 hour or as the pa-
tient’s condition requires.
d) Document the episode, including all treatments and the patient’s re-
sponse, according to institutional policies.
F. Patient and caregiver education
1. Before cytotoxic therapy, inform the patient and family that chemother-
apy and biotherapy agents have the potential for early complications. In-
struct them to immediately report signs and symptoms of extravasation,
flare, hypersensitivity, or infusion reactions.
Table 16. Grading Criteria for Allergic Reactions, Anaphylaxis, and Cytokine-Release Syndrome
Grade
Adverse Event 1 2 3 4 5
Allergic reaction Transient Intervention or infu- Prolonged (e.g., not rapidly re- Life-threatening Death
flushing or sion interruption indicat- sponsive to symptomatic medica- consequences; ur-
rash, drug fe- ed; responds promptly to tion and/or brief interruption of in- gent intervention
ver < 38°C (< symptomatic treatment fusion); recurrence of symptoms indicated
100.4°F); inter- (e.g., antihistamines, following initial improvement; hos-
vention not indi- NSAIDs, narcotics); pro- pitalization indicated for clinical se-
cated phylactic medications in- quelae (e.g., renal impairment, pul-
dicated for ≤ 24 hours monary infiltrates)
Anaphylaxis – – Symptomatic bronchospasm, with Life-threatening Death
or without urticaria; parenteral in- consequences; ur-
tervention indicated; allergy-related gent intervention
edema/angioedema; hypotension indicated
Cytokine- Mild reaction; Therapy or infusion in- Prolonged (e.g., not rapidly re- Life-threatening Death
release infusion inter- terruption indicated but sponsive to symptomatic medica- consequences;
syndrome ruption not in- responds promptly to tion and/or brief interruption of in- pressor or ventila-
dicated; inter- symptomatic treatment fusion); recurrence of symptoms tory support indi-
vention not indi- (e.g., antihistamines, following initial improvement; hos- cated
cated NSAIDs, narcotics, IV pitalization indicated for clinical se-
fluids); prophylactic med- quelae (e.g., renal impairment, pul-
ications indicated for ≤ monary infiltrates)
24 hours
IV—intravenous; NSAIDs—nonsteroidal anti-inflammatory drugs
Note. From Common Terminology Criteria for Adverse Events [v.4.03], by the National Cancer Institute Cancer Therapy Evaluation Program, 2010. Re-
trieved from http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
168 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
2. Document all patient teaching. Schulmeister and Camp-Sorrell (2000)
stated that “plaintiffs in extravasation lawsuits typically deny being in-
formed of the risk of extravasation or state that they were led to believe
that the risk was minuscule” (p. 532).
3. After therapy, instruct the patient and family about the importance of
immediately reporting symptoms of any delayed reaction.
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Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9
Side Effects of Cancer
Therapy
A. Myelosuppression: Neutropenia, anemia, and thrombocytopenia
1. Myelosuppression is a condition manifested by a significant decrease in
the number of neutrophils, megakaryocytes, and erythrocytes within the
bone marrow (NCI, n.d.). Myelosuppression is a dose-limiting toxicity
of systemic chemotherapy (Camp-Sorrell, 2011). Terms used in this sec-
tion include the following.
a) Neutropenia: A significant reduction in the absolute number of circu-
lating neutrophils in the blood. The absolute neutrophil count (ANC)
is the basis for neutropenia classification and is generally defined as
an ANC < 1,500 neutrophils/microliter (mcl) (Watts, 2009). NCCN
(2013f) and the Infectious Diseases Society of America (Freifeld et
al., 2011) define neutropenia as < 500 neutrophils/mcl or < 1,000
neutrophils/mcl with the expectation that the neutrophil count will
decline to < 500 neutrophils/mcl over 48 hours. NCI CTEP (2010)
outlines the grading of neutropenia.
(1) Mild: ANC < lower limit of normal (LLN)–1,500 neutrophils/mcl
(2) Moderate: ANC < 1,500–1,000 neutrophils/mcl
(3) Severe: ANC < 1,000–500 neutrophils/mcl
(4) Life-threatening: ANC < 500 neutrophils/mcl
b) Anemia: In adults, anemia is defined as a hemoglobin (Hgb) < 11 g/
dl or > 2 g/dl below baseline (NCCN, 2013c). Other references for
adults in industrialized nations identify 14 g/dl for men and 12 g/dl
for women as lower limits for normal Hgb. A decrease in the hema-
tocrit (Hct) level or number of red blood cells (RBCs) can be used
to define anemia, but Hgb is the value used most often because it re-
flects physiologic consequences of anemia (Means & Glader, 2009).
NCI CTEP (2010) outlines the grading of anemia.
(1) Grade 1: 10 g/dl to < LLN
(2) Grade 2: 8.0–9.9 g/dl
(3) Grade 3: 6.5–7.9 g/dl
(4) Life-threatening: < 6.5 g/dl
c) Thrombocytopenia: Platelet count below the LLN, 400–150 × 109/L
(Liles & Knupp, 2009). NCI CTEP (2010) outlines the grading of de-
creased platelet count.
(1) Mild: < LLN–75,000/mcl
(2) Moderate: < 75,000–50,000/mcl
(3) Severe: < 50,000–25,000/mcl
(4) Life-threatening: < 25,000/mcl
d) Cytopenia: The lack of cellular elements in circulating blood
e) Pancytopenia: A depression of the normal bone marrow elements; white
cells, red cells, and platelets in the peripheral blood (Harmening, 2009)
f) Nadir: Following cytotoxic therapy, the time or level at which the
lowest blood cell count is reached (O’Leary, 2010). The nadir varies 171
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
172 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
with individual agents but usually occurs 7–10 days after treatment
(Camp-Sorrell, 2011).
g) Hematopoiesis
(1) The processes involved in the production of all blood cells
from hematopoietic stem cells (HSCs). In adults, most hema-
topoiesis occurs in the bone marrow in myeloid tissue (see
Figure 21).
(2) The process begins with HSCs, also called pluripotent stem cells
(Bell, Harmening & Hughes, 2009; Koury, Mahmud, & Rhodes,
2009). These are the most primitive type of blood cell and the
source of all hematopoietic cells. Pluripotent stem cells are able
to self-renew and maintain their numbers because they have the
capacity to proliferate, differentiate, and mature into all cell lines.
With each stem cell division, one daughter cell stays in the stem
cell pool while the other daughter cell leaves the stem cell pool
and becomes committed to a distinct cell line. These commit-
ted progenitor cells differentiate and mature in the bone mar-
row. Whether HSCs proliferate or differentiate is determined
by the body’s needs in response to exogenous (e.g., high alti-
tude) or endogenous (e.g., stress, infection, hemorrhage, drug
therapy) influences. Once released into the bloodstream, ma-
ture cells have a varied life span (see Table 17).
2. Most chemotherapy agents cause some degree of myelosuppression. The
degree and duration of chemotherapy-related myelosuppression is re-
lated to the agent’s mechanism of action (e.g., cell cycle–specific drugs
are associated with rapid cytopenias).
3. Neutropenia: Chemotherapy-induced neutropenia (CIN) is the prima-
ry dose-limiting toxicity associated with systemic chemotherapy (Har-
mening, Marty, & Strauss, 2009). It has significant negative clinical con-
sequences for patients with cancer, including life-threatening infections,
prolonged hospital stays, dose reductions, and dose delays.
a) Normal physiology of neutrophils (see Figure 21): Neutrophils and
monocytes stem from the colony-forming unit–granulocyte-macro-
phage progenitor cell. The earliest identifiable cell of the neutrophil
lineage is the myeloblast. Differentiation from a myeloblast to a seg-
mented neutrophil takes 7–11 days. Normal adult bone marrow pro-
duces approximately 1 × 1011 neutrophils each day (Harmening, Mar-
ty, et al., 2009). The major steps of development follow (Bell et al.,
2009).
(1) The pluripotent stem cell gives rise to the myeloblast, the ear-
liest form of the neutrophil. During this phase, the nucleus is
round. At the end of this phase, granules are evident as the cell
transitions to a promyelocyte.
(2) Promyelocytes have a large nucleus, averaging three to five
times larger than the cytoplasm of the cell. During this phase,
the granules begin to fade.
(3) During the myelocyte phase, primary granules decrease and sec-
ondary neutrophilic granules appear. Myelocytes may have nu-
clei that are round, oval, or flattened on one side.
(4) Metamyelocytes are observed with indented nuclei that make
them appear bean-shaped.
(5) Band neutrophils evolve when the indentation of the nucleus
is more than half the width of the nucleus. At this point, the
cell is approximately 24 hours from maturation into a segment-
ed neutrophil. In the presence of acute infection or inflamma-
tion, bands are released early from the marrow and complete
maturation in circulation.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 173
Figure 21. Hematopoiesis
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
174 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Table 17. Life Spans of Blood Components
Blood Component Typical Life Span
Red blood cell 90–120 days
Platelet 8–10 days
Neutrophil < 1 day to approximately 5.4 days
Monocyte 5 days, but dependent on many factors
Macrophage Dependent on many factors
Eosinophil 8–18 hours in blood and 2–5 days in tissue
Basophil 1–2 days
Tissue mast cell Cutaneous: 1 year; mucosal: 1–2 weeks
B lymphocyte Depends on type and subtype
T lymphocyte Depends on type and subtype
Natural killer cell Approximately 10 days
Note. Based on information from Kitamura, 1989; Milot & Filep, 2011; Min et al., 2012; Nayak et al., 2013;
Park & Bochner, 2010; Pillay et al., 2010; Whitelaw, 1966; Zhang, Wallace, et al., 2007.
(6) In the segmented neutrophil phase, the nucleus has two to five
lobes connected to each other by fine strands.
b) Locations of neutrophils (Bell et al., 2009).
(1) The bone marrow of a healthy adult contains both mature seg-
mented neutrophils and immature neutrophils in various stag-
es of development. Neutrophils leave the bone marrow for the
blood through pores that form between the marrow parenchy-
ma and venous blood vessels.
(2) Once in the bloodstream, these cells join the functional
pool by circulating or lining blood vessel walls as marginat-
ed cells, meaning they are adhering to endothelial cells lin-
ing the blood vessel. Neutrophils exist in the bloodstream
as mature and immature cells. These cells perform a critical
role in the body’s defense by generating chemotactic agents
(e.g., endotoxin-activated serum [Anderson, Glover, & Rob-
inson, 1978]) in response to infection. The result is activa-
tion of neutrophil defense and movement of neutrophils to
the site of infection.
(3) Neutrophils leave the blood for tissue by migrating through en-
dothelial cells, a process called diapedesis. After neutrophils enter
the tissue, they do not return to circulation or the bone marrow.
c) Pathophysiology
(1) The bone marrow must constantly produce neutrophils because
the life span of a neutrophil is estimated to be only 7–12 hours
(see Table 17). Chemotherapeutic agents suppress bone mar-
row activity and damage stem cells, preventing them from con-
tinuing the maturation process. Therefore, chemotherapy de-
creases the neutrophil count as mature neutrophils die and are
not replaced (Camp-Sorrell, 2011).
(2) The WBC nadir depends on the specific drugs and dosages
used. A prolonged nadir may occur if stem cells fail to repop-
ulate quickly following high-dose chemotherapy (O’Leary,
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 175
2010). Neutropenia occurs 8–12 days following chemothera-
py and resolves 21–28 days after chemotherapy.
(a) Cell cycle–specific agents (e.g., antimetabolites) are gen-
erally less damaging because they primarily affect cells in
a specific phase of the cell cycle. Severe neutropenia can
develop when cell cycle–specific drugs are used in dose-
intensification and combination chemotherapy regimens
(Camp-Sorrell, 2011).
(b) Cell cycle–nonspecific agents (e.g., alkylating agents, ni-
trosoureas) are damaging to cells in all phases of the cell
cycle, thereby causing more damage to stem cells. The ex-
tent of neutropenia with these agents is dependent on dose,
schedule, and agent. For example, oxaliplatin as a single
agent is expected to cause mild neutropenia, but in regi-
mens with 5-FU and leucovorin, toxicity can be much high-
er (Camp-Sorrell, 2011).
(c) Some cell cycle–nonspecific agents (e.g., nitrosoureas) pro-
duce a delayed and prolonged neutropenia.
i. In adults, nadir occurs at 21–46 days, with recovery at
35–60 days (Wilkes & Barton-Burke, 2012).
ii. In children, nadir with BCNU (carmustine) occurs
at 21–35 days, with recovery at 42–50 days (Hennessy
& Scott, 2008).
d) Risk factors for developing neutropenia: Risk assessment for CIN
should be done prior to each cycle of therapy, including initial ther-
apy (see Figure 22) (NCCN, 2013d; O’Leary, 2010).
e) Fever and febrile neutropenia: Fever is defined as a one-time oral
temperature > 101°F (38.3°C) or oral temperature of 100.4°F
Figure 22. Risk Factors for Developing Febrile Neutropenia
Patient Related
• Older than 65 years
• Female
• Poor performance status
• Poor nutritional status
• Low neutrophil count at the beginning of a treatment cycle
• Renal dysfunction
• Liver dysfunction, especially elevated bilirubin
• Cardiovascular disease
• Recent surgery
• Preexisting infection
• Open wounds
Disease Related
• Advanced disease stage
• Tumor involvement of the bone marrow
• Type of malignancy: hematologic (leukemia, myelodysplastic syndromes), breast, lung,
colorectal, ovarian, and lymphoma
• Preexisting, prolonged, or previous episode of neutropenia
Treatment Related
• Previous myelosuppressive chemotherapy or radiation
• Treatment intent (curative intent rather than palliative)
• Planned relative dose intensity (≥ 85%)
• Use of specific medications (e.g., immunosuppressive drugs)
• Chemotherapy intensity (i.e., dose dense, high dose, myeloablative)
Note. From Putting Evidence Into Practice: Improving Oncology Patient Outcomes; Prevention of Infection (p.
7), by M. Irwin, C. Erb, C. Williams, B.J. Wilson, and L.J. Zitella, 2013, Pittsburgh, PA: Oncology Nursing Soci-
ety. Copyright 2013 by the Oncology Nursing Society. Reprinted with permission.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
176 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
(38°C) lasting one hour. Febrile neutropenia occurs when the ANC
is < 500/mcl or < 1,000/mcl with anticipated decline to < 500/mcl
over the next 48 hours and fever as defined previously (NCCN,
2013f).
f) Risk assessment
(1) Assess for febrile neutropenia risk prior to each treatment cy-
cle (Irwin, Erb, Williams, Wilson, & Zitella, 2013). Increased
infection risk is present in patients with fever in the presence
of neutropenia.
(2) Risk factors for developing febrile neutropenia (NCCN, 2013f)
(a) Advanced age
(b) Low neutrophil count at the beginning of chemothera-
py cycle
(c) Tumor involvement of bone marrow
(d) Poor performance status
(e) Renal dysfunction
(f) Liver dysfunction, especially elevated bilirubin
(g) Previous myelosuppressive chemotherapy or radiation
(h) Preexisting infection, open wounds, or recent surgery
(i) Chemotherapy regimens (e.g., high-dose therapy, dose-
dense therapy)
(j) Use of specific medications including but not limited to
phenothiazines, diuretics, and immunosuppressive drugs
g) Clinical manifestation of infection in patients with neutropenia
(Camp-Sorrell, 2011; Freifeld et al., 2011; NCCN, 2013f; O’Leary,
2010; Shelton, 2011)
(1) A fever > 100.4°F (38°C) is the most reliable, and often the
only, sign of infection in patients with neutropenia. Normal-
ly, WBCs cause the classic signs of infection (e.g., redness,
edema, pus). Extremely neutropenic patients, however, may
not be able to manifest the usual signs of infection (NCCN,
2013f).
(2) Common sites of infection and corresponding signs and symp-
toms in neutropenic patients
(a) GI tract: Fever, abdominal pain, alimentary mucositis (mu-
cositis at any level of the digestive tract), diarrhea
(b) Respiratory tract: Fever, cough, dyspnea on exertion, adven-
titious breath sounds, chest discomfort, asymmetric chest
wall movement, nasal flaring
(c) Genitourinary tract: Fever, dysuria, frequency, urgency, he-
maturia, cloudy urine, flank pain, perineal itching, vagi-
nal discharge
(d) Head and neck: Swelling, itching, redness or drainage of
eyes, pain or discharge of ears, nasal congestion or drain-
age, oral ulcerations, difficulty swallowing, fever
(e) Indwelling devices (e.g., VADs, ventricular peritone-
al shunts): Fever, erythema, pain or tenderness, edema,
drainage, induration at site
(f) Dermatologic and mucous membranes: Erythema, tender-
ness, warm skin, edema (especially in axilla, mouth, sinuses
and perineal or rectal areas), rashes, itching, skin lesions,
fever, draining open wounds
(g) Central nervous system (CNS): Change in mental status,
headache, seizure, vision changes, photosensitivity, fever,
nausea, lethargy
(h) Hematologic/immunologic: Decrease in diastolic blood
pressure, headache, oliguria, fever, flushed appearance
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 177
(3) Septic shock associated with neutropenia has a high mortality
rate (Vusirikala, 2009).
h) ANC calculation: Use laboratory data to assess neutropenia by calcu-
lating the ANC. Note that neutropenia can occur when the total WBC
count is within a normal range (4,000–10,000/mcl) (Camp-Sorrell,
2011). Consequently, calculating the ANC is essential to achieving a
correct assessment of neutrophil status. To calculate ANC, ANC = %
(polys + bands) × WBC.
(1) Obtain complete WBC count including differential. The differ-
ential will include mature neutrophils, also referred to as segs
for segmented neutrophils or PMNs/polys for polymorphonu-
clear neutrophils. In addition, less mature neutrophils will be
present; these are known as bands.
(2) Add the total number of mature polys and less mature neutro-
phil bands.
(3) Convert sum from (2) to a percentage.
(4) Multiply total WBC count by total neutrophil percentage (pol-
ys + bands). ANC calculation example: WBC = 1,500, polys =
30; bands = 5.
(a) Add polys and bands: 30 + 5 = 35.
(b) Convert sum to percentage: 35 ÷ 100 = 0.35 = 35%.
(c) Multiply WBC count by percentage to find ANC: 1,500; ×
0.35 = 525/mcl.
i) Collaborative management
(1) Nurses play an important role in preventing infection in patients
with neutropenia and cancer through evidence-based nursing
practice, research, and patient education (Irwin et al., 2013).
(a) Hand hygiene: Proper hand hygiene is the most effective
measure to prevent the spread of infection. It reduces the
risk of healthcare-associated infections by decreasing per-
son-to-person transmission of pathogens (CDC, 2012; Fre-
ifeld et al., 2011; Irwin et al., 2013).
(b) Diet: No recent studies have linked neutropenic diets (re-
stricting fresh fruits and vegetables) with a lower risk of
infection for neutropenic patients with cancer. Dietary
precautions regarding the omission of fresh fruit and veg-
etables remain unsupported (Gardner et al., 2008). Un-
cooked fruits and vegetables should be thoroughly washed
(Freifeld et al., 2011; Irwin et al., 2013). Basic safe food
handling practices, such as avoiding uncooked and un-
dercooked meats, seafood, and eggs and unwashed fruits
and vegetables, should be employed (Freifeld et al., 2011;
Wilson, 2002).
(c) Environment: Protective or strict isolation studies reveal
no significant differences in documented infections, fe-
brile episodes, or antibiotic use for patients with CIN.
Protective isolation has no effect on the host’s endoge-
nous flora and no impact on organisms transmitted by
water or food (Freifeld et al., 2011).
i. In general, patients with CIN do not require specific
room ventilation.
ii. Allogeneic hematopoietic stem cell transplantation
(HSCT) recipients are recommended to be placed in
rooms with HEPA filtration with > 12 air exchanges
per hour. Air pressure in these rooms should be pos-
itive when compared to surrounding areas, such as
hallways, toilets, and anterooms.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
178 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
(d) Plants and flowers: No research studies are available that
evaluate the potential harm of plants and flowers to pa-
tients with CIN (Irwin et al., 2013).
i. Because fresh or dried flowers could expose patients
with cancer to Aspergillus and Fusarium, they should be
kept out of patient rooms (Freifeld et al., 2011).
ii. If plants must be present, plant care should be done
by staff not directly caring for patients (Sehulster &
Chinn, 2003).
iii. If caregivers are unable to avoid plant care, they should
wear gloves and perform hand hygiene after remov-
ing gloves.
(e) Treatment with colony-stimulating factors (CSFs) (see Ta-
ble 9)
i. Granulocyte macrophage–colony-stimulating factor
(GM-CSF) (sargramostim) (Genzyme Corp., 2009b)
ii. Granulocyte–colony-stimulating factor (G-CSF) (fil-
grastim, pegfilgrastim [Amgen, 2012c, 2013a]). NCCN
(2013d) recommends use of these drugs when the risk
of febrile neutropenia is > 20%.
iii. The manufacturer recommends initiation of G-CSF
no earlier than 24 hours following chemotherapy.
iv. The manufacturer of G-CSF warns that safety of ad-
ministration simultaneously with chemotherapy has
not been established. Rationale is the potential sen-
sitivity of rapidly dividing myeloid cells to cytotoxic
agents (Amgen, 2012c, 2013a).
(f) Preventing trauma to the patient’s skin and mucous mem-
branes (Freifeld et al., 2011; O’Leary, 2010; Shelton,
2011)
i. Provide meticulous care for all indwelling devices.
ii. Prevent pressure sores and constipation.
iii. Change water in pitchers, denture cups, and nebuliz-
ers at least daily.
iv. Consider risk-benefit ratio for invasive proce-
dures (e.g., thoracentesis, paracentesis, VAD place-
ment).
v. Use only an electric razor for shaving.
vi. Protect skin from cuts and burns. Immediately cleanse
and treat any wound that breaks the skin.
vii. Use a soft toothbrush for frequent (minimum of three
to four times daily) oral care. Allow toothbrush to dry
before storing (Brown, 2010).
(g) Protective measures that patients can follow (Brown, 2010;
O’Leary, 2010; Shelton, 2011)
i. Report fever, chills, and other signs and symptoms of
infection at onset.
ii. Personal hygiene
• Wash hands frequently with soap and water or an
antiseptic hand rub. Hands may remain colonized
with microorganisms if they are not dried proper-
ly after washing.
• Bathe daily.
• Avoid activities that may compromise skin integrity.
• Wear gloves when working in the garden.
• Perform frequent (three to four times per day) oral
assessment and care.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 179
• Cleanse the perineal area from front to back after
toileting.
• Avoid exposure to pathogens or people who are ex-
periencing signs and symptoms of contagious con-
ditions.
iii. Protective measures
• Do not share eating utensils.
• Do not eat meat or produce that has not been ei-
ther cooked or washed.
• Adhere to safe food handling practices, and avoid
consuming food when safety of preparation, stor-
age, or serving is not guaranteed.
• Do not provide direct care for pets or farm animals;
avoid contact with animal excreta.
• Refrain from direct or indirect contact with rep-
tiles, fish, and birds.
• Avoid exposure to fresh or dried plants and flow-
ers because of risk of Aspergillus infection. Plant care
may be done by staff not directly providing care to
the patient.
• Do not enter, travel through, or stay in an area of
construction or renovation or where construction
material or debris has been placed or where fields
have recently been plowed.
• Consider vaccination for influenza and pneumo-
nia (CDC, 2011).
• Avoid contact with people who have been vac-
cinated with a live vaccine within the past 30
days.
(2) Management of neutropenic fever: Use of CSFs after a patient
is diagnosed with febrile neutropenia is not recommended (de
Naurois et al., 2010; Freifeld et al., 2011). To manage neutrope-
nic fever, the clinician should take the following steps.
(a) Obtain cultures (NCCN, 2013f).
i. Urine: If symptomatic, with catheter, or if urinalysis
is abnormal
ii. Blood: Two sets (one set includes two bottles). If pa-
tient has a central VAD, options include
• One peripheral and one central VAD, which may
assist in identifying central VAD as the source of
bloodstream infection
• Both peripheral
• Both from central VAD.
iii. Stool: For diarrhea, obtain Clostridium difficile assay
and enteric pathogen screen.
iv. Skin: Aspirate/biopsy skin lesions. Vesicular or ulcer-
ated skin lesions require viral cultures.
v. VAD cutaneous site: Consider routine fungal/Myco-
bacterium culture if inflammation is present.
vi. Throat/nasopharynx: When respiratory viral symp-
toms are present, especially during seasonal outbreaks
(b) Conduct site-specific history and physical examination with
attention to identifying the source of infection (NCCN,
2013f).
i. Assess VADs, skin, lungs, sinus, mouth, pharynx, esoph-
agus, bowel, rectum, and perivaginal and perirectal ar-
eas for signs and symptoms of infection.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
180 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
ii. Obtain historical data including comorbidities, date
and regimen of last chemotherapy, previous infections,
recent antibiotic therapy/prophylaxis, medications,
and human immunodeficiency virus (HIV) status. Ex-
plore exposure risks, including anyone at home with
similar symptoms, pets, travel, recent blood product
transfusion, or exposure to tuberculosis.
(c) Obtain a chest x-ray if respiratory symptoms are present.
(d) Once initial cultures have been obtained, administer em-
piric broad-spectrum antibiotics as ordered until organism
source is identified.
(e) Monitor blood culture reports daily and anticipate antibi-
otic therapy based on findings.
4. Anemia
a) Erythropoiesis: The process of erythrocyte (RBC) production in the
bone marrow (Bell et al., 2009; Dessypris & Sawyer, 2009)
(1) The kidneys are the primary producers of erythropoietin (EPO),
the growth factor that stimulates pluripotent stem cells to pro-
duce RBCs.
(2) RBC production is regulated by oxygen levels. When oxygen
levels are low, the kidney releases EPO to stimulate pluripotent
stem cells to produce more RBCs.
b) Normal physiology of erythrocytes (see Figure 21) (Bell et al.,
2009)
(1) In the bone marrow, the pluripotent stem cell becomes an
erythrocyte via a series of maturation phases that takes about
five days. The five major stages follow.
(a) The earliest identifiable stage is the pronormoblast (rubri-
cyte). These cells take about 12 hours to divide into baso-
philic normoblast daughter cells.
(b) In approximately 20 hours, the normoblast cells contin-
ue maturation marked by accumulation of more RNA and
Hgb. When they divide, they become polychromatophil-
ic normoblasts.
(c) Polychromatophilic normoblasts are smaller than their
precursor cells, and nucleoli are no longer visible. Prolif-
eration is apparent in this phase (about 30 hours) as poly-
chromatophilic normoblasts outnumber cells in earlier
development by 3:1. Under normal circumstances, poly-
chromatophilic normoblasts are absent in adult periph-
eral blood. Small numbers are normal in the peripheral
blood of newborns.
(d) Orthochromatic normoblasts are derived in about 48 hours
from polychromatophilic normoblasts. In this phase, the
nucleus is unable to synthesize DNA, thereby ending cell
division.
(e) In the polychromatophilic erythrocyte (reticulocyte)
phase, the nucleus is phagocytized after being pushed
out of the cell. The reticulocyte either remains in the
bone marrow for several days to mature or is released
and matures in the spleen for one to two days. At this
point, the erythrocyte holds approximately two-thirds of
its Hgb content.
(2) Without a nucleus, mature erythrocytes cannot synthesize Hgb.
They are able to transport oxygen from the lungs to tissue and,
because of their flexible form, move easily through microcir-
culation to do so.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 181
(3) Iron is essential for RBC production. Iron reaches the precur-
sor cells bound to transferrin, where it is used for heme syn-
thesis and stored as ferritin in bone marrow reticuloendothe-
lial cells, liver, and spleen. Dietary sources provide and main-
tain iron stores.
(4) RBC mass and volume: Homeostasis of erythropoiesis is a con-
tinuous process driven by oxygen levels and EPO response. The
average number of circulating RBCs in adults ranges from 4.7–
6.1/mm3 in men and 4.2–5.4/mm3 in women but can vary by
up to 10% (Hughes, 2009).
(5) EPO is a hormone primarily (90%) produced by the peritubu-
lar cells of the kidneys and to a lesser extent in the liver. The
plasma half-life of EPO is six to nine hours. Levels vary as they
respond to internal (e.g., decreased Hgb level) and external
(e.g., high altitude) signals of low oxygen tension within kid-
ney tissue. During anemia or hypoxemia, EPO is secreted into
the plasma and stimulates activity of erythrocyte precursor cells.
As a result, the reticulocyte count is elevated by an early and
increased number of polychromatophilic cells released from
the bone marrow.
(6) RBC life span: A typical RBC has a life span of approximately
120 days in peripheral circulation (see Table 17). It travels 200–
300 miles before being removed in a systematic process by mac-
rophages. The turnover is generally 1% per day. The duration
of RBC life span, time for maturation in the bone marrow, and
low turnover explain why anemia occurs later than neutrope-
nia and thrombocytopenia following myelosuppressive thera-
py (Camp-Sorrell, 2011).
c) Pathophysiology
(1) Many causes for anemia exist in patients with cancer. Myelosup-
pressive therapy, bone marrow involvement, inadequate EPO
levels, and RBC destruction all may contribute to the diagnosis
of anemia (Camp-Sorrell, 2011; Miller, 2010).
(2) Classification of anemia based on RBC size: Mean corpuscular
volume, which reflects the size of RBCs, is used in the differ-
ential diagnosis of microcytic, normocytic, or macrocytic ane-
mia (see Table 18) (Glassman, 2009; Means & Glader, 2009;
Miller, 2010).
d) Incidence
(1) Many patients (40%–70%) experience some degree of ane-
mia during or following systemic chemotherapy (Calabrich
& Katz, 2011). Severity may increase with comorbidities, con-
current radiation therapy, and insufficient nutritional in-
take. The incidence of anemia in patients with hematologic
malignancies has been reported as three times higher than
in those with solid tumors (Birgegård, Gascón, & Ludwig,
2006).
(2) Cancer diagnosis, frequency of treatments, regimen, and dos-
ing schedule all may contribute to onset, severity, and duration
of anemia (Glassman, 2009).
e) Risk factors
(1) Medications that suppress bone marrow function, interfere with
erythrocyte development and function, or suppress EPO pro-
duction (Bottomley, 2009)
(a) Platinum drugs are known to be nephrotoxic (Calabrich
& Katz, 2011).
(b) Biotherapies (e.g., alemtuzumab [Genzyme Corp., 2009a])
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
182 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Table 18. Classifications of Common Cancer-Related Anemias
Anemia Type Description Differential Diagnosis
Microcytic Decreased MCV (< 80 fL) Iron deficiency
RBCs small in size Anemia of chronic disease
Thalassemia minor
Sideroblastic anemia
Normocytic Normal MCV (80–100 fL) Anemia of chronic disease
RBCs normal in size Hemolytic anemia
Aplastic anemia
Renal failure
Macrocytic Increased MCV (> 100 fL) B12 deficiency
RBCs large in size Folate deficiency
Myelodysplastic syndromes
Low reticulocyte Decreased RBC production Anemia of chronic disease
count < 0.5%–1.5% of erythrocytes Aplastic anemia
Iron deficiency
Vitamin B12 deficiency
Folate deficiency
Bone marrow suppression or infiltra-
tion
High reticulocyte Increased RBC destruction Hemolysis
count > 0.5%–1.5% of erythrocytes Chemotherapy-induced
Autoimmune
fL—femtoliters; MCV—mean corpuscular volume; RBC—red blood cell
Note. Based on information from Loney & Chernecky, 2000; Lynch, 2006.
From “Cancer-Related Anemia: Clinical Review and Management Update,” by B. Hurter and N.J. Bush,
2007, Clinical Journal of Oncology Nursing, 11, p. 350. doi:10.1188/07.CJON.349-359. Copyright 2007 by
Oncology Nursing Society. Reprinted with permission.
(c) Antituberculosis agents: Isonicotinylhydrazine (isoniazid),
pyrazinamide, and cycloserine (Bottomley, 2009)
(d) High-dose chemotherapy for HSCT
(2) Malignancies that originate or metastasize to the bone marrow
and suppress RBC precursors
(3) Radiation therapy to areas of the skeleton involved with hema-
topoiesis (NCCN, 2013c)
(4) Acute or chronic blood loss directly related to tumor invasion
(5) Advanced age: Places patients at risk for anemia of malignan-
cy (Mayden, 2011)
(6) Poor nutrition: Anorexia, nausea, vomiting, stomatitis, early
satiety, and diarrhea may contribute to decreased oral intake
and absorption of nutrients. Lack of calorie, protein, vitamin,
and mineral intake, reflected in weight loss or weakness, com-
promises cellular functions, including erythrocyte production
(Cunningham & Huhmann, 2011; Miller, 2010).
(7) Comorbidities
(a) Renal insufficiency: Chemotherapy agents known to have
nephrotoxic properties (e.g., cisplatin, carboplatin) place
patients at risk because kidney function is essential for
EPO production. When EPO levels are low, more hypox-
ia is required to stimulate EPO response (Dessypris &
Sawyer, 2009).
(b) Alcohol abuse and liver dysfunction (Bottomley, 2009)
(c) Cardiopulmonary disease (Means & Glader, 2009; NCCN,
2013c)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 183
(8) Female gender (Spivak, Gascón, & Ludwig, 2009)
f) Clinical manifestations (Means & Glader, 2009)
(1) Cardiopulmonary
(a) Dyspnea, hypoxia
(b) Tachycardia, heart murmurs
(c) Orthostatic hypotension
(2) Integumentary
(a) Pallor of oral mucous membranes, conjunctivae, lips, nail
beds, and palms of hands or soles of feet
(b) Hair loss, thinning, and early graying
(c) Brittle fingernails and toenails
(d) Cyanosis
(e) Hypothermia
(3) Neuromuscular
(a) Headache, dizziness
(b) Drowsiness, restlessness, inability to concentrate
(c) Paresthesias
(d) Fatigue, weakness
(4) Decreased urine output
g) Adverse outcomes (Calabrich & Katz, 2011; Spivak et al., 2009)
(1) Because low tissue oxygenation is related to reduced sensitivi-
ty of tumors to radiation therapy and some chemotherapy, hy-
poxia may adversely affect treatment outcomes.
(2) Low oxygen levels are directly associated with fatigue and weak-
ness and may adversely affect QOL.
(3) Hypoxic tissue promotes angiogenic factors that may contrib-
ute to tumor growth.
(4) Postoperative mortality is increased in the presence of anemia.
(5) Survival times of anemic patients are shorter compared to those
without anemia for most tumor types.
h) Management (Mitchell, 2010a)
(1) Fatigue is an early and frequent symptom of anemia with signif-
icant negative impact on QOL. Interventions should be aimed
at identifying and managing fatigue.
(a) Encourage frequent rest periods to conserve energy.
(b) Use exercise when benefits outweigh risks.
(c) Explore complementary therapies (e.g., relaxation, mas-
sage, healing touch [Mitchell, Beck, Hood, Moore, & Tan-
ner, 2009]) with potential to minimize fatigue.
(d) Assess nutritional intake for adequate content and quan-
tity.
(e) Teach patients and significant others the importance of
hydration.
(2) Monitor laboratory results related to anemia (see Table 19)
and take appropriate action when abnormal (e.g., B12 and iron
deficiencies).
(3) Interventions for hypoxia
(a) Provide supplemental oxygen.
(b) Teach energy conservation.
(c) Consider measures to increase Hgb (Lemoine & Gobel,
2011).
i. Blood transfusions
ii. Erythropoiesis-stimulating agents (ESAs) (see Ta-
ble 20)
iii. The manufacturer’s black box warning is supported
by eight randomized studies that each demonstrat-
ed decreased overall survival and locoregional con-
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
184 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Table 19. Laboratory Assessment of Anemia: Normal Values (Adults)
Laboratory Test Normal Value
Red blood cell count Male: 4.7–6 million cells/mcl; female: 4.2–5.4 million cells/mcl
Hemoglobin Male: 13.5–18 g/dl; female: 12–16 g/dl
Hematocrit Male: 42%–52%; female: 37%–47%
Mean corpuscular volume 78–100 fL
Mean corpuscular hemo- 27–31 pg/cell
globin
Red cell distribution width 11.5%–14%
Reticulocyte count 0.5%–1.85% of erythrocytes
Ferritin Male: 20–300 ng/ml; female: 15–120 ng/ml
Serum iron Male: 75–175 mcg/dl; female: 65–165 mcg/dl
Total iron-binding capacity 250–450 mcg/dl
Serum erythropoietin level Male: 17.2 mU/ml; female: 18.8 mU/ml
Coombs test (direct and Negative
indirect)
Serum B12 190–900 pg/ml
Serum folate > 3.5 mcg/L
Note. Based on information from Cullis, 2011; Knovich et al., 2009; Van Vranken, 2010.
From “Anemia of Chronic Disease,” by B. Faiman in D. Camp-Sorrell and R.A. Hawkins (Eds.), Clinical Man-
ual for the Oncology Advanced Practice Nurse (3rd ed.), in press, Pittsburgh, PA: Oncology Nursing Society.
Copyright 2014 by the Oncology Nursing Society. Reprinted with permission.
trol when ESAs were used in patients diagnosed with
advanced breast, cervical, head and neck, lymphoid,
and non-small cell lung cancer. The FDA implement-
ed a risk management program (known as a risk eval-
uation and mitigation strategy, or REMS), requir-
ing prescribers of ESAs to enroll patients in the ESA
APPRISE (Assisting Providers and Cancer Patients
with Risk Information for the Safe Use of ESAs) On-
cology Program. This program has prescriber and
patient requirements aimed at ensuring safe use of
these agents (Amgen Inc., 2012a; NCCN, 2013c).
5. Thrombocytopenia
a) Normal physiology of platelets (see Figure 21) (Bell et al., 2009)
(1) The thrombocyte (platelet) precursor megakaryocyte is the larg-
est hematopoietic cell descending from the pluripotent stem
cell. The goal of thrombopoiesis is to produce and release ma-
ture platelets so that a normal level (150,000–400,000/mcl) is
circulating at any given time.
(2) The major steps in thrombopoiesis
(a) Maturation begins with megakaryoblasts that increase in
amounts of cytoplasm and nuclear components as they be-
come promegakaryocytes.
(b) During the promegakaryocyte phase, the nucleus contin-
ues to enlarge and becomes lobulated in preparation for
the megakaryocyte phase.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 20. Growth Factors
Mechanism Route of
Classification of Action Drug Administration Indications Side Effects Nursing Considerations
Colony- Stimulates eryth- Darbepoetin SC, IV Treatment of anemia associated with Shortness of breath, cough, Increased risk of death and serious
stimulating ropoiesis via the (Aranesp®) chronic renal failure whether or not the low blood pressure during cardiovascular events exists if ad-
factor same mecha- patient is receiving dialysis dialysis, abdominal pain, ministered when hemoglobin is >
nism as endog- Treatment of anemia in patients where edema of arms and legs, 12 g/dl.
enous erythro- anemia is caused by concomitantly ad- hypertension, skin rash, Ensure adequate iron stores in pa-
poietin ministered chemotherapy and, upon ini- urticaria, pure red cell tients prior to and during use.
tiation, there is a minimum of two addi- aplasia, myalgia, infection, Agent may be administered every 1,
tional months of planned chemotherapy fatigue edema, diarrhea, 2, or 3 weeks, but dosing schedule
thrombotic events should be consistent.
Use lowest effective dose.
Do not shake vials or syringes con-
taining drug.
Store in refrigerator.
Do not freeze.
(Amgen Inc., 2012a)
Stimulates eryth- Epoetin alfa SC Treatment of anemia associated with renal Hypertension, skin rash, ur- Increased risk of death and serious
ropoiesis via the (Procrit®, failure whether or not the patient is re- ticaria, pure red cell apla- cardiovascular events exists if ad-
same mecha- Epogen®) ceiving dialysis sia, myalgia, infection, fa- ministered when hemoglobin is >
nism as endog- Treatment of anemia associated with treat- tigue, edema, diarrhea, 12 g/dl.
enous erythro- ment using zidovudine in HIV-infected thrombotic events Ensure adequate iron stores in pa-
poietin patients tients prior to and during use.
Treatment of anemia in patients with non- Agent may be given three times
myeloid malignancies where anemia is weekly or once weekly.
caused by concomitant use of chemo- Use lowest effective dose.
therapy for minimum of two months Do not shake vials or syringes con-
Chapter 9. Side Effects of Cancer Therapy
Treatment of anemia in patients scheduled taining drug.
to undergo elective noncardiac, nonvas- Store in refrigerator.
cular surgery to reduce the need for allo- Do not freeze.
geneic red blood cell transfusions (Amgen Inc., 2012b; Janssen Prod-
Contraindicated when goal of chemothera- ucts, LP, 2012)
py is curative
185
(Continued on next page)
186
Table 20. Growth Factors (Continued)
Mechanism Route of
Classification of Action Drug Administration Indications Side Effects Nursing Considerations
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Colony- Regulates the Filgrastim SC, IV To decrease the incidence of infection in Allergic reactions including Store in refrigerator.
stimulating production of (G-CSF, patients with nonmyeloid malignancies urticaria, rash, and facial Do not freeze.
factor (cont.) neutrophils with- Neupogen®) who are receiving myelosuppressive edema; acute respirato- Agent may be diluted with 5% dex-
in the bone mar- cancer therapies associated with severe ry distress syndrome, nau- trose in water.
row neutropenic fever sea, vomiting, bone pain Do not dilute with saline solutions.
To reduce the time to neutrophil recovery secondary to rapid growth Do not shake.
and duration of fever following induction of myeloid cells in the Filgrastim is not to be administered in
or consolidation chemotherapy in pa- bone marrow, fever, se- the 24 hours prior to chemotherapy
tients with AML vere sickle-cell crisis in pa- through 24 hours after chemothera-
To reduce the duration of neutropenia and tients with sickle-cell dis- py completion. SC dosing continues
associated sequelae in patients receiv- order; risk of rare splen- daily up to 14 days, until postnadir
ing myeloablative chemotherapy prior to ic rupture ANC > 10,000/mm3 is achieved.
marrow transplant (Amgen Inc., 2013a)
To mobilize hematopoietic progenitor cells
into peripheral blood for collection via
leukapheresis
For chronic administration to reduce the
incidence and duration of sequelae of
neutropenia in patients with congenital,
cyclic, or idiopathic neutropenia
Regulates the Pegfilgrastim SC To decrease the incidence of infection re- Allergic reactions includ- Pegfilgrastim is cleared by neutrophil
production of (Neulasta®) lated to neutropenia in patients with non- ing urticaria, rash, and fa- receptor binding with serum clear-
neutrophils with- myeloid malignancies receiving myelo- cial edema; acute respi- ance directly related to number of
in the bone mar- suppressive chemotherapy ratory distress syndrome, neutrophils. Do not administer in
row nausea, vomiting, bone the period beginning 14 days before
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
pain secondary to rap- until 24 hours after administration of
id growth of myeloid cells cytotoxic chemotherapy.
in the bone marrow, fever, Administer as a single 6 mg injection
sickle-cell crisis in patients once per chemotherapy cycle.
with sickle-cell disorder; in- The 6 mg fixed dose should not be
jection-site reaction; risk of administered to children or adoles-
rare splenic rupture cents weighing < 45 kg.
Store in refrigerator.
Do not freeze.
Do not shake.
(Amgen Inc., 2012c)
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 20. Growth Factors (Continued)
Mechanism Route of
Classification of Action Drug Administration Indications Side Effects Nursing Considerations
Colony- Induces com- Sargramos- SC, IV Following induction chemotherapy in pa- Edema, capillary leak syn- Dilute in NS solution for IV use.
stimulating mitted progeni- tim (GM- tients with AML to shorten neutrophil re- drome, pleural or pericar- Store in refrigerator.
factor (cont.) tor cells to divide CSF, Leu- covery and reduce incidence of infection dial effusions, dyspnea, fe- Do not freeze.
and differenti- kine®) In patients for the mobilization of hemato- ver, abdominal pain, head- Do not shake.
ate in the gran- poietic progenitor cells for collection via ache, chills, diarrhea, oc- Do not administer through in-line fil-
ulocyte-macro- leukapheresis and to speed engraftment casional transient supra- ter.
phage pathways following autologous transplantation of ventricular arrhythmia, Monitor CBC for elevated WBC and
including neu- progenitor cells bone pain secondary to platelet count.
trophils, mono- To accelerate myeloid recovery following rapid growth of myeloid Safety and effectiveness have not
cytes/macro- allogeneic BMT cells in the bone marrow been established for pediatric pa-
phages, and my- In patients with failure of engraftment fol- tients.
eloid-derived lowing BMT (Genzyme Corp., 2009b)
dendritic cells
Leukocyte Binds to G-CSF Tbo-filgras- SC To reduce duration of severe neutropenia Bone pain; allergic reac- Safety and effectiveness has not
growth factor receptors and tim in patients with nonmyeloid malignancies tions including angioneu- been established in patients young-
(short acting) stimulates pro- receiving myelosuppressive anticancer rotic edema, dermatitis, er than age 18.
liferation of neu- drugs associated with a clinically signifi- drug hypersensitivity, hy- Administer first dose no sooner than
trophils cant incidence of febrile neutropenia persensitivity, rash, prurit- 24 hours following chemotherapy
ic rash, and urticaria; sick- or within 24 hours prior to chemo-
le-cell crisis; acute respi- therapy.
ratory distress syndrome; (Teva Pharmaceuticals USA, 2012d)
splenic rupture
Thrombopoi- Stimulation of Oprelvekin SC To prevent severe thrombocytopenia and Anaphylaxis; dilutional ane- Store in refrigerator.
etic growth megakaryocy- (IL-11, Neu- reduce the need for platelet transfusions mia; diarrhea; dizziness; Do not freeze.
Chapter 9. Side Effects of Cancer Therapy
factor topoiesis and mega®) in patients with nonmyeloid malignancies fever; fluid retention result- Reconstitute with sterile water.
thrombopoiesis receiving chemotherapy with high risk of ing in peripheral edema, Should be used within 3 hours of re-
severe thrombocytopenia pulmonary edema, dys- constitution.
pnea, capillary leak syn- Do not shake or freeze following re-
drome, atrial arrhythmias, constitution.
and exacerbation of pre- Protect from light.
existing pulmonary effu- Dosing should begin 6–24 hours af-
sions; headache; nausea, ter completion of chemotherapy.
vomiting; insomnia; rhini- Discontinue when postchemother-
tis; cough; injection-site re- apy platelet nadir > 50,000/mcl and
actions 2 days before next chemothera-
py cycle.
(Wyeth Pharmaceuticals, 2011)
AML—acute myeloid leukemia; ANC—absolute neutrophil count; BMT—bone marrow transplantation; CBC—complete blood count; G-CSF—granulocyte–colony-stimulating factor; GM-CSF—granulocyte macrophage–
187
colony-stimulating factor; HIV—human immunodeficiency virus; IL—interleukin; IV—intravenous; mcl—microliter; NS—normal saline; SC—subcutaneous; WBC—white blood cell
188 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
(c) When the cell reaches the megakaryocyte phase, invagina-
tion of the cytoplasm occurs to begin delineation of indi-
vidual platelets.
(d) When the megakaryocyte completes maturation, its mem-
brane ruptures and all of the cytoplasm separates into
platelets. One megakaryocyte is able to release thousands
of platelets.
(e) Platelets are released into circulation as the cytoplasm
extends through a basement membrane of the bone
marrow. Continued separation of the platelet-form-
ing cytoplasm may occur after the cells reach the sinus.
The life span of circulating platelets is seven to eight
days (see Table 17). There is no reserve in the bone
marrow.
(3) When blood vessel wall integrity is damaged, platelets are
incorporated into the vessel wall and assist the endotheli-
al cells in regaining vessel integrity by releasing platelet-de-
rived growth factor (Harmening, Escobar, & McGlasson,
2009).
(4) Platelet plug formation involves adhesion and aggregation of
platelets in response to vascular damage. Platelets are able to
fulfill this vital role in hemostasis only when normal in num-
ber and function.
(5) Aggregation is a platelet-to-platelet interaction usually occur-
ring 10–20 seconds after loss of vascular integrity and platelet
adhesion.
(6) Secondary hemostasis is accomplished by fibrin clot formation.
If this process is flawed, decreased fibrin production and insta-
bility of the formed clot result.
b) Pathophysiology (Camp-Sorrell, 2011)
(1) Thrombocytopenia after chemotherapy is evident in approxi-
mately 8–14 days and is directly related to bone marrow sup-
pression.
(2) Severity varies with drug, dose, and schedule.
(3) For some agents (e.g., gemcitabine, carboplatin, dacarbazine,
5-FU, lomustine, mitomycin C, thiotepa, trimetrexate), it is a
dose-limiting toxicity.
c) Risks and incidence: The following are known to cause thrombocy-
topenia (Kobos & Bussel, 2008).
(1) Myelosuppressive chemotherapy (e.g., carboplatin, gemcitabine)
or radiation therapy to marrow-producing skeletal sites
(2) Biotherapy (e.g., IFN)
(3) Comorbidities (e.g., liver disease)
(4) Destruction of platelets in the presence of autoimmune disease
(e.g., immune thrombocytopenic purpura) or disseminated in-
travascular coagulation (DIC)
(5) Bone marrow infiltration of primary or metastatic malig-
nancies
(6) Drug therapy affecting platelet function (Rodriguez & Gobel,
2011)
(a) Aspirin
(b) Nonsteroidal anti-inflammatory drugs (NSAIDs)
(c) Quinine and quinidine
(d) Thiazide diuretics (e.g., furosemide)
(e) Benzene and benzene derivatives
(f) Tricyclic antidepressants
(g) Antibiotics
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 189
i. High-dose beta-lactam antibiotics (e.g., piperacillin,
ampicillin)
ii. Cephalosporins and moxalactam
(h) Heparin
(7) Herbal agents (e.g., ginkgo, garlic, ginger, turmeric)
d) Clinical manifestations (Camp-Sorrell, 2011; Rodriguez & Gobel, 2011)
(1) Cardiopulmonary
(a) Adverse changes in peripheral pulses, tachycardia, hypo-
tension, orthopnea
(b) Dyspnea, tachypnea, adventitious breath sounds, hemoptysis
(2) Head and neck
(a) Petechiae of oral or nasal membranes
(b) Epistaxis
(c) Periorbital edema, subconjunctival hemorrhage, eye pain,
blurred or double vision
(3) Integumentary system
(a) Petechia, bruising, pallor, or acrocyanosis anywhere on skin
or mucous membranes
(b) Bleeding from surgical, device, or wound sites
(4) Neurologic
(a) Change in mental status, confusion, restlessness, lethargy
(b) Widening pulse pressure, abnormal change in pupil
size, diminished reflexes, loss of motor strength or co-
ordination
(c) Headache or seizures
(5) Gastrointestinal
(a) Abdominal pain or distention
(b) Rectal bleeding, tarry stools, hematemesis
(c) Enlarged, palpable spleen
(6) Genitourinary
(a) Menorrhagia
(b) Hematuria, dysuria, low urine output
e) Management
(1) Monitor laboratory findings and take appropriate action.
(a) Obtain platelet count, prothrombin time, partial throm-
boplastin time, Hgb, Hct, D-dimer, fibrinogen, and fibrin.
(b) Test stool, urine, and emesis for occult blood.
(2) Maintain safe environment.
(a) Instruct patients to avoid activities that may cause injury.
(b) Assess the home environment and promote the use of non-
skid rugs, nightlights, and ambulatory assistive devices to
prevent falls.
(3) Educate patients and families on ways to maintain skin integri-
ty by (Camp-Sorrell, 2011; Rodriguez & Gobel, 2011)
(a) Using soft toothbrush
(b) Blowing nose gently
(c) Using electric razor versus straight blade razor
(d) Using emery board versus metal nail files
(e) Using water-soluble lubricants for sexual intercourse
(f) Avoiding any sexual activity that may compromise skin or
mucous membrane integrity
(g) Avoiding use of tampons
(h) Using laxatives or stool softeners to avoid constipation
(i) Refraining from using mechanical oral irrigation or aggres-
sive dental flossing
(j) Avoiding dental and other invasive procedures.
(4) Medications and treatments (Rodriguez & Gobel, 2011)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
190 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
(a) Administer platelet transfusions.
(b) Consider administering IL-11 (oprelvekin) (see Table
20).
B. GI and mucosal side effects
1. Nausea and vomiting: Nausea and vomiting (n/v) are two of the
most feared side effects of cancer treatment (NCI, 2011a). Health-
care providers underestimate the incidence of nausea (Grunberg,
2012). Emesis is better controlled than nausea (Basch et al., 2011).
Oncology nurses must be knowledgeable and proactive when treating
CINV.
a) Definitions
(1) Nausea is an unpleasant subjective experience that is de-
scribed as a “wavelike” feeling occurring in the stomach and/
or back of the throat that may be accompanied by vomiting
(NCI, n.d.).
(2) The autonomic nervous system is involved in the development
of n/v. Physical manifestations include tachycardia, diaphoresis,
light-headedness, dizziness, pallor, excess salivation, and weak-
ness (Camp-Sorrell, 2011).
(3) Retching is a rhythmic contraction involving the esophagus, di-
aphragm, and abdominal muscles in an attempt to eject stom-
ach contents. Retching in the absence of vomiting is known as
dry heaves (Camp-Sorrell, 2011).
(4) Vomiting is the forceful expulsion of gastric, duodenum, or je-
junum contents through the mouth (NCI, n.d.).
b) Pathophysiology
(1) Mechanisms of emesis (see Figure 23): Nausea, retching, and
vomiting are independent phenomena that can occur sequen-
tially or as separate entities. The subjective nature of nausea
prevents a clear understanding of it; however, mechanisms of
vomiting related to chemotherapy administration are becom-
ing better understood.
(a) Vomiting results from the stimulation of a complex process
that involves the activation of various pathways and neu-
rotransmitter receptors (see Figures 23 and 24).
(b) Vomiting occurs when certain neural structures in the
brain stem, collectively called the vomiting center (VC),
are stimulated. The VC is activated by the visceral and
vagal afferent pathways from the GI tract, the chemo-
receptor trigger zone (CTZ), the vestibular apparatus,
and the cerebral cortex. Decreased motility and reverse
motility occur when the VC is stimulated (Camp-Sorrell,
2011).
(c) Chemotherapy stimulates enterochromaffin cells, caus-
ing them to release serotonin (5-hydroxytryptamine-3
[5-HT3]). The vagus nerve plays a key role in emesis caused
by chemotherapy, radiation therapy to the epigastrium,
and abdominal distention or obstruction. Serotonin re-
lease causes the activation of the vagus nerve, which stim-
ulates vomiting through either the CTZ or the VC (Camp-
Sorrell, 2011). Serotonin is primarily involved in acute n/v
(Rojas & Slusher, 2012).
(d) The CTZ, a highly vascular area, lies at the surface of
the fourth ventricle, close to the VC. The CTZ is not
confined within the blood-brain barrier. Therefore, it
can detect chemical stimuli in the cerebrospinal fluid
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 191
Figure 23. Mechanics of Emesis
Sensory input (pain, smell, sight) Higher cortical Memory, fear, anticipation
centers
Histamine antagonists
Muscarinic antagonists Benzodiazepines
Dopamine antagonists
Cannabinoids
Neurokinin-1 receptor antagonists
Chemotherapy Chemoreceptor
Anesthetics trigger zone Vomiting center
(area postrema, 4th (medulla)
Opioids
ventricle)
Neurokinin-1 receptor
antagonists
5-HT3-antagonists
Sphincter
modulators
Chemotherapy Labyrinths Surgery
Stomach
Surgery Small intestine
Radiotherapy
Gastroprokinetic Neuronal pathways
agents
Sites of action of drugs
Factors that can cause
nausea and vomiting
and the blood. The CTZ plays a role in CINV as well as
in emesis associated with other causes such as anesthet-
ics and opioids.
(e) Substance P is found in vagal afferent neurons and binds
to neurokinin-1 (NK1) receptors, causing vomiting. Stimu-
lation of the NK1 receptor by substance P is believed to be
the main trigger for delayed n/v, which led to the discov-
ery of aprepitant, an NK1 receptor antagonist.
(f) Motion sickness and labyrinthitis are the most common
stimuli to the vestibular apparatus of the inner ear that in-
duce n/v. The vestibular apparatus may play a minor role
in CINV. Surgery can induce vomiting through stimulation
of the vestibular system.
(g) Memory, fear, anticipation, pain, and an unpleasant smell
can trigger n/v at the cerebral cortex.
(h) Factors that can cause n/v include chemotherapy, biother-
apy, targeted therapy, radiation therapy, surgery, opioids,
and other medications.
(i) Other potential causes of n/v (Rangwala, Zafar, & Aber-
nethy, 2012)
i. Psychophysiologic (e.g., anxiety, anticipatory n/v)
ii. Bowel obstruction (partial or complete)
iii. Vestibular disturbance
iv. Brain metastasis
v. Hypercalcemia, hyperglycemia, or hyponatremia
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
192 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Figure 24. Neuroreceptors
Corticosteroid Dopamine-2
Histamine
Neurokinin-1
Chemoreceptor Trigger Zone,
Vomiting and Vestibular Centers,
Serotonin and GI Tract
(5-HT3) Muscarinic
Cannabinoid
Opioid
Acetylcholine
Note. Based on information from National Comprehensive Cancer Network, 2013b.
vi. Uremia
vii. Gastroparesis
(2) Patterns of therapy-related emesis (NCCN, 2013b)
(a) Anticipatory n/v: A conditioned response that occurs most
commonly before treatment and can be triggered by a par-
ticular smell, taste, or sight
i. Anticipatory n/v can occur during treatment and
may last one to two days after therapy. This usually
is a result of a previous unpleasant experience with
uncontrolled n/v, and it may be worse in patients
with high levels of anxiety. Anticipatory nausea usu-
ally occurs after two or three cycles of chemothera-
py. To minimize the risk of this side effect, adequate
antiemetic control with initial treatments is essen-
tial. Infants and young children usually do not ex-
perience anticipatory n/v.
ii. Incidence: Anticipatory n/v occurs in 18%–57% of pa-
tients as a result of classical conditioning from stim-
uli associated with chemotherapy (e.g., odors, tastes
of drugs, visual cues). Nausea is more common than
vomiting (NCCN, 2013b).
iii. Risk factors that may increase susceptibility to antici-
patory n/v (NCI, 2011a)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 193
• Having a history of poorly controlled CINV with
previous encounters
• Being young or middle-aged (e.g., patients young-
er than age 50)
• Being of female gender
• Having high levels of anxiety prior to and during
treatment
• Feeling warm, hot, dizzy, or sweaty after chemo-
therapy
• Having a susceptibility to motion sickness
• Having a history of pregnancy-induced n/v
• Feeling generalized weakness after chemotherapy
(b) Acute n/v: Starts within minutes to hours after chemother-
apy administration and may last up to 24 hours depending
upon the agent (NCCN, 2013b)
i. The type, dose, route, and administration schedule of
chemotherapy influence the severity and risk of acute
n/v (Roila et al., 2010).
ii. Combination chemotherapy may cause more n/v than
single-agent therapy. Antiemetics for combination
chemotherapy should be administered based on the
agent with the highest emetogenic potential (Basch
et al., 2011).
iii. Incidence is determined by the emetogenicity of
the chemotherapy agents (see Tables 21 and 22)
and whether pretreatment with an antiemetic agent
occurred (Basch et al., 2011; Camp-Sorrell, 2011;
NCCN, 2013b).
iv. Current treatment guidelines published by NCCN
and ASCO are based on four categories of emetogen-
ic potential for IV antineoplastics: high, > 90%; mod-
erate, 30%–90%; low, 10%–30%; and minimal, < 10%
(Grunberg et al., 2011; NCCN, 2013b).
v. Risk factors that increase susceptibility to acute n/v
(NCI, 2011a; NCCN, 2013b)
• Type and dose of antitumor treatment used (see Ta-
bles 21 and 22)
–– Gender: Women experience more acute n/v
than men.
–– Age: Patients older than age 50 experience less
n/v than patients younger than 50.
–– Alcohol use: Patients with a history of chronic
or high alcohol intake generally have less severe
nausea than those without such a history (intake
less than four drinks per week) (Irwin, Lee, Rod-
gers, Starr, & Webber, 2012).
–– Advanced-stage disease
–– Fatigue
–– Pain
–– Tumor burden
–– Concomitant medical conditions (e.g., obstruc-
tion, pancreatitis, hepatic metastases)
–– Presence of strong taste disturbances during che-
motherapy
–– High level of pretreatment anxiety
–– Susceptibility to GI distress
–– Poor performance status
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
194 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Table 21. Emetogenic Potential of Intravenous Antineoplastic Drugs
Incidence Agent Onset (hours) Duration (hours)
High (90%–100%) Cisplatin (> 50 mg/m2) 1–6 24–48+
Dacarbazine 1–3 1–12
Ifosfamide (≥ 10 g/m )
2
– –
Epirubicin (> 90 mg/m ) 2
– –
Doxorubicin (> 60 mg/m ) 2
– –
Mechlorethamine 0.5–2 8–24
Melphalan: high dose 0.3–6 6–12
Streptozocin 1–6 12–24
Cytarabine: high dose (> 1 g/m ) 2
1–4 12–48
Carmustine (> 250 mg/m ) 2
– –
Cyclophosphamide (> 1,500 mg/m ) 2
– –
AC combination (doxorubicin or epirubicin + cyclophos- – –
phamide)
Moderate (30%–90%) Carmustine (≤ 250 mg/m2) 2–4 4–24
Cisplatin (< 50 mg/m2) – –
Cyclophosphamide (< 1,500 mg/m2) 4–12 12–24
Clofarabine – –
Arsenic trioxide – –
Aldesleukin (> 12–15 MIU/m2) – –
Azacitidine – –
Procarbazine 24–27 Variable
Etoposide: high dose 4–6 24+
Carboplatin – –
Busulfan – –
Bendamustine – –
Lomustine 4–6 12–24
Dactinomycin 2–5 24
Daunorubicin – –
Plicamycin 1–6 12–24
Actinomycin D 1–12 24–48
Cytarabine (> 200 mg/m2) 1–12 24–48
Doxorubicin (≤ 60 mg/m2) 4–6 6+
Epirubicin (≤ 90 mg/m2) – –
Idarubicin 6–12 24+
Ifosfamide (< 10 g/m2) – –
Interferon alfa (≥ 10 MIU/m2) – –
Irinotecan – –
Melphalan – –
Methotrexate (≥ 250 mg/m ) 2
1–12 24–72
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 195
Table 21. Emetogenic Potential of Intravenous Antineoplastic Drugs (Continued)
Incidence Agent Onset (hours) Duration (hours)
Moderate (cont.) Temozolomide – –
Oxaliplatin 1–6 24
Low (10%–30%) Aldesleukin (≤ 12 MIU/m2) – –
Cabazitaxel – –
Cytarabine (100–200 mg/m2) – –
Mitoxantrone 4–6 6+
Docetaxel – –
Doxorubicin (liposomal) – –
Eribulin – –
5-Fluorouracil 3–6 24+
Mitomycin C 1–4 48–72
Etoposide – –
Gemcitabine – –
Interferon alfa (> 5–10 MIU/m2) – –
Topotecan 6–12 24–72
Ixabepilone – –
Methotrexate (> 50 mg/m2 but < 250 mg/m2) – –
Paclitaxel, albumin bound – –
Pemetrexed – –
Pentostatin – –
Pralatrexate – –
Romidepsin – –
Thiotepa – –
Paclitaxel – –
Minimal (< 10%) Bleomycin 3–6 –
2-Chlorodeoxyadenosine – –
Alemtuzumab – –
Asparaginase – –
Bevacizumab – –
Bortezomib – –
Cetuximab – –
Cladribine – –
Cytarabine (< 100 mg/m ) 2
6–12 3–12
Decitabine (< 100 mg/m ) 2
– –
Denileukin diftitox – –
Interferon alfa (≤ 5 MIU/m ) 2
– –
Ipilimumab – –
6-Mercaptopurine 4–8 –
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
196 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Table 21. Emetogenic Potential of Intravenous Antineoplastic Drugs (Continued)
Incidence Agent Onset (hours) Duration (hours)
Minimal (cont.) Methotrexate (< 50 mg/m2) 4–12 3–12
Nelarabine – –
Ofatumumab – –
Pegasparaginase – –
Peginterferon – –
Vinblastine 4–8 –
Hydroxyurea – –
Teniposide – –
Vincristine – –
Vinorelbine – –
Fludarabine – –
Rituximab – –
Trastuzumab – –
Temsirolimus – –
Valrubicin – –
AC—anthracycline + cyclophosphamide; MIU—million international units
Note. Based on information from Basch et al., 2011; Grunberg et al., 2011; National Comprehensive Cancer Network, 2013b.
From “Chemotherapy Toxicities and Management” (p. 473), by D. Camp-Sorrell in C.H. Yarbro, D. Wujcik, and B.H. Gobel (Eds.), Cancer Nursing: Principles
and Practice (7th ed.), 2011, Burlington, MA: Jones and Bartlett. Copyright 2011 by Jones and Bartlett. Adapted with permission.
–– History of hyperemesis during pregnancy or morn-
ing sickness throughout pregnancy
(c) Delayed n/v: Occurs at least 24 hours after chemotherapy
administration (NCCN, 2013b).
i. Chemotherapy metabolites may cause increased de-
layed n/v because of an ongoing effect on the CNS
and/or GI tract (Camp-Sorrell, 2011).
ii. Occurs commonly with cisplatin, carboplatin, cyclo-
phosphamide, and doxorubicin
iii. Cisplatin is associated with the highest incidence of
delayed n/v and may last for up to 6 days.
iv. Patients who experience acute n/v are more likely to
have delayed n/v (Roila et al., 2010).
c) Risk factors
(1) Cisplatin-containing regimens (60%–90% of patients) (Roila
et al., 2010)
(2) High-dose chemotherapy
(3) Cyclophosphamide, ifosfamide, doxorubicin
(4) Poorly controlled n/v with prior chemotherapy cycles
d) Assessment: Determine the potential causes of n/v, the specific type(s),
and the level of emetogenicity (see Tables 21 and 22). Refer to Ta-
ble 23 for assessment of n/v.
(1) Chemotherapy (NCCN, 2013b)
(a) Evaluate the emetogenic potential of all chemotherapy
agents the patient will be taking and ensure the patient has
prescriptions for antiemetics.
(b) Use of oral antineoplastic therapy is increasing. It is im-
portant to consider the emetogenic potential of these
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 197
Table 22. Emetogenic Potential of Oral Antineoplastic Drugs
Level Agent
High Hexamethylmelamine
Procarbazine
Moderate Cyclophosphamide
Temozolomide
Vinorelbine
Imatinib
Low Capecitabine
Tegafur-uracil
Etoposide
Sunitinib
Fludarabine
Everolimus
Lapatinib
Lenalidomide
Thalidomide
Minimal Chlorambucil
Hydroxyurea
Melphalan
Methotrexate
6-Thioguanine
Gefitinib
Sorafenib
Erlotinib
L-Phenylalanine mustard
Note. From MASCC/ESMO Antiemetic Guideline 2013 (Slide 16), by Multinational Association of Supportive
Care in Cancer, 2013. Retrieved from http://www.mascc.org/antiemetic-guidelines. Copyright 2013 by Multi-
national Association of Supportive Care in Cancer. All rights reserved worldwide. Reprinted with permission.
drugs and treat as appropriate (NCCN, 2013b) (see Ta-
ble 22).
(2) Biotherapy (IFN or IL-2)
(a) Patients receiving biologic agents may experience n/v as
part of a flu-like syndrome (see Table 9 in Chapter 4).
(b) Biotherapy involving the infusion of mAbs may be associ-
ated with n/v during the infusion.
(3) Targeted therapies: Many targeted drugs, which are primarily
administered orally, have emerged in the past decade. Each one
is unique in terms of mechanism of action and side effects. The
majority of currently FDA-approved targeted drugs are associat-
ed with minimal to low n/v risk (Roila et al., 2010).
(4) Physical causes: Tumor obstruction, gastroparesis, constipation,
increased intracranial pressure, brain metastasis, vestibular dys-
function, uncontrolled pain
(5) Metabolic causes: Hypercalcemia, hyponatremia, hyperglyce-
mia, uremia, increased creatinine
(6) Other medications (e.g., opioids, antibiotics)
(7) Psychological causes: Anxiety, fear, emotional distress
e) Potential complications of n/v
(1) Discomfort
(2) Delay of treatment
(3) Interference with QOL (e.g., impaired mobility, fatigue)
(4) Dehydration
(5) Metabolic disturbances
(6) Anorexia and weight loss
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
198 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Table 23. National Cancer Institute’s Common Terminology Criteria for
Adverse Events: Nausea and Vomiting
Adverse Event Grade Description
Nausea 1 Loss of appetite without alteration in eating habits
2 Oral intake decreased without significant weight loss, dehydra-
tion, or malnutrition
3 Inadequate oral caloric or fluid intake; tube feeding, parenteral
nutrition, or hospitalization indicated
4 –
5 –
Vomiting 1 1–2 episodes (separated by 5 minutes) in 24 hours
2 3–5 episodes (separated by 5 minutes) in 24 hours
3 ≥ 6 episodes (separated by 5 minutes) in 24 hours; tube feed-
ing, total parenteral nutrition, or hospitalization indicated
4 Life-threatening consequences; urgent intervention indicated
5 Death
Note. From Common Terminology Criteria for Adverse Events [v.4.03], by the National Cancer Institute
Cancer Therapy Evaluation Program, 2010. Retrieved from http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03
_2010-06-14_QuickReference_8.5x11.pdf.
(7) Physical debilitation from malnutrition
(8) Straining of abdominal muscles
(9) Increased intracranial pressure
(10) Aspiration
f) Collaborative management—Pharmacologic actions: See Table 24.
(1) The goal of antiemetic therapy is complete control of CINV
(NCCN, 2013b).
(a) Choose antiemetics appropriate to the chemotherapeu-
tic regimen.
(b) Consider level of emetogenicity based on route of admin-
istration and dose administered. Choose antiemetic reg-
imen based on the drug with the highest emetogenicity
along with patient-specific risk factors (Roila et al., 2010).
(c) Patient response to pharmacologic interventions for n/v
may change over time and requires frequent assessment
and modification as appropriate (Basch et al., 2011).
(d) Administer antiemetics to cover the expected emetogenic
period of the chemotherapy agent, considering the dura-
tion and pattern of emesis. Antiemetics should be admin-
istered each day of chemotherapy and for two days after
the completion of chemotherapy as appropriate (Basch et
al., 2011).
(e) Note: Steroids may be contraindicated for patients receiv-
ing biotherapy agents because of their immunosuppressive
effects. This is agent-specific and should be considered pri-
or to use. The benefit of steroids for minimizing hypersen-
sitivity reactions or treating n/v may outweigh the risks re-
lated to immunosuppression. Glucocorticoids are contra-
indicated with IL-2 and IFN therapy (NCCN, 2013b).
(2) To manage acute n/v (NCCN, 2013b)
(a) For patients receiving IV agents categorized as high risk
(> 90% frequency) of emesis: Use a three-drug combina-
tion of a 5-HT3 antagonist, an NK1 antagonist, and a corti-
costeroid before chemotherapy. Alternatively, an olanzap-
ine-containing regimen may be used consisting of olanzap-
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 24. Commonly Used Agents for the Prevention and Treatment of Chemotherapy-Induced Nausea and Vomiting
Mechanism
Classification of Action Drug Route, Dose, and Schedule Indications Side Effects Nursing Considerations
Antipsychotic Action in multi- Olanzapine 2.5–5 mg PO BID Breakthrough n/v Dry mouth, weight gain, Drug is contraindicated in older adult pa-
ple CINV recep- dizziness, sedation tients with dementia.
tor sites
Anxiolytic CNS depressant, Alprazolam 0.5–2 mg PO TID beginning Prevention of anticipato- Sedation, confusion, Decrease starting dose to 0.25 mg PO BID
interferes with the night before treatment ry n/v hyperactivity, agita- or TID in older adult patients, patients with
afferent nerves tion, dizziness, light- advanced liver disease, or patients with
from cerebral headedness, halluci- other pertinent comorbidities.
cortex causing nations
sedation
CNS depressant, Lorazepam 0.5–2 mg PO, sublingual or IV; Prevention of anticipato- Sedation, confusion, Use with caution in older adult patients or
interferes with every 4–6 hours ry n/v hyperactivity, agita- those with hepatic or renal dysfunction.
afferent nerves For anticipatory n/v: 0.5–2 mg In combination with other tion, dizziness, light- Give first dose the night before treatment
from cerebral PO beginning the night be- antiemetics as needed headedness, halluci- and the morning of chemotherapy for an-
cortex causing fore to treatment and the for acute or delayed n/v nations ticipatory n/v.
sedation morning of treatment
Cannabinoid Interacts with Dronabinol 5–10 mg PO every 3 or 6 Treatment of CINV af- Sedation, vertigo, eu- Incidence of paranoid reactions or abnor-
cannabinoid re- hours. ter standard antiemetics phoria, dysphoria, dry mal thinking increases with maximum
ceptors have failed mouth, tachycardia, doses.
orthostasis Use with caution in patients with history of
psychiatric illness.
Nabilone 1–2 mg PO BID Treatment of CINV af- Sedation, vertigo, eu- Incidence of paranoid reactions or abnor-
Maximum recommended dose ter standard antiemetics phoria, dysphoria, dry mal thinking increases with maximum
is 6 mg given in divided dos- have failed mouth, tachycardia, doses.
Chapter 9. Side Effects of Cancer Therapy
es TID. orthostasis Use with caution in patients with history of
psychiatric illness.
Corticoste- Antiprostaglan- Dexametha- 12 mg IV or PO day 1 of che- Prevention of n/v caused Administer slowly over Adding a corticosteroid increases the ef-
roid din synthesis ac- sone motherapy; 8 mg IV or PO by highly and moderate- at least 10 minutes ficacy of antiemetic regimens by 15%–
tivity days 2–4 of chemotherapy ly emetogenic chemo- to prevent perianal 25%. Add dexamethasone to 5-HT3 reg-
therapy or vaginal burning or imens.
Prevention of delayed n/v itching.
Insomnia, anxiety, acne
Dopamine Blocks dopamine Haloperidol 0.5–2 mg PO or IV every 4–6 Prevention of delayed n/v Sedation, extrapyrami- Administering haloperidol with diphenhydra
antagonist receptors hours or treatment of break- dal symptoms, dysto- mine 25–50 mg PO or IV prevents extra-
through n/v nia, dizziness, ortho- pyramidal symptoms; occurs more com-
stasis monly in younger patients.
Drug is highly sedating.
199
(Continued on next page)
200
Table 24. Commonly Used Agents for the Prevention and Treatment of Chemotherapy-Induced Nausea and Vomiting (Continued)
Mechanism
Classification of Action Drug Route, Dose, and Schedule Indications Side Effects Nursing Considerations
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Dopamine Metoclo- 10–40 mg PO or IV every 4–6 Prevention of n/v caused Sedation, extrapyrami- Incidence of drowsiness is greater with high
antagonist pramide hours by moderately emeto- dal symptoms, dysto- doses.
(cont.) genic chemotherapy nia, dizziness, ortho- Drug may cause diarrhea.
Prevention of delayed n/v stasis
or treatment of break-
through n/v
Prochlorper- Doses vary: 10 mg PO or IV Prevention of delayed n/v Sedation, extrapyrami- Drug is not used for pediatric patients.
azine every 4–6 hours or treatment of break- dal symptoms, dysto- Drug is highly sedating.
Also available: 25 mg supposi- through n/v nia, dizziness, ortho-
tories every 12 hours stasis
Neurokinin-1 Neurokinin-1 re- Aprepitant Capsules: 125 mg PO day 1 of Prevention of acute and Constipation, hiccups, Drug is given in combination with a corti-
antagonist ceptor antagonist chemotherapy, then 80 mg delayed CINV in com- loss of appetite, diar- costeroid and 5-HT3 antagonist on day 1
PO days 2 and 3 bination with other anti- rhea, fatigue and a corticosteroid on days 2 and 3.
emetics Consider a 50% dose reduction of oral
methylprednisolone and dexamethasone
and a 25% dose reduction of IV methyl-
prednisolone. (Aprepitant increases the
AUC of steroids 1–3-fold.)
Use with caution in patients receiving che-
motherapy that is primarily metabolized
through CYP3A4.
Efficacy of oral and hormonal contracep-
tives during administration of aprepitant
may be compromised; use alternative or
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
backup contraception method.
Coadministration with warfarin may de-
crease INR; monitor closely.
Consider drug interactions prior to admin-
istration.
Fosaprepitant 150 mg IV day 1 or 115 mg Prevention of acute and Infusion-site reactions Drug is given in combination with a cortico-
dimeglumine day 1 followed by aprepi- delayed CINV (e.g., pruritus, indura- steroid and 5-HT3 antagonist on day 1.
tant 80 mg PO daily on days tion, erythema—3%), Administer over 20–30 minutes in a 150 ml
2 and 3 hypersensitivity, con- normal saline minibag (contraindicated
stipation, hiccups, with lactated Ringer’s solution).
loss of appetite, diar- Consider a 50% dose reduction of oral
rhea, fatigue methylprednisolone and dexamethasone
and a 25% dose reduction of IV methyl-
prednisolone. (Fosaprepitant increases
the AUC of steroids 1–3-fold.)
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 24. Commonly Used Agents for the Prevention and Treatment of Chemotherapy-Induced Nausea and Vomiting (Continued)
Mechanism
Classification of Action Drug Route, Dose, and Schedule Indications Side Effects Nursing Considerations
Neurokinin-1 Neurokinin-1 re- Fosaprepitant Use with caution in patients receiving che-
antagonist ceptor antagonist dimeglumine motherapy that is primarily metabolized
(cont.) (cont.) (cont.) through CYP3A4.
Efficacy of oral and hormonal contracep-
tives during administration of fosaprepi-
tant may be compromised; use alternative
or backup contraception method.
Coadministration with warfarin may de-
crease INR; monitor closely.
Consider drug interactions prior to use.
Serotonin Serotonin recep- Dolasetron 100 mg PO or 100 mg IV 30 Prevention of acute CINV Headache, diarrhea, Dolasetron precipitates with dexametha-
antagonist tor antagonist minutes before chemother- dizziness, fatigue, ab- sone in D5W.
apy normal LFTs Dolasetron can be administered as a rap-
id IV bolus.
Granisetron 2 mg PO or 1 mg PO BID up to Prevention of acute CINV Headache, asthenia, di- Granisetron can be administered by rap-
1 hour before chemotherapy; arrhea, constipation, id IV bolus.
0.01 mg/kg (max 1 mg) IV 30 fever, somnolence, Instruct patients to take oral formulation
minutes before chemotherapy QTc prolongation with milk or food.
Granisetron Transdermal patch containing Prevention of n/v in pa- Constipation; may Drug is contraindicated in patients with
transdermal 34.3 mg of granisetron; one tients receiving mod- mask a progressive known hypersensitivity to granisetron or
(Sancuso®) patch delivers 3.1 mg per 24 erately and/or highly ileus and/or gastric any of the components of the patch.
hours. Apply a single patch emetogenic chemother- distention caused by Remove patch if severe skin reactions oc-
to the upper outer arm a apy for up to 5 consecu- the underlying condi- cur (allergic, erythematous, macular, or
Chapter 9. Side Effects of Cancer Therapy
minimum of 24–48 hours be- tive days tion; headache, skin papular rash or pruritus). Avoid direct ex-
fore chemotherapy. rash, QTc prolonga- posure of application site to natural and
Patch can be worn for up to 7 tion artificial light while wearing the patch and
days (depending upon the for 10 days after removing it.
duration of the regimen). Re-
move patch a minimum of
24 hours after completion of
chemotherapy.
Ondansetron 16–24 mg PO or 8–12 mg IV Prevention of n/v asso- Headache, diarrhea, Ondansetron and dexamethasone are com-
(maximum 32 mg/day); in- ciated with single-day fever, constipation, patible.
fuse IV dose over 15 min- highly and moderately transient increase in
utes; give 30 minutes before emetogenic chemother- SGOT, SGPT, hypo-
chemotherapy. apy in adults tension, QTc prolon-
Orally disintegrating tablet for- gation
mulation: 8 mg
201
(Continued on next page)
202
Table 24. Commonly Used Agents for the Prevention and Treatment of Chemotherapy-Induced Nausea and Vomiting (Continued)
Mechanism
Classification of Action Drug Route, Dose, and Schedule Indications Side Effects Nursing Considerations
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Serotonin Palonosetron 0.25 mg fixed IV dose; infuse Prevention of acute n/v Headache, constipation Mean terminal elimination half-life is ap-
antagonist over 30 seconds; give 30 associated with initial proximately 40 hours.
(cont.) minutes prior to chemothera- and repeated courses Palonosetron is the first 5-HT3 receptor an-
py on day 1. of moderately and high- tangonist approved for delayed n/v.
0.5 mg PO; give once, 30 min- ly emetogenic chemo- Repeat dosing within a 7-day interval is not
utes prior to chemotherapy therapy and the preven- recommended until further evaluated.
on day 1. tion of delayed n/v asso- Drug is not currently used for pediatric pa-
ciated with initial and re- tients.
peat courses of moder-
ately emetogenic che-
motherapy
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
AUC—area under the time-versus-concentration curve; BID—twice daily; CINV—chemotherapy-induced nausea and vomiting; CNS—central nervous system; D5W—5% dextrose in water; 5-HT3—5-hydroxytryp-
tamine-3; INR—international normalized ratio; IV—intravenous; LFT—liver function test; n/v—nausea and vomiting; PO—by mouth; QTc—QT interval corrected; SGOT—serum glutamic-oxaloacetic transaminase;
SGPT—serum glutamic-pyruvic transaminase; TID—three times daily
Note. Based on information from Camp-Sorrell, 2011; Irwin et al., 2012; Merck & Co., Inc., 2009; National Comprehensive Cancer Network, 2013b.
Chapter 9. Side Effects of Cancer Therapy 203
ine, palonosetron, and a corticosteroid. Lorazepam may be
used in combination with the aforementioned antiemetics
to improve control in high-risk regimens. Consider adding
an H2 blocker or proton pump inhibitor.
i. Administration of a corticosteroid with a 5-HT3 an-
tagonist has been found to improve the control of
n/v when compared to a 5-HT3 antagonist alone and
is recommended for acute nausea in highly emeto-
genic regimens by NCCN (2013b), ASCO (Basch et
al., 2011), and the Multinational Association of Sup-
portive Care in Cancer (MASCC) (Roila et al., 2010).
ii. If the antitumor regimen contains steroids (e.g., CHOP),
additional steroids are not needed (NCCN, 2013b).
iii. There is no difference in efficacy between IV and PO
5-HT3 antagonists (Basch et al., 2011).
iv. Anthracycline and cyclophosphamide regimens are
classified as highly emetogenic and should be treated
as such (Basch et al., 2011; NCCN, 2013b).
v. Oral aprepitant (days 1–3) and IV fosaprepitant (day
1 only) have equal efficacy (Basch et al., 2011).
vi. For patients receiving high-dose chemotherapy with
HSCT, a 5-HT3 antagonist combined with a corticoste-
roid is recommended (Basch et al., 2011).
(b) For patients receiving IV agents classified as moderate risk:
Use a two-drug combination of a 5-HT3 antagonist and a
corticosteroid. An NK1 antagonist and lorazepam may be
considered for select patients. Consider adding an H2 block-
er or proton pump inhibitor.
i. NCCN (2013b) guidelines recommend palonosetron as
the preferred 5-HT3 antagonist. If it is not available, an-
other 5-HT3 is acceptable. Alternatively, an olanzapine-
containing regimen may be used consisting of olan-
zapine, palonosetron, and a corticosteroid.
ii. Consider adding an NK1 antagonist for patients in
whom corticosteroids are contraindicated (Basch et
al., 2011).
(c) For patients receiving IV agents classified as low risk: Use
an agent such as a corticosteroid daily, metoclopramide,
prochlorperazine, or an oral 5-HT3 antagonist. Lorazepam
may be added. An H2 blocker or proton pump inhibitor
may be considered (NCCN, 2013b).
(d) For patients receiving IVs agents classified as minimal risk:
No routine prophylaxis is necessary. Ongoing assessment
for the occurrence of n/v should be performed. If n/v oc-
curs, treat per low-risk guidelines (NCCN, 2013b).
(e) For patients receiving oral agents with high to moderate
risk: Use an oral 5-HT3 antagonist daily. Consider loraze-
pam oral or sublingual PRN and an H2 blocker or proton
pump inhibitor (NCCN, 2013b).
(f) For patients receiving oral agents with low to minimal risk:
Administer PRN antiemetics (e.g., metoclopramide, pro-
chlorperazine, haloperidol), and if n/v occurs, add a 5-HT3
antagonist. Consider lorazepam and an H2 blocker or pro-
ton pump inhibitor if appropriate (NCCN, 2013b).
(g) For patients undergoing multiple consecutive days of che-
motherapy: Each day, use antiemetics appropriate to the risk
category of the chemotherapy to be administered that day.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
204 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
(3) To manage delayed n/v (NCCN, 2013b)
(a) Delayed n/v is a significant problem for patients with can-
cer who are receiving chemotherapy; prevention is the pri-
mary goal. NK1 antagonists and longer-acting 5-HT3 antag-
onists can help improve management of n/v in this setting.
(b) For patients at risk for delayed n/v (e.g., patients receiving
cisplatin) (NCCN, 2013b)
i. Use an NK1 antagonist in combination with a cortico-
steroid beginning on day 1 for delayed n/v.
ii. Use a single agent such as a corticosteroid, a 5-HT3
antagonist, or a dopamine antagonist.
iii. Consider adding lorazepam and an H2 blocker or pro-
ton pump inhibitor.
iv. Use a combination of the previously listed antiemetics
based on patient-specific needs (see Table 24).
v. Note: Metoclopramide is rarely used for pediatric pa-
tients.
(4) To manage anticipatory n/v: Use the most active antiemetic reg-
imen appropriate to the chemotherapy being given. Such reg-
imens must be used with the initial chemotherapy rather than
after assessment of the patient’s emetic response to less-effec-
tive treatment.
(a) Benzodiazepines (lorazepam or alprazolam) are the pri-
mary drugs used for the treatment of anticipatory n/v. Ad-
minister beginning the night before treatment (see Table
24) (NCCN, 2013b).
(b) Consider the addition of nonpharmacologic interventions
(e.g., relaxation, music therapy, hypnosis), which can be
helpful in this type of nausea [see g later in this section])
(NCCN, 2013b).
(5) For patients experiencing breakthrough n/v despite optimal
prophylaxis in current or prior cycles, ascertain that the best
regimen is being given based on the emetogenic potential of
the regimen (NCCN, 2013b).
(a) Conduct a careful evaluation of risk, antiemetic agents, dis-
ease, concurrent conditions, and medication factors.
(b) Consider adding an antianxiety agent to the regimen.
(c) Consider adding other antiemetic agents from different
drug classifications, using caution to avoid overlapping side
effects (see Table 24).
(d) Multiple agents used in combination may be required to
control n/v.
(e) Around-the-clock scheduling is suggested (NCCN, 2013b).
(f) Consider adding nonpharmacologic interventions in con-
junction with antiemetics per patient preference.
g) Collaborative management: Nonpharmacologic interventions should
be used in conjunction with antiemetics.
(1) Music therapy is the controlled use of music to influence phys-
iologic, psychological, and emotional responses. Music thera-
py may be beneficial to some patients at risk for CINV (Irwin
et al., 2012). It is often combined with other nonpharmacolog-
ic interventions. If music therapy is used, it should be in con-
junction with antiemetics.
(2) The effectiveness of exercise as an intervention for n/v has not
been established. Further study is warranted (Irwin et al., 2012).
(3) Acupressure wristbands have been used with some success. Acu-
pressure is a form of massage using pressure to localized areas
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 205
to reduce symptoms such as n/v (NCI, 2011a). In a Cochrane
Database systematic review (Ezzo et al., 2006), acupressure was
found to have no significant benefit for delayed n/v. This re-
view found acupressure to have some benefit in acute nausea
but not vomiting.
(4) Acupuncture and electroacupuncture currently are being stud-
ied for the treatment of CINV.
(a) Acupuncture is the insertion of fine-gauge needles at spe-
cific points.
(b) Electroacupuncture is the use of electric pulses with acu-
puncture needles to increase stimulation.
(c) Research is needed to determine which of these treatments
may be more beneficial. Based on the results of studies to
date, acupuncture is likely to be effective for treatment of
CINV when combined with antiemetics. Further study is
needed to determine effectiveness in acute versus delayed
n/v when combined with currently recommended anti-
emetics (Ezzo et al., 2006).
(5) Behavioral interventions such as progressive muscle relax-
ation and guided imagery have been studied either alone or in
combination with pharmacologic agents to prevent or control
CINV. These behavioral methods have shown success and may
be used as adjunct therapies with pharmacologic interventions
(Irwin et al., 2012).
(6) Dietary interventions (NCI, 2011a)
(a) Encourage patients to eat small, frequent meals.
(b) Encourage patients to choose healthful foods.
(c) Encourage patients to avoid overeating.
(d) Medicate patients prior to meals so that the antiemetic ef-
fect is active during and immediately after eating.
(e) Consider medicating with an H2 blocker or proton pump
inhibitor to prevent dyspepsia, as it may mimic nausea.
(f) Encourage patients to avoid fatty, spicy, and highly salted
foods and foods with strong odors.
(g) Determine and repeat past measures that have been effec-
tive in controlling n/v.
(h) Encourage patients to eat cold or room-temperature foods
because these emit fewer odors than hot foods.
(i) Suggest that patients cook meals between chemothera-
py regimens, when they are not nauseated, and freeze the
meals for later use, or suggest that another family mem-
ber cook meals.
(j) Encourage patients to eat favorite foods when not experi-
encing n/v to prevent permanent dislike of these foods.
(k) Use ginger for CINV only per patient preference. Ginger is
thought to function as a 5-HT3 antagonist, NK1 antagonist,
antihistamine, and prokinetic (Haniadka, Rajeev, Palatty,
Arora, & Baliga, 2012). Effectiveness of ginger for CINV
has not been established and requires further study (Irwin
et al., 2012). Additional randomized controlled clinical tri-
als using ginger with patients receiving chemotherapy are
needed to prove safety and benefit (Haniadka et al., 2012).
(l) Initiate dietary consult as needed.
h) Patient and family education
(1) Instruct adult patients to notify the staff if n/v persists for > 24
hours or if they are unable to maintain fluid intake. Ensure that
parents of pediatric patients know to notify staff if vomiting per-
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
206 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
sists for more than two hours. In children, just a few hours of
vomiting can cause dehydration.
(2) Remind patients as necessary to take antiemetics before arriv-
ing for treatment. Ensure that antiemetics have been taken pri-
or to administration of chemotherapy.
(3) Follow up 24–48 hours after outpatient treatment to ensure ad-
herence to and effectiveness of the antiemetic regimen (Camp-
Sorrell, 2011).
(4) Refer patient to educational resources such as NCI’s “Eating
Hints: Before, During, and After Cancer Treatment” (NCI, 2009).
2. Diarrhea
a) Definition: Diarrhea is defined as loose or watery stools. Diarrhea re-
sulting from administration of chemotherapy or specific biotherapy
agents is a frequent problem. Left untreated or inadequately treated,
diarrhea can lead to severe dehydration, hospitalization, treatment de-
lays, dose reductions, and even death (Stein, Voigt, & Jordan, 2010).
b) Pathophysiology: The pathophysiology and etiology of diarrhea in
patients with cancer can be multifaceted. All possible causes of diar-
rhea need to be considered to treat the patient appropriately. The
most common mechanisms of chemotherapy-induced diarrhea are
osmotic, secretory, and exudative (NCI, 2012a).
(1) Osmotic diarrhea: Osmotic diarrhea usually is related to injury
to the gut, dietary factors, or problems with digestion. Water is
drawn into the intestinal lumen, resulting in increased stool vol-
ume and weight. Lactose intolerance is an example of this type
of diarrhea. New-onset lactose intolerance can occur in patients
undergoing cancer treatment (Andreyev, Davidson, Gillespie, Al-
lum, & Swarbrick, 2012; Roy, Komanapalli, Shojamanesh, Bashir,
& Choudhary, 2013). Osmotic diarrhea is associated with large
stool volumes and sometimes is improved with fasting or elimi-
nation of the causative factor (e.g., lactose, sorbitol).
(2) Secretory diarrhea: The small and large intestines secrete more
fluids and electrolytes than can be absorbed. Infection and in-
flammation of the gut; damage to the gut caused by chemo-
therapy, radiation, or GVHD; and certain endocrine tumors
can cause secretory diarrhea. The imbalance between absorp-
tion and secretion leads to production of a large volume of flu-
id and electrolytes in the small bowel. This type of diarrhea is
associated with large volumes and may require a period of bow-
el rest with parenteral nutrition following by slow diet progres-
sion as tolerated (Muehlbauer, 2014).
(3) Exudative diarrhea: This type is caused by alterations in muco-
sal integrity, epithelial loss, enzyme destruction, and defective
absorption of the colon. Mucosal inflammation and ulceration
caused by inflammatory diseases, cancers, and cancer treatment
may result in the outpouring of plasma, proteins, mucus, and
blood into the stool, all of which can result in exudative diar-
rhea. This type of diarrhea is characterized by more than six
stools per day (Field, 2003).
c) Chemotherapy agents presenting the highest risk of diarrhea (Stein
et al., 2010)
(1) Irinotecan
(2) 5-FU
(3) Paclitaxel
(4) Dactinomycin
(5) Capecitabine
d) Examples of chemotherapy agents that may cause diarrhea
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Chapter 9. Side Effects of Cancer Therapy 207
(1) Fludarabine
(2) Cytarabine
(3) Idarubicin
(4) Mitoxantrone
(5) Pentostatin
(6) Floxuridine
(7) Topotecan
(8) Cisplatin
(9) Oxaliplatin
(10) Docetaxel
(11) Pemetrexed
(12) Hydroxyurea
e) Biotherapy agents that may cause diarrhea
(1) IL-2
(2) IFNs
f) Targeted agents that may cause diarrhea
(1) mAbs: Ipilimumab is associated with diarrhea (32%, all grades),
abdominal pain, mucus or blood in stool, and immune-mediat-
ed enterocolitis. Loperamide and corticosteroids are used for
treatment. Discontinuation of ipilimumab may be necessary.
Evaluate abdominal pain with diarrhea for perforation or peri-
tonitis, which has been reported with ipilimumab (Bristol-Myers
Squibb Co., 2013; Rubin, 2012) (see Table 10 in Chapter 4).
(2) Bortezomib
(3) Dasatinib
(4) Erlotinib
(5) Gefitinib
(6) Imatinib mesylate
(7) Lapatinib
(8) Lenalidomide
(9) Sunitinib
(10) Temsirolimus
(11) Thalidomide
(12) Vorinostat
g) Incidence of diarrhea following cytotoxic therapy
(1) The incidence of diarrhea varies greatly depending upon the
agent(s) used.
(2) The specific agent, dose, schedule, and combination with other
anticancer therapies all influence the severity of chemotherapy-
induced diarrhea.
h) Clinical manifestations and consequences: If manifestations are se-
vere, the course of action may be to modify or hold the causative
agent, which could compromise the benefit of the regimen. The clin-
ical manifestations of diarrhea include the following (NCI, 2012a).
(1) Dehydration: Diarrhea dehydrates pediatric patients very quickly.
(2) Orthostasis
(3) Life-threatening hypokalemia, metabolic acidosis, hypercalce-
mia, malnutrition
(4) Cardiovascular or renal compromise
(5) Impaired immune function following frequent episodes of che-
motherapy-induced diarrhea
(6) Perianal skin breakdown, discomfort, or infection
(7) Reduced absorption of oral medications
(8) Pain (abdominal cramping)
(9) Anxiety
(10) Exhaustion
(11) Decreased QOL
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
208 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
i) Risk factors
(1) Radiation therapy to the pelvis, abdomen, or lower thoracic and
lumbar spine can lead to destruction of the cells of the lumen
of the bowel and can be an acute or chronic toxicity.
(2) 5-FU in combination with high-dose leucovorin (500 mg/m2)
or 5-FU administered as a weekly bolus (versus continuous in-
fusion) (Goldberg et al., 2004)
(3) Irinotecan is associated with both acute and delayed diarrhea.
Irinotecan combined with bolus 5-FU and leucovorin is associ-
ated with increased morbidity and mortality related to diarrhea
(Pfizer Inc., 2012a; Stein et al., 2010).
(4) EGFR-targeted therapies (Stein et al., 2010)
(a) Grade 3 and 4 CTCAE (NCI CTEP, 2010) is < 10%.
(b) Cetuximab or panitumumab: Grade 2 is approximately 21%
and grade 3 is 1%–2%.
(c) Small molecule EGFR tyrosine kinase inhibitors (e.g., er-
lotinib, gefitinib, lapatinib): All grades of diarrhea may oc-
cur in up to 60% of patients.
(5) Multitargeted tyrosine kinase inhibitors (Stein et al., 2010)
(a) Sorafenib and sunitinib: 30%–50% incidence (all grades)
(b) Imatinib, a Bcr-Abl protein tyrosine kinase inhibitor: 30%
incidence although severe diarrhea is rare
(6) Immunosuppression
(7) Intestinal resection or gastrectomy
(8) Manipulation of bowel during surgery, which may cause diar-
rhea or ileus
(9) Intestinal infection secondary to mucositis and neutropenia
(e.g., infection with Rotavirus, Escherichia coli, Shigella, Salmonel-
la, Giardia, or Clostridium difficile)
(10) GVHD
(11) Dietary causes (e.g., lactose intolerance; ingestion of caffeine, alco-
hol, or spicy or fatty foods; use of hyperosmotic dietary supplements)
(12) Inflammatory conditions, such as diverticulitis, irritable bowel
syndrome, or ulcerative colitis
(13) Malabsorption, partial bowel obstruction, bowel edema, mo-
tility disruption
(14) Anxiety and stress
j) Assessment: Accurate assessment is vital in determining the cause
and type of diarrhea; knowing the cause and type can be crucial to
proper treatment.
(1) Mistakenly using an antidiarrheal to treat diarrhea caused by
infection can intensify diarrhea severity and infectious compli-
cations (Curry, 2013).
(2) Irinotecan causes two distinct forms of diarrhea (early and late
onset), and each requires a different management strategy (see
Table 7 in Chapter 3).
(3) Fluoropyrimidine-induced diarrhea (e.g., 5-FU) risk factors
(Stein et al., 2010)
(a) Female gender
(b) Caucasian race
(c) Presence of diabetes
(4) Assess stool.
(a) Assess the pattern of elimination and stool character in re-
lation to treatments (e.g., onset, duration, frequency, con-
sistency, amount, odor, color).
(b) Assess for presence of nocturnal diarrhea, which can be
associated with diabetic autonomic neuropathy or infec-
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 209
tions. Loss of sleep or interrupted sleep during the night
may increase fatigue.
(c) Grade diarrhea according to CTCAE criteria (NCI CTEP,
2010). See Table 25.
(d) Check for presence of blood or mucus in the stools.
(e) Monitor the patient for incontinence.
(5) Conduct a physical examination: The presence of fever, blood in
the stool, abdominal pain, weakness, or dizziness warrants medical
attention to rule out infection, bowel obstruction, and dehydration
(Benson et al., 2004). The steps of a physical examination follow.
(a) Auscultate for bowel sounds.
(b) Palpate and assess the abdomen.
(c) Assess for fecal impaction. Avoid manual rectal assessment
in patients who are thrombocytopenic or neutropenic.
(d) Look for signs of malnutrition, dehydration, electrolyte im-
balance, and infectious process.
(e) Ask about pain experienced during or after defecation.
(f) Assess for fever, weakness, and dizziness.
(g) Determine if blood has been present in the stool (occult
or gross).
(h) Assess perianal area for skin breakdown and signs and symp-
toms of infection.
(6) Take a diet history (Engelking, 2008).
(a) Determine if dietary habits have changed. Be especially
aware of clues that indicate rapidly increased amount of
fiber in the diet.
(b) Assess for intake that could contribute to diarrhea (e.g., ir-
ritating foods, alcohol, coffee, fiber, fruit, lactose-contain-
ing foods/fluids, sorbitol-based gum, candy, herbal teas
that may contain laxatives).
(c) Assess for food or lactose intolerance or allergies.
(7) Take a medication history: Assess for use of the following (Mi-
cromedex, 2013; Muehlbauer, 2014).
(a) Antacids (especially those containing magnesium)
(b) Antibiotics
(c) Antihypertensives
Table 25. National Cancer Institute’s Common Terminology Criteria
for Adverse Events: Diarrhea
Grade Description
1 Increase of < 4 stools/day over baseline; mild increase in ostomy output compared
to baseline
2 Increase of 4–6 stools/day over baseline; moderate increase in ostomy output com-
pared to baseline
3 Increase of ≥ 7 stools/day over baseline; incontinence; hospitalization indicated; se-
vere increase in ostomy output compared to baseline; limiting self-care ADL*
4 Life-threatening consequences; urgent intervention indicated
5 Death
* Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications,
and not bedridden.
ADL—activities of daily living
Note. From Common Terminology Criteria for Adverse Events [v.4.03], by the National Cancer Institute
Cancer Therapy Evaluation Program, 2010. Retrieved from http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03
_2010-06-14_QuickReference_8.5x11.pdf.
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210 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
(d) Potassium or calcium supplements
(e) Diuretics
(f) Caffeine
(g) Theophylline
(h) NSAIDs
(i) Antiarrhythmic drugs
(j) Laxatives or stool softeners
(k) Promotility agents (metoclopramide)
(l) Magnesium oxide
(8) Assess for other possible contributing factors.
(a) Travel history (outside the United States)
(b) Use of alternative therapies (e.g., dietary supplements,
herbal remedies)
(c) Opioid withdrawal
(9) Take objective measurements (Engelking, 2008).
(a) Monitor intake and output.
(b) Monitor weight.
(c) Monitor laboratory data.
i. Check stool culture results for presence of infection.
ii. Check serum chemistries for electrolyte imbalance,
specifically potassium. Albumin may be decreased
with diarrhea.
iii. Assess complete blood count (CBC) to determine if
neutropenia or infection is present.
(d) Check skin turgor.
(e) Check vital signs.
k) Collaborative management
(1) Monitor number, amount, and consistency of bowel move-
ments. For patients with colostomies, an increase in the num-
ber of loose stools daily should be monitored to assess for che-
motherapy-induced diarrhea.
(2) Replace fluid and electrolytes, including potassium. Electrolytes
and fluids are absorbed in the small intestine. When diarrhea
occurs, these substances quickly pass through the small intes-
tine without being absorbed. This can cause severe fluid and
electrolyte disturbances.
(3) Administer antidiarrheal medication as appropriate once in-
fection has been ruled out. This will reduce stool frequency,
volume, and peristalsis. Reassess the severity of chemotherapy-
induced diarrhea at the appropriate interval after antidiarrheal
medication. Table 26 lists antidiarrheal medications.
(a) NCCN currently does not have a guideline for management
of chemotherapy-induced diarrhea.
(b) Loperamide and octreotide are the only drugs that have es-
tablished efficacy in chemotherapy-induced diarrhea. Fur-
ther study is warranted to define the role of other pharma-
cologic interventions (Muehlbauer et al., 2009).
(4) Consider the use of antibiotics for patients with persistent diar-
rhea and signs of infection (Benson et al., 2004).
(5) Probiotics: The role of probiotics in chemotherapy-induced
diarrhea is an area of investigation. The appropriate strain(s),
dosage, and administration schedules need to be determined
(Guandalini, 2011; Muehlbauer et al., 2009).
(6) See Figure 25 for an example of chemotherapy-induced diar-
rhea treatment guidelines.
l) Patient and family education (Muehlbauer, 2014; NCI, 2012a): Pro-
vide the following instructions.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 26. Common Antidiarrheal Medications
Classification Mechanism of Action Drug Route, Dose, and Schedule* Side Effects* Nursing Considerations*
Antimotility Slows GI transit time Diphenoxylate HCl Adults: Individualize dosage. Initial Dry mouth, urinary re- Invasive bacterial diarrhea, pseudomembranous
agents and promotes reab- with atropine sul- dose is 10 mg followed by 5 mg PO tention, confusion, se- colitis
sorption of water from fate (Lomotil®) QID; maximum dose is 20 mg/day. dation, restlessness In patients with advanced liver disease, drug may
bowel; antiperistaltic precipitate hepatic coma.
Do not use in children younger than age 2.
Loperamide Adults: 4 mg PO initially, followed by Constipation, fatigue, Invasive bacterial diarrhea
(Imodium® A-D) 2 mg PO after each unformed stool; urinary retention, Do not use in children younger than age 2.
do not exceed 16 mg/day. Exception: drowsiness, dizziness
Doses are higher for late-onset irino-
tecan-induced diarrhea (2 mg every
2 hours).
Somatostatin Inhibits growth hor- Octreotide (Sand- Adults: 100–150 mcg SC or IV TID. Abdominal discomfort, Drug may interact with insulin, oral hypoglycemic
analog mone, glucagon, and ostatin®) Doses may be escalated to 500 mcg flatulence, constipation, medications, beta-blockers, or calcium channel
insulin; prolongs intes- SC or IV TID or by continuous IV infu- diarrhea, nausea, diz- blockers. Insulin requirements may be decreased.
tinal transit time; in- sion 25–50 mcg/hr. ziness, headache, car- Observe for hyperglycemia/hypoglycemia.
creases sodium and diac dysrhythmias, bra- Drug may decrease levels of cyclosporine when
water absorption dycardia given concurrently.
Drug may increase risk of developing gallstones.
Recommended after failure of Imodium or in pa-
tients with complicated diarrhea. Complicated di-
arrhea is defined as involving abdominal cramp-
ing, nausea and vomiting, fever, sepsis, neutrope-
nia, or bleeding.
Sandostatin LAR Depot is under investigation for
the treatment of chemotherapy-induced diarrhea.
Chapter 9. Side Effects of Cancer Therapy
Anticholinergic Antagonist of acetyl- Atropine Adults: Used for early-onset choliner- Dry mouth, blurred vi- Antacids interfere with absorption of atropine.
choline gic diarrhea (e.g., irinotecan induced), sion, photophobia, con- Drug is contraindicated in patients with closed-
0.25–1 mg PO or SC stipation, xerostomia, angle glaucoma.
tachyarrhythmia
* Consult product information for complete list of contraindications, drug interactions, and dosage ranges.
GI—gastrointestinal; IV—intravenous; PO—oral; QID—four times daily; SC—subcutaneous; TID—three times a daily
Note. Based on information from Benson et al., 2004; Engelking, 2008; Gibson & Stringer, 2009; Micromedex, 2013; Stein et al., 2010; and manufacturers’ prescribing information.
211
212 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Figure 25. Proposed Algorithm for the Assessment and Management of Treatment-Induced Diarrhea
EVALUATE
• Obtain history of onset and duration of diarrhea
• Describe number of stools and stool composition (e.g., watery, blood in stool, nocturnal)
• Assess patient for fever, dizziness, abdominal pain/cramping, or weakness (i.e., rule out
risk for sepsis, bowel obstruction, dehydration)
• Medication profile (i.e., to identify diarrheogenic agents)
• Dietary profile (i.e., to identify diarrhea-enhancing foods)
UNCOMPLICATED ADDED RISK FACTORS COMPLICATED
CTC grade 1–2 diarrhea CTC grade 3 or 4 diarrhea or grade
with no complicating 1 or 2 with one or more of the follow-
signs or symptoms ing signs or symptoms
• Cramping
• Nausea/vomiting (≥ grade 2)
MANAGEMENT • Decreased performance status
• Stop all lactose-containing products, alcohol, and high-osmolar supplements • Fever
• Drink 8–10 large glasses of clear liquids a day (e.g., Gatorade or broth) • Sepsis
• Eat frequent small meals (e.g., bananas, rice, applesauce, toast, plain pasta) • Neutropenia
• Instruct patient to record the number of stools and report symptoms of life-threatening sequelae • Frank bleeding
(e.g., fever or dizziness upon standing) • Dehydration
• For grade 2 diarrhea, hold cytotoxic chemotherapy until symptoms resolve and consider dose
reduction
TREATMENT
• Administer standard dose of loperamide: initial dose of 4 mg followed by 2 mg every 4 hours or
after every unformed stool
• Consider clinical trial
Progression to severe diarrhea
(NCI grades 3–4 with or without
Reassess 12–24 hours later Diarrhea unresolved fever, dehydration, neutropenia,
and/or blood in stool)
Diarrhea resolving Persistent diarrhea (NCI grades 1–2)
• Continue instruction for dietary modification • Administer loperamide 2 mg every 2 hours
• Gradually add solid foods to diet • Start oral antibiotics
• Discontinue loperamide after 12-hour diarrhea- • Observe patient for response
free interval RT-induced: Oral antibiotics not generally recom-
RT-induced: Continue loperamide mended
Reassess 12–24 hours later
Diarrhea resolved Progression to severe diarrhea
• Continue instructions for dietary modification (NCI grades 3–4 with or without
• Gradually add solid foods to diet Diarrhea unresolved fever, dehydration, neutropenia,
• Discontinue loperamide after 12-hour diarrhea- and/or blood in stool)
free interval
RT-induced: Continue loperamide
Persistent diarrhea (NCI
grades 1–2) (no fever, de-
hydration, neutropenia,
and/or blood in stool) ADMIT TO HOSPITAL*
• Administer octreotide (100–150 mcg SC
TID or IV [25–50 mcg/hr] if dehydration
is severe with dose escalation up to 500
EVALUATE IN OFFICE/OUTPATIENT CENTER mcg TID)
• Check stool workup (blood, fecal leukocytes, Clostridium difficile, Salmonella, Escherichia coli, • Start IV fluids and antibiotics as needed
Campylobacter, infectious colitis) (e.g., fluoroquinolone)
• Check CBC and electrolytes • Stool workup, CBC, and electrolyte pro-
• Perform abdominal exam file
• Replace fluids and electrolytes as appropriate • Discontinue cytotoxic chemotherapy until
• Discontinue loperamide and begin second-line agent all symptoms resolve; restart chemother-
––Octreotide (100–150 mcg SC TID with dose escalation up to 500 mcg TID) apy at reduced dose
––Other second-line agent (e.g., tincture of opium)
RT-induced: Continue loperamide or other oral agent; no workup required
* For radiation-induced cases and select patients with chemotherapy-induced diarrhea consider intensive outpatient management, unless the patient has
sepsis, fever, or neutropenia.
CBC—complete blood count; CTC—Common Toxicity Criteria; NCI—National Cancer Institute; RT—radiotherapy; SC—subcutaneous; TID—three times
daily
Note. Based on information from Benson et al., 2004.
From “Management of Cancer Treatment–Related Diarrhea Issues and Therapeutic Strategies,” by S. Kornblau, A.B. Benson III, R. Catalano, R.E. Cham-
plin, C. Engelking, M. Field, … S. Wadler, 2000, Journal of Pain and Symptom Management, 19, p. 125. Copyright 2000 by U.S. Cancer Pain Relief Com-
mittee. Adapted with permission.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 213
(1) Start antidiarrheal medications at the specified time. With
certain chemotherapeutic agents, antidiarrheal medication
should be provided so that patients can self-administer at
the onset.
(2) Avoid foods high in insoluble fiber (e.g., raw fruits and vegeta-
bles), greasy or fried foods, lactose, skins, seeds, legumes, caf-
feine, alcohol, and hyperosmotic liquids (Muehlbauer et al.,
2009). These may be stimulating or irritating to the GI tract.
(3) Include foods high in soluble fiber or pectin in their diets and
low insoluble fiber foods such as rice noodles, bananas, white
toast, skinned turkey or chicken, fish, and mashed potatoes
(Muehlbauer et al., 2009).
(4) Maintain fluid intake by drinking 8–10 large glasses each day of
clear fluids (e.g., bouillon; weak, tepid decaffeinated tea; gel-
atin; sports drinks). Water alone lacks the needed electrolytes
and vitamins. Carbonated and caffeinated drinks contain rela-
tively few electrolytes and may worsen diarrhea. Fluids with glu-
cose are useful because glucose absorption drives sodium and
water back into the body.
(5) Limit the use of sugar-free candies or gum made with sugar al-
cohol (sorbitol) (NCI, 2012a).
(6) Eat food at room temperature if not tolerated otherwise. Hot
and cold foods may aggravate diarrhea.
(7) Limit or avoid milk and dairy products.
(8) Avoid hyperosmotic supplements (e.g., Ensure®), which can con-
tribute to the production of loose, high-volume stools (Muehl-
bauer et al., 2009).
(9) Clean the rectal area with mild soap and water after each bowel
movement, rinsing well, and patting dry with a soft towel. Clean-
ing decreases the risk of infection and skin irritation.
(10) Apply moisture-barrier ointment to protect perianal skin.
(11) Take warm sitz baths to relieve pain related to perianal inflam-
mation. Anesthetic creams or sprays may help to relieve pain
related to inflammation.
(12) Understand when diarrhea can be self-managed and when to
seek help.
(13) Report excessive thirst, fever, dizziness or light-headedness, pal-
pitations, rectal spasms, excessive cramping, watery or bloody
stools, and continued diarrhea despite antidiarrheal treatment.
These symptoms can be life threatening.
3. Mucositis: Mucositis is a common complication of both systemic cytotox-
ic therapy and radiation therapy. Severe mucositis is reported in > 90%
of patients with head and neck cancer who are receiving concurrent che-
motherapy and radiation (Sonis, 2011) and in the majority of patients
undergoing HSCT (Raber-Durlacher, Elad, & Barasch, 2010). It is asso-
ciated with decreased QOL and increased risk of infections, hospitaliza-
tions, opioid use, parenteral nutrition, and dose reductions and delays
(Murphy, 2007; Rosenthal, 2007).
a) Definitions
(1) Mucositis: A general term referring to inflammation of any mu-
cosal membranes, including the oral cavity
(2) Stomatitis or oral mucositis: Any inflammatory condition of oral
tissue including mucosa, dentition, periapices, and periodonti-
um (Eilers & Million, 2011). Stomatitis includes oral infections.
(3) Alimentary tract mucositis: Inflammation and mucosal damage
occurring in the mouth (stomatitis) and extending the entire
length of the alimentary tract
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
214 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
b) Pathophysiology: Oral mucositis traditionally has been attributed to
the direct effects of cytotoxic drugs or radiation on epithelial stem
cells. More recently, evidence has suggested that microvascular inju-
ry and connective tissue damage in the submucosa precede epithe-
lial damage. Oral mucositis is now described as having five phases
(Sonis, 2011).
(1) Initiation: Stomatotoxic drugs and radiation therapy generate
reactive oxygen species that damage DNA, resulting in cell, tis-
sue, and blood vessel damage in the mucosa.
(2) Upregulation and generation of messenger signals: Che-
motherapy and radiation therapy activate nuclear factor-кB
(NF-кB). This results in upregulation of a large number of genes
and release of proinflammatory cytokines, such as TNF-alpha
(TNF-α), IL-1 beta (IL-1β), and IL-6. These and other cytokines
are responsible for tissue injury and apoptosis.
(3) Signaling and amplification: In addition to causing direct tis-
sue damage, proinflammatory cytokines activate the production
of tissue-damaging TNF-α, IL-1β, and IL-6, and other cytokines
that alter mucosal tissues.
(4) Ulceration: Tissue injury in the oral mucosa appears as ulcers
that penetrate through the epithelium to the submucosa. Bac-
teria penetrate the submucosa and stimulate macrophage activ-
ity, which increases the release of proinflammatory cytokines.
Angiogenesis also is stimulated.
(5) Healing: Signals from extracellular tissues stimulate epithelial
proliferation until the mucosa returns to its normal thickness.
Tissues do not return completely to normal, however, placing
them at increased risk for future injury.
c) Incidence of oral mucositis
(1) Incidence varies based on type of chemotherapy, dose, and sched-
ule. Radiation therapy directed at mucosa increases the risk,
and incidence varies depending on the dose, field, and wheth-
er chemotherapy is used concurrently. Overall, 30%–100% of
patients treated for cancer will develop some degree of muco-
sitis (Brown, 2011).
(2) HSCT recipients
(a) Up to a 100% risk
(b) Factors such as intensity of treatment regimen, transplant
type, and use of total body irradiation can affect incidence
(Raber-Durlacher et al., 2010).
(3) Incidence in patients undergoing head and neck radiation ther-
apy is 65%–90% (Sonis, 2011).
d) Risk factors
(1) Mucosal cells have a rapid mitotic rate and are susceptible to
chemotherapy and radiation (Raber-Durlacher et al., 2010).
The following classes of chemotherapy agents are associated
with mucositis.
(a) Antimetabolites: Increased risk noted with bolus delivery
of 5-FU
(b) Antitumor antibiotics
(c) Alkylating agents: Increased risk noted with high-dose mel-
phalan
(d) Plant alkaloids
(e) Rapamycin (mTOR) inhibitors
(2) Biologic agents, particularly IL-2 and IFN
(3) Neutropenia
(4) Drugs or therapies that alter mucous membranes (Wujcik, 2014)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 215
(a) Oxygen therapy: Dries out the mucosal lining
(b) Anticholinergics: Decrease salivary flow
(c) Phenytoin: Causes gingival hyperplasia
(d) Steroids: Can result in fungal overgrowth
(5) Total body irradiation or radiation therapy to the head or neck
(6) Dental disease and poor oral hygiene (Brown, 2011)
(7) Ill-fitting dentures: Irritate the mucosa and break integrity
(8) Advanced age and youth (Brown, 2011)
(a) Older adult patients may be at risk because of degenera-
tive changes, decreased salivary flow, diminished keratini-
zation of mucosa, and increased prevalence of gingivitis.
(b) Younger patients are prone to develop oral mucositis more
frequently than older patients because of their increased
rate of basal cell turnover (Treister & Woo, 2013).
(9) History of alcohol and tobacco use: Alcohol and tobacco irri-
tate the mucosa. Tobacco affects microcirculation, which may
delay healing (Eilers & Million, 2011).
(10) Poor nutrition: Reduced nutritional intake delays healing.
(11) Consumption of irritating foods: Acidic or spicy foods may in-
flame and traumatize mucosa (Wujcik, 2014).
(12) Dehydration alters mucosal integrity.
(13) Patients with head and neck cancer are at especially high risk if
they have surgery followed by radiation therapy. Patients with
cancers of the mouth and oropharynx are at highest risk (>
90%) (Sonis, 2011).
(14) Leukemia, lymphoma, and HSCT put patients at risk because
treatment involves drugs with a great potential to produce oral
mucositis and cause prolonged neutropenia.
(15) Methotrexate for prophylaxis of GVHD following HSCT (Bren-
nan, von Bültzingslöwen, Schubert, & Keefe, 2006; Cutler et
al., 2005)
(16) Hepatic or renal impairment: Inadequate metabolism or excre-
tion of certain mucotoxic cytotoxic agents
(17) Combined chemotherapy and radiation is associated with a
greater risk of mucositis (Eilers & Million, 2011).
e) Clinical manifestations
(1) The pattern of mucositis varies both by drug regimen and
by individual. Intensity and duration vary by type of drug,
dose, and frequency of administration (Raber-Durlacher et
al., 2010).
(a) Chemotherapy-induced oral mucositis develops most of-
ten four to seven days following standard-dose chemother-
apy and peaks within two weeks (Raber-Durlacher et al.,
2010).
(b) HSCT recipients experience mucositis three to five days
following the conditioning regimen.
(c) Patients receiving head and neck radiation therapy experi-
ence mucositis during week two of therapy, and it can last
for weeks to months (Raber-Durlacher et al., 2010).
(2) Intensity increases with higher doses of cytotoxic drugs. Drugs
that are not usually stomatotoxic at standard doses (e.g., cyclo-
phosphamide) can cause cellular damage to the mucosa at high
doses (Keefe et al., 2007).
(3) Signs and symptoms (Eilers & Million, 2011)
(a) Changes in taste and ability to swallow
(b) Hoarseness or decreased voice strength
(c) Pain when swallowing or talking
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
216 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
(d) Changes in the color of the oral mucosa (e.g., pallor, er-
ythema of varying degrees, white patches, discolored le-
sions or ulcers)
(e) Changes in oral moisture (e.g., amount of saliva, quality
of secretions)
(f) Edema of oral mucosa and tongue
(g) Mucosal ulcerations
f) Assessment
(1) Use a standardized assessment tool or scale when performing a
physical examination. Scales designed for clinical use take into
account symptoms, signs, and functional disturbances associat-
ed with oral mucositis and assign an overall score. The follow-
ing are three common tools.
(a) Oral Assessment Guide: This tool contains eight categories
that reflect oral health and function (Eilers, Berger, & Pe-
terson, 1988) (see Table 27).
(b) WHO (1979)
(c) CTCAE: This tool consists of a 1–5 grading index that is as-
sociated with descriptions of oral mucosal changes (see Ta-
ble 28) (NCI CTEP, 2010).
(2) After removing dental appliances, examine the outer lips, teeth,
gums, tongue, soft and hard palate, and buccal mucosa for col-
or, moisture, integrity, and cleanliness (Brown, 2011).
(3) Assess for changes in taste, voice, ability to swallow, pain, and
discomfort.
(4) Examine the saliva for amount and quality.
g) Collaborative management: Currently, no standard of care exists for
the prevention and treatment of oral mucositis. MASCC, in collabora-
tion with the International Society for Oral Oncology, issued clinical
practice guidelines in 2004 with suggestions and recommendations
based on literature published between 1966 and 2001. The guidelines
were revised in 2005 and again in 2007 (Keefe et al., 2007). ASCO has
published guidelines as well (Hensley et al., 2009).
(1) Oral care protocols, including patient education, should be in-
stituted to reduce the severity of oral mucositis from chemo-
therapy and radiation therapy (Brown, 2011). Patient educa-
tion may improve compliance with oral care, frequency, and
ability to cope with mucositis.
(a) Provide patient education, which is essential in promoting
good oral hygiene (Dodd, 2004).
(b) Benefits of oral care may include decreased risk of in-
fection, decreased pain, and elevated microbial flora
(Brown, 2011).
(c) Conduct a pretreatment dental evaluation with attention
to potentially irritating teeth surfaces, underlying gingivi-
tis, periodontal infection, and ill-fitting dentures. Crucial
dental work should be done before chemotherapy begins.
Removing braces may be necessary in adult and pediatric
patients if they are to undergo transplantation or if pro-
longed periods of neutropenia are anticipated.
(d) Emphasize intake of high-protein foods and increased flu-
id intake (> 1,500 ml/day).
(2) Prevention of oral mucositis (Keefe et al., 2007; Peterson et
al., 2012)
(a) Oral cryotherapy (ice chewing) is recommended for pa-
tients receiving bolus 5-FU for GI malignancies, bolus eda-
trexate, or high-dose melphalan.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 217
Table 27. Oral Assessment Guide
Numeric and Descriptive Ratings
Tools for
Category Assessment Methods of Measurement 1 2 3
Voice Auditory Converse with patient. Normal Deeper or raspy Difficulty talking or
painful
Swallow Observation Ask patient to swallow. Normal swallow Some pain on swal- Unable to swallow
To test gag reflex, gently place lowing
blade on back of tongue and
depress.
Observe result.
Lips Visual/palpa- Observe and feel tissue. Smooth and pink Dry or cracked Ulcerated or bleeding
tory and moist
Tongue Visual and/or Feel and observe appearance Pink and moist Coated or loss of pa- Blistered or cracked
palpation of tissue. and papillae pillae with a shiny
present appearance with or
without redness
Saliva Tongue Insert blade into mouth, touch- Watery Thick or ropy Absent
blade ing the center of the tongue
and the floor of the mouth.
Mucous Visual Observe appearance of tissue. Pink and moist Reddened or coated Ulcerations with or
membranes (increased white- without bleeding
ness) without ul-
cerations
Gingiva Tongue Gently press tissue with tip of Pink, stippled, Edematous with or Spontaneous bleed-
blade and vi- blade. and firm without redness ing or bleeding with
sual pressure
Teeth or Visual Observe appearance of teeth Clean and no de- Plaque or debris in Plaque or debris
dentures (or or denture-bearing area. bris localized areas generalized along
denture- (between teeth if gum line or den-
bearing area) present) ture-bearing area
Note. Table courtesy of June Eilers, PhD, APRN-CNS, BC, The Nebraska Medical Center. Used with permission.
(b) Chlorhexidine is not recommended for treatment of muco-
sitis (Harris, Eilers, Harriman, Cashavelly, & Maxwell, 2008;
Keefe et al., 2007; Worthington et al., 2011).
(c) Consider use of a keratinocyte growth factor to reduce the
severity and duration of oral mucositis in patients with he-
matologic malignancies undergoing high-dose chemother-
apy and total body irradiation for autologous HSCT (Keefe
et al., 2007; Raber-Durlacher et al., 2013).
(3) Prevention of GI mucositis (Keefe et al., 2007)
(a) Either ranitidine or omeprazole is recommended for the
prevention of epigastric pain after treatment with cyclo-
phosphamide, methotrexate and 5-FU, or 5-FU with or
without levcovorin.
(b) Amifostine has been suggested for reducing the severity
of esophagitis caused by the combination of chemother-
apy and radiation therapy for non-small cell lung can-
cer (Keefe et al., 2007). However, ASCO does not recom-
mend the routine use of amifostine for the prevention of
esophagitis in patients receiving concurrent chemothera-
py because of insufficient evidence (Hensley et al., 2009).
In a 2011 Cochrane review, amifostine was found to have
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
218 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Table 28. National Cancer Institute’s Common Terminology Criteria
for Adverse Events: Oral Mucositis
Grade Description
1 Asymptomatic or mild symptoms; intervention not indicated
2 Moderate pain, not interfering with oral intake; modified diet indicated
3 Severe pain, interfering with oral intake
4 Life-threatening consequences; urgent intervention required
5 Death
Note. From Common Terminology Criteria for Adverse Events [v.4.03], by the National Cancer Institute Cancer
Therapy Evaluation Program, 2010. Retrieved from http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010
-06-14_QuickReference_8.5x11.pdf.
weak evidence of benefit for prevention of any mucositis
(Worthington et al., 2011).
(c) Other agents that have been studied include sucralfate,
aloe vera, glutamine, G-CSF, honey, and antibiotic lozenges
containing polymyxin, tobramycin, and amphotericin. Evi-
dence of benefit was weak in small studies that included these
agents. Further study is required (Worthington et al., 2011).
(d) Low-level laser therapy is recommended for the prevention
of oral mucositis in adult patients receiving HSCT condi-
tioned with high-dose chemotherapy with or without total
body irradiation. It is also recommended for patients with
head and neck cancer undergoing radiation without con-
current chemotherapy (Migliorati et al., 2013).
(4) Treatment: Currently, no evidence-based recommendations ex-
ist for the treatment of established oral mucositis. Interventions
are aimed at symptom relief and preventing further tissue dam-
age. These interventions may include the following (Harris et
al., 2008; Keefe et al., 2007).
(a) Encourage the use of oral agents to promote cleansing,
moisture, and comfort (see Table 29).
(b) Encourage patients to brush, floss, and rinse to maintain
mucosal health.
(c) Administer systemic pain medications for mucositis pain.
MASCC guidelines recommend the use of patient-controlled
analgesia in HSCT recipients experiencing oral mucositis
pain (Keefe et al., 2007).
(d) Culture mucosal lesions so that appropriate antimicrobial
agents can be prescribed. Candidal lesions look like whit-
ish or cream-colored plaques on the mucosa and often are
treated while cultures are pending.
h) Patient and family education: Stress the goals of keeping the oral cav-
ity clean, moist, and intact to prevent further damage to the muco-
sa during mucotoxic therapy (Harris et al., 2008; Keefe et al., 2007).
To do this, patients should
(1) Perform a daily oral self-examination, and report signs and
symptoms of mucositis.
(2) Comply with an oral hygiene program. Oral hygiene should be
performed after every meal and at bedtime. If mild to moderate
dysfunction is present, the frequency of oral hygiene should be
increased to every two to four hours. If the condition progress-
es to a more severe dysfunction, hourly care may be indicated.
The program should include the following.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 219
Table 29. Commonly Used Agents for Mucositis Management
Agent Efficacy Comments
Bland rinses
0.9% saline Formal evaluation is lacking. Inexpensive rinsing solution
solution
Sodium bicarbon- Formal evaluation is lacking. Creates an alkaline environment that promotes bacte-
ate rial microflora
Unpleasant taste may affect adherence.
Recommended by NCI
0.9% saline/sodi- Formal evaluation is lacking. Inexpensive rinsing solution
um bicarbonate ½ teaspoon salt mixed with 2 tablespoons sodium bi-
carbonate with 32 ounces of water
Unpleasant taste may affect adherence.
Recommended by NCI
Rinse, multiagent Data demonstrating efficacy are lacking for prevention Various agents include antihistamines, lidocaine, and
and treatment of mucositis. Mylanta®.
Agents may be useful for pain or discomfort only.
Patients may experience numbness, which can cause
potential injury.
Alcohol-based elixirs should be avoided.
Discontinue if patient experiences discomfort related
to rinse (e.g., nausea and vomiting)
Coating agents, mucosal protectants
Sucralfate Most data demonstrate no statistically significant differ- Mucosal coating agent
suspension ence in oral mucositis severity, pain intensity scores, Poor tolerability and potential for GI side effects (e.g.,
and other subjective symptoms (e.g., taste altera- nausea and rectal bleeding) (Harris et al., 2008)
tion, dry mouth). Not recommended for practice (Har-
ris et al., 2008). A Cochrane review published in 2011
found that some benefit may exist for the reduction of
oral mucositis. Further studies are needed (Worthing-
ton et al., 2011).
Gelclair® Bioadherant oral gel forms a coating to make a barrier. May be helpful for improvement of swallowing and
Provides moisture and is flavorful pain scores
Not recommended for prevention or treatment of oral
mucositis
MuGard™ Mucoadhesive oral wound rinse that forms a protec- Dose is 5 ml. Rinse in mouth for at least 1 minute.
tive coating over the oral mucosa. Indicated for the Coat entire oral cavity. If necessary, up to 10 ml may
management of mucositis/stomatitis (which may be be used to coat entire oral cavity.
caused by radiation therapy or chemotherapy) and all
types of oral wounds.
Tissue protectants
Amifostine Recommended for reduction of esophagitis induced by Tissue protector
simultaneous chemotherapy and radiation therapy in Studies needed to determine role in prevention of oral
patients with non-small cell lung cancer (Keefe et al., mucositis
2007). However, ASCO does not recommend the rou-
tine use of amifostine for the prevention of esophagi-
tis in patients receiving concurrent chemotherapy be-
cause of insufficient evidence (Hensley et al., 2009).
Antiseptic agents
Chlorhexidine Overall, data demonstrate no significant change in Contains alcohol
oral mucositis severity or suppression of any type of Reports of rinse-induced discomfort, taste alteration
oral microflora. A 2011 Cochrane review found no Not recommended for oral mucositis (Keefe et al.,
benefit over placebo for the prevention of mucositis 2007)
(Worthington et al., 2011). Can turn teeth brown
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
220 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Table 29. Commonly Used Agents for Mucositis Management (Continued)
Agent Efficacy Comments
Hydrogen Mixed results: Linked to exacerbation or dryness, sting- Repeated use as a rinse is not recommended; long-
peroxide ing, pain, and nausea; some reports of intensification term use is discouraged.
of symptoms as a result of glossodynia (burning sen- At full potency, it may break down new granulation tis-
sation) sue and disrupt normal oral flora due to damage of
fibroblasts and keratinocytes.
Povidone-iodine Possesses antiviral, antibacterial, and antifungal effica- Potency limits use in patients with new granulation tis-
cy; less tolerable than normal saline sue. Swallowing is contraindicated.
No evidence that this agent is more effective than pla-
cebo (Worthington et al., 2011)
Antimicrobial agents
Acyclovir (and its Antiviral –
analogs) Not recommended for prevention of oral mucositis
Antimicrobial Not recommended for prevention of radiation-induced More research is needed.
lozenges oral mucositis
Anti-inflammatory agents
Kamillosan® liquid Unfavorable results in clinical trials Most patients appear to develop mucositis despite
rinse treatment.
Chamomile Lacks data demonstrating its efficacy Anti-inflammatory, antipeptic properties reported
Inexpensive, readily available, and innocuous
Oral corticoste- No significant difference in degree of mucositis com- Data are limited; definitive conclusions cannot be
roids pared to placebo drawn.
Benzydamine Nonsteroidal anti-inflammatory analgesic Only recommended for the prevention of oral muco-
Anti–tumor necrosis factor activity sitis in patients with solid tumors of the head and
neck receiving radiation therapy (Keefe et al., 2007).
In a 2011 Cochrane review, this agent was found to
have weak, unreliable evidence for the reduction of
mucositis (Worthington et al., 2011).
Analgesics
Topical lidocaine Limited data; may provide significant relief of limited du- Requires frequent application; may lead to decreased
ration sensitivity and additional trauma and impair taste
perception
Prophylaxis is not recommended.
Topical capsaicin Pilot data demonstrated marked reduction in oral pain. Clinical potential possibly linked to reepithelialization
and elevation of pain threshold
Further study is warranted.
Morphine Topical morphine has limited utility. Patient-controlled Oral alcohol-based formulations may cause burning.
analgesia using morphine is recommended for pa- Comprehensive pain assessments should be per-
tients undergoing HSCT. formed to adequately treat pain associated with mu-
cositis.
Antiproliferative, mucosal protectant, cytokine-like agents and growth factors
GM-CSF Some data indicate reduction in oral mucositis severity Oral mouthwashes are not recommended.
and pain; others do not. High rate of drug discontinuation because of intolera-
No evidence of benefit with duration or severity of oral ble side effects, including local skin reaction, fever,
mucositis (Worthington et al., 2011) bone pain, and nausea when administered subcu-
taneously.
G-CSF Weak, unreliable evidence of benefit for prevention of Further study is needed to draw any conclusion.
mucositis (Worthington et al., 2011)
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 221
Table 29. Commonly Used Agents for Mucositis Management (Continued)
Agent Efficacy Comments
Keratinocyte Approved for prevention of oral mucositis in patients un- 60 mcg/kg/day IV for 3 days prior to the preparatory
growth factor-1: dergoing autologous HSCT receiving high-dose che- regimen and for 3 days post-transplant
Palifermin motherapy or total body irradiation Further study is needed in other patient populations.
Other
Cryotherapy (ice Demonstrates consistent reduction in incidence and se- Not recommended in patients with head and neck
chips) verity of oral mucositis among patients receiving bo- cancers
lus 5-FU Apply ice chips to mouth 5 minutes before bolus 5-FU
Also recommended for bolus edatrexate chemotherapy therapy and continue for 30 minutes after (Peterson
infusion and high-dose melphalan infusions in HSCT et al., 2012).
Not recommended in patients receiving capecitabine
or oxaliplatin because of potential discomfort with
exposure to coldness (Harris et al., 2008)
L-Glutamine Essential amino acid, poorly absorbed Has not been shown to prevent mucositis
Not recommended systemically for prevention of GI mu- IV formulation under investigation
cositis
ASCO—American Society of Clinical Oncology; 5-FU—5-fluorouracil; G-CSF—granulocyte–colony-stimulating factor; GI—gastrointestinal; GM-CSF—gran-
ulocyte macrophage–colony-stimulating factor; HSCT—hematopoietic stem cell transplantation; IV—intravenous; NCI—National Cancer Institute
Note. Based on information from Bensinger et al., 2008; Brown, 2011; Harris et al., 2008; National Cancer Institute, 2012b; Peterson et al., 2013; Raber-
Durlacher et al., 2013; Worthington et al., 2011.
From “Nursing Interventions and Supportive Care for the Prevention and Treatment of Oral Mucositis Associated With Cancer Treatment,” by J. Eilers, 2004,
Oncology Nursing Forum, 31(Suppl. 4), pp. 19–20. Copyright 2004 by the Oncology Nursing Society. Adapted with permission.
(a) Floss the teeth with dental tape at least once daily or as ad-
vised by the clinician (Harris et al., 2008). However, patients
who do not regularly floss should not do so while immuno-
suppressed (Eilers & Million, 2011).
(b) Brush all tooth surfaces with a soft toothbrush for at least
90 seconds at least twice daily. Allow toothbrush to air dry
before storing, and replace toothbrush frequently (Har-
ris et al., 2008). Sponge swabs are not as effective as tooth-
brushes and should be avoided when cleaning the teeth ex-
cept in patients who cannot tolerate a toothbrush because
of severe pain with mucositis. However, sponge swabs may
be beneficial for cleaning the mucous membranes of the
oral cavity (Eilers & Million, 2011).
(c) Cleanse the oral cavity after meals, at bedtime, and at oth-
er times by vigorously swishing the mouth with an appro-
priate cleansing rinse (see Table 29). Oral rinsing should
be done to remove excess debris, hydrate the oral mucosa,
and aid in the removal of organisms (Eilers & Million, 2011;
Harris et al., 2008). Patients should use one tablespoon of
rinse to swish in the oral cavity for 30 seconds and then ex-
pectorate (Harris et al., 2008).
(d) Apply water-based moisturizers to lips.
(e) Maintain hydration
(f) Consider the use of oral moisturizers to promote comfort
if xerostomia exists (Eilers & Million, 2011).
(g) Avoid irritating agents, including commercial mouthwash-
es containing phenol, astringents, or alcohol; highly abra-
sive toothpastes; acidic, hot, or spicy foods and beverag-
es; rough foods; alcohol; tobacco; poorly fitting dentures;
braces; and lemon-glycerin swabs and solutions (Harris
et al., 2008).
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
222 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
(h) Recommendations for patients with dentures (NCI,
2012b)
i. Clean dentures twice a day and rinse them well.
ii. Soak dentures in an antibacterial solution when they
are not being worn.
iii. Clean denture soaking cups and change soaking so-
lution daily.
iv. Remove dentures and other oral devices when clean-
ing the mouth. If mouth sores are present, or if the
mouth is inflamed or painful, avoid using removable
oral devices to prevent further irritation.
(i) Instruct patients to report pain associated with mucositis.
Treat pain with oral topical agents or systemic opioids or
nonopioids. Avoid oral topical agents that contain alcohol
(Eilers & Million, 2011).
4. Anorexia
a) Definitions
(1) Anorexia: Loss of a desire to eat (NCI, n.d.) (see Table 30)
(2) Cachexia: “Cancer cachexia is defined as a multifactorial syn-
drome characterized by an ongoing loss of skeletal muscle mass
(with or without loss of fat mass) that cannot be fully reversed
by conventional nutritional support and leads to progressive
functional impairment. The pathophysiology is characterized
by a negative protein and energy balance driven by a variable
combination of reduced food intake and abnormal metabo-
lism” (Fearon et al., 2011, p. 490) (see Figure 26).
b) Pathophysiology
(1) The two entities are interrelated. Lack of food intake is only
one factor that contributes to weight loss, muscle wasting, and
malnutrition.
(2) Anorexia/cachexia results from a complicated process involv-
ing numerous physiologic and psychological factors.
(a) Tumor effect (Inui, 2002)
i. Obstruction of the GI tract can lead to nutrient mal-
absorption, nausea, vomiting, and pain.
ii. Proinflammatory cytokines such as IL-6, IL-1, TNF-α,
and IFN alfa may be released by the tumor and cause
satiety and metabolic abnormalities. These agents may
serve as tumor promoters and contribute to a negative
prognosis (MacDonald, 2007; Tisdale, 2010).
Table 30. National Cancer Institute’s Common Terminology Criteria
for Adverse Events: Anorexia
Grade Description
1 Loss of appetite without alteration in eating habits
2 Oral intake altered without significant weight loss or malnutrition; oral nutritional
supplements indicated
3 Associated with significant weight loss or malnutrition (e.g., inadequate oral caloric
and/or fluid intake); tube feeding or total parenteral nutrition indicated
4 Life-threatening consequences; urgent intervention indicated
5 Death
Note. From Common Terminology Criteria for Adverse Events [v.4.03], by the National Cancer Institute
Cancer Therapy Evaluation Program, 2010. Retrieved from http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03
_2010-06-14_QuickReference_8.5x11.pdf.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 223
Figure 26. Cancer Cachexia
Diagnostic Criteria
• Weight loss > 5% over the past 6 months; or
• Body mass index < 20 and any degree of weight loss > 2%
• Appendicular skeletal muscle index consistent with sarcopenia (another wasting syndrome)
and weight loss of > 2%
Stages of Cancer Cachexia
• Precachexia: Weight loss of < 5%, along with other symptoms such as impaired glucose tol-
erance or anorexia
• Cachexia: Weight loss > 5% or other symptoms and conditions consistent with the diagnos-
tic criteria for cachexia
• Refractory cachexia: Patients experiencing cachexia who are no longer responsive to cancer
treatment, have a low performance score, and have a life expectancy of < 3 months
Note. Based on information from Fearon et al., 2011.
iii. Metabolic abnormalities may lead to elevated blood
glucose, amino acid, and free fatty acid levels, result-
ing in early satiety and appetite suppression.
iv. Neurohormonal abnormalities may directly affect the
hypothalamic appetite center.
v. Hypercalcemia secondary to bony involvement or
paraneoplastic syndrome may lead to nausea, vomit-
ing, and anorexia.
(b) Treatment effects (Cunningham & Huhmann, 2011)
i. Surgery may result in malabsorption, obstruction, and
fluid and electrolyte abnormalities.
ii. Chemotherapy and radiation therapy side effects in-
clude nausea, vomiting, mucositis, taste changes, xe-
rostomia, constipation, and diarrhea.
iii. Combination therapy results in a greater number of
adverse effects.
(c) Psychosocial effects
i. Cancer-related depression often coexists with an-
orexia and cachexia, especially with patients who
are at a late stage or have multiple symptoms (Jimé-
nez et al., 2011).
ii. The prevalence of depression among patients with
cancer is estimated to be 10%–30%, compared to
5%–10% in the general medical population (Illman
et al., 2005).
iii. Anxiety, fear, grief, fatigue, pain, and the patient’s
reaction to body image changes may contribute to
anorexia.
(3) Cachexia results in decreased survival and adherence to che-
motherapy and increased treatment toxicity (Blum & Strass-
er, 2011).
c) Incidence: Historical data demonstrated an overall incidence of an-
orexia/cachexia in patients with cancer of 50%, increasing to 80%
before death (Inui, 2002).
d) Risk factors (Cunningham & Huhmann, 2011; Del Fabbro, Dalal, &
Bruera, 2006)
(1) Advanced cancer
(2) Solid tumor: Most common types are head and neck, GI, and lung.
(3) Chronic illness such as pulmonary disease and congestive heart
failure
(4) Increased prevalence in the very young and older adults
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
224 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
(5) Surgery, radiation, chemotherapy, biotherapy, and targeted
therapies
(6) Multimodal therapies
e) Clinical manifestations (Cunningham & Huhmann, 2011; Strasser
& Bruera, 2002)
(1) Involuntary weight loss of > 5% of usual weight
(2) Changes in appetite
(a) Changes in taste and smell
(b) Early satiety
(3) Changes in GI tract function
(a) Dysmotility
(b) Inactivation of bile salts or pancreatic enzymes
(c) Partial or complete obstruction
(4) Loss of muscle mass
(5) Loss of adipose tissue
(6) Fatigue and weakness
(7) Immune system impairment
(8) Metabolic dysfunction
(9) Hypoalbuminemia
f) Assessment
(1) Monitor weight: Compare with pretreatment weight.
(2) Obtain a diet history or have patient complete a food diary for
several days.
(3) Measure body composition.
(a) Triceps skinfold thickness estimates body fat.
(b) Mid-arm muscle circumference estimates muscle mass.
(4) Laboratory results
(a) Laboratory tests generally are nonspecific for malnutrition
(Cunningham & Huhmann, 2011). The practitioner will
evaluate patient labs for the presence of contributing fac-
tors that may be corrected.
(b) Assess for endocrine abnormalities (e.g., thyroid dysfunc-
tion, metabolic abnormalities, hypogonadism) (NCCN,
2013e).
(5) Assess functional status (Chang, Xia, & Kasimis, 2005; Ottery,
1994).
(a) The Patient-Generated Subjective Global Assessment and
the Functional Assessment of Anorexia/Cachexia Thera-
py are easy-to-use tools that patients complete in the clin-
ical setting.
(b) Functional status tools include symptom distress and QOL
questions.
(c) Validated cachexia assessment tools based on updated def-
initions are being investigated (Blum & Strasser, 2011).
g) Collaborative management: The extent of nutrition intervention de-
pends on the cause of weight loss and overall goals of the patient,
family, and healthcare team.
(1) Treatment of the cancer is the primary objective.
(2) Symptom management: Management of symptoms such as n/v,
mucositis, oral candidiasis, diarrhea, constipation, taste chang-
es, dysphagia, xerostomia, fatigue, pain, and depression may
improve anorexia. (See the discussion of management in the
specific sections of this publication.)
(3) Pharmacologic intervention: Progestins and corticosteroids are
the only two classes of drugs to have demonstrated effective-
ness as appetite stimulants (Adams et al., 2009; NCCN, 2013e).
(a) Progestins (Berenstein & Ortiz, 2012; Dy & Apostol, 2010)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 225
i. Megestrol acetate is most commonly used.
ii. Improves appetite and weight gain in patients with
cancer; however, it does not improve QOL.
iii. Mechanism of action is not well established.
iv. Optimal dose is not defined but ranges from 100–
1,600 mg/day.
v. Side effects include deep vein thrombosis, edema, im-
potence in men, and GI disturbances.
(b) Corticosteroids (Adams et al., 2009; NCCN, 2013e)
i. Mechanism of action is unknown but may be related
to euphoric and anti-inflammatory effects.
ii. Effects are short-lived.
iii. Many side effects, both short and long term, can oc-
cur, including immunosuppression, hyperglycemia,
and muscle wasting.
(4) Nonpharmacologic interventions (Adams et al., 2009; NCCN,
2013e)
(a) Interventions may not increase weight or length of surviv-
al but may improve QOL.
(b) Refer to a dietitian for nutritional counseling. This has been
shown to improve dietary intake.
(c) Provide high-calorie/high-protein oral supplements as
needed and tolerated.
(d) Enteral or parenteral nutrition: Consider if the disease or
treatment interferes with the patient’s ability to eat or to
absorb nutrients (NCCN, 2013e).
i. Enteral: Patients must have a functioning bowel. Com-
plications include aspiration pneumonia, electrolyte
abnormalities, diarrhea, and infection.
ii. Parenteral: Includes central parenteral nutrition,
which requires a central VAD, and peripheral par-
enteral nutrition. Complications include high infec-
tion rate.
h) Patient education
(1) Provide written handouts, stressing high-calorie/high-protein
foods.
(2) Monitor and record weight weekly, using the same scale at the
same time of the day.
(3) Encourage small, frequent meals.
(4) Provide an attractive setting for meals.
(5) Encourage physical activity.
(6) Use measures to control n/v, mucositis, dry mouth, taste chang-
es, and other side effects of treatment.
(7) Include patients in family activities to avoid isolation, even if pa-
tients have no appetite. Do not force patients to eat.
(8) Remind families that patients’ lack of appetite is caused by the
effects of the disease and treatment and is not their fault.
(9) Refer to community resources as needed, such as home care
and Meals on Wheels.
(10) Refer patients for psychosocial interventions and emotional
support.
5. Constipation
a) Definition: Excessively hard, dry bowel movements that are infre-
quent and a result of decreased rectal emptying or filling (Camp-
Sorrell, 2011). Constipation may be a presenting symptom of the
cancer diagnosis, a side effect of therapy, the result of tumor pro-
gression, or unrelated to the cancer or therapy. Depression and
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
226 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
anxiety caused by cancer treatment or pain can lead to constipa-
tion, either alone or with other functional and physiologic disor-
ders. The most common causes are inadequate fluid intake and use
of pain medications.
b) Pathophysiology: Infrequent and difficult bowel evacuation, which
can be associated with abdominal bloating, pain, and discomfort. De-
creases in fluid and fiber intake and in exercise/activity contribute to
the severity of constipation (Connolly & Larkin, 2012).
(1) Common contributing factors include advanced age, autonom-
ic nervous system dysfunction, spinal cord compression from
tumor, metabolic effects, dehydration, immobility, cancer treat-
ment, and medications such as opioids and tricyclic antidepres-
sants (Woolery et al., 2008).
(2) Certain chemotherapy agents that cause n/v may contribute
to constipation, as n/v may result in decreased oral intake or
slowed peristaltic movement in the GI tract. In the absence of
food intake, fewer stools are produced, transit time increases,
and the stool becomes hard and difficult to eliminate.
(a) Agents that decrease motility include vinca alkaloids. Au-
tonomic nervous system dysfunction can result in upper
colon impaction, colicky abdominal pain, and paralytic il-
eus. Rectal emptying is decreased when nonfunctional af-
ferent and efferent pathways from the sacral cord are in-
terrupted (Camp-Sorrell, 2011).
(b) Vincristine, vinorelbine, and vinblastine can cause neuro-
toxicity that affects the smooth muscles of the GI tract, lead-
ing to decreased peristalsis or paralytic ileus.
(c) Vincristine may damage the mesenteric plexus of the colon.
(3) Opioids profoundly affect the bowel’s ability to maintain ap-
propriate motility. They are the primary cause of medication-
induced constipation (Bohnenkamp & LeBaron, 2010).
c) Incidence
(1) Clinically, constipation is a common problem for patients with
cancer occuring in 50%–95% of patients. Patients receiving opi-
oids are at highest risk (Woolery et al., 2008).
(2) Constipation has been reported in 20%–35% of patients re-
ceiving vinblastine, especially in high doses or after prolonged
treatment (Engelking, 2008).
(3) Constipation, abdominal pain, and paralytic ileus are common
side effects of vincristine (Chu & DeVita, 2012).
(4) Vinorelbine may cause severe constipation, with an overall in-
cidence of all grades of 35% (Sagent Pharmaceuticals, 2009).
(5) Constipation occurs in up to 55% of patients receiving thalid-
omide (Celgene Corp., 2013b) and approximately 38% of pa-
tients receiving lenalidomide (Celgene Corp., 2013a).
(6) Bortezomib causes constipation in 42% of patients (Millenni-
um Pharmaceuticals, 2012).
d) Clinical consequences
(1) Abdominal or rectal discomfort or pain
(2) Nausea and/or vomiting
(3) Anorexia
(4) Impaction/obstruction
(5) Ileus
(6) Anal fissures
(7) Hemorrhoids
(8) Ruptured bowel and life-threatening sepsis
e) Risk factors (Woolery et al., 2008)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 227
(1) Advanced age
(2) Mechanical pressure on the bowel (e.g., bowel obstruction sec-
ondary to tumor in the GI tract, pressure from ascites)
(3) Damage to the spinal cord from T8 to L3, which causes com-
pression of nerves that innervate the bowel
(4) Decreased mobility
(5) Dehydration
(6) Poor nutritional intake
(7) Low dietary fiber intake
(8) Metabolic and endocrine disorders
(a) Hypercalcemia
(b) Hypothyroidism
(c) Hypokalemia
(d) Diabetes mellitus
(9) Use of certain medications (Woolery et al., 2008)
(a) Neurotoxic chemotherapy drugs
(b) Anticholinergic medications
(c) Diuretics
(d) Opioids
(e) Aluminum- and calcium-based antacids
(f) Calcium and iron supplements
(g) Tricyclic antidepressants
(h) Antihypertensives
(i) Antispasmodics
(j) 5-HT3 antagonists
(k) NSAIDs
(l) Barbiturates
(10) Overuse of laxatives
f) Assessment
(1) Assess patterns of elimination, including the amount and fre-
quency of elimination and the urge to defecate, character and
volume of the stool, and use of laxatives, stool softeners, or
other measures to enhance bowel function. Note that small
amounts of loose stool may indicate constipation as the liquid
stool passes around a stool mass. Small, pellet-like stool indi-
cates slow colonic transit time, and long, thin pieces of stool
may indicate stenosis or hemorrhoids (Bohnenkamp & LeB-
aron, 2010).
(2) Assess patients’ usual dietary patterns, focusing on fluid and fi-
ber intake.
(3) Assess mobility, activity level, and functional status.
(4) Assess for abdominal pain, distention, and presence or absence
of bowel sounds.
(5) Assess for the presence of straining, rectal pressure, excessive
flatulence, or cramping.
(6) Determine facts about the patient’s last bowel movement (e.g.,
when it occurred, amount, consistency, color, presence of blood).
(7) Determine current medication usage.
(8) Use laboratory results to assist in metabolic evaluation.
(9) Perform abdominal palpation and rectal examination if appro-
priate. A rectal examination is not routinely performed in pedi-
atric patients. Rectal or stoma manipulation for examinations,
enemas, or suppositories should be avoided in myelosuppressed
patients because of the risk for bleeding, fissures, or abscesses
(NCI, 2012a; Woolery et al., 2008).
(10) Use radiographic imaging to differentiate between mechanical
obstruction and decreased motility from an ileus.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
228 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
g) Collaborative management: No evidence has shown any one laxa-
tive to be more efficacious than another (Woolery et al., 2008). The
cause of the constipation should be considered prior to beginning
treatment. NCCN (2013e) palliative care guidelines offer guidance
for the treatment of constipation.
(1) Pharmacologic interventions
(a) Bulk-forming laxatives (e.g., methylcellulose, psyllium,
calcium polycarbophil): Cause water to be retained in the
stool. Must be taken with at least 200–300 ml of water to
avoid intestinal obstruction and are of limited use in pa-
tients who cannot tolerate fluids (Bohnenkamp & LeBar-
on, 2010; Woolery et al., 2008). Side effects include flatu-
lence, abdominal distention and bloating, mechanical ob-
struction, and anaphylactic reactions (Woolery et al., 2008).
(b) Lubricant laxatives (e.g., mineral oil, glycerin supposito-
ries): Coat and soften the stool. Excessive doses can lead
to malabsorption of fat-soluble vitamins and rectal seep-
age with perianal irritation (Bohnenkamp & LeBaron,
2010).
(c) Saline laxatives (e.g., magnesium salts, sodium phosphate):
Contain magnesium or sulfate ions. Act by drawing water
into the gut. Are of little use in a daily prevention program
and are used most often for acute evacuation of the bow-
el. Hypermagnesemia or hyperphosphatemia can occur
with renal insufficiency (Bohnenkamp & LeBaron, 2010).
(d) Osmotic laxatives (e.g., lactulose, sorbitol, polyethylene gly-
col [PEG]): Attract and retain water in the bowel, resulting
in softer stool. Side effects include abdominal pain, disten-
tion, and gas (Bohnenkamp & LeBaron, 2010).
(e) PEG with or without electrolytes is considered a hyperos-
motic laxative and increases the water content of stool.
NCCN (2013e) recommends PEG for persistent consti-
pation. Woolery et al. (2008) recommended that electro-
lytes not be administered with PEG when kidney function
is compromised.
(f) Detergent laxatives (e.g., docusate sodium): Have a direct
action on the intestines by allowing water and fats to pen-
etrate into dry stool and decreasing electrolyte and water
absorption from the colon. Appropriate for short-term use
when straining is to be avoided.
(g) Stimulant laxatives (e.g., bisacodyl, senna): Act directly on
the colon to stimulate motility and are activated by bacte-
rial degradation in the intestine. Most commonly used in a
prophylactic plan. Side effects include abdominal discom-
fort, electrolyte abnormalities, and hepatotoxicity (Wool-
ery et al., 2008).
(h) Suppositories: Stimulate the intestinal nerve plexus and
cause rectal emptying. Not indicated for long-term bow-
el management.
(i) Prokinetic agents (e.g., metoclopramide, 10–20 mg by
mouth every six hours): Promotes motility in the upper
GI tract and hastens gastric emptying and intestinal tran-
sit time. Exhibits antiemetic properties, which are the re-
sult of central and peripheral dopamine receptor inhibi-
tion. Doses are higher when used for CINV (Micromedex,
2013). Consider adding a prokinetic agent for constipa-
tion that is not associated with obstruction (NCCN, 2013e).
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 229
(j) Methylnaltrexone is approved for opioid-induced consti-
pation in patients with advanced illness who are receiving
palliative care. It is a peripherally acting opioid receptor
antagonist that has shown efficacy in preventing opioid-
induced constipation without diminishing pain, palliation,
or precipitating opioid withdrawal. Dosing is 0.15 mg/kg SC
every other day, not more often than once a day (NCCN,
2013e). Most common adverse effects reported were flat-
ulence, abdominal pain, dizziness, diarrhea, nausea, and
hyperhidrosis. This drug is contraindicated with known or
suspected mechanical GI obstruction (Salix Pharmaceuti-
cals, Inc., 2012).
(k) Use a combination laxative-stool softener prophylactical-
ly for patients receiving vinca alkaloids (Engelking, 2008).
(2) Other
(a) Include increased physical activity or passive exercise as ap-
propriate in a bowel retraining regimen. This promotes the
urge to defecate by helping to move feces into the rectum.
(b) Help patients to maintain usual bowel habits during hospi-
talization. Provide privacy and comfort. Avoid use of a bed-
pan when constipation exists.
(c) Increase fluid and fiber intake and obtain a nutritional con-
sult (Woolery et al., 2008).
(d) Begin management with oral medications.
(e) Rotating opioids may decrease constipation (e.g., switching
from a long-acting oral morphine to a transdermal fentan-
yl patch) (Woolery et al., 2008).
(f) Patient and family education
i. Increase fluid intake: Encourage patients to drink at
least eight 8-oz glasses of fluid daily unless medical-
ly contraindicated. Drinking warm or hot liquids be-
fore a defecation attempt may help to stimulate bow-
el movement (Woolery et al., 2008).
ii. Increase fiber in diet: Fiber causes feces to pass through
intestines more rapidly and decreases the occurrence
of fecal impaction.
• High-fiber foods include 100% whole-grain cere-
als, breads, and bran; fruits such as prunes, peach-
es, apples, raisins, and dates; and vegetables such as
squash, broccoli, carrots, and celery (NCI, 2012a).
• Advise patients that they may experience abdominal
discomfort, flatulence, or a change in bowel habits
in the first few weeks after increasing fiber intake.
• Fiber tolerance will develop, and such effects can
be minimized by slowly titrating fiber consumption.
• Adults should consume 25–30 g/day total if toler-
ated (NCI, 2012a). This approach is contraindicat-
ed in patients who are at risk for bowel obstruction
(NCI, 2012a).
• Fiber should not be recommended in patients with
cancer who have inadequate fluid intake (NCI,
2012a).
(3) Encourage patients to exercise regularly. Regular exercise stim-
ulates GI motility.
(4) Teach diaphragmatic breathing and abdominal muscle exercis-
es; these help to increase muscle tone, which assists with defe-
cation (Engelking, 2008).
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
230 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
(5) Help patients to develop a regular bowel program.
(6) Instruct patients to report constipation and to be aware of the
complications associated with constipation, such as fecal im-
paction.
(7) Stress that patients should call a physician to initiate a bowel
program if three days pass without a bowel movement.
(8) Ensure that all patients who are prescribed opioids are started
on pharmacologic and nonpharmacologic interventions to pre-
vent constipation and maintain bowel program until opioids are
discontinued (Bohnenkamp & LeBaron, 2010).
6. Perirectal cellulitis
a) Definition: Inflammation and edema of the perineal and rectal area
b) Pathophysiology
(1) Minimal tears of the anorectal mucosa allow infection. The
most common anaerobic organisms include Bacteroides fragilis,
Peptostreptococcus, Prevotella, Fusobacterium, Porphyromonas, and
Clostridium. The most common aerobic bacteria include Staph-
ylococcus aureus, Streptococcus, and Escherichia coli. Community-
acquired methicillin-resistant Staphylococcus aureus (known as
MRSA) has been implicated in rectal abscess infections (Valesky
& Kifaieh, 2012).
(2) Infection starting as a local abscess can lead to systemic sepsis.
c) Incidence: Overall incidence has decreased in the past decade, pre-
sumably because of the early use of empiric antibiotics in febrile neu-
tropenic patients. Perirectal abscesses are more common in patients
with anorectal cancer or hematologic malignancies and may be pres-
ent at initial diagnosis (Valesky & Kifaieh, 2012).
d) Risk factors
(1) Chronic neutropenia or thrombocytopenia
(2) Constipation: The passage of hard stool causes trauma to the
rectal mucosa.
(3) Diarrhea: Caustic fluid irritates and breaks down perirectal tissue.
(4) Perirectal mucositis caused by chemotherapy and/or radia-
tion therapy
(5) Any rectal trauma, such as rectal stimulation or the use of rec-
tal thermometers, enemas, or suppositories
(6) Hemorrhoids or anal fissures/abscesses
e) Assessment
(1) Ask patients if they are experiencing perineal and/or rectal dis-
comfort. Fear of defecation related to pain may not be report-
ed and may increase risk of constipation. A large majority of pa-
tients with anal abscess will complain of dull, aching, or throb-
bing pain, which may worsen when sitting or before defecation.
(2) Monitor for the presence of fever.
(3) Perform a physical examination of the perineal area. The en-
trance site for the infective agent may be a small tear that shows
minimal irritation. Conversely, localized tenderness, gross swell-
ing, fluctuance, erythema, and drainage may be observed if an
abscess is present. An abscess of the perirectal area may pro-
duce bloody, purulent, or mucoid drainage. Obtain a culture,
if possible, for identification of infectious organisms (Valesky
& Kifaieh, 2012).
(4) Consider abdominal/pelvic CT (NCCN, 2013f) if an abscess
is suspected. MRI and ultrasound are also used for diagnosis
of an abscess. Look for and document tissue sloughing and
necrosis.
f) Collaborative management (NCCN, 2013f)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 231
(1) Ensure that antibiotic coverage includes a specific antianaerobic
agent in addition to broad-spectrum aerobic coverage. Consider
Enterococcus or Candida coverage if appropriate (NCCN, 2013f).
(2) Administer antipyretic medications to relieve fever.
(3) Teach and encourage patients to take sitz baths or use gentle
external perineal irrigation.
(4) Administer stool softeners, and encourage patients to eat a low-
bulk diet. Consult a dietitian as needed.
(5) Inspect the perirectal mucosa frequently for any signs of irrita-
tion or skin breakdown.
g) Patient and family education
(1) Teach patients and significant others to
(a) Maintain meticulous perineal hygiene, especially in the
presence of neutropenia.
(b) Apply appropriate barrier creams and medicated creams.
(c) Monitor carefully for any signs of infection or worsening
of tissue integrity.
(2) Ensure that patients and significant others are able to
(a) Identify the risk factors for perirectal cellulitis.
(b) Implement measures that minimize the risk of developing
perirectal cellulitis.
(c) Identify situations that require prompt professional inter-
vention.
i. Pain, redness, or swelling in the affected area
ii. Body temperature > 100.4°F (38°C)
C. Cutaneous toxicity: Chemotherapy and its cutaneous side effects are an in-
creasingly common source of injury to the skin, hair, and nails. For years,
the cutaneous side effects from conventional cytotoxic chemotherapeutic
agents have been observed and described in detail. More recently, the emer-
gence of targeted chemotherapy drugs has widened the spectrum of adverse
cutaneous side effects seen in patients with cancer (Choi, 2011). See Table
31 for cutaneous reactions and management of toxicities from chemother-
apy, biotherapy, and targeted agents.
1. Over the past decade, cancer therapy has increasingly shifted toward tar-
geting specific pathways involved in the pathogenesis of malignancy. The
EGFR inhibitors (EGFRIs) are one of the best known examples of tar-
geted therapy that are used both as first-line and adjuvant chemothera-
py for solid organ cancers. These agents are less likely than traditional
cytotoxic chemotherapeutics to cause myelosuppression, infection, nau-
sea, vomiting, and diarrhea. However, dermatologic adverse events from
EGFRIs, small molecule inhibitors, and mAbs such as gefitinib, erlotinib,
cetuximab, lapatinib, and panitumumab are significantly more common
than with cytotoxic agents, are symptomatic, and manifest in cosmeti-
cally sensitive areas (Wu, Balagula, Lacouture, & Anadkat, 2011). As the
number of agents and uses for targeted therapies increase, so does the
need to recognize and treat the dermatologic side effects of these agents.
2. Pathophysiology
a) EGFR is normally expressed in the epidermis, sebaceous glands, and
hair follicular epithelium, where it plays a number of important roles
in the maintenance of normal skin health, including control of dif-
ferentiation, protection against damage induced by ultraviolet radi-
ation, inhibition of inflammation, and acceleration of wound heal-
ing (Melosky et al., 2009).
b) Although not fully understood, inhibition of EGFR is believed to
cause follicular occlusion and rupture because of premature epithe-
lial differentiation and an increase in the expression of genes that
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
232
Table 31. Cutaneous Reactions to Antineoplastic Agents
Cutaneous
Reaction General Comments Chemotherapy Biotherapy and Targeted Therapy
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Hair changes: A number of chemotherapy drugs can cause hair changes and Hair changes: Bexarotene, carboplatin, Alopecia: Axitinib, eltrombopag, eribulin, pazopanib, pe-
Alopecia, hir- hair loss. Dose, route of administration, combination of drugs, cisplatin, cyclophosphamide, dactino- gylated IFN alfa-2b, vemurafenib (Wolters Kluwer
sutism, hypertri- and other individual characteristics will influence occurrence as mycin, doxorubicin, etoposide, hexa- Health, Inc., 2012); cetuximab (Bristol-Myers Squibb
chosis well as degree of hair loss. methylmelamine, ifosfamide, paclitax- Co. & ImClone Systems, 2012); gefitinib (AstraZene-
Hair changes may occur 2–3 months after initiation of EGFRI el, vincristine ca Pharmaceuticals, 2010); panitumumab (Amgen Inc.,
therapy, with hair thinning and developing a dry, brittle, or curly Alopecia: Carboplatin, cisplatin, cyclo- 2013b); sorafenib (Bayer HealthCare Pharmaceuticals
texture (Segaert & Van Cutsem, 2005). phosphamide, Ara-C, dacarbazine, Inc., 2011)
Hirsutism is characterized by excess hair growth in women in ana- dactinomycin, daunorubicin, doxorubi- Alopecia, hirsutism, hypertrichosis: everolimus (Wolters
tomic sites where growth is typically a male characteristic (beard, cin, etoposide, 5-FU, hydroxyurea, ifos- Kluwer Health, Inc., 2012)
mustache, chest, and abdomen) (Lacouture et al., 2010). famide, methotrexate, vinblastine, vin- Hair color changes and alopecia: sunitinib (Pfizer Inc.,
Hypertrichosis is characterized by hair density or length beyond cristine (Kamil et al., 2010) 2012c)
the accepted limits of normal in a particular body region or a
particular age or race (Lacouture et al., 2010).
Trichomegaly Increased hair growth of the eyelashes and eyebrows is rare but Cyclosporine, gemcitabine (Bouché et Cetuximab (Bristol-Myers Squibb Co. & ImClone Sys-
can occur (Segaert & Van Cutsem, 2005). al., 2005) tems, 2012); gefitinib, IFN alfa-2b (Bouché et al., 2005);
Trichomegaly is associated with patient discomfort and can lead to panitumumab (Amgen Inc., 2013b)
corneal abrasions and further ocular complications. Ocular chang-
es may occur within 1–2 weeks of treatment (Boucher et al., 2011).
Trichomegaly can be treated with lash clipping every 2–4 weeks.
Referral to an ophthalmologist is indicated for patients with ir-
ritation or persistent discomfort. Topical eflornithine cream has
been well tolerated (Lacouture et al., 2011).
Waxing or electrolysis may be recommended (Braiteh et al., 2008;
Segaert & Van Cutsem, 2005).
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Paronychia Paronychia is characterized by tender, edematous, often purulent Bleomycin, cyclophosphamide, docetax- Cetuximab (Bristol-Myers Squibb Co. & ImClone Sys-
inflammation of the nail fold. Fingernails and toenails may be af- el, doxorubicin, hydroxyurea, metho- tems, 2012); gefitinib (AstraZeneca Pharmaceuticals,
fected, with the first digits the most commonly affected (Lacouture trexate 2010); panitumumab (Amgen Inc., 2013b)
et al., 2011).
It is often delayed, developing 4–8 weeks after start of therapy
and occurring in 12%–58% of patients (Potthoff et al., 2011;
Segaert & Van Cutsem, 2005).
Encourage preventive measures, such as keeping hands dry and
out of water if possible, wearing gloves while cleaning (e.g.,
household, dishes), avoiding friction and pressure on the nail
fold or manipulation of the nail, and wearing comfortable shoes
(Lacouture et al., 2011; Potthoff et al., 2011).
Treatment may include white vinegar (1:10) or bleach soaks (1/4
cup bleach in 3 gallons of water) or topical agents (Wu et al.,
2011). Oral antibiotics or surgical intervention may be indicated
(Lacouture et al., 2010).
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 31. Cutaneous Reactions to Antineoplastic Agents (Continued)
Cutaneous
Reaction General Comments Chemotherapy Biotherapy and Targeted Therapy
Nail changes – Cyclophosphamide, daunorubicin, doxo- Cetuximab (Bristol-Myers Squibb Co. & ImClone Sys-
rubicin, ifosfamide (Kamil et al., 2010) tems, 2012); gefitinib (AstraZeneca Pharmaceuticals,
2010); panitumumab (Amgen Inc., 2013b); temsirolimus
(Wyeth Pharmaceuticals, 2012)
Nail shedding Loss of all or a portion of the nail (Lacouture et al., 2010) Bleomycin, cisplatin, docetaxel, doxoru- Everolimus (Wolters Kluwer Health, Inc., 2012)
(onycholysis) bicin, melphalan, mitoxantrone, topical
5-FU, vincristine, weekly paclitaxel ad-
ministration (Huang & Anadkat, 2011;
Hussain et al., 2000)
Dystrophy Transverse midline linear groove in the nail plate Bleomycin, hydroxyurea Dystrophy and nail changes are common with EGFRIs.
Beau lines Transverse ridges across the nail plate. These findings are be- Bleomycin, cisplatin, docetaxel (tax- Beau lines and nail changes are common with EFGRIs.
nign, dose related, and resolve with cessation of chemotherapy anes), doxorubicin, melphalan, vin-
(Huang & Anadkat, 2011). cristine (Huang & Anadkat, 2011);
capecitabine, hydroxyurea
Hyperpigmen- Hyperpigmentation is the darkening of an area of skin or nails Alkylating agents are most common- –
tation caused by increased melanin. ly associated with mucocutaneous hy-
Cutaneous hyperpigmentation associated with chemotherapeu- perpigmentation (Huang & Anadkat,
tics can present in localized or generalized patterns affecting the 2011).
skin, teeth, or nails (Huang & Anadkat, 2011). Bleomycin, busulfan, cyclophosphamide,
Patients should avoid sun exposure or use effective sun barrier dacarbazine, daunorubicin, docetaxel,
preparations to minimize the risk of hyperpigmentation. Sun ex- doxorubicin, etoposide, 5-FU, hydroxy-
posure aggravates hyperpigmentation. urea, melphalan, methotrexate, nitro-
Chapter 9. Side Effects of Cancer Therapy
Bleaching creams are not helpful; the hyperpigmentation will fade gen mustard, nitrosoureas, paclitaxel
spontaneously with time (months) (Segaert & Van Cutsem, (Vassallo et al., 2001); dactinomycin, if-
2005). osfamide, prednisolone, 6-mercaptopu-
It occurs most commonly in people of Mediterranean descent. rine (Kamil et al., 2010)
Darkening may occur within 2–3 weeks of chemotherapy/biother- Flagellate streaks of hyperpigmentation
apy and persist for months following the completion of therapy. caused by nail scratching the skin have
Postinflammatory hyperpigmentation is seen following acneform been reported with parenteral and in-
eruption or other causes of skin inflammation such as eczema trapleural administration of bleomycin
or an inflamed sebaceous cyst (Segaert & Van Cutsem, 2005). (Camp-Sorrell, 2011).
233
(Continued on next page)
234
Table 31. Cutaneous Reactions to Antineoplastic Agents (Continued)
Cutaneous
Reaction General Comments Chemotherapy Biotherapy and Targeted Therapy
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Rash Manifestation of mAb-induced skin rash: Rash appears to be dose Docetaxel, paclitaxel (Hetherington et Axitinib—rash: all grades, 13%; grades 3–4, < 1% (Wolt-
related and generally evolves within 1–3 weeks of the start of al., 2007); bendamustine HCI (Cepha- ers Kluwer Health, Inc., 2012)
treatment. No association has been observed between mAb- lon, Inc., 2012); Ara-C, asparaginase, Cetuximab—rash: grades 1–4, 89%; grades 3–4, 12%
mediated skin rash and past or preexisting skin abnormalities carboplatin, cyclophosphamide, dacar- (Bristol-Myers Squibb Co. & ImClone Systems, 2012)
such as acne or rosacea (Melosky et al., 2009). bazine, 5-FU, hydroxyurea, ifosfamide, Crizotinib—rash: 10% (Wolters Kluwer Health, Inc., 2012)
lomustine, methotrexate, vinblastine, Denosumab—rash: 3%–11%; dermatitis: 11%; eczema:
vincristine (Kamil et al., 2010) 11% (Wolters Kluwer Health, Inc., 2012)
Ara-C can cause skin peeling (Kamil et Eltrombopag—rash: 3% (Wolters Kluwer Health, Inc., 2012)
al., 2010). Erlotinib—rash: any grade, 75%; grade 3, 8%; grade 4, <
1% (Astellas Pharma US, Inc., & Genentech, Inc., 2012)
Everolimus—rash: 18%–59% (Wolters Kluwer Health, Inc.,
2012)
Ipilimumab—rash: all grades, 19%–29%; grade 3–5, 2%;
dermatitis: grade 2, 12%; grades 3–5, 2%–3% (Wolters
Kluwer Health, Inc., 2012)
Lapatinib—rash: all grades, 28%; grade 3, 2%; grade 4,
0% when given in combination with capecitabine (Ge-
nentech, Inc., 2011); dry skin: all grades, 10%; grades
3–4, 0% when given in combination with capecitabine
(GlaxoSmithKline, 2012)
Ofatumumab—rash: 14% (Wolters Kluwer Health, Inc.,
2012)
Panitumumab—skin rash: all grades, 22%; grades 3–4,
1% (Amgen Inc., 2013b)
Pazopanib—rash: 8% (Wolters Kluwer Health, Inc., 2012)
Pegylated IFN alfa-2b—rash: 6%–36% (Wolters Kluwer
Health, Inc., 2012)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Pertuzumab—rash: 34% (Wolters Kluwer Health, Inc., 2012)
Pralatrexate—rash: all grades, 15%; grades 3–4, 0%
(Wolters Kluwer Health, Inc., 2012)
Romidepsin—dermatitis/exfoliative dermatitis: 4%–27%
(Wolters Kluwer Health, Inc., 2012)
Sorafenib—rash/desquamation: all grades, 19%, grade 3,
1% (Bayer HealthCare Pharmaceuticals Inc., 2011)
Sunitinib—rash: all grades, 29%; grades 3–4, 2% (Pfizer
Inc., 2012c)
Trastuzumab—rash: 18%; herpes simplex: 2%; acne: 2%;
trastuzumab + paclitaxel—rash: 38% (Genentech, Inc.,
2012b)
Vemurafenib—rash: 37%–54%; grade 3, 7%–8% (Wolters
Kluwer Health, Inc., 2012)
Vandetanib—rash: all grades, 53%; grades 3–4, 9%
(Wolters Kluwer Health, Inc., 2012)
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 31. Cutaneous Reactions to Antineoplastic Agents (Continued)
Cutaneous
Reaction General Comments Chemotherapy Biotherapy and Targeted Therapy
Acneform An EGFRI-mediated rash generally follows a well-character- – Cetuximab—acneform rash: grades 1–4, 87%; grades
eruptions or ized clinical course. Within the first week of treatment, pa- 3–4, 17% (Bristol-Myers Squibb Co. & ImClone Sys-
papulopustular tients experience sensory disturbance with erythema and tems, 2012)
rash edema; from weeks 1–3, the papulopustular eruption man- Erlotinib—rash: all grades, 75%; grade 3, 8%; grade 4, <
ifests, followed by crusting at week 4. Despite successful 1% (Astellas Pharma US, Inc., & Genentech, Inc., 2012)
treatment, erythema and dry skin may persist in the areas Everolimus—acne: 3%–25% (Wolters Kluwer Health, Inc.,
previously affected by skin rash through weeks 4–6 (Melosky 2012)
et al., 2009). Gefitinib—acne: all grades, 10.9%–25%; grade 1, 19%;
It generally presents as a diffuse erythema over the face and grade 2, 6%; grades 3–4, 0%; dermatitis acneform:
body, progressing to follicular papules and pustules resembling 5.8%; rash/acne: 65.6% (AstraZeneca Pharmaceuti-
acne. cals, 2010)
Causative chemotherapy agents should be discontinued. Caus- Lapatinib—dermatitis acneform: all grades, 44%; grade 3,
ative EGFRIs may not need to be discontinued. < 1%; grade 4, 0% (GlaxoSmithKline, 2012)
The disorder is characterized by an eruption consisting of papules Panitumumab—acne dermatitis: all grades, 57%; grades
(a small, raised pimple) and pustules (a small pus-filled blis- 3–4, 7%; acne: all grades, 13%; grades 3–4, 1% (Am-
ter), typically appearing on the face, scalp, and upper chest and gen Inc., 2013b)
back. Unlike acne, this rash does not present with whiteheads or Temsirolimus—acne: all grades, 10%; grades 3–4, 0%
blackheads and can be symptomatic, with itchy or tender lesions (Wyeth Pharmaceuticals, 2012)
(Lacouture et al., 2010). Vandetanib—dermatitis acneform/acne: grades 3–4,
See text for grading and management of papulopustular rash. 1%. Withhold treatment for grade 3 or higher. Consider
dose reduction or permanent discontinuation upon im-
provement of symptoms (Wolters Kluwer Health, Inc.,
2012).
Erythema Condition generally presents as a macular-papular erythematous Infrequently associated with chemother- Vemurafenib—maculopapular rash: 9%–21%; papular
multiforme lesion that may progress to vesicles and also can progress to apy. High-dose combination chemo- rash: 5%–13%; skin papilloma: 21%–30%; hyperkera-
Chapter 9. Side Effects of Cancer Therapy
Stevens-Johnson syndrome and toxic epidermal necrolysis. therapy produces highest risk. Char- tosis: 24%–28%; cutaneous squamous cell carcinoma:
Record description, presentation, and severity (use a grading acterized by lesions over the extremi- all grades, 24%; grade 3, 22%–24% (Wolters Kluwer
scale). Consult with physician regarding possible etiology. Con- ties and often involving mucous mem- Health, Inc., 2012)
sider discontinuing offending chemotherapy agent. Causative branes. Busulfan, etoposide, procar-
EGFRIs may not need to be discontinued. bazine, hydroxyurea, bleomycin, meth-
Examine areas of tissue breakdown, and attend to comfort mea- otrexate, and cytarabine are associ-
sures with skin care and pain management strategies (see ated with these lesions, which some-
guidelines in text). times progress to generalized blistering
(Camp-Sorrell, 2011).
Can occur with allopurinol, carba
mazepine, phenytoin sodium, sulfa
drugs, and various antibiotics, anticon-
vulsants, and antituberculoid agents
(Plaza et al., 2013)
235
(Continued on next page)
236
Table 31. Cutaneous Reactions to Antineoplastic Agents (Continued)
Cutaneous
Reaction General Comments Chemotherapy Biotherapy and Targeted Therapy
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Erythema Daunorubicin, doxorubicin, 5-FU,
multiforme ifosfamide, vinblastine (Kamil et al.,
(cont.) 2010); amifostine, cladribine, cyclo-
phosphamide, docetaxel,
gefitinib, mechlorethamine, mitomycin
C, mitotane, paclitaxel, tamoxifen
(Wolters Kluwer Health, Inc., 2012)
Bexarotene (Targretin®)—maculopapu-
lar rash: 6% (Ligand Pharmaceuticals,
2011)
Blistering of the – 5-FU, vinblastine (White & Cox, 20011) IL-2 (White & Cox, 2006)
skin
Xerosis Abnormal dryness of the skin, mucous membranes, or conjuncti- Bexarotene—dry skin: 9.4%–10.7%; Axitinib—dry skin: 10% (Wolters Kluwer Health, Inc., 2012)
va (Segaert & Van Cutsem, 2005) rash: 16.7%, severe, 2%; exfolia- Cetuximab—dry skin: 49%; pruritus: 40% (Bristol-Myers
Treatment of mild or moderate xerosis consists of thick moistur- tive dermatitis: 9.5%, moderate to se- Squibb Co. & ImClone Systems, 2012)
izing creams without fragrances or potential irritants. Moistur- vere, 1%–3% (Ligand Pharmaceuti- Erlotinib—rash: all grades, 75%; grade 3, 8%; grade 4, <
izers should be occlusive, emollient creams that are generally cals, 2011) 1%; dry skin: all grades, 12%; grades 3–4, 0% (Wolters
packaged in a jar or tub rather than a lotion that can be pumped Kluwer Health, Inc., 2012)
or poured. Specific creams can include urea, colloidal oatmeal, Gefitinib—dry skin: all grades, 13%; grade 1, 12%; grade
and petroleum-based creams. 2, 1%; grades 3–4, 0% (AstraZeneca Pharmaceuticals,
For scaly areas of xerosis, ammonium lactate or lactic acid 2010)
creams can be used. Greasy creams may be used on the limbs Pegylated IFN alfa-2b—dry skin: 11% (Wolters Kluwer
for better control of xerosis but are cautioned on the face and Health, Inc., 2012)
chest, along with extremely hairy sites, because of the risk for Sorafenib—pruritus: all grades, 14%; grade 3, < 1%; dry
folliculitis secondary to occlusion. skin: 10% (Bayer HealthCare Pharmaceuticals Inc., 2011)
Sunitinib—dry skin: all grades, 15%; grades 3–4, < 1%
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
For more severe xerosis causing inflammation with or without ec-
zema, topical steroid creams may be necessary. Topical reti- (Pfizer Inc., 2012c)
noids and benzoyl peroxide gels are not recommended because Temsirolimus—dry skin: all grades, 11%; grades 3–4, 1%;
of their drying effect (Lacouture et al., 2011). rash: all grades, 47%; grades 3–4, 10% (Wyeth Pharma-
ceuticals, 2012)
Vandetanib—dry skin: 15% (Wolters Kluwer Health, Inc.,
2012)
Vemurafenib—dry skin: 16%–19%; seborrheic keratosis:
10%–14% (Wolters Kluwer Health, Inc., 2012)
Painful fissures Skin fissures and deep cracks in the skin can form as a result of – EGFRI therapy can lead to painful fissures.
significant xerosis and often occur in the fingertips, palms or Panitumumab—all grades, 20%; grades 3–4, 1% (Amgen
knuckles, and the soles. Fissures are a late side effect of EGFRI Inc., 2013b)
therapy, occurring around 30–60 days into therapy. They can be
very painful and create risk for infection (Lacouture et al., 2011).
Cyanoacrylate glue (liquid bandage formulations) may be helpful
in protecting the fissures (Segaert & Van Cutsem, 2005).
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 31. Cutaneous Reactions to Antineoplastic Agents (Continued)
Cutaneous
Reaction General Comments Chemotherapy Biotherapy and Targeted Therapy
Painful fissures Treat topically with propylene glycol 50% in water for 30 minutes
(cont.) under plastic occlusion every night, followed by application of
hydrocolloid dressing, antiseptic baths, or topical application of
silver nitrate (Potthoff et al., 2011).
Painful fissures on toes: Use protective footwear and a topical
corticosteroid, thick moisturizer, or barrier cream (petroleum jel-
ly, zinc oxide) (Wu et al., 2011).
Telangiectasia Disorder is characterized by local dilation of small vessels re- Topical carmustine and mechlorethamine Scattered telangiectasia can be seen with the develop-
sulting in red discoloration of the skin or mucous membranes (nitrogen mustard) cause vessel fragility ment of any acneform eruption caused by EGFRIs.
(Lacouture et al., 2010). and destruction (Camp-Sorrell, 2011).
Early during the development of acneform eruption or with subse-
quent flares of the rash, scattered telangiectasia may appear on
the face, on and behind the ears, and on the chest, back, and
limbs, usually in the vicinity of a follicular pustule. Unlike oth-
er telangiectasia, the lesions tend to fade over months, usually
leaving some hyperpigmentation (Lacouture et al., 2010).
Telangiectasia caused by treatment with EGFRIs, unlike spontane-
ous telangiectasia, will gradually disappear over months. In select
cases, electrocoagulation or pulsed dye laser therapy can be ap-
plied to accelerate disappearance (Segaert & Van Cutsem, 2005).
Radiation may cause telangiectasia, which is thought to be relat-
ed to the destruction of the capillary bed. It generally is consid-
ered a permanent change in the vessel (Haas, M.L., 2011).
Stevens-John- Stevens-Johnson Syndrome is a rare, serious disorder in which Cases of Stevens-Johnson Syndrome and Gefitinib—0.04% (AstraZeneca Pharmaceuticals, 2010)
son syndrome the skin and mucous membranes react severely to a medication toxic epidermal necrolysis, some fatal, Ipilimumab—2%–3% (Wolters Kluwer Health, Inc., 2012)
Chapter 9. Side Effects of Cancer Therapy
or infection. It often begins with flu-like symptoms, followed by a have been reported when bendamus- Vemurafenib—Stevens-Johnson syndrome has been ob-
painful red or purplish rash that spreads and blisters, eventually tine HCI (Treanda®) was administered served. Discontinue drug permanently (Wolters Kluwer
causing the top layer of the skin to die and shed. concomitantly with allopurinol and other Health, Inc., 2012).
Stevens-Johnson Syndrome presents a medical emergency that medications known to cause these syn-
usually requires hospitalization. Treatment focuses on eliminat- dromes. The relationship to Treanda can-
ing the underlying cause, controlling symptoms, and minimizing not be determined (Cephalon, Inc., 2012).
complications (Mayo Clinic Staff, 2011). Stevens-Johnson Syndrome has been re-
ported with allopurinol, amifostine, as-
paraginase, bleomycin, bortezomib,
capecitabine, cetuximab, chlorambu-
cil, cladribine, cyclophosphamide, cyta-
rabine, docetaxel, doxorubicin, etopo-
side, 5-FU, gefitinib, imatinib, lenalido-
mide, letrozole, levamisole, methotrex-
ate, paclitaxel, procarbazine, rituximab,
and thalidomide.
237
(Continued on next page)
238
Table 31. Cutaneous Reactions to Antineoplastic Agents (Continued)
Cutaneous
Reaction General Comments Chemotherapy Biotherapy and Targeted Therapy
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Toxic epidermal Toxic epidermal necrolysis is most commonly drug induced. How- Bendamustine HCI—in combination with Gefitinib—0.04% (AstraZeneca Pharmaceuticals, 2010)
necrolysis ever, the disorder has other potential etiologies, including infec- rituximab, one case of toxic epidermal Ipilimumab—dermal ulceration, necrotic, bullous, or hem-
tion, malignancy, and vaccinations. toxic epidermal necrolysis is necrolysis occurred. Toxic epidermal orrhagic dermatitis: 2%–3% (Wolters Kluwer Health,
idiosyncratic, and its occurrence is not easily predicted. necrolysis has been reported with ritux- Inc., 2012)
Some authors believe that Stevens-Johnson syndrome (also imab. Report and withhold bendamustine Vemurafenib—toxic epidermal necrolysis has been ob-
known as erythema multiforme major) is a manifestation of the and/or rituximab (Cephalon, Inc., 2012). served. Discontinue drug permanently (Wolters Kluwer
same process involved in toxic epidermal necrolysis, with the lat- Toxic epidermal necrolysis has been re- Health, Inc., 2012).
ter involving more extensive necrotic epidermal detachment. ported with allopurinol, amifostine, as-
toxic epidermal necrolysis involves > 30% of the body surface, paraginase, bleomycin, bortezomib,
whereas Stevens-Johnson syndrome involves < 10% (Cohen et capecitabine, cetuximab, chlorambu-
al., 2013). cil, cladribine, cyclophosphamide, cyta-
rabine, docetaxel, doxorubicin, etopo-
side, 5-FU, gefitinib, imatinib, lenalido-
mide, letrozole, levamisole, methotrex-
ate, paclitaxel, procarbazine, rituximab,
and thalidomide.
Acral erythema Generally presents as dysesthesia (altered sensation of the skin) High-dose cytarabine, capecitabine, Axitinib—2% (Wolters Kluwer Health, Inc., 2012)
with tingling in the hands and feet progressing to pain docetaxel, doxorubicin, 5-FU, floxuri- Everolimus—4% (Wolters Kluwer Health, Inc., 2012)
After 4 or 5 days of intense edematous erythema and even fis- dine, liposomal doxorubicin, methotrex-
sures of the palms, soles, and digital joints, progression to des- ate, paclitaxel (Camp-Sorrell, 2011)
quamation and reepithelialization occurs. It resolves 5–7 days
after therapy is discontinued. The etiology is not clear but may
be related to drug concentration in eccrine glands of the palms
and soles.
Applying cold compresses and elevating hands and feet during
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
drug administration may minimize incidence and degree of tox-
icity.
Skin care and comfort measures are instituted as soon as symp-
toms are evident. Supportive care may include wound dress-
ings, analgesia (pain relief), and cold compresses.
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 31. Cutaneous Reactions to Antineoplastic Agents (Continued)
Cutaneous
Reaction General Comments Chemotherapy Biotherapy and Targeted Therapy
Palmar-plantar It first appears as mild redness on the palms and soles with tin- Bleomycin, capecitabine, cisplatin, cy- Hand-foot skin reaction is common with multikinase inhib-
erythrodyses- gling sensations in the hands, usually at the fingertips; symp- clophosphamide, cytarabine, dauno- itors, shown to occur in 9%–62% of patients, and devel-
thesia (hand- toms progress to a more intense burning pain and tenderness. rubicin, docetaxel, doxifluridine, doxo- ops within the first 2–4 weeks of treatment (Eaby-San-
foot syndrome) Palms and soles appear edematous, and patients may have diffi- rubicin, etoposide, 5-FU (given in pro- dy et al., 2012).
culty walking or grasping objects. Ulceration may occur if thera- longed infusion), floxuridine, fludara- Axitinib—all grades, 27%; grades 3–4, 5% (Wolters Kluw-
py is not stopped. bine, gemcitabine, hydroxyurea, idaru- er Health, Inc., 2012)
Incidence and severity of symptoms are related to protracted ex- bicin, ixabepilone, liposomal encapsu- Everolimus—5% (Wolters Kluwer Health, Inc., 2012)
posure of cells to the drug. Symptoms usually develop 2–12 lated doxorubicin, methotrexate, mito- Lapatinib—palmar-plantar erythrodysesthesia when given
days after administration of chemotherapy. Early recognition and tane, thiotepa, vinorelbine (Degen et with capecitabine: all grades, 53%; grade 3, 12%; grade
cessation of drug administration are critical to symptom man- al., 2010; Huang & Anadkat, 2011; Ka- 4, 0% (GlaxoSmithKline, 2012)
agement (Morse, 2014). mil et al., 2010; Morse, 2014; Wolters Pazopanib—6% (Wolters Kluwer Health, Inc., 2012)
Symptoms may include flaking, swelling, small blisters, or small Kluwer Health, Inc., 2012) Sorafenib—34%–48% (Degen et al., 2010)
sores. Incidence of 50% (though reports vary) Sorafenib—all grades, 21%; grade 3, 1% (Bayer Health-
Prevention and treatment include reducing exposure of hands and in patients receiving liposome-encap- Care Pharmaceuticals Inc., 2011)
feet to friction and heat by having patients avoid sulated doxorubicin. Incidence corre- Sorafenib + bevacizumab—all grades, 79%; grades 2–3,
• Hot water (washing dishes, long showers, hot baths) lates with higher doses and increased 57% (Degen et al., 2010)
• Impact on their feet (jogging, aerobics, walking, jumping) number of cycles (Morse, 2014). Sunitinib—all grades, 19%–36%; grade > 3, 6%–23%
• Use of tools that require them to squeeze their hand on a hard (Degen et al., 2010)
surface (garden tools, household tools, kitchen knives) Combination therapy:
• Rubbing (applying lotion, massaging). Docetaxel + capecitabine—
Dose reduction may minimize the risk of recurrence (Huang & 56%–63% (Degen et al., 2010)
Anadkat, 2011). Doxorubicin + continuous 5-FU—
89% (Degen et al., 2010)
Photosensitivity Sunburn occurring after minimal sun exposure High-dose methotrexate, dacarbazine, Patients treated with EGFRIs may develop photosensi-
Appears as an erythematous response to UV radiation; skin ap- 5-FU, trans-retinoic acid, vinblastine tivity characterized by erythema from UV-induced dam-
Chapter 9. Side Effects of Cancer Therapy
pears red with erythema, edema, and possibly vesicles. (Camp-Sorrell, 2011) age. Erythema may be painful and associated with des-
Patients are instructed to wear protective clothing and a hat when quamation. In severe cases, photosensitivity and ery-
in the sun, avoid direct sunlight when possible, especially during thema may be disabling or life threatening (Boucher et
peak hours of 10 am and 3 pm, and avoid tanning beds. They al., 2011).
should wear a sunscreen with an SPF higher than 15 (Camp- Cetuximab (Bristol-Myers Squibb Co. & ImClone Sys-
Sorrell, 2011). tems, 2012); panitumumab (Amgen Inc., 2013b); vande-
In addition to measures take to avoid sun exposure, patients treat- tanib, vemurafenib (Wolters Kluwer Health, Inc., 2012)
ed with EGFRIs are advised to wear sunscreen with an SPF of
30 or higher (Potthoff et al., 2011).
239
(Continued on next page)
240
Table 31. Cutaneous Reactions to Antineoplastic Agents (Continued)
Cutaneous
Reaction General Comments Chemotherapy Biotherapy and Targeted Therapy
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Transient Urticaria is characterized as multiple swollen, raised areas on the Aldesleukin can cause erythema and The offending agent may need to be discontinued if the
erythema or skin that are intensely itchy and appear primarily on the chest, pruritus that may progress into a prurit- reaction is severe or associated with systemic reactions
urticaria back, extremities, face, and scalp. It usually occurs within hours ic papular rash (Prometheus Laborato- such as a generalized rash (Morse, 2014).
of chemotherapy and disappears within a few hours. It may be ries Inc., 2012). IFN alfa-2a and IFN alfa-2b can cause dry, scaling, itchy
generalized or local at the site of chemotherapy or along the Asparaginase can cause urticaria, fever, skin or a pruritic maculopapular reaction (Hoffmann-La
vein. chills, and hypotension (skin testing is Roche Inc., 2008; Merck Sharp & Dohme Corp., 2013a).
advised). Panitumumab—erythema: all grades, 65%; grades 3–4,
Bleomycin can cause erythema over 5% (Amgen Inc., 2013b)
pressure points and hyperpigmentation Sunitinib—erythema: all grades, 12%; grade 3, < 1%
(Camp-Sorrell, 2011). (Pfizer Inc., 2012c)
Chlorambucil, methotrexate, melphalan, Vemurafenib—erythema: 8%–14% (Wolters Kluwer
and thiotepa can cause urticaria and Health, Inc., 2012)
angioedema.
Arsenic trioxide can cause urticaria
(Camp-Sorrell, 2011).
Cytarabine can cause transient erythe-
ma.
Ara-C, asparaginase, carboplatin, dau-
norubicin, and prednisolone can cause
urticaria (Kamil et al., 2010).
Doxorubicin can cause an erythematous
flare with pruritus at the IV site and
along the vein.
Oxaliplatin can cause delayed urticaria
(Villée et al., 2010).
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Skin – – Pazopanib—3% (Wolters Kluwer Health, Inc., 2012)
depigmentation
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 31. Cutaneous Reactions to Antineoplastic Agents (Continued)
Cutaneous
Reaction General Comments Chemotherapy Biotherapy and Targeted Therapy
Pruritus or May be localized or generalized; symptoms may worsen with de- Alkylating agents, antimetabolites, antibi- Axitinib—pruritus: 7% (Wolters Kluwer Health, Inc., 2012)
itching hydration. Encourage patients to drink 8–10 glasses of fluid per otics, plant alkaloids, and nitrosoureas Cetuximab—pruritus: grades 1–4, 16%; grades 3–4, <
day and minimize salt and alcohol intake. The agents most associated with hyper- 1%; skin disorders: grades 1–4, 4%; grades 3–4, 0%
Recommended skin care includes the use of medicated baths, sensitivities include doxorubicin, dau- (Bristol-Myers Squibb Co. & ImClone Systems, 2012)
anesthetic creams, and emollient creams. Mild soap designed norubicin, cytarabine, L-asparaginase, Erlotinib—dry skin: 12%; pruritus: all grades, 7.4%–13%;
for sensitive skin should be used, and perfumes, deodorants, paclitaxel, and cisplatin (National Can- grade 3, < 1% (Astellas Pharma US, Inc., & Genentech,
cosmetics, and starch-based powders avoided. Massage, pres- cer Institute, 2011b). Inc., 2012)
sure, or rubbing with a soft cloth should be suggested instead of Asparaginase, cisplatin, carboplatin, cy- Gefitinib—pruritus: all grades, 17.6%; grade 1, 7%; grade
scratching (Camp-Sorrell, 2011). tarabine, daunorubicin, doxorubicin, 2, 1%; grades 3–4, 0% (AstraZeneca Pharmaceuticals,
Wearing loose-fitting clothing and clothing made of cotton or oth- etoposide, IFN alfa-2a and IFN alfa- 2010)
er soft fabrics can alleviate pruritus. Use antibiotics if pruritus is 2b, melphalan, and teniposide can all Panitumumab—pruritus: all grades, 57%, grades 3–4,
secondary to infection. Use oral antihistamines, with increased cause a rash. 2%; skin exfoliation: all grades, 25%; grades 3–4, 2%
doses at bedtime. Sedatives, tranquilizers, and antidepressants Temsirolimus—pruritus: all grades, 19%; (Amgen Inc., 2013b)
may be useful treatments. Aspirin seems to reduce itching in grades 3–4, 1% (Wyeth Pharmaceuti- Pegylated IFN alfa-2b—pruritus: 12% (Wolters Kluwer
some patients but increases it for others. Aspirin combined with cals, 2012) Health, Inc., 2012)
cimetidine may be effective for patients with Hodgkin lympho- Bendamustine HCI—pruritus: 8% (Ceph- Pralatrexate—pruritus: all grades, 14%; grade 3, 2%;
ma or polycythemia vera. Use of distraction, relaxation, positive alon, Inc., 2012) grade 4, 0% (Wolters Kluwer Health, Inc., 2012)
imagery, or cutaneous stimulation is encouraged. A cool, humid Actinic keratoses—topical 5-FU, cispla- Sorafenib—pruritus: all grades, 14%; grade 3, < 1% (Bay-
environment may prevent skin from itching (National Cancer In- tin, cytarabine, dacarbazine, dactino- er HealthCare Pharmaceuticals Inc., 2011)
stitute, 2011b). mycin, docetaxel, doxorubicin, pen- Sunitinib—pruritus: 12%; dry skin: all grades, 23%; grade
Skin moisturizer and urea- or polidocanol-containing lotions are tostatin, 6-thioguanine, vincristine 3, < 1% (Pfizer Inc., 2012c)
suitable to soothe pruritus. Systemic treatment with oral H1-an- (Huang & Anadkat, 2011) Vandetanib—pruritus: 11% (Wolters Kluwer Health, Inc.,
tihistamines such as cetirizine, loratadine, or fexofenadine, as 2012)
well as clemastine, may provide relief of itching for patients with Vemurafenib—pruritus: 23%–30%; actinic keratosis: 8%–
grade 2–3 pruritus (Potthoff et al., 2011). 17%, seborrheic keratosis: 10%–14% (Wolters Kluwer
Health, Inc., 2012)
Chapter 9. Side Effects of Cancer Therapy
ARA-C—cytosine arabinoside; EGFRI—epidermal growth factor receptor inhibitor; 5-FU—5-fluorouracil; GVHD—graft-versus-host disease; IFN—interferon; IL—interleukin; IV—intravenous; mAb—monoclonal antibody;
241
SPF—sun protection factor; UV—ultraviolet
242 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
stimulate inflammation, apoptosis, and cell attachment. This altered
permeability barrier may allow for the promotion of bacterial over-
growth, further exacerbating cutaneous injury and development of
the characteristic skin rash (Melosky et al., 2009).
c) EGFRI treatment induces a complex pattern of tissue injury and in-
flammatory cell recruitment, damaging the basal epidermis, the sweat
and sebaceous glands, and hair follicles (Potthoff et al., 2011).
d) Skin toxicities include rash (papulopustular), xerosis, painful cracks
and fissures on the palms and soles, paronychia, pruritus, and abnor-
mal hair and eyelash growth (Mittmann & Seung, 2011).
e) Rash presentation: The presentation can be divided into four stages
beginning with sensory disturbance accompanied by edema and ery-
thema. The characteristic rash of papules and pustules, which is pre-
dominantly but not exclusively folliculocentric in distribution, ap-
pears subsequently. This is followed by a postinflammatory phase of
erythema and telangiectasias. For patients with darker skin tone, a
fourth phase of postinflammatory hyperpigmentation may be pres-
ent and can be long lasting (Wu et al., 2011).
f) The pathology and etiology of rash associated with HER1/EGFR-tar-
geted agents are distinct from acne vulgaris. Histopathology confirms
a sterile eruption consisting of follicular papules and pustules in an
acneform distribution.
g) Noninflammatory comedones (blackheads and whiteheads) have
not been described as part of the EGFRI rash (Pomerantz, Mirvish,
& Geskin, 2010).
h) Rash associated with HER1/EGFR-targeted agents is dominated by pus-
tules that can develop an impetiginous, honey-combed crust in serious
cases. Yellowish-brown crust overlying inflammatory eruptions with
oozing of fluid from lesions may be indicative of a secondary bacteri-
al infection (Mitchell, Perez-Soler, Van Cutsem, & Lacouture, 2007).
i) Pustules show an intrafollicular collection of neutrophils—the hall-
mark of infectious folliculitis. Pustules often contain pus and are ac-
companied by dry skin and pruritus (Pérez-Soler et al., 2005).
j) Differentiation of rash etiology and characteristics: HER1/EGFR-tar-
geted agent–associated rash should not be confused with acne vul-
garis, steroid-induced rash, or cellulitis; the rashes are separate enti-
ties and vary in their characteristics.
(1) Acne vulgaris has a unique pathology. Acne is characterized clin-
ically by both noninflammatory lesions known as comedones,
as well as inflammatory papules, pustules, and nodules (Pérez-
Soler et al., 2005).
(2) Patients taking steroids for cancer therapy may develop steroid-
induced acne, a monomorphous eruption with widespread, 2–3
mm, firm, erythematous papules primarily on the trunk. Culture
will not reveal any purulent material (Pérez-Soler et al., 2005).
(3) EGFRI rash differs from cellulitis. Cellulitis typically presents
with a localized area of warmth, erythema, and tenderness and
can be associated with fever (Pérez-Soler et al., 2005).
k) Rash terminology
(1) Described in phenotypic (observable traits) terms related to its
appearance and location (Pérez-Soler et al., 2005)
(2) Terms pustular/papular rash, pustular eruption, or follicular and
intrafollicular pustular eruptions are preferred to the commonly
used terms “acneform” and “acne-like” for description (Pomer-
antz et al., 2010).
(3) Accurate rash description is essential for proper treatment. See
Figure 27.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 243
Figure 27. Pustular/Papular Rash Presentations
Papular Lesions on the Chest V-Shaped Papulopustular Eruption
Follicular Pustules Confluent Pustules
Note. From “Clinical Signs, Pathophysiology and Management of Skin Toxicity During Therapy With Epidermal Growth Factor Receptor Inhibitors,” by S.
Segaert and E. Van Cutsem, 2005, Annals of Oncology, 16, p. 1427. doi:10.1093/annonc/mdi279. Copyright 2005 by the European Society for Medical On-
cology. Reprinted with permission.
3. Incidence
a) Pustular/papular rash, the most frequent EGFRI-induced skin toxic-
ity, occurs in 45%–100% of patients (Potthoff et al., 2011). The rash
usually develops in cosmetically sensitive areas. Pruritic and tender
erythematous papules and pustules develop in skin with a high den-
sity of sebaceous glands (scalp, face, upper chest, and back) (Lacou-
ture et al., 2011). The rash generally appears 8–10 days after the start
of therapy and peaks approximately two weeks after initiation, dimin-
ishing after four to six weeks of EGFRI therapy (Eaby-Sandy, Grande,
& Viale, 2012; Lynch et al., 2007). Time to first rash appearance may
be related to the agent and dose (Pérez-Soler et al., 2005). The rash
may change in intensity throughout the course of treatment and usu-
ally resolves within one to three months after treatment is stopped
(Lynch et al., 2007).
(1) Papulopustular rash (45%–100%)
(2) Xerosis (7%–35%)
(3) Periungual inflammation (12%–16%)
(4) Alopecia (12%–14%)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
244 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
(5) Ocular reactions (4%–12%) are characteristic of EGFRIs, re-
sulting in significant ocular discomfort and potential visual blur
(Lacouture, 2007).
(a) Trichomegaly
(b) Conjunctivitis
(c) Keratoconjunctivitis sicca
(d) Lacrimation
b) Factors associated with an increased risk of developing rash with erlo-
tinib include nonsmokers, fair skin, and age older than 70. Men tak-
ing cetuximab and those younger than 70 are at increased risk. Se-
vere rash is more frequent with mAbs (10%–17%) than with low-mo-
lecular-weight tyrosine kinase inhibitors (5%–9%).
4. Grading rash severity: Accurate grading of dermatologic adverse events
due to EGFRIs is necessary for drug toxicity determination, integrant
comparisons, and supportive grading scale. The CTCAE version 4.0 (NCI
CTEP, 2009) is widely accepted throughout the oncology community as
the standard classification and severity grading scale for adverse events
in cancer therapy clinical trials and other oncology settings. However, it
was not designed specifically for this class of agents and may result in un-
derreporting and poor grading of distinctive adverse events (Lacouture
et al., 2010). The standard grading of dermatologic toxicity employs the
NCI CTCAE version 4.03 (NCI CTEP, 2010) (see Table 32). The MASCC
Study Group has proposed a new grading scale for EGFRI-induced der-
matologic adverse events. The group believes a class-specific grading scale
is needed to help standardize assessment and improve reporting of these
dermatologic adverse events (Lacouture et al., 2010).
5. Skin reactions are associated with significant morbidity and can lead to dose
reductions or premature discontinuation of chemotherapy. The adverse
effect of cutaneous reactions on patients’ QOL is only beginning to be
understood (Wu et al., 2011). EGFRIs frequently induce a variety of skin
effects that are predictive and often severe enough to warrant delaying
treatment or even permanent discontinuation (Cotliar, 2011).
6. Collaborative management
a) Treatment of rash is largely dependent on the patient’s symptoms.
EGFRI-induced skin reactions can be effectively treated at all stages
and all grades, and dermatologic effects induced by EGFRIs are be-
lieved to be reversible (Potthoff et al., 2011). Skin care recommen-
dations while receiving EGFRI treatment include the following (Pot-
thoff et al., 2011, unless otherwise cited).
(1) Instruct patients to use gentle soaps and shampoos for person-
al hygiene (i.e., pH-5 neutral bath and shower formulations)
and tepid water. Avoid alcohol-containing lotions or gels in fa-
vor of oil-in-water creams or ointments. Clean, smooth towels
are recommended to reduce potential risk of infection. Pat skin
to dry; avoid rubbing. Avoid hot blow-drying the hair.
(2) A dermatologist-approved makeup (e.g., Dermablend®) can
be used, although any type of foundation may be useful. Re-
move makeup with a hypoallergenic liquid cleanser (e.g., Neu-
trogena®, Cetaphil®, Dove®, Ivory Skin Cleansing Liquid Gel®)
(Pérez-Soler et al., 2005). Avoid manipulation of the skin be-
cause of risk of infection.
(3) Instruct patients to shave with caution and avoid excessive beard
growth. Use regular shaving razor with sharp multiblades and
shaving cream emollients and moisturizing aftershave. Avoid us-
ing an electric shaver and aftershave containing alcohol (Pinto
et al., 2011).
(4) Smooth-cotton clothes should be worn instead of synthetic fabrics.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 245
Table 32. National Cancer Institute Common Terminology Criteria for Adverse Events Categories
Relevant to EGFRI-Associated Dermatologic Toxicity
Toxicity Grade Description
Dry skin 1 Covering < 10% BSA and no associated erythema or pruritus
2 Covering 10%–30% BSA and associated with erythema or pruritus; limiting instrumental ADL
3 Covering > 30% BSA and associated with pruritus; limiting self-care ADL
4 –
5 –
Definition: A disorder characterized by flaky and dull skin; the pores are generally fine, and the texture is a papery thin texture.
Papulopus- 1 Papules and/or pustules covering < 10% BSA, which may or may not be associated with symptoms of pruri-
tular rash tus or tenderness
2 Papules and/or pustules covering 10%–30% BSA, which may or may not be associated with symptoms of
pruritus or tenderness; associated with psychosocial impact; limiting instrumental ADL
3 Papules and/or pustules covering > 30% BSA, which may or may not be associated with symptoms of pruri-
tus or tenderness; limiting self-care ADL; associated with local superinfection with oral antibiotics indicated
4 Papules and/or pustules covering any percent BSA, which may or may not be associated with symptoms
of pruritus or tenderness and are associated with extensive superinfection with IV antibiotics indicated; life-
threatening consequences
5 Death
Definition: A disorder characterized by an eruption consisting of papules (small, raised pimples) and pustules (small pus-filled blisters),
typically appearing on the face, scalp, and upper chest and back. Unlike acne, this rash does not present with whiteheads or blackheads
and can be symptomatic, with itchy or tender lesions.
Paronychia 1 Nail fold edema or erythema; disruption of the cuticle
2 Localized intervention indicated; oral intervention indicated (e.g., antibiotic, antifungal, antiviral); nail fold ede-
ma or erythema with pain; associated with discharge or nail plate separation; limiting instrumental ADL
3 Surgical intervention or IV antibiotics indicated; limiting self-care ADL
4 –
5 –
Definition: A disorder characterized by an infectious process involving the soft tissues around the nail.
Pruritus 1 Mild or localized; topical intervention indicated
2 Intense or widespread; intermittent; skin changes from scratching (e.g., edema, papulation, excoriations, li-
chenification, oozing/crusts); oral intervention indicated; limiting instrumental ADL
3 Intense or widespread; constant; limiting self-care ADL or sleep; oral corticosteroid or immunosuppressive
therapy indicated
4 –
5 –
Definition: A disorder characterized by an intense itching sensation.
ADL—activities of daily living; BSA—body surface area; EGFRI—epidermal growth factor receptor inhibitor; IV—intravenous
Note. From Common Terminology Criteria for Adverse Events [v.4.03], by National Cancer Institute Cancer Therapy Evaluation Program, 2010. Retrieved
from http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
246 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
(5) Instruct patient to avoid skincare products that contain alco-
hol or other harsh additives and detergents or other household
cleaning products (Eaby, Culkin, & Lacouture, 2008).
(6) Nails should be cut straight across until the nails no longer ex-
tend over the fingers or toes. Cuticles should not be trimmed
because of an increased risk of nail bed infection (Potthoff et
al., 2011). Advise patients to avoid pushing back cuticles or bit-
ing fingernails and to avoid wearing tight-fitting shoes, which
can exacerbate toenail changes. Instruct patients to wear rub-
ber or cotton-lined gloves while washing dishes, gardening, or
cleaning (Eaby et al., 2008).
(7) Instruct patients to avoid sun exposure. Sunscreen should be
applied daily to exposed skin areas regardless of the season.
Hypoallergenic sunscreens with high sun protection factor (at
least 30), para-aminobenzoic acid (PABA)-free, ultraviolet A
and B (UVA/UVB) protection, preferably broad spectrum and
containing zinc oxide or titanium dioxide are recommended.
Recommend that patients wear a hat and protective clothing
for sun protection.
(8) Moisturize the skin when EGFRI therapy is started, with emollients
free of perfume, alcohol, and petroleum jelly (e.g., Neutrogena
Norwegian Formula® hand cream, Vaseline Intensive Care® Ad-
vanced Healing Lotion) to prevent dryness (OncUView, 2011a).
Hypoallergenic moisturizing creams, ointments, and emollient
should be used once daily to smooth the skin and to prevent and
alleviate skin dryness; greasy creams should be avoided for ba-
sic care (e.g., pure petroleum). Such creams might facilitate the
development of folliculitis because of their occlusive properties.
(9) Instruct patient not to use topical acne medications, (e.g., ret-
inoids, alpha hydroxy acid, benzoyl peroxide gel or cream)
which may irritate and worsen EGFRI-induced rash because of
their drying effects (Potthoff et al., 2011).
b) Recommendations for management of EGFRI-associated rash are
available from MASCC and NCCN (see Figure 28).
c) Patients should be referred to a dermatologist if lesions have an un-
characteristic appearance or distribution or if necrosis, blistering, or
petechial purpuric lesions are present (Segaert & Van Cutsem, 2005).
7. Secondary infection: Signs of secondary infection can be subtle, espe-
cially in patients who are neutropenic or taking systemic steroids (Pérez-
Soler et al., 2005).
a) The pustules associated with HER1/EGFR inhibitors are notably ster-
ile with negative cultures or staining for bacteria, fungi, and yeast
(Segaert & Van Cutsem, 2005).
b) Inflammatory-based pustules should be sterile, but experience shows
that secondary infections are common.
(1) Most common presentation of a secondary infection is an in-
crease in pustules.
(2) Significant oozing of fluid from lesions or an abrupt change in
their appearance may be present.
(3) Secondary infection of skin rash may occur at later stages, which
includes impetiginization, an important complication caused by
staphylococci or streptococci. Staphylococcus aureus is the most
frequently detected infectious agent; less frequent infections
include herpes simplex, herpes zoster, and dermatophytes. Ab-
scesses may require incision and drainage to prevent sepsis. Bac-
terial swabs should be taken and anti-infective treatment start-
ed (Potthoff et al., 2011).
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 247
Figure 28. Recommendations for Prevention and Management of EGFRI Rash
MASCC NCCN
Preventive/Prophylactic Preventive/Prophylactic
• Systemic • Systemic
–– Minocycline 100 mg dailya or doxycycline 100 mg BIDb –– Oral semisynthetic tetracycline agents (doxycycline or mino-
• Topical cycline)
–– Hydrocortisone 1% cream with moisturizer and sunscreen –– Doxycycline 100 mg BID in combination with
BID • Topical
–– Hydrocortisone 1%, skin moisturizer, and sunscreen.
Treatment
• Topical Treatment
–– Alclometasone 0.05% cream • Topical
–– Fluocinonide 0.05% cream BID –– Topical steroids and antibiotics, such as clindamycin and
–– Clindamycin 1% erythromycin, may be useful.
• Systemic • Systemic
–– Doxycycline 100 mg BID –– Oral antibiotics include doxycycline or minocycline.
–– Minocycline 100 mg daily –– Systemic steroids are not typically used, but published case
–– Isotretinoin at low doses of 20–30 mg/day reports have suggested their use in specific settings.
–– Administer isotretinoin reactively (based on anecdotal or
nonrandomized studies).
Not Recommended
Pimecrolimus 1% cream, tazarotene 0.05% cream, sunscreen as a single agent, tetracycline 500 mg BID, vitamin K1 cream, acitretin,
oil-in-water topical trolamine emulsion
a
Minocycline is less photosensitizing.
b
Doxycycline should be used in patients with renal impairment.
BID—twice daily; EGFRI—epidermal growth factor receptor inhibitor; MASCC—Multinational Association of Supportive Care in Cancer; NCCN—National
Comprehensive Cancer Network
Note. Based on information from Burtness et al., 2009; Eaby-Sandy et al., 2012; Lacouture et al., 2011.
(4) Inspect rash regularly, culturing pustules in early-onset rash to
determine if Staphylococcus aureus is present.
(5) Frequent culturing enables assessment of the extent of second-
ary infection, the type of colonizing bacteria, and effectiveness
of treatments.
(6) If antibiotic resistance is suspected, culture the pustules to de-
termine bacterial strain before treating.
8. Rash and response/survival
a) Incidence and severity of papulopustular rashes are associated with
a better prognosis and therefore are considered to predict response
of a tumor to the EGFRI (Gutzmer et al., 2012). Studies addressing
EGFRI-induced rash suggest that its severity is a surrogate marker for
efficacy of the therapy (Potthoff et al., 2011).
b) Data suggest a correlation of rash incidence and severity with clinical
response and increased survival time, leading investigators to imple-
ment “dose-to-rash” strategies, in which a patient’s EGFRI dose is pro-
gressively escalated until rash of a specified grade appears. A consistent
relationship between rash and response has not been observed with
all EGFRIs studied in clinical trials to date (Pomerantz et al., 2010).
9. Psychosocial issues
a) Skin toxicities from EGFRIs can have a significant impact on patients’
physical, emotional, and social function. These side effects may in-
terfere with treatment adherence, but patients may accept them as
part of their experience with cancer or as a sign of response to ther-
apy (Romito et al., 2010; Wagner & Lacouture, 2007).
b) The majority of cases do not require withdrawal of EGFRI treatment.
Suspension of EGFRI treatment should only be temporary, allowing
for diminution of the rash (Lynch et al., 2007).
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
248 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
c) Most significant skin toxicities and health-related QOL factors (Wag-
ner & Lacouture, 2007)
(1) Inability to work
(2) Sleep disturbances
(3) Interference with activities of daily living
(4) Disruption of hobbies
(5) Skin pain, burning, itching, and irritation
(6) Increased facial hair
(7) Depression, frustration, anxiety, and worry
(8) Disruption of social life
10. Patient and family education
a) Instruct patients about the potential EGFRI-related symptoms of der-
matologic toxicities as part of supportive measures (Boucher, Olson,
& Piperdi, 2011).
(1) Include information about potential toxicities including rash,
pruritus, xerosis, photosensitivity, and erythema.
(2) Provide information on preventive and management measures.
b) Ensure that family and other support systems (friends, clergy, vis-
iting nurses, homecare personnel) can provide encouragement to
patients to help rebuild their self-esteem and self-belief. Discuss the
potential for anxiety or depression (Boucher et al., 2011; Eaby et
al., 2008; Lacouture, 2007; Oishi, 2008; Wagner & Lacouture, 2007).
c) Follow-up phone calls promote communication with patients regard-
ing their treatment experience. It is an opportunity for nurses to ed-
ucate and give supportive care (Boucher et al., 2011).
11. Combination radiation and EGFRI therapy
a) Significant in-field toxicity can occur when radiation therapy and
EGFRIs are given concomitantly (Bernier et al., 2008).
b) Most people experience grade 1 (using version 2.0 of NCI CTEP’s
Common Toxicity Criteria) or mild toxicities, but 20%–25% of peo-
ple experience severe dermatitis with the combination of radiation
and EGFRI therapy (Wu et al., 2011).
c) Management guidelines for radiation dermatitis in the setting of
EGFRI papulopustular rash include minimizing the radiation dose
exposure of the epidermis, keeping the treated area clean and dry,
and applying topical medications such as hydrocortisone for a lim-
ited time (Bernier et al., 2008; Miller et al., 2011; Wu et al., 2011).
d) The ONS Putting Evidence Into Practice (PEP) (Baney et al., 2011)
resource on radiation dermatitis addresses the management of radi-
ation dermatitis and coexisting EGFRI rash. Information is available
at www.ons.org/practice-resources/PEP/radiodermatitis.
12. Chemotherapy agents associated with radiation enhancement and ra-
diation recall
a) Radiation enhancement: Bleomycin, dactinomycin, doxorubicin, 5-FU
with and without cisplatin, hydroxyurea, 6-mercaptopurine, meth-
otrexate, paclitaxel, gemcitabine, chlorambucil, and capecitabine
(Wolters Kluwer Health, Inc., 2012)
b) Radiation recall: Arsenic trioxide, bleomycin, capecitabine, cyclo-
phosphamide, cytarabine, dactinomycin, daunorubicin, docetaxel,
doxorubicin (free and liposomal), etoposide, 5-FU, gemcitabine,
hydroxyurea, idarubicin, lomustine, melphalan, methotrexate, pa-
clitaxel, pemetrexed, tamoxifen, and vinblastine (Wolters Kluwer
Health, Inc., 2012)
13. Multiple drugs are in development, including anti-EGFR mAb therapies
that inhibit dimerization of EGFR/HER receptors on the external sur-
face of the cell and small molecules that inhibit pathways such as RAS
(K-ras), BRAF (B-raf), and tyrosine kinase.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 249
14. Toxic erythema of chemotherapy (TEC) is chemotherapy-induced iat-
rogenic injury of the skin (Choi, 2011).
a) Numerous cutaneous side effects have been reported from traditional
chemotherapy drugs, including cytarabine, anthracyclines (including
doxorubicin), 5-FU, capecitabine (5-FU prodrug), taxanes (includ-
ing docetaxel), and methotrexate. Reports include clinical and his-
tologic findings that have significant overlap. The clinically descrip-
tive term toxic erythema of chemotherapy has been introduced as an eas-
ily understood clinical name for numerous entities (see Figure 29).
b) Clinical findings of TEC include areas of erythema that may be ac-
companied by edema, most often involving the hands, feet, and inter-
triginous zones, such as the axillae and inguinal folds. Less frequent-
ly, the elbows, knees, and ears are involved.
c) Patches or plaques typically develop within two days to three weeks fol-
lowing drug administration. Associated symptoms of pain, burning, par-
esthesia, and pruritus are frequently present. Areas of intense erythema
can be accompanied by development of a dusky discoloration, petechi-
ae, or sterile bullae, which can be followed by erosions. Typically, spon-
taneous resolution and desquamation occur without specific therapy,
and if the chemotherapeutic agent is given again at the same or high-
er dose, recurrences are possible and may be more intense with high-
er doses. In certain cases, a delayed onset of 2–10 months can be seen,
particularly in patients receiving lower-dose, continuous IV infusions.
d) Treatment options have been of variable success and include bland
emollients, analgesics, cool compresses, topical corticosteroids, and
topical antibiotics for erosions. It is important for oncologists and der-
matologists to recognize TEC, understanding that the reaction is not
allergic or infectious in nature and thus avoiding unnecessary label-
ing of drug allergies or use of antimicrobials (Choi, 2011).
15. See Figures 30–35 for examples of specific cutaneous manifestations of
EGFRI- and chemotherapy-induced toxicities.
Figure 29. Entities Included in Toxic Erythema of Chemotherapy
• Ara-C (cytarabine) ears
• Burgdorf reaction
• Chemotherapy-associated eccrine reactions
• Eccrine squamous syringometaplasia, chemotherapy induced
• Epidermal dysmaturation, chemotherapy induced
–– Epidermal dystrophy
• Erythrodysesthesia
–– Acral erythema
–– Acral erythrodysesthesia
–– Chemotherapy-induced acral erythema (CIAE or CAE)
–– Hand-foot syndrome
–– Palmar-plantar erythema
–– Palmar-plantar (palmoplantar) erythrodysesthesia
–– Toxic acral erythema
–– Toxic erythema of the palms and soles
• Intertriginous eruption associated with chemotherapy
–– Intertrigo-like eruption, chemotherapy-induced
–– Flexural erythematous eruption
–– Intertrigo dermatitis
• Neutrophilic eccrine hidradenitis, chemotherapy-associated
–– Chemotherapy-induced hidradenitis
–– Drug-induced hidradenitis
Note. Based on information from Choi, 2011.
From “Toxic Erythema of Chemotherapy: A Useful Clinical Term,” by J.L. Bolognia, D.L. Cooper, and E.J.
Glusac, 2008, Journal of the American Academy of Dermatology, 59, p. 525. Copyright 2008 by American
Academy of Dermatology, Inc. Adapted with permission.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
250 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Figure 30. Trichomegaly Figure 31. Paronychia of the Nail
Note. From “Clinical Signs, Pathophysiology and Note. From “Clinical Signs, Pathophysiology and
Management of Skin Toxicity During Therapy With Management of Skin Toxicity During Therapy With
Epidermal Growth Factor Receptor Inhibitors,” by Epidermal Growth Factor Receptor Inhibitors,” by
S. Segaert and E. Van Cutsem, 2005, Annals of S. Segaert and E. Van Cutsem, 2005, Annals of
Oncology, 16, p. 1428. Copyright 2005 by the Eu- Oncology, 16, p. 1428. Copyright 2005 by the Eu-
ropean Society for Medical Oncology. Reprinted ropean Society for Medical Oncology. Reprinted
with permission. with permission.
Figure 32. Hyperpigmentation Figure 33. Fissure
Note. From “Clinical Signs, Pathophysiology and Note. From “Clinical Signs, Pathophysiology and
Management of Skin Toxicity During Therapy Management of Skin Toxicity During Therapy With
With Epidermal Growth Factor Receptor Inhib- Epidermal Growth Factor Receptor Inhibitors,” by
itors,” by S. Segaert and E. Van Cutsem, 2005, S. Segaert and E. Van Cutsem, 2005, Annals of
Annals of Oncology, 16, p. 1428. Copyright 2005 Oncology, 16, p. 1428. Copyright 2005 by the Eu-
by the European Society for Medical Oncology. ropean Society for Medical Oncology. Reprinted
Reprinted with permission. with permission.
D. Alopecia
1. Overview: Alopecia is one of the most common and distressing side ef-
fects of chemotherapy. Hair loss was identified as the most traumatic
aspect of chemotherapy by 47% of female patients in a study by McGar-
vey, Baum, Pinkerton, and Rogers (2001). A portion of these patients
may choose not to receive chemotherapy because of an intense fear of
this side effect (McGarvey et al., 2001; Münstedt, Manthey, Sachsse, &
Vahrson, 1997). In young adults age 18–38, men and women reported
equally negative experiences related to chemotherapy-induced alope-
cia (Hilton, Hunt, Emslie, Salinas, & Ziebland, 2008). Chemotherapy-
induced alopecia most commonly occurs on the scalp; however, it can
occur anywhere on the body including facial (beards, eyebrows, eyelash-
es), axillary, and pubic hair. Chemotherapy-induced alopecia negatively
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 251
affects an individual’s per-
Figure 34. Acral Erythema
ceptions of body image,
sexuality, and self-esteem.
2. Pathophysiology: The
pathobiology of the re-
sponse of human hair fol-
licles to chemotherapy re-
mains largely unknown.
Cells responsible for hair
growth have high mitotic
and metabolic rates. Cer-
tain cytotoxic agents dis-
rupt the proliferative phase
of hair growth. Approxi-
mately 90% of hair folli- Note. From “Painful Blistered Hands and Feet,” by C.
cles on the scalp are in the Coyle and V. Wenhold, 2001, Clinical Journal of On-
anagen (growth) phase of cology Nursing, 5, p. 230. Copyright 2001 by the On-
cology Nursing Society. Reprinted with permission.
the hair cycle at any given
time (Trüeb, 2010). The
two major types of chemotherapy-induced alopecia exist: telogen efflu-
vium and anagen effluvium.
a) Telogen effluvium involves < 50% of the scalp and results in hair thin-
ning. Hair enters the telogen, or resting, phase and results in shed-
ding three to four months after drug administration. Cytotoxic drugs
that can cause this type of alopecia are methotrexate, 5-FU, and ret-
inoids (Yeager & Olsen, 2011).
b) Anagen effluvium is the most common form of chemotherapy-induced
alopecia. Because most hair follicles are in the anagen (growth) phase,
chemotherapy damages these rapidly growing cells, leading to damage
of the inner root sheath cells or the hair shaft integrity. The hair shaft is
no longer anchored and falls out easily or breaks off at the scalp. Hair
falls out spontaneously or during washing or combing. Chemotherapeu-
tic agents such as cyclophosphamide, daunorubicin, doxorubicin, eto-
poside, ifosfamide, and paclitaxel are associated with this type of dam-
age. The hairs remain in the telogen phase after damage occurs until
the chemotherapy is completed, at which time they can enter the ana-
gen phase again and hair regrowth resumes (Yeager & Olsen, 2011).
3. Incidence
a) As many as 65% of patients undergoing chemotherapy will experi-
ence alopecia to some degree (Trüeb, 2010).
b) The extent of alopecia depends on the mechanism of action of the
drug, administration route, drug dose, serum half-life, duration (e.g.,
bolus versus continuous infusion), the response of the patient, the use
of combination chemotherapy, and the condition of the hair prior to
treatment (Chon, Champion, Geddes, & Rashid, 2011).
4. Risk factors
a) Type of cytotoxic drug(s) administered
(1) The drugs that present the highest risk of alopecia are cyclo-
phosphamide, daunorubicin, epirubicin, doxorubicin, eto-
poside, ifosfamide, docetaxel, paclitaxel, camptothecins, and
vinorelbine (Trüeb, 2010) (see Table 33).
(2) Combination chemotherapy is associated with a higher inci-
dence of alopecia than single-agent therapy.
(3) Molecularly targeted agents such as mAbs, which target EGFR,
and small molecular inhibitors of EGFR have been associated
with diffuse alopecia that is generally reversible (Chon et al.,
2011; Donovan, Ghazarian, & Shaw, 2008).
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
252 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Figure 35. Palmar-Plantar Erythrodysesthesia (Hand-Foot Syndrome)*
Grade 1
Minimal skin changes or dermatitis (e.g., ery-
thema, edema, hyperkeratosis), swelling, tin-
gling, and/or discomfort of hands or feet not
disrupting normal activities
Grade 2
Painful skin changes (e.g., peeling, blisters,
bleeding, edema, hyperkeratosis), erythema
and swelling of hands or feet and/or discom-
fort limiting instrumental activities of daily liv-
ing (ADLs)
Grade 3
Severe skin changes (e.g., peeling, blisters,
bleeding, edema, hyperkeratosis, moist des-
quamation, ulceration) with pain, or severe dis-
comfort limiting self-care ADLs
* Grading criteria based on information from National Cancer Institute Cancer Therapy Evaluation Program, 2010.
Note. Photos courtesy of Susan Moore, RN, MSN, ANP, Chicago, IL. Used with permission.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 253
Table 33. Risk of Chemotherapy-Induced Alopecia for Antineoplastic Agents
Classification High Risk Moderate Risk Mild Risk
Alkylating agents Cyclophosphamide Mechlorethamine Carboplatin
Ifosfamide Methotrexate Cisplatin
Antimetabolites – Amsacrine Capecitabine
Busulfan 5-Fluorouracil
Cytarabine Fludarabine
Gemcitabine Hydroxyurea
Thiotepa
Antitumor anti- Daunorubicin – Bleomycin
biotics Doxorubicin Mitoxantrone
Epirubicin
Camptothecins Irinotecan – –
Topotecan
Epipodophyllo- Etoposide – –
toxins
Targeted ther- – – Tyrosine kinase inhibitors
apies
Taxanes Docetaxel – –
Paclitaxel
Vinca alkaloids Vinorelbine – Vinblastine
Vincristine
Note. Based on information from Chon et al., 2011; Trüeb, 2009.
(4) Multitargeted tyrosine kinase inhibitors (e.g., sorafenib, suni-
tinib) have been associated with alopecia (Chon et al., 2011).
b) High-dose chemotherapy: Busulfan-containing regimens used for BMT
or HSCT have been linked to permanent hair loss, although this is rare
(Machado, Moreb, & Khan, 2007; Tosti, Piraccini, Vincenzi, & Misciali,
2005; Vowels, Chan, Giri, Russell, & Lam-Po-Tang, 1993).
c) Certain noncytotoxic medications (e.g., propranolol hydrochloride,
heparin sodium, lithium carbonate, prednisone, vitamin A, andro-
gen preparations)
d) Certain medical conditions (e.g., hypothyroidism, aging)
e) Poor hair condition before cytotoxic treatment
f) Concomitant or previous radiation therapy to the head (local effect)
5. Clinical manifestations: Scalp dryness, soreness, pruritus, and rash can
occur before, during, or after hair loss.
a) Degrees of alopecia (NCI CTEP, 2010)
(1) Grade 1: Hair loss of < 50% of normal for that individual that
is not obvious from a distance but only on close inspection; a
different hair style may be required to cover the hair loss, but
it does not require a wig or hairpiece to camouflage.
(2) Grade 2: Hair loss of 50% or greater compared to normal for
that individual that is readily apparent to others; a wig or hair-
piece is necessary if the patient desires to completely camou-
flage the hair loss; associated with psychosocial impact.
b) Expected time frame and pattern (Chon et al., 2011)
(1) Hair shedding begins approximately one to three weeks after
administration of the drug and may last one to two months af-
ter initiation of therapy.
(2) Pattern: Hair loss tends to occur first on the crown and sides of
head above the ears.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
254 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
(3) Chemotherapy-induced alopecia is generally reversible.
(4) Hair regrowth begins one to three months after discontinua-
tion of chemotherapy.
(5) Regrown hair may demonstrate changes in color, structure, or
texture and, in some patients, hair density may continue to be
reduced after treatment.
(6) Permanent alopecia following chemotherapy, although rare, can
occur with high-dose busulfan and cyclophosphamide following
HSCT, long-term use of EGFR inhibitors, and after treatment
with taxanes (Donovan et al., 2008; Machado et al., 2007; Miteva
et al., 2011; Tallon, Blanchard, & Goldberg, 2010).
6. Collaborative management: Alopecia is a constant reminder of disease
and greatly affects patients’ sense of self. Patients may experience pri-
vacy issues because alopecia is often associated with having cancer. Cur-
rently, no approved pharmacologic treatment is available for prevention
of alopecia caused by cytotoxic therapy. Multiple pharmacologic and bi-
ologic therapies are being studied, such as epidermal growth factor, ke-
ratinocyte growth factor, cytokines, antioxidants, and apoptosis inhibi-
tors (Yeager & Olsen, 2011).
a) Scalp hypothermia, although used in the past with mixed results, is
not currently recommended in patients with hematologic malignan-
cies and remains controversial in patients with nonhematologic ma-
lignancies. Patients should only consider this therapy if enrolled in
a clinical trial and/or with approval from their primary oncologist.
Patients may experience headaches, excessive coldness, or feelings
of claustrophobia (Trüeb, 2010).
(1) There is long-standing concern that reducing circulation to the
scalp through vasoconstriction may create a sanctuary site for
malignant cells, resulting in scalp metastasis.
(2) In six of seven randomized controlled trials published prior to
2004, investigators demonstrated a reduction in alopecia when
scalp hypothermia was used. However, these studies were small
and did not characterize the exact methods for cooling and ef-
fect on long-term survival (Grevelman & Breed, 2005).
(3) Randomized clinical trials are needed to determine the prop-
er technique for application, efficacy, and safety of scalp cool-
ing in preventing chemotherapy-induced alopecia (Grevelman
& Breed, 2005).
b) Topical minoxidil prolongs the anagen phase and may increase hair
follicle size. It appears to be most effective if used while hair still ex-
ists. Minoxidil has been associated with decreased severity and dura-
tion but does not eliminate chemotherapy-induced alopecia (Chon
et al., 2011).
7. Patient and family education: Ask patients to verbalize feelings related to
hair loss. Increasing patients’ knowledge may give them a sense of con-
trol as their appearance changes (Borsellino & Young, 2011). Advise pa-
tients and caregivers about the following (Batchelor, 2001; Chon et al.,
2011; Hesketh et al., 2004).
a) The cause of alopecia and the time frame of hair loss and regrowth
b) Strategies to manage hair loss and regrowth
(1) Most strategies are literature-based and have not been tested in
randomized controlled clinical trials.
(2) Use shampoos without detergents, menthol, salicylic acid, alco-
hol, or heavy perfumes.
(3) Avoid using permanent waves, bleach, and coloring agents on
hair, as well as vigorous brushing, hot rollers, and excessive heat
with hair dryer use.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 255
(4) Avoid excessive brushing or combing. Use a soft brush.
(5) Consider cutting hair in a short style or shaving the head.
(6) Protect the scalp from the cold and sun with hats, scarves, wigs,
and sunscreen. Consider cotton head coverings because they
will not slip off.
(7) Protect the eyes with sunglasses or clear-glass glasses if lashes
become thin or fall out completely; dust or particles can enter
the eye more easily and cause irritation.
(8) Instruct patients that new hair that grows after completion of
therapy may differ from the original hair in color or texture.
c) Local resources for support (e.g., wig salons, scarf and turban cata-
logs, support groups)
(1) “Look Good Feel Better” is a program offered by the Person-
al Care Products Council Foundation through community or-
ganizations such as the American Cancer Society to provide
guidance and support regarding wigs and other head cover-
ings, makeup, and skin care (Personal Care Products Council
Foundation, 2012).
(2) Computerized imaging programs to simulate baldness and the
look of various types and colors of wigs may be useful and can
decrease distress related to hair loss (McGarvey et al., 2010).
d) A wig may be covered by the patient’s insurance, which will help to de-
fray costs. A prescription written for “hair prosthesis” may be required.
(1) Wigs can be synthetic or made of actual human hair, with
the latter being more costly. Salons or stores that specialize
in wigs can provide a discussion of the pros and cons of each
type of wig with the client. Synthetic wigs may be damaged
by excessive heat during styling. Manufacturers’ care guide-
lines should be followed.
(2) Wig specialists may have an easier time matching a wig to the
patient’s usual style if the patient consults the stylist before hair
loss begins or provides pictures. It may be helpful to preserve a
portion of normal hair prior to complete hair loss to allow for
color and texture matching.
(3) If a wig is purchased prior to hair loss, it should be adjustable
so that the size can be decreased as the hair loss occurs (Per-
sonal Care Products Council Foundation, 2012).
(4) A variety of scarves and turbans are available and assist with pro-
tection of the scalp and prevention of heat loss.
E. Cardiovascular toxicity
1. Cardiovascular toxicity includes changes in conduction pathways (dys-
rhythmias), vasculature (hypotension, hypertension, Raynaud phenom-
enon), coronary arteries (unstable angina, acute myocardial infarction),
cardiac myocytes (cardiomyopathy), and pericardial fluid accumulation
(Anderson & Sawyer, 2008; Broder, Gottlieb, & Lepor, 2008; Chen, 2009;
Fadol & Lech, 2011; Sereno et al., 2008; Viale & Yamamoto, 2008). In
some cases, cardiac dysfunction cannot be linked to a specific therapeu-
tic agent but reflects the effects of a combination of agents and comor-
bid risk factors (Chung et al., 2008; Fadol & Lech, 2011). These cardio-
vascular toxicities are described in greater detail by chemotherapeutic
drug category in Table 34.
2. Conduction pathway disorders
a) Defined as disturbance in the regular excitation of the heart (Chum-
mun, 2009; Mottram & Svenson, 2011)
b) Pathophysiology (Collins, 2010; Guglin, Aljayeh, Saiyad, Ali, & Cur-
tis, 2009; Palatnik, 2011; Sharam, 2007)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
256
Table 34. Cardiotoxicity of Chemotherapeutic Agents
Classification Drug Incidence Characteristic Effects Nursing Considerations
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Alkylating Cisplatin Oxygen radicals released with antineoplastic ac- Raynaud phenomenon has been report- Maintain magnesium levels > 2 mEq/L (Slovacek
agents tivity can produce acidosis, ischemia, and ar- ed, but no coronary artery disease et al., 2008).
terial vasospasm. It is cumulative, worsening (Bristol-Myers Squibb Co., 2011d).
with long-term exposure, but is reversible as Hypomagnesemia induced by cisplatin has
long as neuropathies resolve. been associated with QT prolongation that
subsequently results in bradycardia and
with atrial or ventricular dysrhythmias (Slo-
vacek et al., 2008).
Cyclophospha- Toxicity is rare with cumulative or standard doses. ECG may show diminished QRS complex. Acute lethal pericarditis, pericardial effusion, cardi-
mide (high-dose) There have been some reports of increased fre- Cardiomegaly, pulmonary congestion, and ac tamponade, and hemorrhagic myocardial ne-
quency with high-dose therapy > 180–200 mg/ cardiac tamponade in children often are crosis may result in rare circumstances (Shaikh
kg/day for 4 days (Bristol-Myers Squibb Co., preceded by complaints of abdominal pain & Shih, 2012).
2005; Shaikh & Shih, 2012). and vomiting (Bristol-Myers Squibb Co., Cardiotoxicity usually is related to high doses for
Pediatric patients with thalassemia have been 2005). short intervals prior to BMT (Viale & Yamamo-
shown to have a potential for cardiac tampon- to, 2008).
ade when cyclophosphamide is given with bu- Cases of cardiomyopathy with subsequent death
sulfan (Bristol-Myers Squibb Co., 2005). have been reported following experimental
high-dose therapy with cytarabine in combina-
tion with cyclophosphamide when used for BMT
preparation (Bristol-Myers Squibb Co., 2005).
Estramustine (es- CHF occurs in 3% of patients; MI in 3% of pa- General fluid retention and exacerbation of Estramustine should be used with caution in pa-
tradiol and nitro- tients (Pfizer Inc., 2011c). preexisting or incipient peripheral edema tients with a history of cerebral vascular or coro-
gen mustard) or CHF have occurred in some patients. nary artery disease.
Men receiving estrogens for prostate can- Because hypertension may occur, blood pressure
cer are at increased risk for thrombosis, should be monitored periodically (Pfizer Inc.,
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
including fatal and nonfatal MI (Pfizer Inc., 2011c).
2011c).
Ifosfamide Cardiotoxicity occurs in < 1% of patients (Baxter Rare cardiac effects such as infusional hy- Establish baseline cardiac status and monitor for
Healthcare Corp., 2009a). Hypotension during potension, dysrhythmias, late hyperten- acute changes.
infusion is possible. sion, and acute heart failure have been re-
ported.
Melphalan Dose-related adverse effects are seen in < 5% Raynaud phenomenon is dose dependent, Teach patients to avoid cold exposure and tobac-
of cases (GlaxoSmithKline, 2003a). occurring only during active therapy and co smoking, both of which will exacerbate pain.
resolving after completion of the cycle.
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 34. Cardiotoxicity of Chemotherapeutic Agents (Continued)
Classification Drug Incidence Characteristic Effects Nursing Considerations
Androgen Abiraterone ac- All grades of hypertension occurred at a rate of Fluid retention with resultant hypertension Use with caution in patients with known heart or
inhibitor etate 8.5%, and 1.3% with grade 3 or 4 toxicity in and dysrhythmias can occur. vascular disease known to be compromised by
registration trials (Janssen Biotech, Inc., 2012). hypertension, hypokalemia, or fluid retention
(Janssen Biotech, Inc., 2012).
Safety of this agent has not been established in
patients with LVEF < 50% or having New York
Heart Association class III or IV heart failure
(Janssen Biotech, Inc., 2012).
Monitor blood pressure and fluid balance at least
monthly during therapy (Janssen Biotech, Inc.,
2012).
Anthracycline Daunorubicin If total dose < 600 mg/m2, incidence is 0%–4.1% Nonspecific arrhythmia, tachycardia, car- Chronic effects are similar to those of doxorubi-
antitumor (Camp-Sorrell, 2011; Teva Pharmaceuticals diomyopathy, pericardial effusion, and/or cin, but higher cumulative doses may be tolerat-
antibiotics USA, 2012a). CHF may occur. Acute left ventricular fail- ed (Camp-Sorrell, 2011).
If total dose is 1,000 mg/m2, incidence is 12% ure can occur with high doses. CHF may Periodic monitoring with echocardiogram or
(Teva Pharmaceuticals, 2012a). be unresponsive to treatment (Teva Phar- MUGA scan is recommended.
maceuticals USA, 2012a).
Acute toxicity unrelated to dose may occur
within hours.
Although rare, myocarditis-pericarditis syn-
drome may be fatal (Barry et al., 2007).
Daunorubicin ci- Chronic therapy > 300 mg/m2 has increased the Cardiomyopathy associated with a decrease Ensure that the patient undergoes a physical ex-
trate liposomal incidence of cardiomyopathy and CHF. in LVEF may occur, especially in patients amination and cardiac evaluation with MUGA
In a phase III study, 13.8% of patients reported a with prior anthracycline experience or pre- scan or echocardiogram before each course
triad of back pain, flushing, and chest tightness existing cardiac disease (Galen US Inc., and at total cumulative doses of 320 mg/m2 (160
Chapter 9. Side Effects of Cancer Therapy
(Galen US Inc., 2011). 2011). mg/m2 for higher-risk patients) and at every 160
mg/m2 thereafter.
Periodic monitoring with echocardiogram or
MUGA scans is recommended.
Triad usually occurs during the first five minutes
of infusion, subsides with infusion interruption,
and generally does not recur if the infusion is re-
sumed at a slower rate (Galen US Inc., 2011).
257
(Continued on next page)
258
Table 34. Cardiotoxicity of Chemotherapeutic Agents (Continued)
Classification Drug Incidence Characteristic Effects Nursing Considerations
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Anthracycline Doxorubicin If total dose is < 550 mg/m2, incidence is 0.1%– ECG changes; nonspecific ST-T wave Chronic effects seen with cumulative doses may
antitumor 1.2% (Camp-Sorrell, 2011; Pfizer Inc., 2011a). changes; premature ventricular and atri- result in CHF.
antibiotics If total dose is > 550 mg/m2, incidence rises ex- al contraction; low-voltage QRS changes; Concomitant administration of other antineoplastics
(cont.) ponentially (Camp-Sorrell, 2011; Pfizer Inc., and sinus tachycardia may occur acutely (e.g., cyclophosphamide, taxanes, trastuzumab)
2011a). during administration (Pfizer Inc., 2011a). has been implicated as a risk factor, although ex-
If total dose is 1,000 mg/m2, incidence is nearly Decreased ejection fraction, sinus tachycar- act synergism is unclear (Camp-Sorrell, 2011).
50% (Camp-Sorrell, 2011; Pfizer Inc., 2011a). dia, and cardiomyopathy with symptoms Cardiotoxicity at lower doses may occur in patients
Incidence may manifest during therapy and of CHF occur later, with peak incidence 7 who received mediastinal radiation and/or patients
last for months to years afterward (Pfizer Inc., years after exposure (Barry et al., 2007). with preexisting heart disease (Barry et al., 2007).
2011a). It was once believed that continuous infu- Perform periodic monitoring of cardiac function
Late effects for pediatric patients: In one study, sion caused more cardiotoxicity than inter- with echocardiogram or MUGA scan through-
some relevant cardiac impairments (12% of mittent delivery, but this has not been sup- out therapy and at least yearly after completion
129 patients) occurred, 3 of which required ported by systematic review (van Dalen et of treatment.
cardiac drug therapy (Bryant et al., 2007). al., 2008). Monitoring of troponin or BNP may be used to
Pericardial effusion may be small and monitor for early changes (Anderson, 2008;
asymptomatic or may be hemorrhagic and Lenihan et al., 2007).
produce acute symptoms. Protect against cardiac toxicity with dexrazoxane
in 10:1 ratio of dexrazoxane to doxorubicin. Pro-
tective agent is administered by IV push or rap-
id infusion 30 minutes prior to doxorubicin (Ng &
Green, 2007; Pfizer Inc., 2011a, 2012d).
Coadministration of coenzyme Q10 has shown
some potential benefit in minimizing cardiotoxic-
ity (Brown & Giampa, 2010; Bryant et al., 2007;
van Dalen et al., 2011).
Doxorubicin lipo- Effects on the myocardium have not been con- Nonspecific arrhythmia, tachycardia, cardio- Pegylated liposomal doxorubicin is believed to be
somal; pegylated firmed. myopathy, and/or CHF may occur. associated with less risk of cardiotoxicity than
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
liposomal doxo- In studies of patients with AIDS-related Kapo- Acute cardiac toxicity in the form of self- the other anthracyclines (Camp-Sorrell, 2011).
rubicin si sarcoma, < 5% experienced cardiac-relat- limiting atrial or ventricular dysrhythmias Experience with large cumulative doses is lim-
ed adverse effects possibly related to the drug may occur with any dose and at any time ited; consider the cardiac risk to be compara-
(Janssen Products, LP, 2013). during the treatment cycle. Second-de- ble to that of conventional doxorubicin formula-
Irreversible toxicity may occur as the total dose gree atrioventricular heart block has been tion and calculate dosages of liposomal doxoru-
nears 550 mg/m2; patients who have received reported (Janssen Products, LP, 2013). bicin with any previous anthracyclines (Shaikh &
mediastinal radiation or concomitant cardiotox- Acute left ventricular failure can occur with Shih, 2012).
ic therapy may experience heart failure at 400 isolated high doses (Janssen Products, Irreversible cardiac damage is dose limiting. Long-
mg/m2 (Janssen Products, LP, 2013). LP, 2013). term cardiac safety is unknown (Camp-Sorrell,
Delayed-onset, dose-related cardiomyopa- 2011).
thy is the most common and well-known Periodic monitoring with echocardiogram or
cardiotoxicity and is likely to be irrevers- MUGA scans is recommended.
ible and unresponsive to treatment. Ten
patients treated with pegylated doxoru-
bicin developed protocol-defined cardi-
ac events, compared with 48 doxorubicin-
treated patients (Rahman et al., 2007).
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 34. Cardiotoxicity of Chemotherapeutic Agents (Continued)
Classification Drug Incidence Characteristic Effects Nursing Considerations
Anthracycline Epirubicin hydro- The probability of developing clinically evident Myocardial toxicity, manifested in its most Active or dormant cardiovascular disease, prior or
antitumor chloride CHF is estimated at approximately 0.9% at a severe form by potentially fatal CHF, may concomitant radiation to the mediastinal or peri-
antibiotics cumulative dose of 550 mg/m2, 1.6% at 700 occur either during therapy with epirubi- cardial area, previous therapy with other anthra-
(cont.) mg/m2, and 3.3% at 900 mg/m2 (Sagent Phar- cin or months to years after termination of cyclines or anthracenediones, or concomitant
maceuticals, 2011; Shaikh & Shih, 2012). therapy (Sagent Pharmaceuticals, 2011). use of other cardiotoxic drugs may increase the
The risk of developing CHF rises rapidly with in- Dysrhythmias include premature ventricular risk of cardiac toxicity.
creasing total cumulative doses in excess of contractions, sinus tachycardia, bradycar- In the adjuvant treatment of breast cancer, the
900 mg/m2; cumulative dose only should be ex- dia, and heart block. maximum cumulative dose used in clinical trials
ceeded with extreme caution (Sagent Pharma- Cardiomyopathy is notably late in onset, oc- was 720 mg/m2.
ceuticals, 2011). curring 6 months to years after therapy. Cardiotoxicity may occur at lower cumulative dos-
High single doses have been associated with es whether or not cardiac risk factors are pres-
acute myocardial ischemia. ent (Sagent Pharmaceuticals, 2011).
Idarubicin Reported to have lower incidence of CHF than Myocardial toxicity, manifested in its most Drug is approved for use with children (Pfizer Inc.,
other anthracyclines, but rate is 1.2% at 150 severe form by potentially fatal CHF, may 2006).
mg/m2 (Pfizer Inc., 2006). occur either during therapy with idarubi-
High-risk populations may have increased inci- cin or months to years after termination of
dence of cardiotoxicity up to 18% (Shaikh & therapy (Pfizer Inc., 2006).
Shih, 2012).
Mitoxantrone Estimated risk is approximately 2.6% in doses of Rare, but potentially fatal, CHF may occur Establish baseline cardiac function.
140 mg/m2. during therapy or years after therapy com- Monitor for cardiotoxicity beyond doses of 100
Maximum dose is considered 160 mg/m2 (Camp- pletion (Shaikh & Shih, 2012). mg/m2.
Sorrell, 2011). Risk is increased by other cardiotoxic medica-
Risk increases with cumulative dose (EMD Sero- tions, mediastinal radiation, or concomitant car-
no, Inc., 2012). diovascular disease.
Chapter 9. Side Effects of Cancer Therapy
Antimetabolites 5-Azacitidine Capillary permeability is dose-related. Pericardial effusion, hypotension, and dys- Toxicity usually is self-limiting and responds to a
Rare hypotension and dysrhythmias have been rhythmias related to compensatory re- drug holiday.
reported (Celgene Corp., 2012). sponse to hypotension may occur. Monitor coadministration with other cardiotoxic
Drug can exacerbate heart failure and QT pro- medications (Celgene Corp., 2012).
longation of other agents (Celgene Corp.,
2012).
259
(Continued on next page)
260
Table 34. Cardiotoxicity of Chemotherapeutic Agents (Continued)
Classification Drug Incidence Characteristic Effects Nursing Considerations
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Antimetabolites 5-FU Incidence of 5-FU cardiotoxicity is dependent Angina, palpitations, sweating, and/or syn- Patients at higher risk for developing cardiotoxic-
(cont.) upon dose and schedule. cope may occur (Sorrentino et al., 2012). ity include those with heart disease, electrolyte
Incidence of 10% has been associated with dos- Angina-like chest pain with or without MI, disturbances, or radiation exposure to the heart
es > 800 mg/m2/day (Yusuf et al., 2008). dysrhythmias, or cardiogenic shock oc- (Singh et al., 2004; Sorrentino et al., 2012; Yusuf
The addition of other antineoplastic agents such curs due to coronary vasospasm. Sudden et al., 2008). It may be treated prophylactical-
as irinotecan or cisplatin may influence the in- death has been reported and is presumed ly or therapeutically with long-acting nitrates or
cidence of cardiotoxicity. Incidence is 1.6%– to be due to acute myocardial ischemia calcium channel blockers (Fadol & Lech, 2011).
3% with bolus regimens but 7.6%–18% with or infarction (Meydan et al., 2005; Paiva 5-FU most commonly is discontinued with cardio-
prolonged infusion (4–5 days) (Fadol & Lech, et al., 2009). ECG changes without symp- toxicity, but careful rechallenge with the agent
2011; Yeh & Bickford, 2009). One report with toms are unusual but have been reported. has been successfully achieved without exacer-
two-day infusional 5-FU (de Gramont regimen) Transient symptomatic bradycardia was re- bation of previous cardiotoxicity (Fadol & Lech,
was 3.9% (Fadol & Lech, 2011). ported in a small group of patients receiv- 2011).
Deaths have been reported from myocardial ing infusional 5-FU (Talapatra et al., 2007).
ischemia, and other severe coronary artery
events have been noted (Akhtar et al., 2011).
Literature suggests the incidence is highest in
the first and second cycles of therapy. In the de
Gramont regimen, symptoms begin at night, a
few hours after the bolus part of the infusion
(Talapatra et al., 2007).
Capecitabine Cardiotoxicity is rare; 1%–18% is associated Angina-like chest pain with or without MI, These adverse events may be more common in
with fluorinated pyrimidine therapy (Roche dysrhythmias, or cardiogenic shock occurs patients with a prior history of coronary artery
Pharmaceuticals, 2011). In a retrospective because of coronary vasospasm. Sudden disease.
analysis of two randomized phase III clinical death has been reported and is presumed Interrupt drug if grade 2 or 3 adverse reactions
trials of capecitabine as a single agent ad- to be associated with acute myocardial occur; discontinue drug for grade 4 toxicity
ministered at 1,250 mg/m2 twice daily for days ischemia or infarction (Roche Pharmaceu- (Roche Pharmaceuticals, 2011).
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
1–14 followed by 7 days of rest, the incidence ticals, 2011).
noted was 3% of patients. Incidence of cardio- ECG changes without symptoms are un-
toxicity of capecitabine has been reported as usual but have been reported. At least one
3%–5% when administered alone or in combi- case report of Raynaud phenomenon has
nation with irinotecan, oxaliplatin, and taxanes been published (Coward et al., 2005).
(Shah et al., 2012; Tsiamis et al., 2011).
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 34. Cardiotoxicity of Chemotherapeutic Agents (Continued)
Classification Drug Incidence Characteristic Effects Nursing Considerations
Antimetabolites Cladribine Incidence of edema and tachycardia is 6%. Tachycardia; edema, generalized and not Most events occurred in patients with a history of
(cont.) Chest pain has been reported (Pfizer Inc., dependent; and chest pain not associated cardiovascular disease or chest tumors.
2011b). with ischemic ECG changes may occur.
Transient decreased LVEF has been reported in Drug has limited effects on QT interval but
up to 27% of patients (Shaikh & Shih, 2012). may exacerbate QT prolongation from
other more potent inhibitors (Pfizer Inc.,
2011b).
Gemcitabine hy- CHF and MI have been reported rarely with the Hypotension, MI, arrhythmia, and hypoten- Age, gender, and infusion time factors: Low-
drochloride use of gemcitabine. sion may occur (Eli Lilly & Co., 2013). er clearance in women and older adults results
Arrhythmias, predominantly supraventricular in in higher concentrations of gemcitabine for any
nature, have been reported very rarely. given dose.
Incidence of hypotension is 11% when given Toxicity is increased when administered more fre-
with cisplatin. A study of doses above 1,000 quently than once weekly or with infusions lon-
mg/m2 on a daily × 5 dose schedule showed ger than 60 minutes (Eli Lilly & Co., 2013).
that patients developed significant hypotension
(Eli Lilly & Co., 2013).
Antitumor Bleomycin Maximum lifetime dose is 400 units, but lower Raynaud phenomenon is infusion-related Perform routine monitoring of echocardiogram
antibiotic doses are recommended when administered and will resolve with discontinuation or once close to maximum tolerated dose.
with other cardiotoxic agents or chest irradia- completion of the agent.
tion involving the heart. Pulmonary fibrosis is Raynaud phenomenon presents initially as
its more common dose-limiting toxicity. Cardio- pain and heaviness of the digits.
myopathy has been reported at similar doses Cardiomyopathy presents as progressive
(Bristol-Myers Squibb Co., 2012a). decline in ejection fraction with dyspnea
Little is known about the incidence or risk fac- as the usual first presenting symptom.
tors for Raynaud phenomenon. It is believed
Chapter 9. Side Effects of Cancer Therapy
that oxygen radical release causes localized
ischemia in poorly perfused areas (Gayraud,
2007).
Gangrenous digits have been reported. This
seems to be idiosyncratic, not dose-related,
and related to rate of infusion (Grünwald et al.,
2005).
Cytokine IFN alfa Raynaud symptoms are rare but potentially se- Raynaud phenomenon with superficial skin Teach patients to report Raynaud symptoms.
vere. Peak incidence is 3 weeks to 3 years af- ulceration or gangrene can occur (Scher- Symptoms resolve with discontinuation of medi-
ter beginning therapy of 3,000,000 units dai- ing Corp., 2012a). cation.
ly. Concomitant administration of hydroxyurea
may increase risk in some patients (Schering
Corp., 2012a).
261
(Continued on next page)
262
Table 34. Cardiotoxicity of Chemotherapeutic Agents (Continued)
Classification Drug Incidence Characteristic Effects Nursing Considerations
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Immune Denileukin diftitox Vascular leak syndrome, also known as CLS, Hypotension can occur, likely related to cap- Accurate intake and output, weight measure-
conjugates with vasodilation, hypotension, and compen- illary permeability and vasodilation from ments, and central venous pressure readings
satory tachycardia occurred in 27% of patients immediate inflammatory responses of the may help to determine total fluid volume and
on registration trials, with 6% requiring hospi- vasculature (Eisai Inc., 2011a). vascular space volume status.
talization, and rare deaths reported. Onset may Dysrhythmias may occur and seem to be re-
be delayed up to 2 weeks after infusion and lated to vasodilation and volume status.
may persist or worsen after discontinuing the
agent (Eisai Inc., 2011a; McCann et al., 2012).
Interleukin IL-2 Side effects appear to be dose related (Shelton, CLS results in hypotension and reduced or- IL-2 should be withheld in patients developing
2012). Risk increases with doses > 100,000 IU/ gan perfusion, which may be severe and ventricular dysrhythmias until cardiac ischemia
kg (Shelton, 2012). Average dose is 600,000 can result in death. CLS may be associat- and wall motion can be assessed.
IU/kg (Prometheus Laboratories Inc., 2012). ed with cardiac arrhythmias (supraventric- Should adverse events occur, dosage should be
Most adverse reactions are self-limiting and usu- ular and ventricular), CHF, angina, pleural withheld, not reduced.
ally, but not invariably, reverse or improve with- and pericardial effusion, myocarditis, chest Patients should have normal cardiac, pulmonary,
in 2–3 days of discontinuing therapy. pain, and (rarely) MI (Prometheus Labora- hepatic, and CNS function at the start of ther-
Hypotension of all grades occurs in 71% of pa- tories Inc., 2012). apy.
tients, but severe grade 4 toxicity occurs in only CLS begins immediately after aldesleukin Cardiac toxicities are worse when administered in
3% (Prometheus Laboratories Inc., 2012). treatment starts. In most patients, a con- conjunction with IFN alfa (Prometheus Labora-
The rate of drug-related deaths in 255 patients comitant drop in mean arterial blood pres- tories Inc., 2012).
with metastatic renal cell carcinoma who re- sure occurs within 2–12 hours after the Medical management of CLS begins with careful
ceived single-agent IL-2 was 4% (11/255); the start of treatment. monitoring of the patient’s fluid and organ perfu-
rate of drug-related deaths in 270 patients with With continued therapy, clinically significant sion status; this is achieved by frequent determi-
metastatic melanoma who received single- hypotension (systolic blood pressure 90 nation of blood pressure and pulse and assess-
agent IL-2 was 2% (6/270) (Prometheus Labo- mm Hg or a 20 mm Hg drop from base- ment of mental status and urine output. Hypovo-
ratories Inc., 2012). line systolic pressure) and hypoperfusion lemia is assessed by catheterization and central
will develop (Prometheus Laboratories pressure monitoring.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Inc., 2012). Electrical changes associated with biotherapeutic
Electrical changes caused by cytokine bio- agents generally necessitate temporary discon-
therapy usually relate to cellular swelling or tinuation of the drug. Once inflammatory effects
inflammatory cytokine release causing dis- have resolved, rechallenge is possible (Shel-
ruption of conduction pathways. Capillary ton, 2012).
permeability and hypovolemia enhance the
risk of supraventricular tachycardia.
HER2 receptor Pertuzumab Decreased LVEF, which included some patients – Assess LVEF prior to initiation of pertuzumab and
agonist with symptomatic heart failure, occurred in at regular intervals (e.g., every 3 months) during
4.4% of treated patients (Genentech, Inc., therapy to ensure that ventricular function is not
2012c). impaired (Genentech, Inc., 2012c).
Withhold both pertuzumab and trastuzumab if sig-
nificant decrease in LVEF, then reassess within
3 weeks. If it continues to be decreased, discon-
tinue both pertuzumab and trastuzumab (Ge-
nentech, Inc., 2012c).
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 34. Cardiotoxicity of Chemotherapeutic Agents (Continued)
Classification Drug Incidence Characteristic Effects Nursing Considerations
Hormone Tamoxifen Rare cases of QT prolongation with dysrhythmia QT prolongation with bradycardia or ven- Monitor ECG for QT prolongation.
or heart failure (Teva Pharmaceuticals USA, tricular dysrhythmias occurs infrequent- Avoid other medications known to prolong the QT
2012c) ly and without clear risk factors such as interval.
dose or longevity of therapy (Slovacek et
al., 2008).
Rare cases of myocardial ischemia and in-
farction have occurred from unclear mech-
anisms but may be a component of hyper-
coagulability (Teva Pharmaceuticals USA,
2012c).
Miscellaneous Arsenic trioxide QT prolongation occurs in 40% of patients treat- QT prolongation with dysrhythmias Check 12-lead ECG prior to therapy and hold if
ed with arsenic trioxide at usual therapeutic Usual onset of QT prolongation > 0.50 msec QTc is > 500 msec (Cephalon, Inc., 2010).
doses (Cephalon, Inc., 2010). was 1–4 weeks after treatment. Check all electrolytes prior to administration of
Dysrhythmias related to prolongation of the QT QT prolongation effects may persist up to medication and replenish prior to therapy. Potas-
have occurred in approximately 10% of cases. 8 weeks after therapy (Cephalon, Inc., sium should be kept > 4 mEq/L, and magnesium
It is usually asymptomatic but can induce ven- 2010). > 1.8 mEq/L (Cephalon, Inc., 2010).
tricular tachycardia. Drug should not be admin- Complete atrioventricular block has been re- Assess for other causes of dysrhythmias prior to
istered unless the QTc is < 500 msec. Therapy ported with arsenic trioxide (Cephalon, administering drug.
can be resumed once the QTc returns to < 460 Inc., 2010).
msec (Cephalon, Inc., 2010).
Eribulin Asymptomatic QT prolongation was present in QT prolongation was noted on day 8 of ther- Monitor QT interval while on therapy.
all patients in a small sample (Eisai Inc., 2013). apy. Increase vigilance of monitoring for patients with
QT prolongation is independent of eribulin heart failure, bradyarrhythmias, and concomitant
concentration. administration of QT-prolonging drugs.
Correct hypokalemia and hypomagnesemia dur-
Chapter 9. Side Effects of Cancer Therapy
ing therapy.
Romidepsin T-wave and ST changes (grade 1): 71%, but few ECG changes are not linked to clinical de- Monitor 12-lead ECG periodically (Glass & Via-
progressed to severe medical consequences compensation and are of uncertain clinical le, 2013).
significance (Glass & Viale, 2013).
Vorinostat VTE with pulmonary embolism occurred in 5% – Teach patients methods to reduce risk of VTE:
of patients in registration trials (Olsen et al., drink fluids and maintain mobility (Glass & Via-
2007). le, 2013).
Consider thromboprophylaxis for patients with ad-
ditional risks for VTE.
Ziv-aflibercept Hypertension – Monitor blood pressure every two weeks or more
frequently as indicated.
Treat with appropriate antihypertensive therapy
(Regeneron Pharmaceuticals, Inc., 2013).
263
(Continued on next page)
264
Table 34. Cardiotoxicity of Chemotherapeutic Agents (Continued)
Classification Drug Incidence Characteristic Effects Nursing Considerations
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Monoclonal Alemtuzumab Cardiac toxicities are uncommon, although in- CHF may present even after one dose, but Use with caution in patients who have received
antibodies cidence is higher when this agent is used in most symptoms present 6–11 weeks after prior antitumor antibiotics that may exacerbate
lymphoproliferative malignancies, especially starting therapy at doses of 30 mg 3 times/ risk of cardiac failure (Genzyme Corp., 2009a).
Sézary syndrome. week (Genzyme Corp., 2009a).
In an 8-patient case series, 4 developed new- No clear cardiac pathology was detectable on
onset CHF caused by left ventricular dysfunc- endomyocardial biopsy despite permanent
tion (Lenihan et al., 2004). reduction in ejection fraction.
Dysrhythmias: Atrial fibrillation has been re-
ported, but it is unclear if they are related to
capillary leak and hypotension.
The proposed mechanism of all cardiotoxicity
associated with alemtuzumab is that of cy-
tokine release.
Bevacizumab Significant hypertension occurred in 5%–18% of Hypertension and thrombosis or hemorrhage Check baseline vital signs, and monitor with each
patients receiving bevacizumab. It can occur may occur. clinic visit or at least every 2–3 weeks during
as early as two weeks after the start of thera- Hypertension may persist for several weeks therapy (Genentech, Inc., 2012a).
py, and peak incidence is the second month of after discontinuation of bevacizumab (Ge- Establish home routine of twice-daily blood pres-
therapy (Genentech, Inc., 2012a). nentech, Inc., 2012a). sue monitoring while adjusting medications to
CHF was reported in 1.7% of patients overall, CHF occurs more frequently in patients treat hypertension.
but the incidence was as high as 14% in pa- who have received prior anthracyclines or Temporarily suspend treatment if urine shows 3+
tients who received prior anthracyclines (Ge- left chest wall radiation (Genentech, Inc., urine dipstick reading, particularly if accompa-
nentech, Inc., 2012a). 2012a). nied by hypertension.
No clear antihypertensive treatment has been
identified.
Cetuximab Cardiac arrest occurred with 0.2% incidence in Cardiac arrest of unclear etiology, but clear Maintain magnesium level of 2 mEq/L.
patients receiving cetuximab for head and neck hypomagnesemia with this agent could Monitor magnesium level throughout treatment
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
cancer but was not evident in patients receiving cause dysrhythmias related to QT prolon- and up to 8 weeks after conclusion of therapy
for metastatic colorectal cancer (Bristol-Myers gation. (Bristol-Myers Squibb Co. & ImClone Systems,
Squibb Co. & ImClone Systems, 2012). 2012).
Ipilimumab – Hypotension, immune-mediated vasculitis, tem- –
poral arteritis, myocarditis, and pericarditis
can occur (Bristol-Myers Squibb Co., 2013).
Rituximab Cardiotoxicity when used as a single agent is Hypotension and angioedema can occur. Nearly all fatalities have occurred on first infusion.
unknown. Infusion-related complex includes MI, ventricu- Discontinue and medically treat patients who de-
Infusion-related deaths have occurred within 24 lar fibrillation, and cardiogenic shock (Biogen velop clinically significant cardiopulmonary re-
hours of infusion (Biogen Idec, Inc., & Genen- Idec, Inc., & Genentech, Inc., 2013). actions.
tech, Inc., 2013). Although tachydysrhythmias are more com- After symptoms resolve, resume treatment by re-
Incidence of mild to moderate hypotension re- mon, case reports of bradycardia and heart ducing the infusion rate by 50% (Biogen Idec,
quiring treatment interruption was 10% (Biogen block exist and may be related to prolonga- Inc., & Genentech, Inc., 2013).
Idec, Inc., & Genentech, Inc., 2013). tion of the QTc (Grau et al., 2008).
Case reports of dysrhythmias exist.
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 34. Cardiotoxicity of Chemotherapeutic Agents (Continued)
Classification Drug Incidence Characteristic Effects Nursing Considerations
Monoclonal Trastuzumab Incidence of cardiac dysfunction as a single Signs and symptoms of cardiac dysfunction CHF has been associated with disabling cardiac fail-
antibodies agent is 7%. observed in patients treated with trastu- ure, death, and mural thrombosis leading to stroke.
(cont.) Incidence with paclitaxel is 11%. zumab include dyspnea, cough, paroxys- Discontinuing therapy is strongly suggested for
When the drug is combined with anthracycline mal nocturnal dyspnea, peripheral edema, those with significant CHF or asymptomatic
and cyclophosphamide, incidence is 28%. S3 gallop, or reduced ejection fraction (Ge- ejection fraction decreases.
Advanced age may increase the probability of nentech, Inc., 2012b). Exercise extreme caution in treating patients with
cardiac dysfunction (Bird & Swain, 2008; Fran- Prolonging the infusion rate decreases in- preexisting cardiac dysfunction.
kel, 2010; Genentech, Inc., 2012b). fusion-related events for first infusion by Patients should undergo frequent monitoring for dete-
80% and 40% for subsequent infusions riorating cardiac function (Genentech, Inc., 2012b).
(Genentech, Inc., 2012b). Avoid anthracyclines within 24 weeks of trastu-
zumab due to long half-life of drug.
Multikinase Bosutinib Among patients with fluid retention in registration Cause of pericardial effusion is thought Consider dose reductions or temporary interrup-
inhibitors trials, only 3 patients (< 1%) experienced grade to be fluid retention common with agent tions of therapy for symptomatic pericardial effu-
3 or 4 pericardial effusion (Pfizer Inc., 2013a). (Pfizer Inc., 2013a). sions (Pfizer Inc., 2013a).
Lapatinib Grade 4 heart failure with systolic dysfunction QT interval may be prolonged and increase Obtain baseline cardiac evaluation with echocardio-
occurred in 1.6% of patients pooled from multi- the risk for dysrhythmias (GlaxoSmith- gram or MUGA scan (GlaxoSmithKline, 2012).
ple studies; 88% developed reversible disease Kline, 2012). If the ejection fraction drops below the lower lim-
(Perez et al., 2008). The QT prolongation most often occurred in it of normal, lapatinib is stopped for at least 2
Incidence is dependent on lapatinib concentra- individuals who had received prior anthra- weeks, and when ejection fraction is returned to
tion (GlaxoSmithKline, 2012). cyclines. normal and the patient remains asymptomatic,
Onset averages 13 weeks after start of ther- the dose is reduced and resumed at 1,000 mg/
apy and lasts approximately 7 weeks (Per- day (GlaxoSmithKline, 2012).
ez et al., 2008). Monitor for subtle signs of heart failure.
QT prolongation most often leads to brady- Agent will prolong effects of digitalis (GlaxoSmith-
cardia but can cause life-threatening tor Kline, 2012).
Chapter 9. Side Effects of Cancer Therapy
sades de pointes (Shelton, in press-a).
Sorafenib Cardiac failure or asymptomatic left ventricular Cardiac failure, chest pain with myocardi- Monitor blood pressure weekly for the first 6
end-diastolic dysfunction with reduced ejec- al ischemia, and asymptomatic decreased weeks, then periodically throughout therapy.
tion fraction is reported infrequently (< 1%) left ventricular end-diastolic function with Standard antihypertensive agents are recom-
(Force et al., 2007). reduced ejection fraction may occur. mended for management of hypertension.
No clear incidence rate has been identified Vasculitis with hypertension can develop Therapy breaks have been effective for resolution
(Kamba & McDonald, 2007; Patel et al., 2008; (Shaikh & Shih, 2012). of hypertension.
Porta et al., 2007). Asymptomatic myocardial ischemia and Hypertension seems to be related to presence
Cardiac ischemia with MI has been reported acute MI have been reported (Bayer of proteinuria, and both usually are present pri-
rarely (< 1%) (Bayer Healthcare Pharmaceuti- Healthcare Pharmaceuticals Inc., 2011). or to cardiac failure (Force et al., 2007; Porta et
cals Inc., 2011). al., 2007).
Hypertension occurred in 16.9% of patients with Halt all therapy if symptomatic myocardial isch-
renal cell cancer and 9.4% of patients with he- emia occurs temporally related to drug adminis-
patic carcinoma (Bayer Healthcare Pharma- tration (Bayer Healthcare Pharmaceuticals Inc.,
ceuticals Inc., 2011). 2011).
265
(Continued on next page)
266
Table 34. Cardiotoxicity of Chemotherapeutic Agents (Continued)
Classification Drug Incidence Characteristic Effects Nursing Considerations
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Multikinase Sunitinib Incidence of cardiotoxicities was evaluated in Hypertension, cardiac failure, and asymp- See sorafenib.
inhibitors (cont.) phase I and II studies. Hypertension was re- tomatic decreased left ventricular end-di-
ported in 35 of 75 patients with an incidence astolic function with reduced ejection frac-
rate of 47% (Chu et al., 2007; Pfizer Inc., tion can occur.
2012c). This frequency has persisted through
registration trials and current clinical practice.
There are well-established reports of both asymp-
tomatic left ventricular end-diastolic dysfunction
(> 15% reduction in ejection fraction) and cardi-
ac failure; incidence is 28% and 8%, respective-
ly (Chu et al., 2007). Class effect (symptom oc-
curring in most drugs in same category) involves
mitochondrial injury and cardiomyocyte apopto-
sis, suggesting that there is risk for cardiac tox-
icities, but incidence rate is unclear (Chu et al.,
2007; Force et al., 2007; Shaikh & Shih, 2012).
Plant alkaloids Vinblastine Idiosyncratic response to medication can devel- Raynaud phenomenon can occur. Teach patients to avoid cold exposure and tobac-
op that is not dose-related but does not resolve co smoking, which will exacerbate pain.
until the medication is discontinued (APP Phar-
maceuticals, LLC, 2011).
Vincristine There have been isolated reports of Raynaud Raynaud phenomenon has occurred even Advise patients to avoid cold exposure and tobac-
phenomenon with vincristine in adults and ado- with single doses. co smoking, which will exacerbate pain.
lescents. It seems to be dose-related and does
not resolve until the medication is discontinued
(Hospira, Inc., 2013).
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
One study of children associated symptomatic
respiratory-phase heart rate variation with use
of vincristine (Steinherz & Steinherz, 1995).
Vinorelbine There have been rare reports of MI (Pierre Fab- Rare incidence with variable symptoms that Most reports of chest pain were in patients who
tartrate re Pharmaceuticals USA, 2007). may be mistaken for evolving acute cardi- had either a history of cardiovascular disease
Chest pain was reported in 5% of patients ac event. or tumor within the chest (Pierre Fabre Pharma-
(Pierre Fabre Pharmaceuticals USA, 2007). ceuticals USA, 2007).
Hypertension, hypotension, vasodilation, tachy- There is a high level of suspicion for an acute car-
cardia, and pulmonary edema have been re- diac event with symptoms.
ported (Pierre Fabre Pharmaceuticals USA, Temporarily discontinue vinorelbine and perform
2007). cardiac diagnostic tests when patients report
cardiac symptoms. Therapy may be resumed af-
ter resolution of symptoms (Pierre Fabre Phar-
maceuticals USA, 2007).
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 34. Cardiotoxicity of Chemotherapeutic Agents (Continued)
Classification Drug Incidence Characteristic Effects Nursing Considerations
Taxanes Docetaxel Hypotension incidence is 2.8% (1.2% required Drug can cause cardiac adverse effects Drug is well tolerated in older adult patients with
treatment). Incidence related to high-dose similar to other microtubule-inhibiting non-small cell lung cancer (Hainsworth et al.,
treatment is unknown (sanofi-aventis U.S. LLC, agents (Salvatorelli et al., 2006). 2000).
2013). Hypotension may develop during infusion
that resolves with slowing of infusion rate.
CHF occurred in patients also treated with
doxorubicin (> 360 mg/m2).
Sinus tachycardia, atrial flutter, dysrhythmia,
unstable angina, and/or hypertension may
occur (sanofi-aventis U.S. LLC, 2013).
Paclitaxel Asymptomatic bradycardia occurred in almost Asymptomatic bradycardia (40–60 bpm), hy- Obtain a baseline ECG, history and physical, and
30% of patients with ovarian cancer; cardiac potension, and asymptomatic ventricular cardiac assessment before treatment. However,
ischemia occurred in 5% (Bristol-Myers Squibb tachycardia have been reported at all dos- routine cardiac monitoring during infusion is not
Co., 2011f). es (Fadol & Lech, 2011). recommended (Fadol & Lech, 2011).
Significant cardiac events occurred in 3% of all Atypical chest pain with and without cardi-
cases (Bristol-Myers Squibb Co., 2011f). ac ischemia occurs occasionally and orig-
Rare reports exist of cardiac ischemia or MI (Yu- inally was thought to be related to the
suf et al., 2008). agent’s diluent, polyoxyl 40 hydrogenat-
CHF has been reported in patients receiving oth- ed castor oil (Kolliphor® EL, formerly Cre-
er chemotherapy agents (Bristol-Myers Squibb mophor® EL), but this is now less clear
Co., 2011f). (Bristol-Myers Squibb Co., 2011f).
Pericardial effusion can occur.
Tyrosine Axitinib In a controlled clinical trial of patients with re- Median onset of systolic BP > 150 mm Hg BP should be well controlled prior to start of ther-
kinase nal cell cancer, 40% (145/359) developed hy- or diastolic BP > 100 mm Hg was with- apy (Tyler, 2012). Elevated BP should be man-
inhibitors pertension. Grade 3 or 4 hypertension was ob- in the first month of therapy (Pfizer Inc., aged with standard antihypertensive strategies
Chapter 9. Side Effects of Cancer Therapy
served in only 16% (56/359). Hypertensive cri- 2012b). BP increases were observed as and medications. Dose reduction is permitted if
sis was reported in < 1% of patients (Pfizer early as 4 days after the first dose (Pfizer refractory hypertension is present. Discontinua-
Inc., 2012b). Inc., 2012b). tion of axitinib is recommended if hypertension
is severe and persistent despite therapeutic in-
terventions.
267
(Continued on next page)
268
Table 34. Cardiotoxicity of Chemotherapeutic Agents (Continued)
Classification Drug Incidence Characteristic Effects Nursing Considerations
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Tyrosine Crizotinib QT prolongation with dysrhythmias has been ob- Dysrhythmias, particularly bradycardia, can Use with caution in patients with higher risk of de-
kinase served infrequently. Bradycardia grade 1 or 2 occur. veloping prolonged QT interval or with baseline
inhibitors (cont.) has been observed in 5% of patients (Kwon & cardiac disease. Consider periodic monitoring
Meagher, 2012). with ECG in patients with risk factors for QT pro-
longation.
Perform baseline and periodic monitoring of elec-
trolytes with potassium goal 4 mEq/L and mag-
nesium goal 2 mEq/L.
Permanently discontinue the drug for grade 4 QT
prolongation, and hold for grade 3 QT prolonga-
tion until recovery to ≤ grade 1 toxicity. Discon-
tinue if grade 3 QT prolongation recurs (Pfizer
Inc., 2013c).
Dasatinib QTc prolongation: < 1% Toxicity may be enhanced for patients who Administer with caution to patients who have or
Heart failure: 3% previously received anthracyclines (Galin- are at risk for QT prolongation.
sky & Buchanan, 2009). If QT prolongation occurs, stop therapy with da-
satinib until the QT interval returns to normal.
Replenish electrolytes to prevent hypokalemia
and hypomagnesemia.
The decision to resume dasatinib at reduced dose
after cardiotoxicity is an individual clinician deci-
sion (Galinsky & Buchanan, 2009).
Pazopanib QT prolongation occurred in < 1% of patients QT prolongation with dysrhythmias, includ- Use with caution in patients with higher risk of de-
on registration trials, but the risk is still pres- ing torsades de pointes, has been report- veloping prolonged QT interval or with baseline
ent because of its class effect (GlaxoSmith- ed in patients receiving pazopanib (Glaxo- cardiac disease. Consider periodic monitoring
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Kline, 2013). SmithKline, 2013). with ECG in patients with risk factors for QT pro-
Hypertension occurred in 40% of patients with Hypertension is extremely common during longation.
renal cell cancer who received pazopanib therapy. Perform baseline and periodic monitoring of elec-
(GlaxoSmithKline, 2013). It was observed early trolytes with potassium goal of 4 mEq/L and
in the course of treatment. Approximately 39% magnesium goal of 2 mEq/L (Nguyen & Shaya-
experienced hypertension within the first 9 hi, 2012).
days and 90% experienced it during the first 18 Control preexisting blood pressure before be-
weeks of treatment. Only 4%–7% were grade 3 ginning pazopanib therapy (Nguyen & Shaya-
or 4 (GlaxoSmithKline, 2013). hi, 2012).
Myocardial dysfunction in the form of decreased Dose reduction is permitted if hypertension per-
LVEF was only 0.6% with renal cell carcinoma sists despite supportive antihypertensive thera-
but 11% with soft tissue sarcoma, possibly at- pies (GlaxoSmithKline, 2013).
tributable to collective toxicity with other anti-
neoplastic agents (GlaxoSmithKline, 2013).
VTE occurred in 5% of patients in registration tri-
als (GlaxoSmithKline, 2013).
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 34. Cardiotoxicity of Chemotherapeutic Agents (Continued)
Classification Drug Incidence Characteristic Effects Nursing Considerations
VEGF Lenalidomide Chest pain was reported in 8.2% of patients dur- Bradycardia has been reported infrequently, Establish baseline blood pressure, heart rate and
inhibitors ing registration trials, but it is not clear if it was and less often than with thalidomide. Atrial regularity, and ECG findings to identify drug-
related to cardiotoxicities or pulmonary embo- fibrillation has been reported with unidenti- related changes.
lism (Celgene Corp., 2013a). fied frequency (Celgene Corp., 2013a). Monitor heart rate, rhythm, and blood pressure
Hypertension (all grades) occurred in 7.1% of Hypertension (primarily systolic) has been frequently during therapy or with new cardiac
patients receiving lenalidomide during registra- reported with lenalidomide administration symptoms.
tion trials. and is more frequent when the drug is giv- Strongly consider appropriate antithrombotic pro-
VTE occurred in 9.3% of patients receiving le- en with dexamethasone. phylaxis while receiving lenalidomide.
nalidomide with dexamethasone, a rate dou- Rare instances of cardiac ischemia are not-
ble that of patients receiving dexamethasone ed in prescribing information (Celgene
alone (Celgene Corp., 2013a). Corp., 2013a).
Thromboembolism displays no established
pattern of lower or upper extremities or
specific timing during treatment. It is asso-
ciated with patients who are also receiv-
ing high-dose corticosteroids (Elice et al.,
2008).
Thalidomide In a small phase I study, grade 3 dysrhythmias Bradycardia is the most common dysrhyth- Assess patients for dizziness, palpitations, or oth-
occurred in 2% of patients (Sharma et al., mia reported. er symptoms of dysrhythmias.
2006). Thromboembolism displays no established Initiate thromboprophylaxis when not contraindi-
Registration trial reported dysrhythmias, most pattern of lower or upper extremities or cated.
commonly bradycardia not requiring clinical in- specific timing during treatment. It is asso- Lenalidomide is an additional immune modula-
tervention (Celgene Corp., 2013b). ciated with patients who are also receiv- tor with similar actions and cardiotoxicities (Cel-
Incidence of thromboembolism is increased (up ing high-dose corticosteroids (Elice et al., gene Corp., 2013b; Menon et al., 2008).
to 23%), but it is unclear whether this is relat- 2008).
ed to this agent or the cancer (Celgene Corp.,
Chapter 9. Side Effects of Cancer Therapy
2013b).
AIDS—acquired immunodeficiency syndrome; BMT—bone marrow transplantation; BNP—brain natriuretic peptide; BP—blood pressure; bpm—beats per minute; CHF—congestive heart failure; CLS—capillary leak syn-
drome; CNS—central nervous system; ECG—electrocardiogram; 5-FU—5-fluorouracil; HER2—human epidermal growth factor receptor 2; IFN—interferon; IL—interleukin; IU—international units; kg—kilogram; LVEF—
left ventricular ejection fraction; mEq/L—milliequivalent per liter; MI—myocardial infarction; mm Hg—millimeters of mercury; msec—millisecond; MUGA—multigated acquisition; QTc—QT interval corrected; VEGF—vas-
269
cular endothelial growth factor; VTE—venous thromboembolism
270 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
(1) Conduction disturbances are classified according to their ori-
gin (e.g., atrial, ventricular, heart blocks) or their degree of life-
threatening symptoms.
(2) Life-threatening dysrhythmias such as ventricular tachycardia,
ventricular fibrillation, or advanced heart blocks are less com-
mon but may warrant permanent discontinuation of therapy.
Other exacerbating factors such as comorbidities, electrolyte
and acid-base disturbances, or tumor compression often are in-
volved and make it difficult to determine if the disorder is tru-
ly triggered by the chemotherapeutic or biologic agent (Shel-
ton, in press-b)
(a) Electrolyte disturbances (e.g., hypokalemia, hyperkalemia,
hypocalcemia, hypomagnesemia) (Bashir et al., 2007; Pe-
pin & Shields, 2012)
(b) Comorbid health conditions (e.g., chronic obstructive lung
disease, heart disease) (Yusuf, Razeghi, & Yeh, 2008).
(c) Prolonged QT interval (Sauer & Newton-Cheh, 2012;
Scheibly & Tsiperfal, 2009)
(3) Mechanisms of arrhythmogenesis (Guglin et al., 2009; Shel-
ton, in press-b)
(a) Fluid volume loss
(b) Oxygen free radicals released by ischemic cardiomyocytes
(c) Inflammatory capillary permeability within the myocytes
(d) Prolongation of the refractory period and interference
with the action potential of myocytes (Drew et al., 2010;
Scheibly & Tsiperfal, 2009)
(4) Potential negative consequences of dysrhythmias (Desai &
Giugliano, 2012; Hazinski, Samson, & Schexnayder, 2010)
(a) Decreased cardiac output
(b) Thrombus formation within the heart
(c) Cardiac ischemia
(d) Uncomfortable symptoms such as chest tightness, difficul-
ty breathing, or light-headedness.
c) Incidence: The incidence of dysrhythmias specifically associated with
cancer treatments is largely underestimated because of the probable
attribution to other causes (Fadol & Lech, 2011; Guglin et al., 2009;
Sereno et al., 2008). In well-defined cases, the incidence can still only
be imperfectly quantified because preventive measures are always em-
ployed when possible. Incidence rates reported with specific thera-
pies include the following.
(1) Asymptomatic bradycardia occurs in 3%–30% of patients re-
ceiving paclitaxel. More profound cardiac events (e.g., ventric-
ular tachycardia, left-bundle branch block) have been observed
in rare instances (Fadol & Lech, 2011; Yeh & Bickford, 2009).
(2) Bradycardia from thalidomide has been reported with a vari-
able frequency from < 1% to up to 55% of patients treated. The
proposed mechanisms include therapy-related hypothyroidism,
sedative effects, and increased vagal sensitivity (Fadol & Lech,
2011; Guglin et al., 2009).
(3) 10%–20% of dysrhythmias associated with cytokine therapies
such as IL-2 are linked to fluid and electrolyte imbalances (Gug-
lin et al., 2009).
(4) Lower incidence rates of < 5% occur with agents that cause
myocarditis or QT prolongation (Force & Kerkelä, 2008; Gug-
lin et al., 2009).
d) Risk factors (Fadol & Lech, 2011; Guglin et al., 2009; Viale & Yama-
moto, 2008)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 271
(1) Capillary permeability syndrome due to vascular depletion (Gug-
lin et al., 2009; Shelton, 2012)
(2) Myocarditis, pericarditis, or pericardial effusion (Shelton, in
press-c)
(3) Agents with direct cardiotoxicity, including anthracyclines,
fluoropyrimidines (e.g., 5-FU, capecitabine), and trastuzum-
ab (Floyd & Perry, 2008; Gianni, Salvatorelli, & Minotti, 2007)
(4) Medications and conditions known to prolong the QTc, in-
cluding 5-FU, arsenic trioxide, dasatinib, lapatinib, nilotinib,
pazopanib, sunitinib, tamoxifen, temsirolimus, and vorinostat
(Cahoon, 2009; Drew et al., 2010; Fadol & Lech, 2011; Guglin
et al., 2011)
(5) Personal history of heart disease, diabetes mellitus, hyperten-
sion, pulmonary hypertension, or electrolyte disturbances (Viale
& Yamamoto, 2008)
e) Clinical manifestations
(1) Most patients with dysrhythmias report subjective symptoms
such as palpitations, chest discomfort, dyspnea, or dizziness
(Carey & Pelter, 2009a).
(2) Syncope as the first presenting symptom is more common with
ventricular dysrhythmias (Hazinski et al., 2010).
(3) Most patients report diminished functional capacity with atrial
fibrillation. Dyspnea and fatigue are common, and loss of atri-
al contribution to cardiac output (approximately one-third of
cardiac output) leads to worsening of all other cardiac disease
symptoms (Bontempo & Goralnick, 2011).
f) Assessment
(1) Assess patient history for known medical conditions or medi-
cations that may precipitate dysrhythmias. Elimination of pre-
ventable risks may reduce incidence or severity (Jolobe, 2010).
(2) Compare apical and peripheral heart rate (Carey & Pelter,
2009b; Shelton, in press-b).
(3) Auscultate for abnormal heart sounds demonstrating pericar-
dial effusion (muffled) or heart failure (gallops or murmurs)
(Shelton, in press-b).
(4) Perform follow-up assessments of vital signs and symptoms of
dyspnea, hypoxemia (shown as low oxygen saturation), hypo-
tension, or chest discomfort (Hazinski et al., 2010).
(5) Obtain 12-lead ECG.
(6) Maintain ongoing monitoring (continuous or intermittent) of
rhythm (Drew et al., 2010; Shelton, in press-b).
(7) Assess contributing causes of QT prolongation.
g) Collaborative management (Chopra, 2011)
(1) Correct contributing factors such as hypoxemia, anemia, flu-
id imbalance, and electrolyte abnormalities. Administer elec-
trolyte replacement to a goal potassium value > 4 mEq/L and
magnesium value > 2 mEq/L (Hinkle, 2011; Pepin & Shields,
2012; Shelton, in press-b). Optimal calcium levels are not estab-
lished, but ionized calcium levels > 1.1 mEq/L are the usual goal.
(2) Determine if antidysrhythmic agents are warranted (Hazins-
ki et al., 2010).
(a) Antidysrhythmic medications (Carey, Pelter, Cao, & Pillow,
2010; Hazinski et al., 2010; Shelton, in press-a)
(b) Implantable defibrillator, such as pacers, synchronous car-
dioversion, atrial pacing, or ablation (Chatterjee et al.,
2012; Edgerton, 2012; Jackson, Daubert, & Thomas, 2012)
h) Patient and family education (Chopra, 2011; Nair & Asirvatham, 2011)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
272 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
(1) Teach patients and families the symptoms of dysrhythmia and
the potential urgency of treatment.
(2) Advise patients when to call or come to the clinic and, more im-
portantly, to call emergency medical services if they feel short
of breath or dizzy.
(3) Once dysrhythmias are identified in a patient, teach preven-
tive strategies such as hydration or electrolyte replacement.
Emphasize that vomiting or diarrhea may disrupt fluid or elec-
trolyte balance.
(4) If supraventricular tachycardia has occurred, teach patients
to induce vagal maneuvers via coughing or bearing down as if
defecating.
(5) Patients with ventricular dysrhythmias are at risk for sudden
death, and if indicated, family members may be advised to learn
basic life support skills.
(6) Emphasize importance of periodic evaluation of laboratory val-
ues and ECG when at risk for dysrhythmias.
3. Vascular abnormalities
a) Capillary leak syndrome, a condition associated with the use of IL-2,
involves extravasation of fluids and albumin into body issues. The re-
sults are decreased peripheral vascular resistance, hypotension, and
decreased intravascular volume (Xie et al., 2012).
b) Raynaud phenomenon: This syndrome may occur with high-dose cy-
tarabine arabinoside, docetaxel, oprelvekin, suramin, and temsiroli-
mus. Noncardiac arterial vasospasm and insufficiency may present as
Raynaud phenomenon, whereby small distal arterial vessels constrict
and prevent digit circulation (Viale & Yamamoto, 2008). Vasospasm
causes immediate circulatory compromise that leads to local symp-
toms of pain and discoloration of the digits (Boin & Wigley, 2005;
Daher & Yeh, 2008; Kamba & McDonald, 2007; Pope, 2007).
(1) Pathophysiology: Abnormal nerve conduction and vascular di-
ameter contribute to the pathophysiology of vasculitis (Boin &
Wigley, 2005). Endothelial injury with inflammatory mediators
(e.g., taxanes, antiangiogenesis agents) can explain this process
(Gayraud, 2007; Herrick, 2013).
(2) Incidence: Raynaud phenomenon is infrequent. Only case re-
ports are evident with any given therapy regimen (Brydøy et
al., 2009; Gayraud, 2007; Steingart et al., 2012; Ting, Fukshan-
sky, & Burton, 2007).
(3) Risk factors
(a) Certain drug therapy: Cisplatin, gemcitabine, tyrosine ki-
nase inhibitors, IFN, vincristine, and bleomycin (Boin &
Wigley, 2005; Pope, 2007)
(b) Preexisting vascular insufficiency or hypertension (Boin &
Wigley, 2005; Pope, 2007)
(c) Certain malignancies (lymphoma, sarcoma), autoimmune
disorders (rheumatoid arthritis, scleroderma, systemic lu-
pus erythematosus), or hormone imbalance (hypothyroid-
ism, estrogen therapy) (Herrick, 2013)
(d) Exacerbated by extreme hot or cold temperatures or emo-
tional stress (Boin & Wigley, 2005; Gayraud, 2007)
(4) Clinical manifestations
(a) Cool, pale, and painful digits with an area of demarcation
between perfused and nonperfused tissue (Boin & Wigley,
2005; Gayraud, 2007; Pope, 2007)
(b) Onset of symptoms is usually rapid, lasting a few minutes
to several hours, and most often involves the fingers and
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 273
is unilateral. Vascular spasm with low blood flow first leads
to pale-white and painful digits. This is followed by cyano-
sis, reduced pain, and, lastly, flushing with return of circu-
lation accompanied by pain.
(5) Assessment: Obtain health history and examine distal extrem-
ities at every clinic or hospital visit. Raynaud phenomenon is
diagnosed by signs and symptoms in conjunction with a known
risk factor. Raynaud phenomenon is visible and easily confirmed.
Patient report is highly reliable because of the visibility of the
condition and associated pain.
(6) Collaborative management: Advise patients to avoid exposure
to cold and to quit smoking (Pope, 2007). Mild forms are man-
aged with supportive interventions such as wearing gloves when
performing tasks such as removing items from the refrigerator
or placing hand warmers in gloves or pockets in cold weather.
When the condition is severe, initial treatment is calcium chan-
nel blockers, angiotensin-converting enzyme (ACE) inhibitors,
or angiotensin receptor blockers (ARBs) (Herrick, 2013; Pope,
2007; Yusuf et al., 2008).
c) Hypertension: Defined as a systolic blood pressure ≥ 140 mm Hg or a
diastolic blood pressure ≥ 90 mm Hg (Cushman, 2007; U.S. Depart-
ment of Health and Human Services, National Institutes of Health,
National Heart, Lung, and Blood Institute, 2004)
(1) Pathophysiology
(a) Multikinase inhibition results in antiangiogenesis by block-
ing the Bcr-Abl receptor and the actions of VEGF, which
decreases cellular nitric oxide (Daher & Yeh, 2008; Force,
Krause, & Van Etten, 2007; Yusuf et al., 2008). Hyperten-
sion is thought to be related to the loss of VEGF effect on
the vascular endothelial wall, leading to diminished nitric
oxide synthase and loss of vasodilatory effects of nitric oxide
(Kamba & McDonald, 2007; Kurtin, 2009; Subbiah, Leni-
han, & Tsimberidou, 2011; Yusuf et al., 2008).
(b) Lower nitric oxide levels are associated with sodium and wa-
ter retention (Chen & Cleck, 2009; Kajdaniuk, Marek, Marek-
Borgiel, & Kos-Kudła, 2011; Kamba & McDonald, 2007).
(c) Vasoconstriction (Mourad, des Guetz, Debbabi, & Levy,
2008; Sereno et al., 2008; Zeb, Ali, & Rohra, 2007)
(2) Incidence: Hypertension associated with antiangiogenic ther-
apies and multikinase inhibitors occurs with high frequency,
ranging from 4%–67% of cases (Chu et al., 2007; Fadol & Lech,
2011; Floyd & Perry, 2008; Kamba & McDonald, 2007; Mourad et
al., 2008; Patel et al., 2008; Porta, Paglino, Imarisio, & Bonomi,
2007; Viale & Yamamoto, 2008; Yusuf et al., 2008). About 11%–
16% of patients receiving bevacizumab have significant enough
hypertension to require addition or adjustment of antihyper-
tensive medications (Subbiah et al., 2011; Yusuf et al., 2008).
(3) Risk factors
(a) Preexisting hypertension or cardiovascular disease (CVD)
(Kajdaniuk et al., 2011; Steingart et al., 2012; Subbiah et
al., 2011)
(b) Treatment with bevacizumab, pazopanib, sorafenib, suni-
tinib, or vandetanib (Fadol & Lech, 2011). Proteinuria usu-
ally precedes hypertension with bevacizumab therapy (Ger-
ber, 2008; Patel et al., 2008).
(c) Renal insufficiency, hyperthyroidism, Cushing syndrome,
increased intracranial pressure, and hypomagnesemia inde-
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
274 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
pendent of chemotherapy toxicity (Costa, Tejpar, Prenen,
& Van Cutsem, 2011; Houston, 2011)
(4) Clinical manifestations
(a) Blood pressure rises with multikinase inhibitors and anti-
angiogenic agents may be asymptomatic or accompanied
by headache, visual disturbances, fatigue, tachycardia, or
heart failure.
(b) There does not seem to be a specific pattern of primary sys-
tolic or diastolic hypertension; it appears to be reversible
with a therapy break.
(c) Refractoriness to traditional therapy is an important in-
dicator that anticancer therapies are the cause (Force et
al., 2007).
(5) Assessment: Obtain health history and blood pressure measure-
ment at every clinic or hospital visit. Assess for medications (e.g.,
sinus or cold remedies) or clinical conditions that may contrib-
ute to altered blood pressure. The onset of treatment-related
hypertension may occur as early as two weeks into therapy and
peaks by the second month of treatment (Mourad et al., 2008).
Angiogenesis inhibitor therapy–associated hypertension usual-
ly is preceded by proteinuria.
(6) Collaborative management: Vascular constriction–induced hy-
pertension is treated with ACE inhibitors, ARBs, or direct vaso-
dilators (e.g., calcium channel blockers) (Higgins & Williams,
2007; Jurcut et al., 2008; Kolasinska-Malkowska, Filipiak, Gwiz-
dala, & Tykarski, 2008). Diuretics reduce VEGF inhibitor–as-
sociated hypertension by reducing circulating blood volume
(Mourad et al., 2008). Nationally accepted guidelines for man-
agement of hypertension recommend thiazide diuretics as a
first-line measure (Cushman, 2007; Higgins & Williams, 2007;
Kolasinska-Malkowska et al., 2008). Beta-blockers also are an
option for some patients (London, 2008).
d) Venous thromboembolism (VTE)
(1) Endothelial wall damage is thought to have a direct relation-
ship to atherosclerotic events such as VTE, supported by the fact
that VTE occurs with higher incidence in patients treated with
VEGF inhibitors (Force et al., 2007; Kamba & McDonald, 2007).
(2) Incidence: The risk of VTE in patients with cancer ranges from
1.9%–11% based on a variety of risk factors. The addition of
thalidomide increases this risk to as high as 30%, and antian-
giogenic agents increase the risk up to 30%, even in lower-risk
individuals (Yusuf et al., 2008).
(3) Risk factors
(a) Treatment with chemotherapy and biotherapy agents, in-
cluding bevacizumab, cisplatin, erlotinib, lenalidomide,
tamoxifen, thalidomide, and vorinostat (Fadol & Lech,
2011; Zangari, Berno, Zhan, Tricot, & Fink, 2012)
(b) Edema, immobility, dehydration, congestive heart failure,
and ESAs (Connolly, Dalal, Lin, & Khorana, 2012)
(4) Clinical manifestations: Unilateral pain, redness, and swelling
of affected extremity
(5) Assessment: Obtain health history at every clinic or hospi-
tal visit. Assess patients for signs and symptoms of VTE, such
as pain, redness, and swelling of extremities, especially uni-
laterally.
(6) Collaborative management: Refer patients for diagnostic test-
ing (e.g., venous Doppler study). Initiate anticoagulant thera-
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 275
py when indicated, and monitor therapeutic levels when nec-
essary. Discontinue medications thought to contribute to VTE.
e) Patient and family education (Viale & Yamamoto, 2008)
(1) Teach patients the signs and symptoms of vascular complications.
(2) Teach lifestyle changes, such as smoking cessation, low-fat diet,
moderate exercise, and stress management, that may reduce in-
cidence and severity of vascular complications.
(3) Advise patients to report symptoms to care provider so that as-
sessment and preventive strategies can be implemented early.
(4) Hypertension can be life threatening and cause stroke, so pa-
tients should be prepared to recognize signs of a hypertensive
crisis or stroke.
(a) Memory lapses
(b) Blackouts or near syncope
(c) Visual abnormalities
(d) Persistent headache
(e) Slurred words
(f) Numbness or tingling of an extremity
(g) Facial droop
(5) Patients may require guidance with self-administration of anti-
hypertensive agents.
(6) Many antihypertensive agents can cause immediate orthostasis,
dizziness, nausea, and risk of falling.
4. Coronary artery disease: The most common identified is coronary artery
spasm (Prinzmetal or variant angina).
a) Pathophysiology: Ischemic heart disease may be related to atheroscle-
rosis, inflammatory platelet aggregation, anemia, or capillary perme-
ability. Myocarditis-induced edema of myocytes creates increased au-
tomaticity and impaired perfusion. Increased workload and myocar-
dial stress is thought to be the mechanism for myocardial ischemia
and infarction. Thromboses occurring as a result of increased propen-
sity for clotting may involve coronary arteries (Kusama et al., 2011).
b) Incidence: Coronary vasospasm or occlusion occurs rarely, with an in-
cidence of < 1% for most therapies (Yeh & Bickford, 2009).
c) Risk factors: With the use of some drugs, coronary artery spasm leads
to ischemia and possibly infarction (Arima et al., 2009; Floyd & Per-
ry, 2008; Porto et al., 2010; Saif, Shah, & Shah, 2009; Yeh & Bickford,
2009; Yusuf et al., 2008).
(1) Anticancer therapies associated with myocardial ischemia in-
clude bevacizumab, bortezomib, capecitabine, docetaxel, doxo-
rubicin, erlotinib, 5-FU, hydroxyurea, paclitaxel, pazopanib,
rituximab, and sorafenib (Arima et al., 2009; Arunprasath,
Gobu, Dubashi, Satheesh, & Balachander, 2011; Cerny, Has-
san, Smith, & Piperdi, 2009; Kalsch, Wieneke, & Erbel, 2010;
Molteni et al., 2010; Saif et al., 2009; Subbiah et al., 2011;
Takamatsu et al., 2010; Tunio, Hashmi, & Shoaib, 2012; Win-
chester & Bavry, 2010).
(2) Androgen deprivation (Saylor & Smith, 2009)
(3) Cetuximab used for locally advanced squamous cell head and
neck cancer (Bristol-Myers Squibb Co. & ImClone Systems,
2012). Similar events did not occur with cetuximab when used
for treatment of metastatic colorectal cancer.
(4) IL-2 resulting in capillary permeability with myocarditis (Jones
& Ewer, 2006; Muehlbauer, 2011)
(5) Taxane therapy (Londhey & Parikh, 2009): Few patients suffer
coronary artery disease with now-established drug monitoring
and dose attenuation plans.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
276 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
(6) Agents enhancing hypercoagulability, although no relationship
to any specific chemotherapy or biotherapy agent has been dem-
onstrated (Floyd & Perry, 2008; Yusuf et al., 2008).
(7) High-dose chemotherapy. Rare unexplained chest pain with isch-
emic ECG changes that spontaneously resolve (Fadol & Lech,
2011; Yusuf et al., 2008).
(8) Aromatase inhibitors (Bird & Swain, 2008; Towns, Bedard, &
Verma, 2008)
(9) Transarterial chemoembolization, with unclear etiology (Lai
et al., 2010)
d) Clinical manifestations (Hazinski et al., 2010; Jugdutt, 2011; Leeper,
Cyr, Lambert, & Martin, 2011)
(1) Chest pain is the most common manifestation of coronary isch-
emia. Severity may be diminished in patients with chronic ane-
mia. Chest pain may be “pressure-like” and radiate to the back
or neck.
(2) Unexplained dyspnea
(3) Signs/symptoms of reduced cardiac output: Hypotension, oli-
guria, diminished bowel sounds, weak and thready pulses, cool
extremities
(4) Signs/symptoms of cardiac irritability: Irregular pulse, palpita-
tions, dysrhythmias
e) Assessment: Rapid diagnostic test performance (12-lead ECG, serum
cardiac enzymes) with suspicious symptoms to facilitate appropriate
management
(1) Assessment of chest discomfort
(2) Heart rate and rhythm
(3) Central and distal pulse strength and equality
(4) Blood pressure
(5) Heart sounds
(6) Breath sounds, respiratory rate
(7) Jugular venous distention
(8) ECG rhythm by continuous cardiac monitoring: Dysrhythmias
are common; life-threatening ventricular tachycardia or ventric-
ular fibrillation is most common in the first two hours.
(9) Cardiac enzymes (creatine phosphokinase-MB, troponin I, or
troponin T) measured in the serum are elevated when myocar-
dial injury occurs (Gaze, 2011).
(10) Echocardiogram or multigated acquisition (MUGA) scan
(11) Diagnostic right heart catheterization
f) Collaborative management (Daga, Kaul, & Mansoor, 2011; Hazinski
et al., 2010; Jugdutt, 2011)
(1) Administer O2 at a rate sufficient to maintain O2 saturation
above 90% unless otherwise contraindicated.
(2) Implement cardiac monitoring: Observe for dysrhythmias and
ischemic changes, low oxygen saturation, or extremes in blood
pressure.
(3) Obtain order for aspirin 325 mg to be chewed as soon as 12-lead
ECG is performed and ST changes are present.
(4) Consider patient candidacy for reperfusion strategies such as
cardiac catheterization with angioplasty, stent placement, or in-
tracoronary/IV thrombolysis (Iyengar & Godbole, 2011).
(5) Consider ischemia-reducing or myocardial preservation strate-
gies such as administration of nitrates, beta-blockers, or statins
(Ferreira & Mochly-Rosen, 2012; Gerczuk & Kloner, 2012).
(6) Maintain potassium > 4 mEq/L, magnesium > 2 mEq/L, and
ionized calcium > 1 mEq/L (Akhtar, Ullah, & Hamid, 2011).
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 277
(7) Consider discontinuation of antineoplastic agents such as flu-
oropyrimidines, oxaliplatin, sorafenib, or tamoxifen that are
thought to cause cardiac ischemia or infarction (Basselin et
al., 2011; Chang, Hung, Yeh, Yang, & Wang, 2011; Shah, Shah,
& Rather, 2012).
(8) Determine need for follow-up assessment of coronary arteries
and myocardial function with exercise stress testing, cardiac
catheterization, echocardiogram, or MUGA scan (Al-Zaiti, Pel-
ter, & Carey, 2011; Arrighi & Dilsizian, 2012).
g) Patient and family education (Brown, Clark, Dalal, Welch, & Taylor,
2011; Crumlish & Magel, 2011)
(1) Specific risks for this complication based on personal risk fac-
tors and cancer treatment regimen
(2) Reportable symptoms: Chest discomfort, left arm or neck pain,
dyspnea
(3) Activation of emergency medical system
(4) Management of risks for cardiac ischemia that are specific to
oncology (e.g., anemia, cardiac demands of infection, electro-
lyte disturbances)
(5) Cardiac medications and unique considerations in oncology
care (e.g., risk for low blood pressure increased when febrile;
electrolyte disturbances with nausea and vomiting may contrib-
ute to cardiac dysrhythmias)
(6) Referral and education regarding cardiac rehabilitation pro-
grams (Heran et al., 2011)
5. Cardiac failure/cardiomyopathy: Cardiac failure is defined as inadequate
contractile force to eject the required amount of blood for perfusion of
the body (Heart Failure Society of America, 2010; Hunt et al., 2009). It
is classified as primary or secondary based on the primary etiology and
has three types: acute, chronic early, or chronic late.
a) Pathophysiology (Barry, Alvarez, Scully, Miller, & Lipshultz, 2007;
Ewer & Ewer, 2008; Yusuf et al., 2008)
(1) May be confined to the heart or part of a generalized systemic
disease such as anemia or thyrotoxicosis (Fadol & Lech, 2011)
(2) Myocardial muscle dysfunction leads to hyperplasia of cardiac
myocytes and ventricular hypertrophy.
(3) Ventricular dilation occurs as a compensatory mechanism to
permit the heart to fill with more blood and attempt to enhance
cardiac output (Fadol & Lech, 2011; Maitland et al., 2010).
(4) Cancer treatment–related heart failure is usually nonischemic
in nature and the result of direct toxicity to the myocytes (Mar-
tinelli, Carleo, Girelli, & Olivieri, 2011).
(5) Physiologic mechanisms that contribute to heart failure include
available oxygen content (e.g., reduced RBC count with de-
creased oxygen-carrying capacity), myocyte strength, ventricu-
lar hypertrophy, ventricular dilation, and circulating blood vol-
ume (Yusuf et al., 2008).
(a) Anemia results in decreased available oxygen. Reduced ox-
ygen saturation with decreased oxygen delivery causes the
heart to contract stronger and more frequently to deliver
oxygen to tissues. With extended increased workload, the
heart will fail. This is called high-output failure. The conse-
quences are the same as with other etiologic mechanisms.
(b) The etiology of IL-2 cardiac failure is capillary permeabil-
ity with interstitial fluid collection around the myocytes
and eosinophilic infiltration of the heart muscle (Viale &
Yamamoto, 2008).
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
278 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
(c) Renal retention of sodium associated with IL-11 leads to
fluid retention and functional cardiomyositis.
(6) Anthracycline-induced cardiomyopathy is the most-document-
ed etiology of chemotherapy-induced cardiomyopathy associ-
ated with myocyte atrophy. These agents act by DNA intercala-
tion (Barrett-Lee et al., 2009; Barry et al., 2007; Frankel, 2010).
(a) Oxidative stress in the presence of increased free radicals
and decreased antioxidants results in myocyte injury or
death (Viale & Yamamoto, 2008; Yusuf et al., 2008).
(b) Immune-mediated actions cause injury to the plasma mem-
branes of cardiomyocytes.
(7) Cyclophosphamide toxicity is thought to be related to direct en-
dothelial injury (Fadol & Lech, 2011; Viale & Yamamoto, 2008;
Yeh & Bickford, 2009).
(a) May lead to interstitial hemorrhage within the myocytes
(b) Left ventricular wall thickening with hemorrhagic necro-
sis has been reported.
(c) Most closely related to individual doses > 1.5 mg/m2 rath-
er than cumulative dosing
(8) Regardless of etiology, irreversible myocyte damage may oc-
cur prior to changes in ejection fraction or left ventricular wall
thickness (Ewer & Lenihan, 2008).
b) Types of anthracycline toxicity (Barry et al., 2007; Yusuf et al., 2008)
(1) Early-onset anthracycline toxicity (type I)
(a) Occurs during or within one year of completion of anthra-
cycline therapy (Gianni et al., 2007)
i. Severity varies.
ii. Some cases involve stable, asymptomatic abnormali-
ties in left ventricular function.
iii. Other cases are progressive and involve ECG chang-
es, associated signs of cardiomyopathy, changes in ex-
ercise-stress capacity, and overt congestive heart fail-
ure (CHF).
(b) Dose-related: Toxicity increases with higher cumulative
doses and higher maximal doses (Floyd & Perry, 2008; Yu-
suf et al., 2008).
(2) Late-onset anthracycline toxicity (type II) (Barry et al., 2007;
Ganz et al., 2008)
(a) Occurs one year or more after completion of anthracy-
cline therapy
(b) Presumably caused by decreased left ventricular contractil-
ity and inappropriately thin left ventricular wall, elevated
wall stress, and progressive ventricular dysfunction (Ewer
& Lenihan, 2008)
(c) Dose-related: Incidence increases with higher cumulative
doses as well as higher maximal dose.
(d) More common than early-onset anthracycline toxicity
c) Types of nonanthracycline cardiomyopathy (Chen, 2009; Ewer & Ewer,
2008; Ewer & Lenihan, 2008; Yeh & Bickford, 2009; Yusuf et al., 2008)
(1) Acute
(a) Occurs within 24 hours of drug administration
(b) Self-limiting
(c) Not dose related (Camp-Sorrell, 2011)
(d) May cause electrical changes in the heart that an ECG may
reflect
(e) Electrical changes caused by chemotherapy: The most fre-
quent electrical change is decreased voltage.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 279
(f) Chemotherapy can lead to cardiac decompensation and
collapse; however, transient changes usually do not call
for discontinuation of therapy (Ewer & Ewer, 2008; Ewer
& Lenihan, 2008; Ewer & Tan-Chiu, 2007).
(g) Indications to discontinue therapy (Viale & Yamamoto,
2008; Yeh & Bickford, 2009; Yusuf et al., 2008)
i. Acute changes associated with 5-FU (Georgieva et al.,
2007; Sorrentino, Kim, Foderaro, & Truesdell, 2012)
ii. Endothelial damage leading to myocardial necrosis
with use of high-dose cyclophosphamide (Chung et
al., 2008)
iii. Serious arrhythmias resulting from any drug
iv. Acute myocardial infarction after treatment with an
EGFR inhibitor (Bristol-Myers Squibb Co. & ImClone
Systems, 2012)
(2) Subacute
(a) Symptoms appear four to five weeks following therapy.
(b) Fibrinous pericarditis and myocardial dysfunction, which
may be diagnosed with a radionuclide cardiac MUGA scan
(c) Usually reversible
(d) Chemotherapy may or may not be stopped, depending on
the patient’s condition.
(e) Biotherapy usually is discontinued if symptoms of subacute
cardiac toxicity appear.
(3) Chronic
(a) Nonreversible cardiomyopathy may occur weeks or months
after drug administration (Camp-Sorrell, 2011; Floyd & Per-
ry, 2008; Yusuf et al., 2008).
(b) Seen with cumulative doses of cardiotoxic drugs that cause
myocardial weakening because of direct damage to myocytes
(c) Enhanced if radiation therapy has been given to the left
chest, thorax, or mediastinum (Fadol & Lech, 2011; Viale
& Yamamoto, 2008; Yusuf et al., 2008)
(d) Cardiotoxic chemotherapy is stopped if chronic toxicity
occurs.
(e) HER2 receptor blockers such as trastuzumab and lapatinib
may cause cardiomyopathy via inhibition of mitochondri-
al function and the tyrosine kinase pathway (a major met-
abolic pathway) shared by cardiac myocytes (Ewer & Ewer,
2008; Fadol & Lech, 2011; Fiúza, 2009; Gianni et al., 2007;
Perez et al., 2008; Senkus & Jassem, 2011).
i. Inhibition of cardiac tyrosine kinase results in atro-
phy and death of myocytes.
ii. HER2 signaling may be important in protecting car-
diomyocytes from cardiac injury by anthracyclines.
iii. HER2 inhibition (e.g., lapatinib, trastuzumab) may ex-
acerbate cardiotoxic effects of anthracyclines.
(f) Probably reversible (Frankel, 2010; Telli, Hunt, Carlson, &
Guardino, 2007)
(g) Timing: As early as 48 hours after administration and as late
as 89 days (Perez et al., 2008; Suter et al., 2007)
(h) Some multikinase inhibitors (e.g., sunitinib) and antiangio-
genic agents (e.g., bevacizumab) are less direct in inhibit-
ing tyrosine kinase with similar potential for myocyte dys-
function (Chen, 2009; Chu et al., 2007; Force et al., 2007;
Gerber, 2008; Senkus & Jassem, 2011).
(i) Longevity ranges from two to eight weeks (Perez et al., 2008).
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
280 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
(j) Average left ventricular ejection fraction (LVEF) decrease
is 10%–15%; mean value is 40%–43% (Ewer, Lenihan, &
Khakoo, 2007; Frankel, 2010; Perez et al., 2008).
d) Incidence
(1) Anthracyclines produce some degree of cardiac dysfunction
in 50% of patients over a 10–20-year period after exposure.
Approximately 3%–5% develop overt heart failure (Fadol &
Lech, 2011).
(2) Early-onset anthracycline toxicity occurs in 1.6% of children
with cancer treated with anthracycline chemotherapy accord-
ing to Pediatric Oncology Group protocols (Bryant et al., 2007;
Scully & Lipshultz, 2007).
(3) Acute and subacute toxicity occurs infrequently; approximate-
ly 10% of acute toxicities consist of transient electrical chang-
es in the heart (Camp-Sorrell, 2011).
(4) Chronic toxicity is related to cumulative dose.
(5) Some antitumor antibiotics (e.g., epirubicin, idarubicin, mito-
xantrone) produce less cardiac toxicity than do other anthra-
cyclines.
(6) Data suggest that even lower levels of anthracyclines that do
not alter ejection fraction may compromise the heart’s ability
to handle other stressors, thereby increasing the risk of adverse
cardiac events (Ewer & Lenihan, 2008).
(7) Cardiotoxicity incidence with anthracyclines, taxanes, and trastu-
zumab in adjuvant and therapeutic breast cancer treatment has
led to studies to assess best drug order and combinations (Barry
et al., 2007; Ewer & O’Shaughnessy, 2007; Frankel, 2010; Ganz
et al., 2008; Gianni et al., 2007; Perez et al., 2008; Seidman et
al., 2008; Suter et al., 2007).
(a) The HERA (HERceptin® Adjuvant) trial showed higher in-
cidence of heart failure with trastuzumab (3.64%) as com-
pared to lapatinib (1.6%). Preexisting CVD was an exclu-
sion to receive these drugs, so the incidence is thought to
be less than what may occur in the general population.
(b) Prior anthracyclines and cyclophosphamide with con-
comitant trastuzumab caused a 27% incidence of car-
diotoxicity as compared to doxorubicin and cyclophos-
phamide alone.
(c) Paclitaxel with trastuzumab caused 13% incidence of car-
diotoxicity as compared to 1% with paclitaxel alone.
(d) Greatest decrease in left ventricular function is at six- and
nine-month assessments during concomitant therapy (Fran-
kel, 2010).
(8) Chemotherapy-related cardiotoxicity carries a poorer progno-
sis than heart failure from other causes. The two-year mortali-
ty can be > 50% in some populations with severe toxicity (Fad-
ol & Lech, 2011).
e) Risk factors
(1) Direct insult of myofibrils by drugs such as the anthracyclines
doxorubicin, daunorubicin, epirubicin, and idarubicin
(2) Cardiotoxicity can be potentiated when taxanes are given
with other cardiotoxic drugs such as doxorubicin. Paclitax-
el (but not docetaxel) appears to interfere with the pharma-
cokinetic elimination of doxorubicin (Bird & Swain, 2008;
D’Incalci, Schüller, Colombo, Zucchetti, & Riva, 1998; Ewer &
O’Shaughnessy, 2007; Mackey et al., 2008; Perez et al., 2008;
Towns et al., 2008).
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 281
(3) Occasional cases of hemorrhagic myocarditis have been report-
ed in adults who received very high doses of cyclophosphamide,
such as patients who are being prepared for BMT (Satti et al.,
2007). High-dose cyclophosphamide is considered potentially
cardiotoxic for children (Bryant et al., 2007; van Dalen, Caron,
Dickinson, & Kremer, 2011). The effects may be additive with
those of anthracyclines.
(4) Anthracycline-induced cardiotoxicity (Rahman, Yusuf, & Ewer,
2007)
(a) Chemotherapy-induced cardiac toxicity in pediatric patients
is almost always attributable to anthracyclines.
(b) In children and adults, cardiac toxicity has been associated
with all anthracyclines in clinical use (Floyd & Perry, 2008;
van Dalen et al., 2001).
(c) The cumulative dose at which cardiac toxicity occurs var-
ies from drug to drug.
(d) Doxorubicin is the most widely used anthracycline and the
most extensively studied (Fadol & Lech, 2011). It serves as
a model for identifying anthracycline-related cardiomyop-
athies (Yusuf et al., 2008).
(5) Exposure to other agents may potentiate anthracycline-induced
cardiac toxicity.
(a) Mitoxantrone: Reports indicate that it potentiates cardio-
toxicity when administered following anthracyclines or me-
diastinal radiation.
(b) Dactinomycin
(c) Mitomycin C
(d) Bleomycin
(e) Amsacrine
(f) Very-high-dose cyclophosphamide (usually > 100 mg/kg)
(g) Dacarbazine
(h) Vincristine
(i) Diethylstilbestrol diphosphate
(j) Tamoxifen is rarely associated with reduced left ventricu-
lar function (Barr Laboratories, 2007).
(k) Taxanes (e.g., paclitaxel, docetaxel) added to standard anthra-
cycline regimens increase cardiotoxicity (Gianni et al., 2007).
(l) Trastuzumab has been shown to escalate severity of cardio-
toxicity when used simultaneously with anthracyclines or
taxanes (Ewer & Ewer, 2008; Ewer & O’Shaughnessy, 2007;
Gianni et al., 2007; Suter et al., 2007).
i. Does not cause structural myocyte damage like an-
thracyclines
ii. Average reduction in ejection fraction is 10%–15%,
with overt heart failure symptoms occurring in 0%–
3.9% of patients.
iii. Reversible in 88% of cases and permanent drug dis-
continuation not required
(6) High-dose therapy
(a) Administration schedule: Higher doses of cardiotoxic drugs
given over a shorter period demonstrate increased toxicity
(Camp-Sorrell, 2011). Dividing doses into smaller boluses
has been shown to decrease toxicity.
(b) Thoracic irradiation of the lungs or mediastinum: Cardiac
toxicity may occur at lower radiation doses when patients
receive anthracyclines and mediastinal radiation (Yeh &
Bickford, 2009; Yusuf et al., 2008).
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
282 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
(c) High-dose chemotherapy associated with HSCT may cause
a spectrum of subacute to life-threatening cardiomyopathy
peaking in incidence 6–16 days after administration of the
preparative regimen (Chung et al., 2008).
(7) Age
(a) Malnutrition may increase cardiotoxicity. In cases of preex-
isting malnutrition, children are at higher risk than adults
because of biologic and metabolic differences, the high
tissue sensitivity of children, and the intensity of pediat-
ric chemotherapy regimens (Fulbright, Huh, Anderson,
& Chandra, 2010).
(b) Conflicting evidence exists regarding older adults. Older
adults may be at higher risk because of the aging process and
limitations in DNA self-repair, but the incidence of cardio-
toxicity is not clearly increased in older adults unless CVD
is present. Studies of older women receiving adjuvant che-
motherapy with anthracyclines have showed an increased
risk of cardiomyopathy (Gianni et al., 2007).
(8) Preexisting cardiac disease, such as cardiac abnormalities or tu-
mors in the chest, increases risk of cardiomyopathy (Fadol &
Lech, 2011; Yusuf et al., 2008).
(9) Smoking is associated with cardiac changes such as vasoconstric-
tion, hypertension, and atherosclerosis (Fadol & Lech, 2011).
(10) Mediastinal radiotherapy increases risk of cardiomyopathy.
f) Clinical manifestations (Fares, 2008; Heart Failure Society of Ameri-
ca, 2010; Hunt et al., 2009)
(1) Dyspnea is most common clinical finding.
(2) Heart failure usually presents with symptoms of increased work
of the heart, such as tachycardia; full, bounding pulses; gallops;
or murmurs.
(3) Compensatory symptoms that reflect the body’s attempt to im-
prove tissue perfusion of major organs in the face of inadequate
contractile force include tachypnea, distended neck veins, cool
and pale or cyanotic extremities, decreased bowel sounds with
nausea or poor digestion, and decreased urine output.
(4) When the blood cannot enter the heart for a prolonged peri-
od of time, venous congestion occurs. Peripheral and depen-
dent edema is accompanied by hepatosplenomegaly; crackles
are detected on lung auscultation; and pleural or pericardial
effusions may occur.
(5) Late effects of compromised peripheral circulation may be de-
tected by poor distal extremity wound healing.
g) Assessment
(1) Assess daily weights in high-risk patients whether inpatient
or at home. Patient weight gain is a highly sensitive and spe-
cific predictor for decompensating heart failure (Hunt et
al., 2009).
(2) When patients call with symptoms, the ability to determine the
degree of heart failure is dependent upon the patient’s report
of dyspnea, weight gain, or edema.
(3) Assess breath sounds and heart sounds of patients at risk for
cardiomyopathy at every visit.
(4) Anthracycline toxicity diagnosis (Jannazzo, 2007; Jurcut et al.,
2008; Shelton, 2009a)
(a) Cardiac toxicity associated with anthracycline therapy is best
diagnosed by serial endocardial biopsy (Ewer & Lenihan,
2008). The means for doing such a biopsy are not available
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 283
in all institutions, and obtaining the tissue needed for the
biopsy is an invasive procedure. Serial endocardial biopsy
seldom is used in pediatric patients.
(b) MUGA scans are widely used to detect early-onset anthra-
cycline cardiotoxicity. They are reliable indicators of car-
diac damage but may not reflect early reversible changes
(Ewer & Lenihan, 2008; Yusuf et al., 2008).
(5) Three-dimensional color Doppler echocardiography is widely
used to diagnose all types of cardiomyopathy. It is noninvasive
and can measure LVEF, fractional shortening, and left ventric-
ular wall thickness (Ewer & Lenihan, 2008; Jurcut et al., 2008;
Yusuf et al., 2008).
(6) Blood levels of cardiac troponin can detect early myocardiocyte
injury caused by anthracycline toxicity (Anderson, 2008; Ewer
& Lenihan, 2008; Jurcut et al., 2008).
(7) Brain natriuretic peptide levels are used to monitor left ven-
tricular heart failure. They may be elevated postoperatively or
in patients with anemia, atrial fibrillation, cor pulmonale, ven-
tricular hypertrophy, pulmonary embolism, or lung cancer (An-
derson, 2008).
(8) ECG can detect abnormalities in cardiac electrophysiology
caused by cardiotoxicity. The most common abnormal find-
ings are low QRS voltage or tachycardia. Ischemic ST changes
may be present or accompanied by left ventricular strain seen
as ischemia on anterior chest leads 4, 5, and 6.
(9) Assessment before biotherapy (Prometheus Laboratories Inc.,
2012; Shelton, 2009a)
(a) Before treatment with IL-2, obtain baseline evaluation of left
ventricular function to determine eligibility for treatment.
(b) Before treatment with certain mAbs (e.g., trastuzumab)
and chemotherapy agents, establish baseline cardiac func-
tion by MUGA scan and ECG.
(10) Assessment throughout therapy, especially for high-risk patients
(a) Check the results of baseline cardiac studies (e.g., ejection
fraction) before administering the drug. Ejection fraction
may not be the most sensitive indicator and should not be
the only parameter used to assess cardiotoxicity (Ewer &
Lenihan, 2008). Other clinical assessments may include
ventricular dilation, ventricular wall thickness, or wall mo-
tion abnormalities.
(b) Observe for clinical manifestations of CHF (e.g., tachycar-
dia, shortness of breath, nonproductive cough, neck-vein
distention, ankle edema, displaced point of maximal im-
pulse crackles, hepatomegaly).
(11) Calculate and assess the cumulative dose of the applicable drug
(e.g., doxorubicin) and document it in the patient’s record. Car-
diotoxic levels of common anthracyclines are
(a) Doxorubicin 400–450 mg/m2 (Swain, Whaley, & Ewer, 2003)
(b) Daunorubicin 400 mg/m2 (Jannazzo, 2007)
(c) Epirubicin 900 mg/m2 (Ryberg et al., 1998)
(d) Idarubicin 150 mg/m2 (Anderlini et al., 1995).
(12) Assess heart rate, rhythm, and regularity, including murmurs,
split sounds, and extra sounds; a gallop or third heart sound
may indicate insufficiency.
(13) Assess electrolytes (e.g., potassium, calcium); abnormal electro-
lyte levels can interfere with cardiac function.
h) Collaborative management (Fares, 2008; Yusuf et al., 2008)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
284 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
(1) Administer, if part of the protocol in the institution, the cardio-
protective iron-chelating agent dexrazoxane (Zinecard®) during
or prior to the administration of doxorubicin to prevent cardio-
toxicity in some patients (e.g., those with metastatic breast can-
cer who have received > 300 mg/m2 doxorubicin) (Barry et al.,
2007; van Dalen et al., 2011). Iron-chelating agents inhibit the
generation of free radicals. The administration of dexrazoxane
significantly decreased cardiac toxicity in pediatric trials (Bry-
ant et al., 2007). Dexrazoxane is FDA-approved to reduce car-
diac toxicity in adults (Pfizer Inc., 2012d).
(2) Administer liposomal formulation of anthracyclines (liposo-
mal doxorubicin [Doxil®] or liposomal daunorubicin [Dauno-
Xome®]) when indicated. They have demonstrated less cardio-
toxicity, permitting higher dose delivery (Rahman et al., 2007).
(3) Administration over longer periods of time (e.g., 48–72 hours)
is thought to reduce the incidence or severity of cardiac toxic-
ity (Fulbright et al., 2010; Scully & Lipshultz, 2007; van Dalen
et al., 2011).
(4) Administer medications as prescribed to treat CHF and sup-
port cardiac output (e.g., diuretics, inotropic cardiac medi-
cations, vasodilators, oxygen) (Anderson & Sawyer, 2008; Ful-
bright et al., 2010).
(a) ACE inhibitors have been administered to prevent cardio-
myopathy in patients receiving radiation therapy to the left
breast and children receiving total body irradiation (Heart
Failure Society of America, 2010).
(b) Metoprolol tartrate, a beta-blocker, has been used effectively
to treat pediatric patients with severe CHF following doxo-
rubicin therapy (Heart Failure Society of America, 2010).
(c) Develop an activity or exercise plan.
(d) Institute dietary modifications (e.g., a low-salt diet) as nec-
essary for patients with CHF. Omega-3 fatty acids have been
reported to both enhance and abrogate doxorubicin toxic-
ities, but no clinical effects have been proved.
(5) Expect to discontinue or reduce the dose of the cardiotoxic
agent if the patient’s ejection fraction is less than 40% to 45%
(Ewer & Lenihan, 2008; Ewer & Tan-Chiu, 2007).
(6) Monitor results of ECGs; for patients receiving chemothera-
py, an ECG is recommended at three months, six months, and
one year after anthracycline therapy (Barry et al., 2007; Ng &
Green, 2007).
(7) Manufacturer recommendations for monitoring during arse-
nic trioxide therapy (Cephalon, Inc., 2010)
(a) Monitor serum electrolytes twice weekly during induction
and at least weekly during the consolidation phase.
(b) Monitor ECG baseline and weekly during both induction
and consolidation.
(c) Monitor for drugs that prolong QT.
(d) Hold until QTc < 0.46 s (460 msec).
(8) Cardiac troponins I and T and brain natriuretic peptide levels
have been suggested as effective methods of monitoring for im-
mediate and ongoing cardiotoxicity. Elevated levels prior to an-
thracycline administration are thought to imply higher risk for
cardiotoxicity, and levels that rise during therapy may predict
early cardiotoxicity prior to changes in ejection fraction (Leni-
han et al., 2007; Pandey, Gupta, & Wander, 2011; Urbanova, Ur-
ban, Danova, & Simkova, 2008).
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 285
(9) Monitor results of MUGA scans (Genentech, Inc., 2012b).
(10) Before initiation of any agent that is reported as causing heart
failure and at least every three months for the first year, eval-
uate cardiac function by MUGA scan or ECG. Adjuvant breast
cancer therapies that include anthracyclines, cyclophospha-
mide, taxanes, and trastuzumab have special monitoring rec-
ommendations as follows (Frankel, 2010; Rahman et al., 2007;
Yusuf et al., 2008).
(a) Three months after anthracycline and cyclophosphamide
and prior to start of taxanes
(b) After completion of taxanes and before start of trastuzum-
ab; LVEF must be above lower limits of normal and not
> 15% below baseline
(c) At 3, 6, and 15 months after start of trastuzumab
(d) Thereafter, a scan is recommended every five years.
(11) Treat asymptomatic decreases in LVEF associated with trastu-
zumab as follows (Barry et al., 2007; Frankel, 2010; Genentech,
Inc., 2012b; Rahman et al., 2007) (see Table 35).
(a) Resume trastuzumab in four to eight weeks if LVEF returns
to normal and absolute decrease from baseline is ≤ 15%
(Genentech, Inc., 2012b).
(b) Permanently discontinue trastuzumab if decline in LVEF
lasts longer than eight weeks or if trastuzumab was held
more than three times previously (Genentech, Inc., 2012b).
i) Patient and family education (Ewer et al., 2007; Fadol & Lech, 2011;
Frankel, 2010; van Dalen et al., 2011)
(1) Teach patients that cardiotoxicity is a possible side effect of the
drug(s) (e.g., doxorubicin, daunorubicin and liposomal dau-
norubicin, mitoxantrone, high-dose 5-FU, high-dose cyclophos-
phamide, ILs, IFNs, some mAbs) (see Table 34).
(2) Instruct patients about the signs and symptoms of CHF and
when to report to a nurse or physician. Explain that close mon-
itoring for possible late effects may be required even after treat-
ment has ended.
(3) Instruct patients to avoid tobacco and alcohol use because these
agents stimulate the cardiac muscle.
(4) Instruct patients that chronic cardiotoxicity usually is dose-
related and possibly irreversible.
(5) Inform patients and caregivers about strategies to manage symp-
toms at home.
(6) Ensure that patients are familiar with the ongoing protocol for
follow-up care, including the following (Fares, 2008).
(a) A yearly standard physical and history
(b) MUGA scans, echocardiogram, and/or ECG every two to
five years. The number of risk factors determines the in-
Table 35. Trastuzumab Administration for Asymptomatic Decreases in
Left Ventricular Ejection Fraction (LVEF)
Relationship of LVEF < 10% Absolute 10%–15% Absolute ≥ 16% Absolute
and Lower Limit of Decrease From Decrease From Decrease From
Normal Baseline Baseline Baseline
Within normal limits Continue. Continue. Hold × 4 weeks.
Below lower limits of Continue. Hold × 4 weeks. Hold × 4 weeks.
normal
Note. Based on information from Frankel, 2010; Genentech, Inc., 2012b.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
286 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
terval between such tests. Patients with preexisting CVD
or risk factors or receiving multiple agents with potential
cardiotoxicity will have more frequent monitoring of car-
diac function.
(c) 24-hour Holter monitoring every three years
(7) Instruct the patient to obtain a cardiology consult before preg-
nancy, general anesthesia, or the start of a vigorous exercise
program.
(8) Encourage maintenance of a healthful lifestyle that eliminates
tobacco and alcohol and includes exercising regularly and main-
taining an appropriate weight and nutritious diet (Heart Fail-
ure Society of America, 2010).
(9) Stress the importance of lifelong follow-up care with a health-
care provider familiar with the patient’s cancer history, treat-
ment, and risk of late effects.
6. Pericardial effusions
a) Pathophysiology (Bodson, Bouferrache, & Vieillard-Baron, 2011;
Shelton, in press-c)
(1) The space between the visceral and parietal pericardium is
characterized by a negative pressure gradient and is filled with
a small amount of fluid.
(2) The space’s negativity allows for filling and expansion of the
atria and ventricles during the cardiac cycle.
(3) Accumulation of excessive amounts of pericardial fluid causes
a more positive pressure within the space, impeding venous re-
turn into the heart.
(4) Several antineoplastic therapies increase capillary permeability
and enhance the risk of increased pericardial fluid.
(5) Cytarabine has been hypothesized to trigger a hypersensitivi-
ty reaction, with pericardial fluid extravasation occurring 3–28
days after treatment (Fadol & Lech, 2011).
(6) Anthracyclines are thought to produce an acute fibrinous peri-
cardial syndrome that can be early or delayed in onset (Fadol
& Lech, 2011).
b) Incidence
(1) The incidence of pericardial effusion is < 5% across all thera-
pies (Shelton, in press-c).
(2) Prognosis for full recovery when therapy-related is excellent.
c) Risk factors (Bouzas-Mosquera et al., 2008; Fadol & Lech, 2011; Floyd
& Perry, 2008; Yusuf et al., 2008)
(1) Antineoplastic therapies that have clearly been associated with
pericardial effusion include cytosine arabinoside and IL-2.
(2) Other antineoplastic therapies with rare instances of pericardial
fluid accumulation include bleomycin, cyclophosphamide, dau-
nomycin, docetaxel, doxorubicin, imatinib, and methotrexate.
(3) Comorbid health conditions such as hypothyroidism, heart fail-
ure, autoimmune disease, and uremia may increase the inci-
dence of pericardial effusion (Wang et al., 2010).
d) Clinical manifestations
(1) Chest pain, cough, and dyspnea (Gandhi et al., 2008; Shelton,
2009a)
(2) Signs/symptoms of right heart failure are more common with
slowly developing effusions: Edema, weak and thready pulses,
low-voltage QRS on ECG rhythm
e) Assessment (Bodson et al., 2011; Shelton, in press-c; Sisson, 2010)
(1) Vital signs assessment: Assess for weak, thready, or irregular pulses
and hypotension with narrow pulse pressure. Pulsus paradoxus
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 287
is a clinical finding where there are two audible systolic pres-
sures indicative of inefficient contractility.
(2) Heart sounds assessment: Muffled heart sounds indicate signifi-
cant fluid accumulation, although pericardial rub may be present.
(3) Jugular venous pulsations/distention: Elevated bilaterally with
significant pericardial effusion
(4) Signs/symptoms of poor perfusion: Cool or clammy skin, poor
capillary refill, oliguria, diminished bowel sounds, confusion
(5) Diagnostic test data
(a) Chest x-ray: Nonspecific screening tool that usually shows
enlarged cardiac silhouette (Gandhi et al., 2008; Shelton,
in press-c)
(b) Echocardiogram: Can show collapsed right ventricle, ex-
cess fluid in pericardial space, and poor wall motion (Les-
tuzzi, 2010; Lestuzzi et al., 2010; Sagrista-Sauleda, Merce,
& Soler-Soler, 2011)
(c) ECG: Electrical alternans is uncommon but specific; low-
voltage of the QRS; ST-segment elevation in all the pre-
cordial leads (Gandhi et al., 2008; Jung, Seung, & Madias,
2010; Shelton, in press-c)
f) Collaborative management (Bodson et al., 2011; Shelton, 2009a;
Sparano & Ward, 2011)
(1) The majority of effusions are not clinically significant and do
not require active interventions.
(2) Watchful waiting with treatment of the etiologic factor or dis-
continuation of the therapy causing effusion usually is suffi-
cient treatment for drug-related pericardial effusions (Yusuf
et al., 2008).
(3) Immediate emergency management of impending tamponade
is administration of large-volume IV fluids. This will raise the ve-
nous pressure above the pericardial pressure and allow for bet-
ter ventricular filling and improved cardiac output.
(4) On rare occasions, emergency evacuation of pericardial flu-
id may be necessary. When time permits, a planned catheter
drainage in an operative or procedural area is preferred (In-
glis, King, Gleave, Bradlow, & Adlam, 2011; Tam et al., 2009).
g) Patient and family education (Shelton, in press-c)
(1) Teach importance of reporting changes in fatigue, dyspnea,
and edema.
(2) Advise patients to weigh themselves and check for fluid reten-
tion (e.g., weight gain, tight rings, swollen ankles).
(3) Ensure that patients and caregivers understand the importance of
keeping appointments for regular follow-up and diagnostic tests.
F. Pulmonary toxicity
1. Pulmonary toxicity ranges from reversible short-term reactive airway dis-
ease to diffuse permanent fibrosis and structural destruction. Most side
effects are rare, occurring in < 1% of low-risk patients and up to 8% in
high-risk groups (Barber & Ganti, 2011; Chernecky, 2009; Schwaiblmair
et al., 2012). On rare occasions, these toxicities are fatal (Boeck, Haus-
mann, Reibke, Schulz, & Heinemann, 2007; Chikura, Sathi, Lane, & Daw-
son, 2008; Giusti, Shastri, Cohen, Keegan, & Pazdur, 2007; Gupta & Ma-
hipal, 2007; Keijzer & Kuenen, 2007; Leimgruber et al., 2006; Makris et
al., 2007; Vahid & Marik, 2008). As patients survive increasingly aggres-
sive and multimodal therapy and the use of multitargeted therapies be-
comes more commonplace, additional pulmonary toxicities are emerg-
ing. As in the case of acute promyelocytic leukemia (APL) differentia-
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
288 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
tion syndrome (Lamour & Bergeron, 2011; Luesink & Jansen, 2010) or
pulmonary veno-occlusive disease (VOD) (Huertas et al., 2011; Solh,
Arat, Cao, Majhail, & Weisdorf, 2011), it is unclear whether pulmonary
changes are related to the disease, rejection phenomena, chemothera-
py agents, or the combined effects of chemoradiotherapy.
2. Chemotherapy-induced pulmonary toxicities are divided into acute, unde-
fined, and chronic disorders (American Thoracic Society & European Re-
spiratory Society, 2002; Charpidou et al., 2009; Schwaiblmair et al., 2012).
a) Acute disorders occur within minutes to a few months after exposure
to the offending agent. Toxicities usually have a direct effect on the
lungs. Many are believed to be at least partially reversible yet may still
be fatal in their most acute forms. Examples of acute disorders include
bronchospasm, hypersensitivity pneumonitis, alveolar hemorrhage,
retinoic acid syndrome, noncardiogenic pulmonary edema, pulmo-
nary alveolar proteinosis, and interstitial pneumonitis.
b) Chronic disorders occur months to years after exposure. Most chron-
ic disorders cause irreversible lung injury and may be progressive in
nature, leading to severe disability or death. Examples of chronic
lung toxicities include progressive interstitial pneumonitis, organiz-
ing pneumonia, pulmonary VOD, and pulmonary fibrosis.
c) Indeterminate lung toxicities are those conditions that are undefined
or have an unclear trajectory. They may begin with features of both
acute and chronic disorders and are ultimately defined when the de-
gree of alveolar damage is identified.
3. Determining the etiology of pulmonary signs and symptoms in patients
with cancer can be challenging because toxicity can mimic a broad spec-
trum of pathogenic causes, including infectious and neoplastic (Barber
& Ganti, 2011; Charpidou et al., 2009; Meadors, Floyd, & Perry, 2006;
Schwaiblmair et al., 2012). Consequently, it is imperative to understand the
potential for toxicity and to detect pulmonary toxicity as early as possible.
a) Common symptoms of pulmonary toxicities include dyspnea, tachy-
pnea, exercise intolerance, and increased work of breathing. Some
disorders also cause fever, substernal discomfort, and hypoxemia
(Charpidou et al., 2009; Parshall et al., 2012; Schwaiblmair et al.,
2012; Vahid & Marik, 2008).
b) The primary diagnostic test used to differentiate specific conditions
is the CT scan. Although unique findings indicate some disorders,
histologic sampling may be necessary to determine the precise pa-
thology (Torrisi et al., 2011).
4. Interstitial lung disease (ILD) is a heterogeneous group of lung disor-
ders involving damage to the alveoli and surrounding interstitium. ILD
includes acute chemotherapy-induced pneumonitis, pulmonary capil-
lary permeability syndrome, chemotherapy-related adult respiratory dis-
tress syndrome, hypersensitivity/eosinophilic pneumonitis, cryptogen-
ic (of unknown cause) organizing pneumonia, pulmonary fibrosis, and
pulmonary alveolar proteinosis (American Thoracic Society & Europe-
an Respiratory Society, 2002; Charpidou et al., 2009; NCI CTEP, 2010;
Schwaiblmair et al., 2012).
a) Pathophysiology
(1) Postulated pathologic changes (American Thoracic Society &
European Respiratory Society, 2002; Charpidou et al., 2009;
Chernecky, 2009; Schwaiblmair et al., 2012; Silva & Müller, 2009;
Specks, 2012; Vahid & Marik, 2008)
(a) Injury to lung parenchyma
(b) Inflammation of alveoli, alveolar cell walls, interstitial spac-
es, and terminal bronchioles
(c) Release of ILs and transforming growth factors
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 289
(d) Destruction of the alveolar-capillary endothelium leading
to changes in interstitial fibroblasts
(e) Activation of fibroblasts and microfibroblasts, which cause
collagen deposition in the alveolar interstitium
(2) Disease results predominantly from inflammatory features.
(a) Fluid or bloody exudates in alveoli
(b) Fluid between alveoli (interstitial spaces) from degrada-
tion of the alveolar wall
(c) Fibrosis and stiffening of vascular, airway, and alveolar walls
(3) Resolution results in scarring and fibrosis of tissue, beginning
in the interstitium and later involving the alveolar sacs. Pulmo-
nary fibrosis is the chronic continuation of some acute pneu-
monitis syndromes.
(4) Stiff, noncompliant lungs have poor elasticity and cause in-
creased work of breathing.
(5) Chronic exposure to chemotherapy agents may result in chang-
es in lung connective tissue, obliteration of alveoli, and dila-
tion of air spaces leading to a honeycomb appearance on x-
rays and scans.
(6) Increased pulmonary pressure from connective tissue and fi-
brotic banding leads to pulmonary hypertension, cor pulmo-
nale, and heart failure.
(7) Cellular mechanisms of injury (American Thoracic Society &
European Respiratory Society, 2002)
(a) Direct damage: Some chemotherapy agents cause direct
damage to the alveoli and capillary endothelium (e.g., high-
dose cytarabine or mitomycin C) (Chan & King, 2012c;
Forghieri, Luppi, Morselli, & Potenza, 2007; Morgensztern
& Govidan, 2008).
(b) Metabolic damage: Cyclophosphamide metabolism in the
lung leads to the formation of alkylating metabolites and
acrolein, which may cause toxicity (Bein & Leikauf, 2011;
Gupta & Mahipal, 2007; Specks, 2012; Vahid & Marik, 2008).
(c) Multikinase inhibitors (e.g., sorafenib [Ide et al., 2010]), in-
cluding tyrosine kinase inhibitors (e.g., imatinib, dasatinib),
and EGFR inhibitors (e.g., cetuximab, panitumumab) can
cause injury (Barber & Ganti, 2011; Min et al., 2011; Vahid
& Marik, 2008). Inhibition of the tyrosine kinase pathway
may affect the alveoli and pneumocytes.
(d) Acute onset of pulmonary edema (noncardiogenic) is re-
lated to cytokine-induced capillary leak syndrome (Binder,
Hübner, Temmesfeld-Wollbrück, & Schlattmann, 2011; Dis-
el, Paydas, Yavuz, & Karakoc, 2010; Forghieri et al., 2007;
Maldonado, Limper, & Jett, 2012).
(e) Hemorrhagic pneumonitis is parenchymal injury and mi-
crovascular bleeding similar to alveolar hemorrhage but
occurs in both alveolar and interstitial spaces (Balk, 2012).
(f) Hypersensitivity pneumonitis is characterized by an acute
and rapid-onset immunologic alveolar reaction that leads
to capillary permeability, fluid extravasation, and lym-
phocytic or eosinophilic infiltration of the alveoli and
interstitium, impeding gas exchange (Balk, 2012; Kim,
Mishima, & Yoshizawa, 2010; Kim, Song, & Ryu, 2009;
King & Jett, 2013; Lerch, Gyorik, Feilchenfeldt, Mazzuc-
chelli, & Quadri, 2010; Lobera et al., 2008; Maldonado
et al., 2012; Maldonado, Limper, & Jett, 2013a; Zappa-
sodi et al., 2007)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
290 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
(g) Cryptogenic organizing pneumonia, previously called bron-
chiolitis obliterans organizing pneumonia, is characterized by
development of fibrous connective tissue between and in-
volving alveolar and bronchiolar spaces; inflammation ac-
tivation of autoimmune collagen deposition; and obstruc-
tion of the ventilating airways. This disorder may be asso-
ciated with immune disorders (e.g., autoimmune diseas-
es, post-transplant), infectious diseases, hematologic ma-
lignancies, and some antineoplastic medications (Cottin,
& Cordier, 2011; Vasu et al., 2009).
(h) Pulmonary alveolar proteinosis is a syndrome of phospho-
lipidosis and frothy exudates of the distal airways. Although
the triggering mechanisms are not well understood, au-
toimmune activation is suspected. It is characterized by
GM-CSF deficiency. It has most commonly been reported
after HSCT, but it is unclear if it is triggered by medication
exposure or immune deficits (Khan & Agarwal, 2011; Pida-
la, Khalil, & Fernandez, 2011).
b) Incidence varies based upon host and medication-related factors.
Pneumonitis syndromes are infrequent.
(1) Incidence increases when pulmonary toxic agents are adminis-
tered concomitantly with thoracic radiation.
(2) Incidence is influenced by cumulative dose with some agents.
c) Risk factors (Maldonado et al., 2012, 2013a, 2013b; Reck, Mok, Wolf,
Heigener, & Wu, 2011; Vahid & Marik, 2008; Zayen et al., 2011)
(1) The chemotherapy and targeted therapy drugs most common-
ly associated with pulmonary toxicity are all-trans-retinoic acid
(ATRA), bleomycin, busulfan, carmustine, cyclophosphamide,
cytosine arabinoside, everolimus, gemcitabine, methotrexate,
mitomycin, oxaliplatin, rituximab, and tamoxifen (Gemma,
2009; Mizuno et al., 2012).
(a) Agents associated with bronchospasm include asparaginase,
cetuximab, etoposide, gemcitabine, oxaliplatin, rituximab, tax-
anes, trastuzumab, and vinorelbine (Goli, Osman, Koduri, Byrd,
& Roy, 2011; Lee, Gianos, & Klaustermeyer, 2009; Kuntzsch &
Voge, 2009; Syrigou et al., 2011; Vahid & Marik, 2008).
(b) Agents associated with noncardiogenic pulmonary edema
include cytarabine, gemcitabine, interleukins, and vinca al-
kaloids (Binder et al., 2011; Disel et al., 2010; Forghieri et
al., 2007; Maldonado et al., 2012).
(c) Agents associated with hypersensitivity pneumonitis in-
clude bortezomib, imatinib, lenalidomide, methotrex-
ate, oxaliplatin, paclitaxel, procarbazine, and thalidomide
(Balk, 2012; Kim et al., 2009, 2010; King & Jett, 2013; Le-
rch et al., 2010; Lobera et al., 2008; Maldonado et al.,
2012, 2013a; Zappasodi et al., 2007).
(d) Antineoplastic therapies associated with cryptogenic orga-
nizing pneumonia include radiofrequency ablation, radi-
ation therapy, bleomycin, busulfan, everolimus, IFN alfa,
methotrexate, platinum agents, rituximab, sirolimus, ta-
crolimus, temozolomide, thalidomide, and trastuzumab.
(2) Agents associated with nonspecific dyspnea include ATRA, aza-
thioprine, cetuximab, chlorambucil, chlorozotocin, crizotinib,
dasatinib, docetaxel, doxorubicin, erlotinib, etoposide, fluda-
rabine, gemcitabine, ifosfamide, imatinib, irinotecan, lenalid-
omide, lomustine, melphalan, mercaptopurine, mitoxantrone,
nilotinib, panitumumab, pemetrexed, procarbazine, semustine,
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 291
temozolomide, temsirolimus, thalidomide, trastuzumab, vin-
blastine, and vindesine.
(3) General host risk factors for ILD (Amin et al., 2011; Arrieta et
al., 2009; Takeda et al., 2012)
(a) Age: Because the effectiveness of the antioxidant defense
system decreases with age, susceptibility to pulmonary tox-
icity from certain cytotoxic drugs increases significantly af-
ter age 70 (Wagner, Mehta, & Laber, 2007).
(b) Tobacco smoking (Chernecky, 2009)
(c) Deteriorating creatinine clearance affecting drug clear-
ance has been implicated in increased risk for pneumoni-
tis and pulmonary fibrosis (Vahid & Marik, 2008; Yahalom
& Portlock, 2008).
(d) High oxygen concentrations (about 60% fraction of in-
spired oxygen), such as those used during administration
of general anesthesia, can enhance the pulmonary toxici-
ty of bleomycin (Chernecky, 2009; Mazeron et al., 2010).
(e) Prior lung disease (e.g., chronic obstructive lung disease)
or reduced lung reserve (Chernecky, 2009; Xu et al., 2012)
(f) Autoimmune disease enhances release of inflammatory
mediators that increase drug-related pulmonary toxicity
(Chernecky, 2009; Hadjinicolaou et al., 2011; Silva & Mül-
ler, 2009; Varga, 2007).
(4) Treatment-related factors (see Table 36)
(a) Thoracic radiation therapy (Chernecky, 2009; Hadjinico-
laou et al., 2011; Merrill, 2013)
(b) Multidrug regimens such as those including bleomycin, mi-
tomycin, cyclophosphamide, methotrexate, or BCNU (Bind-
er et al., 2011; Boeck et al., 2007; Czarnecki & Voss, 2006;
Leo et al., 2010; Lim, Kim, Choi, & Lee, 2010; Usman, Fa-
ruqui, ud Din, & Zahid, 2010). It has not been determined
whether any single drug is the causative agent or if the in-
teraction of these antineoplastics results in enhanced tox-
icity (Boeck et al., 2007).
(c) Concurrent chemotherapy and radiation therapy, espe-
cially with bleomycin, carmustine, cyclophosphamide, or
doxorubicin, has been associated with interstitial pulmo-
nary pneumonitis (Amin et al., 2011; Chernecky, 2009).
(d) Cumulative dose: Increasing toxicity with increasing dose
is believed to be a result of drug accumulation in the lung
itself. Two patterns of dose-related pulmonary toxicity are
clinically observed.
i. A threshold effect: A definite increase in risk for pulmo-
nary toxicity occurs when a cumulative dose is reached.
• Total lifetime dose of bleomycin exceeding 400 units
(Bristol-Myers Squibb Co., 2012a; Gilligan, 2012)
• Busulfan, in the absence of other predisposing fac-
tors, total dose > 500 mg (GlaxoSmithKline, 2008b)
• Mitomycin maximum dose of 30 mg/m2 (Chan &
King, 2012c)
• Lomustine dose > 1,100 mg/m2 (Bristol-Myers
Squibb Co., 2010a)
ii. A linear effect: Risk for the development of pulmo-
nary toxicity constantly increases as more drug is
administered (e.g., carmustine [Bristol-Myers Squibb
Co., 2011a]).
(e) Long-term treatment (e.g., busulfan, imatinib treatment)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
292
Table 36. Pulmonary Toxicity of Chemotherapeutic Agents
Classification Drug Incidence Characteristic Effects Comments
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Alkylating Busulfan Incidence is rare but serious. Types of toxicity: Interstitial pneumonitis, pulmonary fibrosis, or- Establish baseline pulmo-
agents Busulfan is associated with pulmonary damage and ganizing pneumonia, pulmonary VOD (Bunte et al., 2008; Mal- nary function.
pneumonitis. It occurs in 2.5%–11.5% of patients, donado et al., 2013a) Assess x-rays, PFTs, and
usually those on long-term treatment, although it can Insidious-onset cough, dyspnea, and low-grade fever; broncho- CT scans as indicated.
occur more acutely. pulmonary dysplasia progressing to interstitial pulmonary fi-
Mean time from exposure to interstitial pneumonitis brosis (“busulfan lung”)
toxicity is 4 years, (range = 8 months to 10 years) Bronchopulmonary dysplasia with pulmonary fibrosis is a rare
(Bunte et al., 2008). but serious complication following chronic busulfan therapy.
Risk increases with total doses > 500 mg, concurrent The average onset of symptoms is 4 years after therapy; de-
pulmonary toxic medications, and preexisting lung layed onsets have occurred (range = 8 months to 10 years)
disease (Bunte et al., 2008). (Bunte et al., 2008; GlaxoSmithKline, 2008b).
Chest x-rays show diffuse linear densities, sometimes with reticular
nodular or nodular infiltrates or consolidation. Pleural effusions
have occurred (GlaxoSmithKline, 2008b; Smalley & Wall, 1966).
Chlorambucil Incidence is low. Respiratory dysfunction is usually re- Types of toxicity: Interstitial pneumonitis, organizing pneumonia, Establish baseline pulmo-
ported at high dose but occurs at total doses of 540– pulmonary fibrosis (Dweik, 2013; Maldonado et al., 2012b) nary function.
834 mg (Dweik, 2013; GlaxoSmithKline, 2003b). Pulmonary fibrosis and bronchopulmonary dysplasia in patients
Occurs 6 months to 3 years after initiation of therapy receiving long-term therapy (GlaxoSmithKline, 2003b)
(Dweik, 2013). Biopsy findings may include T-cell infiltration and alveolitis.
Periodic monitoring of PFTs shows decreased lung volumes and
reduced DLCO before clinical symptoms.
Steroid responsive in < 10% of cases (Dweik, 2013)
Cyclophos- Incidence is rare. Diffuse alveolar damage is the most Types of toxicity: Interstitial pneumonitis, pulmonary fibrosis, al- Concomitant oxygen delivery
phamide common manifestation of cyclophosphamide- veolar hemorrhage > 60% FiO2 may exacer-
induced lung disease (Specks, 2012). Edema, fibrosis, alveolar hemorrhage, and fibrin deposition are bate incidence and severity
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
In early-onset toxicity occurring within the first 48 thought to be due to accumulation of the alkylating agent me- (Specks, 2012).
days, no relationship exists among development tabolite acrolein. The metabolite causes lipid peroxidation nor- Treatment involves discon-
of lung injury, dose, and duration of administration mally cleared by pulmonary antioxidant mechanisms, but when tinuing the agent and ad-
(Specks, 2012). accumulated, it erodes the lipid layer and causes microvascu- ministering steroids, which
Incidence of pulmonary toxicity has been reported- lar damage (Bein & Leikauf, 2011; Specks, 2012). have good to variable re-
ly increased in patients who have received concom- Onset of chronic fibrosis can be 15 weeks to 6 years after medi- sponse in early-onset tox-
itant methotrexate or amiodarone and in chronic cation administration. icity (Bristol-Myers Squibb
graft-versus-host disease (Gupta & Mahipal, 2007; Interstitial pulmonary fibrosis has been reported in patients re- Co., 2005; Specks, 2012).
Specks, 2012). ceiving high doses of cyclophosphamide over a prolonged pe- Delayed-onset interstitial fi-
riod (Gupta & Mahipal, 2007). brosis with pleural thick-
Anaphylactic reactions are associated with death. Possible ening is less responsive to
cross-sensitivity with other alkylating agents has been report- corticosteroids.
ed (Bristol-Myers Squibb Co., 2005).
One clinical change in PFTs that has been proved significant-
ly predictive for cyclophosphamide pulmonary toxicity is reduc-
tion of DLCO.
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 36. Pulmonary Toxicity of Chemotherapeutic Agents (Continued)
Classification Drug Incidence Characteristic Effects Comments
Alkylating Ifosfamide Interstitial pneumonitis with pulmonary fibrosis occurs Types of toxicity: Interstitial pneumonitis Methemoglobinemia occurs
agents (cont.) with variable incidence, with the highest incidence Dyspnea, tachypnea, and cough warrant investigation of possi- due to reactions between
of 6% in non-small cell lung cancer (Vahid & Marik, ble pulmonary toxicity (Baxter Healthcare Corp., 2009a). 4-thioifosfamide and glu-
2008). tathione to deplete antiox-
Acute dyspnea with hypoxemia may occur in some pa- idant reserves (Maldona-
tients due to transient methemoglobinemia (Maldo- do et al., 2013a; Vahid &
nado et al., 2013a; Vahid & Marik, 2008). Marik, 2008).
Melphalan Reports of bronchopulmonary dysplasia (GlaxoSmith- Types of toxicity: Bronchospasm, interstitial pneumonitis (Maldo- If a hypersensitivity reaction
Kline, 2003a) nado et al., 2013a) occurs, IV or PO melpha-
Acute hypersensitivity reactions including anaphylaxis Pulmonary fibrosis, interstitial pneumonia, bronchospasm, and lan should not be readmin-
were reported in 2.4% of 425 patients receiving the dyspnea can signal rare hypersensitivity, not pulmonary toxic- istered because hypersen-
injected drug for myeloma (GlaxoSmithKline, 2003a). ity. These patients responded to antihistamine and corticoste- sitivity reactions have been
roid therapy (GlaxoSmithKline, 2003a). reported with PO mel-
phalan (GlaxoSmithKline,
2003a).
Oxaliplatin Associated with pulmonary fibrosis (< 1% of study pa- Types of toxicity: Dyspnea of uncertain significance, broncho- In cases of unexplained re-
tients), which may be fatal (Lobera et al., 2008; Mal- spasm, hypersensitivity pneumonitis, interstitial pneumoni- spiratory symptoms such
donado et al., 2013a; Pasetto & Monfardini, 2006). tis, pulmonary fibrosis, diffuse alveolar hemorrhage, organiz- as nonproductive cough,
Peak incidence of interstitial lung disease is > 3–6 ing pneumonia (Chan et al., 2011; Fekrazad et al., 2010; Garri- dyspnea, crackles, or ra-
months after start of therapy, but not clearly cumula- do et al., 2007; Lobera et al., 2008; Shogbon et al., 2013; Wat- diologic pulmonary infil-
tive dose–related (Lim et al., 2010). kins et al., 2011) trates, oxaliplatin should be
Incidence of events increases with combined therapy Anaphylactic-like reactions, thought to be related to eosinophilic discontinued until further
(Chan et al., 2011). An acute syndrome of grade 3 infiltration of the lungs, are treatable with epinephrine, cortico- pulmonary investigation ex-
or 4 pharyngolaryngeal dysesthesia is seen in 1%– steroids, and antihistamines (Vahid & Marik, 2008). cludes ILD or pulmonary fi-
2% of patients previously untreated for advanced Corticosteroids are of uncertain benefit for interstitial pneumoni- brosis (sanofi-aventis U.S.
colorectal cancer. tis, pulmonary fibrosis, or organizing pneumonia (Chan et al., LLC, 2011b).
Chapter 9. Side Effects of Cancer Therapy
The combined incidence of cough, dyspnea, and hy- 2011; Shogbon et al., 2013).
poxia was 43% (any grade) and 7% (grades 3 and 4) Rare cases of diffuse alveolar hemorrhage have been fatal
in the oxaliplatin plus 5-FU/LV arm compared to 32% (Lobera et al., 2008; Watkins et al., 2011).
(any grade) and 5% (grades 3 and 4) in the irinotecan Previously treated patients experienced subjective sensations of
plus 5-FU/LV arm for patients with previously untreat- dysphagia or dyspnea, without laryngospasm or bronchospasm
ed colorectal cancer (sanofi-aventis U.S. LLC, 2011b). (no stridor or wheezing) (sanofi-aventis U.S. LLC, 2011b).
Temozolo- Dyspnea: 5%–8%; sinusitis: 6%; coughing: 5% (Merck Types of toxicity: Dyspnea of uncertain significance, broncho- Establish baseline pulmo-
mide Sharp & Dohme Corp., 2013b) spasm, interstitial pneumonitis, organizing pneumonia (Kim et nary function and reassess
Interstitial pneumonitis occurs in up to 4.8% of pa- al., 2012; Maldonado et al., 2007) with any respiratory symp-
tients receiving doses exceeding 150–200 mg/m2 Allergic reactions, including rare cases of anaphylaxis, when toms.
(Maldonado et al., 2007; Vahid & Marik, 2008). used with nitrosoureas and procarbazine (Maldonado et al.,
2007; Merck Sharp & Dohme Corp., 2013b)
Pneumonitis with high doses
Organizing pneumonia has been treated with methylpredniso-
lone 1 mg/kg/day with moderate success (Kim et al., 2012).
293
(Continued on next page)
294
Table 36. Pulmonary Toxicity of Chemotherapeutic Agents (Continued)
Classification Drug Incidence Characteristic Effects Comments
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Anticancer Aldesleukin Life-threatening grade 4 respiratory disorders: 3% Types of toxicity: Noncardiogenic pulmonary edema, dyspnea, Establish baseline pulmo-
cytokines (IL-2) (ARDS, respiratory failure, intubation); 1% (apnea) respiratory failure, tachypnea, pleural effusion, wheezing, ap- nary function, and assess
(Prometheus Laboratories Inc., 2012) nea, pneumothorax, hemoptysis (Kai-Feng et al., 2011; Pro- abnormalities that indicate
Adverse events occurred in 10% of patients (N = 525) metheus Laboratories Inc., 2012) ineligibility for high-dose
(Prometheus Laboratories Inc., 2012). Toxicities may worsen with continued exposure or occur more aldesleukin (Prometheus
Dyspnea: 43% quickly with each subsequent therapy cycle (Schwartzentru- Laboratories Inc., 2012).
Lung disorder: 24% (physical findings associated with ber, 2005). Consider fluid limitations
pulmonary congestion, rales, rhonchi) with respiratory symptoms
Respiratory disorder: 11% (ARDS, chest x-ray infil- if blood pressure tolerates
trates, unspecified pulmonary changes) (Letizia & Conway, 1996).
Increased cough: 11% (Prometheus Laboratories Inc., Consider holding or discon-
2012) tinuing dose with refracto-
ry symptoms (Prometheus
Laboratories Inc., 2012;
Siegel & Puri, 1991).
IFN alfa-2b Rare (Merck Sharp & Dohme Corp., 2013a) Types of toxicity: Fever, cough, dyspnea, nonspecific pulmo- Consider holding drug while
nary infiltrates, pneumonitis, pulmonary alveolar proteinosis, evaluating symptoms.
organizing pneumonia (Kai-Feng et al., 2011; Merck Sharp &
Dohme Corp., 2013a)
Oprelvekin Dyspnea: 48%; increased cough: 29%; pleural effu- Types of toxicity: Noncardiogenic pulmonary edema, pleural ef- Fluid retention is reversible
(IL-11) sions: 10% (Kai-Feng et al., 2011; Wyeth Pharma- fusions, dyspnea of uncertain significance within several days of dis-
ceuticals, 2011) Peripheral edema, dyspnea; preexisting fluid collections, includ- continuing oprelvekin (Va-
ing pleural and pericardial effusions or ascites, should be mon- hid & Marik, 2008).
itored. Fluid balance should be
Patients should be advised to immediately seek medical atten- monitored, and appropri-
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
tion if any of the following signs or symptoms develop: swell- ate medical management
ing of the face, tongue, or throat; difficulty breathing, swallow- is advised. Closely monitor
ing, or talking; shortness of breath; or wheezing (Wyeth Phar- fluid and electrolyte status
maceuticals, 2011). in patients receiving chron-
ic diuretic therapy (Kai-
Feng et al., 2011; Wyeth
Pharmaceuticals, 2011).
Antimetabo- Capecitabine Dyspnea: 14% (Genentech, Inc., 2011) Types of toxicity: Interstitial pneumonitis Once dose has been ad-
lites Not considered a major toxicity but has demonstrated Dyspnea, cough, respiratory distress; manage toxicities with justed, it should not be in-
these side effects: 0.1% cough; 0.1% epistaxis, he- symptomatic treatment, dose interruptions, and dose adjust- creased at a later time (Ge-
moptysis, respiratory distress; 0.2% asthma (Genen- ment. nentech, Inc., 2011).
tech, Inc., 2011)
Most reported cases have been in combination with
another pulmonary toxic agent such as oxaliplatin
(Chan et al., 2011; Lim et al., 2010).
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 36. Pulmonary Toxicity of Chemotherapeutic Agents (Continued)
Classification Drug Incidence Characteristic Effects Comments
Antimetabo- Cytarabine Noncardiogenic pulmonary edema in doses > 5 g/m2 Types of toxicity: Noncardiogenic pulmonary edema (previously High-resolution CT will show
lites (cont.) (6–12 hours after dose) (Mayne Pharma, 2011) known as cytarabine syndrome) (Luesink & Jansen, 2010) diffuse bilateral patchy in-
Incidence is approximately 14% of patients, with most A syndrome of sudden respiratory distress, rapidly progressing filtrates (Forghieri et al.,
(approximately 75%) reversible (Breccia et al., 2008, to pulmonary edema, capillary leak syndrome, respiratory fail- 2007).
2012) ure, and ARDS (Jeddi et al., 2008) May be reduced with fluid re-
Cytarabine liposomal: No pulmonary data (Sigma-Tau strictions.
Pharmaceuticals, Inc., 2011)
Fludarabine Cough: 10%*; 44%** Types of toxicity: Alveolitis, noncardiogenic pulmonary edema, Rechallenge after suspected
phosphate Pneumonia: 16%*; 22%** hypersensitivity pneumonitis, pulmonary fibrosis toxicity is contraindicated.
Dyspnea: 9%*; 22%** Pulmonary hypersensitivity reactions such as dyspnea, cough,
Allergic pneumonitis: 0%*; 6%** and interstitial pulmonary infiltrate have been observed.
*N = 101; **N = 32 (Berlex Laboratories, 2006) A clinical investigation using fludarabine phosphate injection in
Rare cases of progression to debilitating or fatal pul- combination with pentostatin for the treatment of refractory
monary fibrosis have occurred (Disel et al., 2010). chronic lymphocytic leukemia in adults showed an unaccept-
ably high incidence of fatal pulmonary toxicity. Therefore, this
combination is not recommended (Berlex Laboratories, 2006).
Corticosteroids are of uncertain benefit (Disel et al., 2010).
Gemcitabine Pulmonary toxicity is reported in 0.2%–13% of pa- Types of toxicity: Dyspnea of uncertain significance, broncho- Prolonged infusion time be-
hydrochloride tients (Shaib et al., 2008; Vahid & Marik, 2008). spasm, noncardiogenic pulmonary edema, ILD, pulmonary fi- yond 60 minutes and dos-
Dyspnea: 23% (severe dyspnea in 3%) (Eli Lilly & Co., brosis, alveolar hemorrhage, pleural effusion, pulmonary VOD, es more than once weekly
2013) radiation recall (Boeck et al., 2007; Kido et al., 2012; Shaib et increase toxicities (Vahid &
Bronchospasm incidence currently is reported as al., 2008; Vahid & Marik, 2008) Marik, 2008).
0.6% (Shaib et al., 2008). Dyspnea, cough, bronchospasm, and parenchymal lung toxicity Risk is increased when ad-
Parenchymal lung toxicity, including interstitial pneu- (rare) may occur. If such effects develop, gemcitabine should ministered with other pul-
monitis, pulmonary fibrosis, pulmonary edema, and be discontinued. Early use of supportive care measures may monary-toxic medications
Chapter 9. Side Effects of Cancer Therapy
ARDS, has been reported rarely (Eli Lilly & Co., help to ameliorate these conditions (Eli Lilly & Co., 2013). (Boeck et al., 2007; Vahid
2013). Respiratory failure and death occurred very rarely in some pa- & Marik, 2008).
Severe pulmonary toxicities likely to be related to tients despite discontinuation of therapy (Czarnecki & Voss, Bronchospasm can be treat-
bronchospastic events, capillary permeability- 2006). ed and resolved with cor-
induced pulmonary edema, or diffuse alveolar hem- Some patients experienced onset of pulmonary symptoms up to ticosteroids. Rechallenge
orrhage have been reported (Vahid & Marik, 2008). two weeks after the last dose (Eli Lilly & Co., 2013). may require premedication
These have led to death in approximately 0.3% of with corticosteroids (Vahid
cases (Binder et al., 2011; Boeck et al., 2007; Vahid & Marik, 2008).
& Marik, 2008).
Late pulmonary fibrosis has been reported in < 1% of
patients (Binder et al., 2011). Incidence increased to
2.7% when administered with other pulmonary tox-
ic agents (Binder et al., 2011; Boeck et al., 2007;
Grande et al., 2007; Maldonado et al., 2013a; Vahid
& Marik, 2008).
295
(Continued on next page)
296
Table 36. Pulmonary Toxicity of Chemotherapeutic Agents (Continued)
Classification Drug Incidence Characteristic Effects Comments
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Antimetabo- Gemcitabine Pulmonary hemorrhage has been associated with a
lites (cont.) hydrochloride 20% mortality rate (Vahid & Marik, 2008).
(cont.) Radiation recall after thoracic irradiation has been re-
ported rarely in patients with lung cancer (Ding et
al., 2011).
Methotrexate The incidence of allergic pneumonitis is 5%–10% Types of toxicity: Hypersensitivity pneumonitis, pulmonary fibro- Readministration with a de-
(Chikura et al., 2008). Toxicity is not dose related, sis, organizing pneumonia (Balk, 2012) sensitization protocol has
but patients who receive treatment more frequent- Fever, dyspnea, cough (especially dry nonproductive), nonspe- been successfully imple-
ly may be more susceptible to lung injury (Chikura et cific pneumonitis, or chronic interstitial obstructive pulmonary mented (Balk, 2012).
al., 2008; Kim et al., 2009). disease (deaths have been reported); pulmonary infiltrates
(Balk, 2012; Chikura et al., 2008; Kim et al., 2009; Teva Phar-
maceuticals USA, 2012b)
Neutrophil-predominant histology is more likely to progress to
pulmonary fibrosis (Kim et al., 2009).
Pemetrexed Postmarketing data show low incidence of ILD with Both ILD and pleural effusions have been reported (Breuer & Establish baseline pulmo-
variable severity. Nechushtan, 2012; Dickgreber et al., 2010). ILD presents ini- nary function and imaging
tially as dyspnea without pulmonary infiltrates (Hochstrasser et to have for comparison if
al., 2012). Pulmonary infiltrates are diffuse with ground-glass respiratory symptoms de-
opacities (Hochstrasser et al., 2012). Pleural effusions occur velop.
in 7%–12% of patients and are more common if premedica- Discontinue medication with
tion with corticosteroids is not performed (Breuer & Nechush- respiratory symptoms un-
tan, 2012). til etiology can be estab-
lished.
Corticosteroids have been
used with anecdotal evi-
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
dence of benefit.
Antitumor Bleomycin Average incidence: 10% of treated patients Types of toxicity: Hypersensitivity pneumonitis, pulmonary fi- Early toxicity may be self-re-
antibiotics sulfate (Bristol-Myers Squibb Co., 2012a) brosis, pulmonary VOD, organizing pneumonia, spontaneous solving. Monitor for early
Dose-related incidence (Gilligan, 2012): pneumothorax warning signs of toxicity to
• < 270 units: 0%–2% The characteristics of bleomycin-induced pneumonitis include avoid irreversible pulmo-
• > 360 units: 6%–18% dyspnea and fine rales. nary damage.
Nonspecific pneumonitis progresses to pulmonary fi- Bleomycin-induced pneumonitis produces patchy x-ray opacities Chest x-rays should be tak-
brosis and death in approximately 1% of patients usually of the lower lung fields that look the same as infectious en every one to two weeks.
(Keijzer & Kuenen, 2007; Specks, 2012). bronchopneumonia or even lung metastases in some patients If pulmonary changes are
More common in patients older than age 70 receiv- (Fyfe & McKay, 2010; Gilligan, 2012). noted, treatment should be
ing total dose > 400 units, concomitant pulmonary- DLCO may be abnormal before other symptoms appear (Fyfe & discontinued.
toxic agents, renal dysfunction, concomitant ra- McKay, 2010).
diation therapy, or oxygen therapy (Bristol-Myers
Squibb Co., 2012a; Fyfe & McKay, 2010; Usman et
al., 2010).
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 36. Pulmonary Toxicity of Chemotherapeutic Agents (Continued)
Classification Drug Incidence Characteristic Effects Comments
Antitumor Bleomycin Toxicity may be lower if drug is not given as IV bolus Exposure to increasing con-
antibiotics sulfate (cont.) (Bristol-Myers Squibb Co., 2012a; Specks, 2012). centrations of oxygen-in-
(cont.) creasing toxicity war-
rants prudently maintain-
ing oxygen levels at room
air (25%) (Bristol-Myers
Squibb Co., 2012a; Cher-
necky, 2009; van Gorselen
& Gerding, 2011).
Oral carnosine to abrogate
bleomycin pulmonary tox-
icity has anecdotal reports
of success (Cuzzocrea et
al., 2007).
Mitomycin Pulmonary toxicity has been reported with single- Types of toxicity: Bronchospasm, noncardiogenic pulmonary Signs and symptoms of
agent therapy and combination chemotherapy, 3%– edema, ILD, pulmonary VOD pneumonitis may be re-
36%, 6–12 months after therapy (Chan & King, Dyspnea, nonproductive cough, crackles, capillary leak, with versed if therapy is institut-
2012c). progressive respiratory dysfunction indicative of ILD (Charpi- ed early. Drug may be dis-
Prior treatment with mitomycin, cumulative doses > 30 dou et al., 2009) continued if dyspnea oc-
mg/m2, and other anticancer drugs may increase risk Severe bronchospasm has been reported following administra- curs even with normal
of toxicity (Bristol-Myers Squibb Co., 2012b; Chan & tion of vinca alkaloids in patients who previously or simultane- chest radiograph. Caution
King, 2012c). ously received mitomycin. Acute respiratory distress occurred should be exercised when
within minutes to hours after the vinca alkaloid injection. The using oxygen because ox-
total doses for each drug varied considerably (Bristol-Myers ygen toxic injury occurs
Squibb Co., 2012b). even the absence of oth-
Pulmonary VOD occurs later after exposure (up to 10 years) and er medication etiologic pre-
Chapter 9. Side Effects of Cancer Therapy
leads to symptoms of pulmonary hypertension (Chan & King, cipitators (Schwaiblmair et
2012c). al., 2012).
Pay careful attention to flu-
id balance, and avoid over-
hydration (Bristol-Myers
Squibb Co., 2012b).
Mitoxantrone Hypersensitivity-like acute pneumonitis occurs vari- Types of toxicity: Hypersensitivity pneumonitis, ILD, organizing Organizing pneumonia de-
ably when given in combination with other chemo- pneumonia (Chan & King, 2012a) tectable on bronchial bi-
therapeutic agents (Vahid & Marik, 2008). Sudden-onset dyspnea and tachypnea with hypoxemia opsy or open lung biop-
Patchy infiltrates on x-ray or CT scan sy usually is responsive to
Usually only occurs when given with other potentially pulmonary corticosteroid treatment
toxic medications (Vahid & Marik, 2008).
297
(Continued on next page)
298
Table 36. Pulmonary Toxicity of Chemotherapeutic Agents (Continued)
Classification Drug Incidence Characteristic Effects Comments
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Differentiating ATRA Incidence of acute differentiation syndrome in patients Types of toxicity: Retinoic acid differentiation syndrome Close monitoring of intake
agent receiving ATRA is 14%–25% with an associated Pulmonary infiltration of differentiating leukemic cells and their and output, weight, vital
mortality of approximately 2% (Patatanian & Thomp- associated chemokines cause inflammatory capillary permea- signs, and breath sounds
son, 2008; Weinberger & Larson, 2012). Severe and bility with sudden and severe hypoxemia (Luesink et al., 2009). may assist early detection.
moderate disease occur with equal frequency. Differentiation syndrome is present with ATRA or arsenic individ- Monitor oxygen saturation for
ually or in combination therapies (Breccia et al., 2008; Luesink early signs of hypoxemia
et al., 2009). on exertion.
Occurs in a bimodal pattern, with 46% developing symptoms in Monitor chest x-ray for pul-
the first week of therapy and an additional 36% having symp- monary infiltrates that may
toms between the third and fourth weeks (Weinberger & Lar- precede clinical symptoms.
son, 2012). Monitor labs for evidence of
Characteristic features of this syndrome include fever, myalgias, renal dysfunction.
arthralgias, weight gain, peripheral edema, respiratory distress
with pulmonary infiltrates, hypotension, hepatic and renal dys-
function, rash, and effusions (Weinberger & Larson, 2012).
Respiratory findings usually include an increased cardiothorac-
ic ratio, peribronchial cuffing, and ground-glass opacities. Con-
solidation and pleural effusions are common. Approximately
40% may have a clear radiograph, although this is uncommon
in severe disease (Montesinos et al., 2009).
Pulmonary hemorrhage has occurred in severe cases of differ-
entiation syndrome but may be difficult to differentiate from co-
agulopathies common in acute progranulocytic leukemia.
Miscellaneous Arsenic tri- Respiratory events (all grades, N = 40): Types of toxicity: Differentiation syndrome (Jeddi et al., 2008; Establish baseline pulmo-
oxide • Cough: 65% Weinberger & Larson, 2012) nary function.
• Dyspnea: 53% These adverse effects usually are not permanent or irrevers- Monitor WBC counts and
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
• Hypoxia: 23% ible and usually do not require interruption of therapy (Cepha- blast percentages.
• Pleural effusion: 20% lon, Inc., 2010).
• Wheezing: 13% Risk increases with high WBC count, high percentage blasts,
Grades 3 and 4: and preexisting lung disease (Luesink & Jansen, 2010).
• Dyspnea: 10%
• Hypoxia: 10%
• Pleural effusion: 3%
(Cephalon, Inc., 2010)
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 36. Pulmonary Toxicity of Chemotherapeutic Agents (Continued)
Classification Drug Incidence Characteristic Effects Comments
Miscellaneous Brentuximab – – Concomitant use with bleo-
(cont.) mycin is contraindicated
because of pulmonary tox-
icity. In a clinical trial that
studied brentoximab with
bleomycin as part of a
combination regimen, non-
infectious pulmonary tox-
icity was greater than with
ABVD (doxorubicin, bleo-
mycin, vinblastine, and da-
carbazine). Cough and
dyspnea were reported,
and imaging showed Inter-
stitial infiltration and inflam-
mation. Most patients re-
sponded to corticosteroids
(Seattle Genetics, Inc.,
2012).
Lenalidomide Dyspnea of uncertain significance in 15%–23%, but Types of toxicity: Dyspnea of uncertain significance, hypersensi- Immediately discontinue
only 4% severe (Barber & Ganti, 2011; Lerch et al., tivity pneumonitis, interstitial pneumonitis, organizing pneumo- medication if pulmonary
2010) nia (Lerch et al., 2010; Thornburg et al., 2007) toxicity is suspected (Cel-
Hypersensitivity reactions are rare (< 1%) but can be gene Corp., 2013a).
severe and progress to irreversible pulmonary fibro-
sis (Lerch et al., 2010).
Chapter 9. Side Effects of Cancer Therapy
Thalidomide Dyspnea of uncertain significance in 50%, but only 4% Types of toxicity: Dyspnea of uncertain significance, hypersen- Consider infectious etiolo-
severe (Barber & Ganti, 2011). sitivity pneumonitis, alveolar hemorrhage, pulmonary fibrosis, gy as higher risk for pulmo-
Other acute pulmonary toxicities are rare and have no organizing pneumonitis, pulmonary VOD with pulmonary hy- nary symptoms than drug
reported incidence rate (Celgene Corp., 2013b). pertension toxicity.
Sudden-onset ground-glass opacities have been noted with tha- Other bleeding symptoms
lidomide. Case reports reflect multiple different etiologies: in- may support suspicion for
fection, interstitial lung toxicity, organizing pneumonia, and al- alveolar hemorrhage in pa-
veolar hemorrhage. It is believed that antiangiogenic proper- tients with respiratory dis-
ties have been temporally associated with alveolar hemor- tress temporally related to
rhage in patients receiving thalidomide (Barber & Ganti, 2011; thalidomide administration
Charpidou et al., 2009; Khalsa et al., 2007; Schwaiblmair et (Khalsa et al., 2007).
al., 2012).
299
(Continued on next page)
300
Table 36. Pulmonary Toxicity of Chemotherapeutic Agents (Continued)
Classification Drug Incidence Characteristic Effects Comments
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Miscellaneous: Bevacizumab Hemoptysis is more common with squamous cell lung Types of toxicity: Hemoptysis, interstitial pneumonia, pleural ef- This medication is always
Antiangiogen- cancer (31%) than with nonsquamous cell lung can- fusion, organizing pneumonia (Barber & Ganti, 2011; Vahid & discontinued when pulmo-
esis agent cer (2%–3%) (Vahid & Marik, 2008). Marik, 2008). nary bleeding of any type
Interstitial pneumonitis and organizing pneumonia in- All toxicities are more common in patients with squamous cell is noted (Genentech, Inc.,
cidence is difficult to quantify because it usually is carcinoma of the lung (Vahid & Marik, 2008). Most common 2012a).
associated with thoracic radiation. clinical presentation is hemoptysis (Vahid & Marik, 2008).
Use of bevacizumab clearly increases risk of radiation pneumo-
nitis syndromes (Lind et al., 2012).
Mechanism of toxicity is unclear but thought to be related to
blocking of VEGF (Hollebecque et al., 2012).
Miscellaneous: Bortezomib Acute pneumonitis syndrome has been reported rare- Types of toxicity: Differentiation syndrome, hypersensitivity pneu- Immediate discontinuation
Proteasome ly in case reports of Japanese patients treated after monitis (Barber & Ganti, 2011) of this drug is recommend-
inhibitor HSCT and an African American patient without his- Sudden respiratory distress with accompanying pulmonary in- ed when pulmonary symp-
tory of transplantation (Ohri & Arena, 2006). filtrates toms occur (Millennium
Proposed pathophysiology is acute vasculitis (Pitini et al., 2007). Pharmaceuticals, 2012).
Inconsistent reversibility or responsiveness to corticosteroids
(Barber & Ganti, 2011)
Monoclonal Alemtuzum- Infusion rate–related dyspnea: 17% Types of toxicity: Dyspnea of uncertain significance, broncho- To ameliorate or avoid infu-
antibodies ab Acute infusion-related events were most common dur- spasm, interstitial pneumonitis sion-related events, pre-
ing the first week of therapy. Alemtuzumab has been associated with infusion-related events medicate patients with an
Incidence (N = 149): including hypotension, rigors, fever, shortness of breath, bron- oral antihistamine and ac-
• Dyspnea: 26% chospasm, chills, and/or rash. etaminophen prior to dos-
• Cough: 25% Side effects include asthma, bronchitis, chronic obstructive pul- ing and monitor closely for
• Bronchitis/pneumonitis: 21% monary disease, hemoptysis, hypoxia, pleural effusion, pleu- infusion-related adverse
• Pneumonia: 16% risy, pulmonary edema, pulmonary fibrosis, pulmonary infiltra- events.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
• Bronchospasm: 9% tion, respiratory depression, respiratory insufficiency, sinusitis,
(Genzyme Corp., 2009a) stridor, and throat tightness (Genzyme Corp., 2009a).
Cetuximab Bronchospasm with hypersensitivity reaction is gen- Types of toxicity: Bronchospasm, interstitial pneumonitis, orga- All dyspnea noted between
erally uncommon (2.5%), but frequent severe reac- nizing pneumonia (Barber & Ganti, 2011; Chua et al., 2009) cycles warrants evaluation
tions (20%) have a geographic propensity (south- ILD has been reported as serious and potentially fatal of PFTs.
east United States through southern Midwest states (Bristol-Myers Squibb Co. & ImClone Systems, 2012). Hold medication until ILD
such as Oklahoma, Arkansas, and Texas) (Chua et Onset of pneumonitis syndromes 2–6 months after start of drug is ruled out. If drug is re-
al., 2009) (Chua et al., 2009). May worsen after discontinuation of med- sumed, administer at
ILD < 1% is idiosyncratic in nature (Bristol-Myers ication. 50% of previous rate
Squibb Co. & ImClone Systems, 2012). Characterized by dyspnea, tachypnea, and activity intolerance. (Bristol-Myers Squibb Co.
Symptoms can progressively worsen even after initial discon- & ImClone Systems, 2012).
tinuation of medication.
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 36. Pulmonary Toxicity of Chemotherapeutic Agents (Continued)
Classification Drug Incidence Characteristic Effects Comments
Monoclonal Panitumumab Bronchospasm: Infusion reactions occur in 4% of pa- Types of toxicity: Bronchospasm, ILD Monitor for infusion reactions
antibodies tients, but severe reactions with bronchospasm oc- ILD is characterized by dyspnea, cough, and pulmonary infil- (Giusti et al., 2007).
(cont.) cur in 1%–2% (Amgen Inc., 2013b; Giusti et al., trates that occur 2–4 months into therapy and worsen even af- Evidence of interstitial pneu-
2007) ter drug discontinuation (Amgen Inc., 2013b; Cohenuram & monitis via PFTs and
ILD: < 1% (Amgen Inc., 2013b; Giusti et al., 2007) Saif, 2007). high-resolution CT scan
prompts permanent dis-
continuation of the drug
(Cohenuram & Saif, 2007).
Rituximab 38% (N = 135) experienced pulmonary events in clin- Types of toxicity: Bronchospasm, hypersensitivity pneumonitis, Interrupt treatment for severe
ical trials. Infusion-related deaths involving pulmo- ILD, alveolar hemorrhage, pulmonary alveolar proteinosis, or- reactions and resume at
nary function occurred in 0.04%–0.07%. ganizing pneumonia 50% reduced infusion rate
Bronchospasm: 8% (Biogen Idec, Inc., & Genentech, Most common adverse events were increased cough, rhinitis, when symptoms resolve.
Inc., 2013) bronchospasm, dyspnea, and sinusitis. The safety of resuming or
ILD incidence was approximately 2%, but up to 4.8% Infusion-related symptom complex includes pulmonary effects: continuing administration
with low lymphocyte counts (Zayen et al., 2011). hypoxia, bronchospasm, dyspnea, pulmonary infiltrates, and of rituximab in patients with
ARDS (Biogen Idec, Inc., & Genentech, Inc., 2013). ILD or organizing pneumo-
Increased pulmonary toxicities are seen in patients with low ab- nitis is unknown (Biogen
solute lymphocyte count (Huang, Liu, et al., 2011). Idec, Inc., & Genentech,
Pulmonary toxicities are more frequent in patients with cancer Inc., 2013).
than in patients with autoimmune disease (Hadjinicolaou et al.,
2011; Subramanian et al., 2010).
Hypersensitivity pneumonitis onsets within days to weeks of ex-
posure and shows eosinophilic infiltration on bronchoscopy
(Tonelli et al., 2009).
Alveolar hemorrhage can be acute in onset and fatal (Ikpeama
& Bailes, 2012).
Chapter 9. Side Effects of Cancer Therapy
Pulmonary alveolar proteinosis occurs more often in patients
with immature lymphocyte cell types and has not been report-
ed in patients with multiple myeloma treated with rituximab
(Borie et al., 2009).
There have been reports of organizing pneumonia presenting up
to 6 months post-infusion and a limited number of reports of
pneumonitis (including interstitial pneumonitis) presenting up
to 3 months post-infusion, some of which resulted in fatal out-
comes (Barber & Ganti, 2011; Borie et al., 2009; Urun et al.,
2012; Wagner et al., 2007).
Treatment with corticosteroids is standard for most toxicity but
is not clearly helpful. Most substantiated with alveolar hemor-
rhage and organizing pneumonia (Maldonado et al., 2013b).
301
(Continued on next page)
302
Table 36. Pulmonary Toxicity of Chemotherapeutic Agents (Continued)
Classification Drug Incidence Characteristic Effects Comments
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Trastuzumab As a single agent: Types of toxicity: Dyspnea of uncertain significance, broncho- Patients with symptomatic in-
• Increased cough: 26% spasm, interstitial pneumonitis, organizing pneumonia, in- trinsic lung disease or ex-
• Dyspnea: 22% creased cough, dyspnea, rhinitis, pharyngitis, pulmonary infil- tensive tumor involvement
In the postmarketing setting, severe hypersensitivity trates, pleural effusions, noncardiac edema, pulmonary insuffi- of the lungs, resulting in
reactions (including anaphylaxis), infusion reactions, ciency, hypoxia, and ARDS (Genentech, Inc., 2012b) dyspnea at rest, may be at
and pulmonary adverse events have been report- Other severe events reported rarely in the postmarketing set- greater risk for severe re-
ed. Severe pulmonary events leading to death have ting include pneumonitis and pulmonary fibrosis (Genentech, actions. Adverse effects in-
been reported rarely (Genentech, Inc., 2012b). Inc., 2012b). crease with combined drug
Interstitial pneumonitis occurred in 1%–2% and was Corticosteroids may be helpful (Vahid & Marik, 2008). therapy (Genentech, Inc.,
severe in only 0.3% (Barber & Ganti, 2011). 2012b).
Incidence of chronic organizing pneumonia was < 1% Rechallenge with this agent
(Vahid & Marik, 2008). is not recommended.
Nitrosoureas Carmustine Although rare, cases of fatal pulmonary toxicity have Types of toxicity: ILD, pulmonary VOD Perform baseline and regu-
been reported. Most of these patients were receiv- Pulmonary infiltrates and fibrosis have been reported to oc- lar PFTs, especially in pa-
ing prolonged therapy with total doses of carmus- cur from 9 days to 43 months after treatment and ap- tients with risk factors or
tine > 1,400 mg/m2. However, reports exist of pulmo- pear to be dose related. Fibrosis may be slowly progressive those who have received >
nary fibrosis in patients receiving lower total doses (Bristol-Myers Squibb Co., 2011a). 800 mg/m2 (Bristol-Myers
(Bristol-Myers Squibb Co., 2011a). When used in high doses (300–600 mg/m2) prior to HSCT, pul- Squibb Co., 2011a).
In a long-term study of carmustine, all participants ini- monary toxicity may occur and may be dose limiting. The pul- CT abnormalities with car-
tially treated before age 5 died of delayed pulmonary monary toxicity of high-dose carmustine may manifest as se- mustine occur in the upper
fibrosis (Bristol-Myers Squibb Co., 2011a). In anoth- vere interstitial pneumonitis, which occurs most frequently in zones of the lungs (Huang,
er report, 40% of those experiencing delayed toxicity patients who have had recent mediastinal irradiation. Hudson, et al., 2011).
after childhood treatment died of pulmonary fibrosis A linear relationship exists between total dose and pulmonary
(Huang, Hudson, et al., 2011). toxicity at doses > 1,000 mg/m2, with 50% of patients devel-
oping pulmonary toxicity at total cumulative doses of 1,500
mg/m2. Risk factors include preexisting lung disease, smok-
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
ing, cyclophosphamide therapy, and recent (within months)
thoracic irradiation. Patients with baseline forced vital capaci-
ty and/or DLCO < 70% of the predicted value are at high risk
(Bristol-Myers Squibb Co., 2011a).
Delayed toxicity after childhood treatment has increased mortal-
ity compared to toxicities from other causes (Huang, Hudson,
et al., 2011).
Other risks for increased pulmonary toxicity with carmustine in-
clude history of lung disease and treatment duration (Charpi-
dou et al., 2009).
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 36. Pulmonary Toxicity of Chemotherapeutic Agents (Continued)
Classification Drug Incidence Characteristic Effects Comments
Nitrosoureas Lomustine Rare; usually occurs with doses > 1,100 mg/ Types of toxicity: ILD, pulmonary fibrosis Establish baseline pulmo-
(cont.) m2 (one reported case at a dose of 600 mg/m2) Pulmonary toxicity onset is characterized by an interval of 6 nary function.
(Bristol-Myers Squibb Co., 2010a). There appeared months or longer from the start of therapy with cumulative dos- Monitor high-risk patients
to be some late reduction of pulmonary function in es of lomustine usually > 1,100 mg/m2 (Bristol-Myers Squibb with PFTs.
all long-term survivors. Co., 2010a).
This form of lung fibrosis may be slowly progres- Delayed-onset pulmonary fibrosis occurring up to 17 years af-
sive and has resulted in death in some cases ter treatment has been reported in patients who received ni-
(Bristol-Myers Squibb Co., 2010a). trosoureas in childhood and early adolescence (1–16 years)
Incidence is increased in childhood survivors treat- combined with cranial irradiation for intracranial tumors
ed before age 5 (Bristol-Myers Squibb Co., (Bristol-Myers Squibb Co., 2010a).
2010a).
Plant Docetaxel Non–dose-related interstitial pneumonitis with pulmo- Types of toxicity: Bronchospasm, hypersensitivity pneumonitis, Pleural effusions may be
alkaloids nary fibrosis occurs in approximately 3%–5% of cas- ILD, pleural effusion, noncardiogenic pulmonary edema (King reversible with diuretics
es, most often manifesting 4–8 weeks after exposure & Jett, 2013) (sanofi-aventis U.S. LLC,
(Leimgruber et al., 2006; sanofi-aventis U.S. LLC, Usual steroid dose to prevent pleural effusions is dexametha- 2013).
2013; Tamiya et al., 2012). sone 4–8 mg the day prior or same day as docetaxel adminis- Pulmonary fibrosis is not
Progression to pulmonary fibrosis occurs in < 1% of tration (King & Jett, 2013). consistently responsive
patients (Lee et al., 2009). Bronchoalveolar lavage in early lung toxicity showed lympho- to corticosteroids (sanofi-
Incidence of ILD is higher (up to 47%) when drug is cytosis in cases of reported hypersensitivity pneumonitis (Sy- aventis U.S. LLC, 2013).
given with gemcitabine (King & Jett, 2013). rigou et al., 2011).
Pleural effusion is more common after cumulative
dose of 400 mg/m2 if no steroid premedications
were given. Incidence is reduced from 20% to 6%
with steroid premedications (Binder et al., 2011).
Etoposide Cases of pulmonary events have been reported in- Types of toxicity: Bronchospasm, interstitial pneumonitis, pulmo- Higher rates of anaphylac-
Chapter 9. Side Effects of Cancer Therapy
frequently: pneumonitis/pulmonary fibrosis, pulmo- nary fibrosis, pulmonary hypertension tic-like reactions have been
nary hypertension in < 1% of patients (Bristol-Myers Anaphylactic-like reactions have occurred during the initial infu- reported in children who
Squibb Co., 2011b). sion of etoposide. Facial/tongue swelling, coughing, diapho- received infusions at con-
Anaphylactic-like reactions characterized by chills, fe- resis, cyanosis, tightness in throat, laryngospasm, back pain, centrations higher than
ver, tachycardia, bronchospasm, dyspnea, and/or and/or loss of consciousness have occurred with aforemen- those recommended. The
hypotension have occurred in 0.7%–4% of patients tioned reactions. An apparent hypersensitivity-associated ap- role of concentration of in-
receiving IV etoposide and in < 1% of patients treat- nea has been reported rarely. fusion (or rate of infusion)
ed with oral capsules (Bristol-Myers Squibb Co., Toxicity is increased with low serum albumin and impaired renal in the development of ana-
2011b; Post et al., 2007). function (Bristol-Myers Squibb Co., 2011b). phylactic-like reactions is
Incidence of ILD is as high as 24% when drug is given Increased methotrexate blood levels when given concomitantly, uncertain.
with methotrexate and cyclophosphamide. but unclear whether this is due to etoposide interaction or de- Treatment is symptomatic
creased clearance (Charpidou et al., 2009). (Bristol-Myers Squibb Co.,
2011b).
303
(Continued on next page)
304
Table 36. Pulmonary Toxicity of Chemotherapeutic Agents (Continued)
Classification Drug Incidence Characteristic Effects Comments
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Plant Etoposide PET scintigraphy may dem-
alkaloids (cont.) onstrate clear ventilation
(cont.) abnormalities with etopo-
side pulmonary toxicity
(Post et al., 2007).
Rechallenge with agent has
been done with premedi-
cations without repeat of
bronchospasm (Collier et
al., 2008).
Paclitaxel Rare for single agent: 2% dyspnea Types of toxicity: Bronchospasm, hypersensitivity pneumonitis, Toxicity is rarely severe or
Rare reports of interstitial pneumonia, lung fibrosis, pulmonary fibrosis, radiation recall (King & Jett, 2013) fatal and often responds
and pulmonary embolism (Bristol-Myers Squibb Co., Rare reports exist of radiation pneumonitis recall phenomenon to corticosteroids (King &
2011f): 8.5%–9% with combined therapy in patients receiving concurrent radiation (Bristol-Myers Squibb Jett, 2013).
Events usually occur with high doses or in combined Co., 2011f; Ding et al., 2011).
therapy (Bristol-Myers Squibb Co., 2011f). Incidence may be higher in weekly rather than every-three-week
dosing (King & Jett, 2013).
Incidence is higher when administered with gemcitabine or radi-
ation (King & Jett, 2013).
Bronchoalveolar lavage in early lung toxicity showed lympho-
cytosis in cases of reported hypersensitivity pneumonitis (Sy-
rigou et al., 2011).
Vinorelbine Shortness of breath was reported in 3% of patients re- Types of toxicity: Bronchospasm, ILD Patients with alterations in
tartrate ceiving vinorelbine and was severe in 2% (Goli et Acute shortness of breath and severe bronchospasm occurred, their baseline pulmonary
al., 2011). most commonly when vinorelbine was used in combination function or with new on-
Rare but severe cases of ILD, most of which were fa- with mitomycin; these adverse events may require treatment set of dyspnea, cough,
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
tal, occurred in patients treated with single-agent with supplemental oxygen, bronchodilators, or corticosteroids, hypoxia, or other symp-
vinorelbine (Mayne Pharma, 2002). particularly when there is preexisting pulmonary dysfunction. toms should be evaluat-
The mean time to onset of these symptoms after vinorelbine admin- ed promptly (Mayne Phar-
istration was 1 week (range = 3–8 days) (Mayne Pharma, 2002). ma, 2002).
Targeted Everolimus Up to 20% of patients experience a cough of unknown Types of toxicity: Cough, ILD, diffuse alveolar hemorrhage, orga- Acute onset of respiratory
therapies: clinical significance while receiving everolimus (No- nizing pneumonia distress warrants immedi-
mTOR vartis Pharmaceuticals Corp., 2012). ate discontinuation of med-
inhibitors The most common significant respiratory toxicity is ication with diagnostic test-
ILD, occurring in 14%–19% of patients, of which 4% ing.
were grade 3 and 0.2% were grade 4 (Dabydeen et
al., 2012; Novartis Pharmaceuticals Corp., 2012).
Pleural effusions occur in 7% of patients receiving
everolimus (Novartis Pharmaceuticals Corp., 2012).
Rare reports (< 0.2%) exist of alveolar hemorrhage
associated with everolimus therapy (Depuydt et al.,
2012; Mizuno et al., 2012; Vandewiele et al., 2010).
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 36. Pulmonary Toxicity of Chemotherapeutic Agents (Continued)
Classification Drug Incidence Characteristic Effects Comments
Targeted Temsirolimus Incidence is 1%–36% of patients treated for renal cell Cases of ILD, some resulting in death, have occurred. Some pa- Some patients with ILD re-
therapies: cancer (Duran et al., 2006; Mizuno et al., 2012; Va- tients with ILD were asymptomatic and others presented with quired discontinuation of
mTOR hid & Marik, 2008). symptoms (Dabydeen et al., 2012; Wyeth Pharmaceuticals, temsirolimus and treatment
inhibitors 2012). with corticosteroids or an-
(cont.) tibiotics.
Targeted Crizotinib ILD is rare, occurring in approximately 1.6% dur- Type of toxicity: ILD Coadministration of other
therapies: ing registration trials, but potentially life threatening ILD presents as dyspnea with pulmonary infiltrates. All cases pulmonary toxic agents or
Multitargeted (Pfizer Inc., 2013c). of ILD presented within the first two months of crizotinib ther- lung irradiation warrants
kinase apy (Pfizer Inc., 2013c). Reports of dyspnea warrant tempo- frequent physical assess-
inhibitor rary discontinuation of agent until ILD can be ruled out (Kwon ment and diagnostic tests
& Meagher, 2012). such as imaging or PFTs.
If treatment-related ILD is
strongly suspected, per-
manent discontinuation of
crizotinib is recommended.
Targeted Dasatinib Pleural effusion occurred in approximately 35% of pa- Types of toxicity: ILD, pleural effusion, pulmonary VOD (Barber & Most pleural effusions are re-
therapies: tients across multiple studies (Bristol-Myers Squibb Ganti, 2011; Montani et al., 2012) versible but may recur with
Tyrosine Co., 2011e; Quintás-Cardama et al., 2007). Most effusions are exudative and characterized by lymphocyt- future treatment (Barber &
kinase ILD and pulmonary VOD are rare but can be fatal (Min ic infiltration of the pleura (Bergeron et al., 2007; Bristol-Myers Ganti, 2011; Bergeron et
inhibitors et al., 2011; Montani et al., 2012). Squibb Co., 2011e). al., 2007).
Most patients who develop grades 3 and 4 pleural effusions Treatment may include in-
have accelerated- or blast-phase chronic myeloid leukemia terruption of medication
(Quintás-Cardama et al., 2007). and administration of di-
Pleural effusion is more prevalent in twice-daily dosing (Quintás- uretics or corticosteroids
Cardama et al., 2007). (Bergeron et al., 2007;
Chapter 9. Side Effects of Cancer Therapy
Symptoms include dyspnea, cough, and chest pain (Bergeron et Quintás-Cardama et al.,
al., 2007; Bristol-Myers Squibb Co., 2011e). 2007).
Erlotinib Incidence is rare (< 1%) except when the drug is giv- Types of toxicity: ILD, pulmonary fibrosis, organizing pneumonia Some patients have shown
en in combination with gemcitabine, where incidence Fatal ILD has been associated with oral erlotinib therapy for clinical improvement with
is approximately 2.5% (Astellas Pharma US, Inc., & lung cancer (Hotta et al., 2010; Liu et al., 2007; Vahid & Marik, corticosteroid treatment
Genentech, Inc., 2012; Vahid & Marik, 2008). 2008). Can occur days to months after exposure. (De Sanctis et al., 2011;
Vahid & Marik, 2008).
Strong suspicion of erlotinib-
induced lung injury war-
rants discontinuation of the
drug (Astellas Pharma US,
Inc., & Genentech, Inc.,
2012).
305
(Continued on next page)
306
Table 36. Pulmonary Toxicity of Chemotherapeutic Agents (Continued)
Classification Drug Incidence Characteristic Effects Comments
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Targeted Gefitinib Cases of ILD have been observed in patients at an Types of toxicity: ILD, diffuse alveolar hemorrhage, pulmonary fi- If acute onset or worsening
therapies: overall incidence of 1%–3%, the highest incidence of brosis, organizing pneumonia of pulmonary symptoms
Tyrosine all tyrosine kinase inhibitors (Hotta et al., 2010). Patients often present with acute-onset dyspnea, sometimes as- (dyspnea, cough, and fe-
kinase Approximately one-third of the ILD cases have been sociated with cough or low-grade fever and often becoming se- ver) occurs, therapy should
inhibitors fatal (Min et al., 2011). vere quickly and requiring hospitalization. be interrupted and symp-
(cont.) Reports indicate that ILD has occurred in patients Increased mortality has been observed in patients with concur- toms promptly investigat-
who have received prior radiation therapy (31%), pri- rent idiopathic pulmonary fibrosis whose condition worsens ed. If ILD is confirmed, dis-
or chemotherapy (57%), and no previous therapy while receiving gefitinib (AstraZeneca Pharmaceuticals, 2010). continue.
(12%) (AstraZeneca Pharmaceuticals, 2010). Alveolar hemorrhage presents within 24–42 days after adminis- Corticosteroids are of uncer-
Incidence of ILD with gefitinib is increased among tration (Barber & Ganti, 2011). tain benefit with ILD but are
smokers, older adults, and those with chronic lung routinely administered.
disease, poor performance status, or concurrent car-
diac disease (Barber & Ganti, 2011).
Imatinib Severe superficial edema and severe fluid retention Types of toxicity: Dyspnea of uncertain significance, hypersensi- These events usually were
mesylate (pleural effusion, pulmonary edema, and ascites) tivity pneumonitis, noncardiogenic pulmonary edema, ILD, pul- managed by interrupting
were reported in 1%–6% of patients taking imatinib monary alveolar proteinosis, pleural effusions imatinib mesylate treatment
for gastrointestinal stromal tumors (Vahid & Marik, Fluid retention events include pleural effusion, ascites, pulmo- and using diuretics or other
2008). nary edema, pericardial effusion, and anasarca. Differentiation appropriate supportive care
Dyspnea was reported in 14%–15% of patients. of these as complications of disease or therapy was difficult to measures. Symptoms often
Interstitial pneumonitis and pulmonary fibrosis are rare ascertain (Ishii et al., 2006). resurface when rechalleng-
(Novartis Pharmaceuticals Corp., 2013). Fluid extravasation and pleural effusions appear to be dose re- ing with this agent (Vahid &
lated, were more common in the blast crisis and accelerated- Marik, 2008).
phase studies (where the dose was 600 mg/day), and were The overall safety profile in
more common in older adults (Vahid & Marik, 2008). However, pediatric patients (39 chil-
a few of these events may be serious or life threatening, and dren studied) was simi-
one patient with blast crisis died with pleural effusion, conges- lar to that found in stud-
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
tive heart failure, and renal failure (Deininger et al., 2003; No- ies of adult patients treat-
vartis Pharmaceuticals Corp., 2013). ed with imatinib; however,
no peripheral edema has
been reported in children
(Novartis Pharmaceuticals
Corp., 2013).
Topoisomer- Topotecan The incidence of grade 3 or 4 dyspnea was 4% in pa- Dyspnea, coughing, and pneumonia are the main pulmonary Establish baseline pulmo-
ase inhibitor hydrochlo- tients with ovarian cancer and 12% in patients with side effects (GlaxoSmithKline, 2008a). nary function.
ride small cell lung cancer (GlaxoSmithKline, 2008a).
Pulmonary fibrosis may occur, but there is only one
documented pathologic confirmation of this compli-
cation (Maitland et al., 2006).
Dyspnea, all grades: 22% (GlaxoSmithKline, 2008a)
ARDS—adult respiratory distress syndrome; ATRA—all-trans-retinoic acid; CT—computed tomography; DLCO—diffusing capacity of the lung for carbon monoxide; FiO2—fraction of inspired oxygen; 5-FU/LV—5-fluoro-
uracil/leucovorin; HSCT—hematopoietic stem cell transplantation; IFN—interferon; IL—interleukin; ILD—interstitial lung disease; IV—intravenous; mTOR—mammalian target of rapamycin; PET—positron-emission to-
mography; PFT—pulmonary function test; PO—by mouth; VEGF—vascular endothelial growth factor; VOD—veno-occlusive disease; WBC—white blood cell
Chapter 9. Side Effects of Cancer Therapy 307
(5) Risk factors for direct injury
(a) Rare reports of interstitial pulmonary infiltrates and acute
alveolitis with hydroxyurea
(b) Metabolic injury
i. Metabolites of cyclophosphamide cause acute pneumo-
nitis that may be hemorrhagic in nature. The mortal-
ity rate associated with this syndrome is approximate-
ly 50% (Specks, 2012).
ii. Renal dysfunction may cause delayed drug excretion
and increase pulmonary toxicity of cyclophosphamide
and bleomycin (Specks, 2012).
(c) Disruption of intracellular kinases
i. Tyrosine kinase inhibitors (e.g., gefitinib, erlotinib)
(Endo, Johkoh, Kimura, & Yamamoto, 2006; Ieki,
Saitoh, & Shibuya, 2003; Vahid & Marik, 2008)
ii. EGFR inhibitors (e.g., cetuximab)
iii. mTOR inhibitors (e.g., temsirolimus) (Barber & Ganti,
2011; Dabydeen et al., 2012; Duran et al., 2006; Klaster-
sky, 2006; Novartis Oncology U.S., n.d.)
(d) Pulmonary edema
i. Biologic agents cause this toxicity (Antoniou, Ferdout-
sis, & Bouros, 2003; Schwartzentruber, 2005). IL-2 is
associated with a high incidence of capillary leak syn-
drome. Pulmonary edema is a dose-limiting toxicity
of high-dose IL-2 therapy (Prometheus Laboratories,
Inc., 2012). Severity depends on the route, dose, and
administration schedule (Schwartzentruber, 2005). It
resolves quickly after therapy ends and diuresis begins.
ii. Docetaxel is associated with fluid retention, alveolar
permeability, and pulmonary infiltrates. This may be
prevented with corticosteroid premedication and is
treated with diuretics (King & Jett, 2013).
iii. Cytosine arabinoside (Forghieri et al., 2007)
iv. Leuprolide acetate (Ferrari, Pezzuto, & Coppola, 2007)
v. Tyrosine kinase inhibitors (e.g., bortezomib, gefitinib,
dasatinib, imatinib mesylate) cause capillary permea-
bility, pulmonary edema, and effusions (Miyakoshi et
al., 2006; Vahid & Marik, 2008).
(e) Hypersensitivity pneumonitis
i. Paclitaxel can cause acute pneumonitis, which no lon-
ger appears to be a hypersensitivity reaction to poly-
oxyl 40 hydrogenated castor oil (Kolliphor® EL, for-
merly Cremophor® EL) emulsifier as originally pos-
tulated (King & Jett, 2013).
ii. Docetaxel: Hypersensitivity pneumonitis occurs in
7%–47% depending on total dose, chemotherapy
schedule, and concurrent administration with gem-
citabine or radiation (Grande, Villanueva, Huidobro,
& Casal, 2007).
iii. Acute methotrexate reaction is likely allergic in ori-
gin (Balk, 2012; Davis, Williams, & Walker, 2003; La-
teef, Shakoor, & Balk, 2005).
iv. Pathologically confirmed hypersensitivity pneumo-
nitis has occurred with bortezomib, imatinib, le-
nalidomide, oxaliplatin, procarbazine, and thalido-
mide, but no clear etiologic mechanisms have been
identified.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
308 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
d) Clinical manifestations: May be difficult to detect when clinical man-
ifestations are subtle
(1) Signs and symptoms
(a) Dyspnea
(b) Tachypnea
(c) Increased work of breathing
(d) Dry, nonproductive cough
(e) Fever occurs in some types of ILD
(f) Hypoxemia: Cyanosis, low oxygen saturation
(g) Anxiety, uneasiness
(h) Weight loss
(i) Fatigue
(2) Timing of signs and symptoms
(a) Hypersensitivity reactions may occur as early as hours af-
ter exposure.
(b) Hypersensitivity pneumonitis occurs 7–10 days after ex-
posure.
(c) Methotrexate hypersensitivity reactions occur 12–18 hours
after first dose (Balk, 2012).
(d) Delayed toxicity may occur 8 months to 10 years after therapy.
e) Assessment
(1) Past medical history
(a) Chemotherapy and biotherapy drug exposure
(b) Other medications known to cause pulmonary toxicity (e.g.,
amiodarone, nitrofurantoin, penicillamine, phenytoin, pro-
cainamide, propranolol, statins, sulfonamides) (Chernecky,
2009; Merrill, 2013; Vahid & Marik, 2008; Xu et al., 2012)
(c) Recent or chronic pulmonary conditions (Klastersky, 2006)
(d) Recent viral illness that predispose to hemorrhagic air-
way disease
(e) Autoimmune or connective tissue disease (Chernecky, 2009;
King, 2012; Varga, 2007)
(f) Occupational exposures such as silica, dusts, coal, and cotton
(Chernecky, 2009; Daba, El-Tahir, Al-Arifi, & Gubara, 2004)
(g) Environmental exposures such as asbestos, gases, and dusts
(Chernecky, 2009; Daba et al., 2004)
(2) Physical examination
(a) Vital signs—tachypnea, tachycardia
(b) Crackles on auscultation
(c) Cough and sputum production; hemoptysis
(d) Pleuritic pain may accompany some disorders (e.g., erlo-
tinib-induced reactions)
(e) Accessory muscle use for breathing
(f) Evidence of poor tissue oxygenation—cyanosis, oliguria,
decreased bowel sounds, altered mentation
(3) Diagnostic tests
(a) Arterial blood gases usually show hypoxemia with respira-
tory alkalosis.
(b) Changes suggesting pulmonary edema were observed in ra-
diographs of patients receiving high-dose IL-2 during ini-
tial registration trials, but the incidence of this toxicity
has been minimized with careful assessment and manage-
ment of hypotension and cardiac dysfunction (Berthiaume
et al., 1995; Prometheus Laboratories Inc., 2012; Siegel &
Puri, 1991).
(c) Chest x-ray showed ground-glass opacities/infiltrates and
interstitial or alveolar thickening of interlobular septum
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 309
(Endo et al., 2006; Stark, 2012). Nodular patterns indicat-
ed fibrosis (Stark, 2012).
(d) Chest CT is highly sensitive and able to differentiate pneu-
monitis from pulmonary embolism or fibrosis that may oc-
cur in patients with cancer experiencing respiratory distress
(Endo et al., 2006; Forghieri et al., 2007).
(e) A sensitive test of pulmonary function is the carbon monox-
ide diffusing capacity, which is reduced prior to symptoms
in many patients (Bahhady & Unterborn, 2003).
(f) Serum markers KL-6, SP-A, and SP-D have been used as
indicators of ILD for some agents (e.g., gefitinib) (Kitaji-
ma et al., 2006).
(g) PET scintigraphy has been helpful for early diagnosis of pul-
monary fibrosis related to etoposide (Post, Grutters, Verzi-
jlbergen, & Biesma, 2007).
(h) Open lung biopsy provides definitive diagnosis.
f) Collaborative management
(1) Pulmonary function testing is a prerequisite for the following
patients being evaluated for biotherapy, particularly for treat-
ment with IL-2 (Letizia & Conway, 1996; Prometheus Labora-
tories Inc., 2012).
(a) Heavy smokers (> 10 cigarettes/day) (Fernander, Schu
macher, Wei, Crooks, & Wedlund, 2008)
(b) Patients with extensive pulmonary disease
(c) Patients with symptoms suggesting decreased pulmonary re-
serve such as exercise intolerance, new cough, or tachypnea
(2) Avoid exceeding maximum recommended doses.
(a) Bleomycin: 400 units total lifetime dose (Bristol-Myers
Squibb Co., 2012a; Gilligan, 2012)
(b) Mitomycin C: 30 mg/m2 (Chan & King, 2012c)
(3) If pulmonary toxicity is suspected, hold chemotherapy and no-
tify prescriber.
(4) Administer oxygen cautiously and only if patient is hypoxemic
(Chernecky, 2009).
(a) Some lung-toxic medications have produced increased tox-
icity (diffuse alveolar damage) with oxygen therapy (e.g.,
bleomycin).
(b) Oxygen can cause absorption atelectasis and loss of surfac-
tant that may exacerbate toxicity risk.
(5) Establish fluid balance goals.
(a) Carefully record intake and output.
(b) Determine if fluid boluses or fluid restrictions are warranted.
(c) Consider using goal “dry” weight to target diuretic thera-
py. Weigh patient on a regular basis.
(d) Diuretics decrease parenchymal edema, drawing fluid from
interstitial spaces. This is not always effective when capil-
lary permeability is impaired and cell and vessel boundar-
ies have been compromised.
(6) Supportive care
(a) Oxygen therapy: When using bleomycin, be alert for ox-
ygen-induced lung damage (Fyfe & McKay, 2010; Gilli-
gan, 2012).
(b) Bronchodilators: Metered dose inhaler provides better de-
livery than nebulizer.
(c) Position for best breathing: Head of bed elevated, tripod
position (arms elevated and extended with knees separat-
ed while leaning forward), legs over side of bed
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
310 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
(7) Treatment of possible etiologies of ILD
(a) Administer corticosteroids as ordered. Corticosteroids usu-
ally are contraindicated for patients receiving biotherapy.
(b) Initiate antimicrobial therapy when infection superimposed
upon other lung toxicity is suspected.
(c) Oral carnosine has been reported as suggestive of reduced
incidence or severity of bleomycin toxicity based upon an
animal study (Cuzzocrea et al., 2007).
(8) Follow-up evaluation of patients at risk
(a) Monitor x-rays and CT scans routinely with disorders that
can produce hypersensitivity, idiopathic, or non–dose-
related toxicities.
i. For targeted therapies (erlotinib, cetuximab, ritux-
imab) recommend at least monthly (Gemma, 2009).
ii. Frequency is based on risk for ILD and may increase
with cumulative dose or added risk factors.
iii. A chest x-ray may be recommended every one to two
weeks to monitor for bleomycin toxicity (Bristol-Myers
Squibb Co., 2012a).
(b) Periodic monitoring of pulmonary function tests for pa-
tients at risk for ILD (baseline and every three months dur-
ing active therapy; often performed years after HSCT) (Al-
Ashkar, Mehra, & Mazzone, 2003; Chernecky, 2009; McCor-
mack, 2013). Most ILD produces restrictive disease. The ra-
tio of forced expiratory volume in one second to forced vi-
tal capacity is most sensitive to detect restrictive disease. Ra-
tios greater than the lower limit of normal indicate restrictive
lung disease. Low forced vital capacity with normal forced ex-
piratory volume in one second and total lung capacity below
the lower limit of normal suggests restrictive lung disease.
(c) Low diffusing capacity of the lung for carbon monoxide
(DLCO) corrected for Hgb and lung volume indicates pa-
renchymal restrictive disease. DLCO may differentiate pa-
renchymal restrictive disease associated with chemother-
apy agents from other physical causes (e.g., obesity, pleu-
ral effusions). It is used more frequently to detect pulmo-
nary fibrosis.
(d) In patients with acute-onset symptomatic disorders such
as alveolar hemorrhage or acute hypersensitivity reac-
tion, screening is not performed given the usual acute
presentation.
(e) Late or delayed onset of lung toxicity may occur and be re-
lated to treatment and host factors, but plans for follow-up
care are not clearly defined (Tashiro et al., 2008).
g) Patient and family education (Camp-Sorrell, 2011)
(1) Provide education regarding symptoms associated with pulmo-
nary toxicity (e.g., cough, dyspnea, chest pain, shallow breath-
ing, chest wall discomfort). Make sure all patients know to seek
medical assistance immediately if symptoms occur.
(2) Inform patients that treatment may be delayed or held until
pulmonary symptoms resolve.
(3) Explore with patients their wishes regarding intubation and re-
suscitation status; establish advance directives.
(4) Teach patients that raising the head of the bed may facilitate
breathing.
(5) Instruct patients to conserve energy by performing daily activ-
ities when their energy level is highest.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 311
(6) Teach patients and significant others methods to decrease symp-
toms of dyspnea (e.g., exercising to tolerance, practicing pursed-
lip breathing, refraining from smoking, using a small fan).
(7) Teach patients to take an opioid (e.g., morphine) as prescribed
by their physician to relieve discomfort caused by air hunger.
(8) Review the safety issues (e.g., flammability) related to oxygen
administration.
5. Alveolar hemorrhage
a) Pathophysiology
(1) Unlike tumor invasion of the upper airways, alveolar hemor-
rhage as a toxicity of antineoplastic therapy occurs in the mi-
crovasculature of small airways. Three types exist (Ikpeama &
Bailes, 2012).
(a) Bland pulmonary hemorrhage occurs due to hydrostatic pres-
sure changes and is most common with coagulopathies, an-
ticoagulant therapy, heart failure, or renal failure.
(b) Diffuse alveolar hemorrhage occurs as a result of direct
lung injury causing alveolar edema and development of
hyaline membranes. Toxic metabolites from cyclophos-
phamide and gemcitabine produce lung toxicity by this
mechanism.
(c) Pulmonary/capillary vasculitis is an autoimmune process re-
sulting in the fibrinous destruction of alveolar basement
membranes. It is caused by agents that trigger immunolog-
ic mechanisms (e.g., rituximab).
(2) Vascular endothelial wall destruction by chemotherapy or chemo-
radiotherapy causes microcapillary bleeding.
(3) Repeated episodes of alveolar hemorrhage may lead to pulmo-
nary fibrosis.
b) Incidence: Alveolar hemorrhage incidence rates are 1.9% in pa-
tients receiving nonmyeloablative transplant regimens (Wanko,
Broadwater, Foltz, & Chao, 2006), as high as 10.3% in those un-
dergoing myeloablative HSCT (Majhail, Parks, DeFor, & Weisdorf,
2006; Wanko et al., 2006), and < 5% in pediatric transplant recip-
ients (Heggen et al., 2002). More current data are limited given
the heterogeneity of transplant preparative regimens and rejection
protection practices.
c) Risk factors
(1) Alveolar hemorrhage is most well-documented in the setting
of HSCT, although some acute pneumonitis syndromes may
be hemorrhagic in nature (Alexandrescu et al., 2004; Carron
et al., 2001; Lin et al., 2005).
(2) Alveolar hemorrhage has been rarely associated with normal
doses of bevacizumab, cyclophosphamide, etoposide, everolim-
us, gefitinib, gemcitabine, oxaliplatin, and sirolimus (Depuydt
et al., 2012; Lara & Schwarz, 2010; Patel et al., 2010; Vahid &
Marik, 2008; Vandewiele, Vandecasteele, Vanwalleghem, & De
Vriese, 2010).
(3) Concomitant pulmonary infection may be present with adeno-
virus, cytomegalovirus, dengue fever, Epstein-Barr virus, and
Strongyloides (parasite) (Lara & Schwarz, 2010).
(4) Non-oncologic drugs can cause alveolar hemorrhage (e.g., ami-
odarone, crack cocaine, nitrofurantoin, propylthiouracil, valpro-
ate) (Ikpeama & Bailes, 2012; Lara & Schwarz, 2010).
(5) Unlike other bleeding syndromes, pulmonary hemorrhage is
not always related to platelet counts or coagulation values.
d) Clinical manifestations (Ikpeama & Bailes, 2012; Lara & Schwarz, 2010)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
312 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
(1) Onset of bleeding is often sudden, over a single day. It usual-
ly begins within the first two weeks after the preparative regi-
men of HSCT.
(2) Symptoms include dyspnea, fever, cough, chest discomfort, and
profound hypoxemia.
(3) Hemoptysis occurs in up to one-third of patients. Pink, frothy
sputum and blood in bronchoalveolar specimens may be found
(Lara & Schwarz, 2010).
(4) Hypoxemia-related symptoms include agitation, confusion, air
hunger, cyanosis, tachycardia, and bradycardia.
e) Assessment
(1) Breath sounds (early crackles and diminished breath sounds as
the airways become filled with bloody exudate)
(2) Oxygen saturation (decreased)
(3) Sputum (increase in quantity and change in quality)
(4) Hgb, platelet count, and coagulation parameters: Hgb may not
fall until bleeding is life threatening.
(5) Nonspecific findings of inflammation: Increased erythrocyte
sedimentation rate, leukocytosis (if not marrow suppressed)
(6) Pulmonary function tests (increased DLCO with hypoxemia) if
patient is able to participate
(7) Chest x-ray or CT scan: Bilateral patchy, irregular interstitial
infiltrates
(8) Bronchoalveolar lavage: Bloody returns, higher yield than in-
stilled, and positive hemosiderin-laden macrophages in the spu-
tum (Lara & Schwarz, 2010; Vahid & Marik, 2008).
f) Collaborative management
(1) Corticosteroids are standard treatment, although they have not
been proved effective in treatment of medication-induced al-
veolar hemorrhage (Grigoriyan, Rishi, Molina, Homer, & Man-
thous, 2007; Lara & Schwarz, 2010).
(a) Methylprednisolone at doses of 500–2,000 mg IV daily for
approximately five days
(b) No standard tapering regimen is recommended. Close ob-
servation for rebleeding during steroid tapering is recom-
mended to guide practice.
(2) Coagulation factors can be administered, although no one ther-
apy has been proved effective (Grigoriyan et al., 2007). Unprov-
en coagulation therapies include IV aminocaproic acid and co-
agulation factor VII (Heslet, Nielson, & Nepper-Christensen,
2012; Lara & Schwarz, 2010).
(3) Consider noninvasive or invasive mechanical ventilation with
positive pressure to produce intra-alveolar pressure and re-
duce bleeding.
(4) Experimental therapies are based upon suspected etiologic
factor and include plasma exchange and IV immunoglobulin
(Lara & Schwarz, 2010).
(5) Ensure adequate airway clearance with bronchodilator thera-
py, adequate hydration, and deep endotracheal suctioning as
needed. Retained blood can cause secondary infection and
worsened hypoxemia.
(6) Provide supportive management of dyspnea.
6. APL differentiation syndrome/retinoic acid syndrome
a) Pathophysiology
(1) Occurs with APL (M3 leukemia), previously known as retinoic
acid syndrome because of its association with administration of
ATRA, but the name was changed as it was realized that the syn-
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 313
drome occurs with any effective initial treatment for APL (Au
& Kwong, 2008; Fenaux, Wang, & Degos, 2007).
(2) Caused by rapid proliferation and differentiation of WBCs.
This results in immunologic stimulation by vasoactive cytokines,
thus creating inflammatory capillary permeability of the lungs
and a widespread erythematous rash (Ahmed et al., 2007; Bi &
Jiang, 2006; Weinberger & Larson, 2012).
(3) It is more a condition of tumor responsiveness to therapy than
a toxicity.
b) Incidence
(1) It occurs in approximately 25% of patients with APL receiving
induction therapy (Weinberger & Larson, 2012). It also has oc-
curred in other settings of retinoid administration, emphasiz-
ing the need for monitoring when administering any retinoid
or differentiating agent (DiNardo et al., 2008).
(2) It has been reported to occur in 10%–15% of patients receiv-
ing combination retinoid and chemotherapy and is more prev-
alent in patients with high WBC counts (Fenaux et al., 2007;
Luesink et al., 2009).
c) Risk factors (Au & Kwong, 2008; Breccia et al., 2012; Fenaux et al.,
2007; Jeddi et al., 2008; Luesink et al., 2009; Montesinos et al., 2009;
Montesinos & Sanz, 2011; Weinberger & Larson, 2012)
(1) Increased body mass index; only validated risk factor that predicts
for presence of syndrome (Breccia et al., 2012; Jeddi et al., 2008)
(2) Induction therapy with active disease; does not occur during
consolidation therapy when there is no active leukemia
(3) High WBC count may or may not be associated with increased
risk, but it is clear that rapid rise of WBC count, or large per-
centage of immature cells, is related to the presence of retino-
ic acid syndrome (Weinberger & Larson, 2012).
(4) Acute leukemia, M3 subtype, expression of CD13 on APL blast
cells
(5) ATRA treatment
(6) Arsenic trioxide
(7) Bortezomib
d) Clinical manifestations (Montesinos et al., 2009; Montesinos & Sanz,
2011; Weinberger & Larson, 2012)
(1) Fever, dyspnea, cough, hypotension, crackles, hypoxemia, mus-
culoskeletal pain (e.g., arthralgias, myalgias), effusions, edema,
weight gain > 5 kg from baseline
(2) Rash can be diffuse, erythematous, and nonpruritic and is more
common in severe cases (Weinberger & Larson, 2012).
(3) Renal dysfunction may occur but is often slower in onset than
other symptoms, so may be noted after recognition of the syn-
drome.
(4) About one-half of patients have symptoms within one week, and
the rest develop symptoms between the third and fourth week
of induction therapy (Montesinos et al., 2009).
(5) NCI toxicity scale labels weight gain < 3 kg without respiratory
distress as grade 1, weight gain with mild-moderate respiratory
symptoms grade 2, severe symptoms requiring hospitalization
as grade 3, symptoms requiring ventilatory support as grade 4,
and death as grade 5 (NCI CTEP, 2010).
e) Assessment
(1) Breath sounds and oxygen saturation
(2) Intake and output, weight; monitor for overhydration, which
may worsen respiratory symptoms.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
314 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
(3) Laboratory
(a) WBC count with differential daily; assessment of blast per-
centage
(b) Periodic assessment of Hgb, Hct, and platelet count, as ane-
mia and thrombocytopenia are common
(c) Periodic evaluation of coagulation parameters and plate-
let count; DIC may be present.
(d) Renal function tests to monitor for impairment; it is un-
clear if dysfunction is related to hypotension or thrombo-
sis (Weinberger & Larson, 2012).
(4) Chest x-ray or CT: Nodular or ground-glass opacities with patchy
bilateral distribution, consolidation, air bronchograms, promi-
nent septal lines, and possible pleural effusions, although up to
40% of patients will have no initial x-ray findings of peribron-
chial cuffing and increased cardiothoracic ratio (Luesink &
Jansen, 2010; Montesinos, 2009; Weinberger & Larson, 2012).
f) Collaborative management
(1) Prevention
(a) Immediate administration of chemotherapy when WBC
count rises
(b) Platelet goal 50,000/mcl
(c) Fluid management (strict intake and output)
(2) Although the clinical benefit is still unclear, immediate treat-
ment with corticosteroids (Tallman & Altman, 2009) and con-
ventional chemotherapy are still believed by some to improve
outcomes.
(a) Dexamethasone, which usually inhibits inflammatory che-
mokines, does not appear to be effective in reduction of this
syndrome’s clinical manifestations (Luesink et al., 2009).
(b) If treatment with steroids is selected, the usual treatment is
dexamethasone 10 mg IV twice daily for at least three days
(Patatanian & Thompson, 2008).
(c) Even with steroid treatment, the syndrome carries an ap-
proximate 10% mortality rate (Ahmed et al., 2007; Fenaux
et al., 2007).
(3) Noninvasive or invasive mechanical ventilation with positive
pressure
(4) Removal of pleural or pericardial effusions
7. Pleural effusions: Defined as accumulation of excess fluid in the pleu-
ral space that impairs lung expansion. Four to six liters of pleural fluid
usually pass daily through the potential space between the visceral and
parietal pleura (Light, 2011).
a) Pathophysiology: Excess fluid is retained in the pleural space, which
restricts full alveolar expansion (Light, 2011; Muzumdar, 2012).
(1) Major causes of pleural effusion are obstruction to fluid out-
flow and pleural irritation leading to exudative capillary per-
meability into the space (Muzumdar, 2012).
(2) Transudative effusions are produced by passive capillary per-
meability and characteristic of fluid overload, heart failure, or
hypothyroidism.
b) Incidence of drug-related pleural effusions (Alagha, Tummino, So-
falvi, & Chanez, 2011; Light, 2011)
(1) Incidence varies and is dependent upon agent, dose, schedule,
and comorbid conditions.
(2) Pleural effusions can be detected radiographically in 42%–52%
of patients receiving IL-2. In general, no intervention is required,
and effusions resolve after IL-2 is discontinued (Shelton, 2009b).
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 315
(3) Incidence can be as high as 54% with some agents (Kim, Goh, Kim,
Cho, & Kim, 2011; Quintás-Cardama et al., 2007; Valent, 2011).
c) Risk factors
(1) Pleural effusions are a common complication of cancer and oth-
er medical disorders, such as cirrhosis, gout, heart failure, in-
fections, pneumonia, pulmonary embolism, renal failure, rheu-
matoid conditions, or hypothyroidism, and medications such as
valproate and clozapine (Findik, 2012; Light, 2011).
(2) When associated with chemotherapy and biologic therapies,
pleural effusions are the result of capillary permeability that
is temporally related to administration of the offending agent.
Chemotherapy and biotherapy agents that have been associat-
ed with development of pleural effusions include (Alagha et al.,
2011; Krenke & Light, 2011)
(a) Bortezomib (Oudart et al., 2012; Pitini, Arrigio, Altavilla,
& Naro, 2007)
(b) Cytosine arabinoside
(c) Cyclophosphamide (high-dose)
(d) Dasatinib (Bergeron et al., 2007; Ishii, Shoji, Kimura, & Ohya-
shiki, 2006; Kim et al., 2011; Quintás-Cardama et al., 2007)
i. Onset 1–55 days, average 35 days
ii. Increased incidence with twice-daily dosing and high-
er daily dose (> 100 mg/day)
(e) Docetaxel (Toh et al., 2007)
(f) Erlotinib (Toh et al., 2007)
(g) Imatinib (2%–6%) (Bergeron et al., 2007; Ishii et al., 2006;
Kantarjian et al., 2012)
(h) Oprelvekin (Kai-Feng, Hong-Ming, Hai-Zhou, Li-Rong, &
Xi-Yan, 2011; Wyeth Pharmaceuticals, 2011)
d) Clinical manifestations and assessment (Alagha et al., 2011; Light,
2011; Muzumdar, 2012)
(1) Patients present with tachypnea, dyspnea, increased work of
breathing, abnormal chest excursion, and fatigue.
(2) Large pleural effusions are easily documented by an upright
chest x-ray.
(3) Smaller effusions are seen on chest CT.
(4) Tyrosine kinase inhibitor–induced pleural effusions are char-
acterized by exudative features and lymphocytic infiltration of
the pleura.
e) Collaborative management (Kaifi et al., 2012)
(1) In most cases, pleural effusions are uncomplicated and sponta-
neously resolve upon discontinuing the causative agent (Alagha
et al., 2011; Light, 2011; Quintás-Cardama et al., 2007).
(2) Dose reduction has been successful at eliminating pleural ef-
fusion related to dasatinib (Bergeron et al., 2007; Galinsky &
Buchanan, 2009).
(3) Concomitant corticosteroids have been effective at reducing
the severity of pleural effusions related to docetaxel.
(4) Other treatment strategies have included albumin supple-
mentation, fluid restrictions, diuretics, and corticosteroids,
but these interventions do not have a body of evidence to sup-
port use (Alagha et al., 2011; Bergeron et al., 2007; Quintás-
Cardama et al., 2007).
(5) Medical or surgical pleurodesis is rarely required to treat drug-
induced pleural effusion.
(a) On rare occasions, thoracentesis has been performed as a
temporary measure or to rule out other causes of the effusion.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
316 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
(b) Tunneled or temporary pleural catheters have been used
with persistent drug-related pleural effusion (Chalhoub,
Harris, Castellano, Maroun, & Bourjeily, 2011).
8. Pulmonary alveolar proteinosis/pulmonary alveolar phospholipopro-
teinosis
a) Pathophysiology
(1) Distal airway disorder characterized by accumulation of lipo-
proteinaceous exudate with surfactant components and cell
fragments that stain positive for periodic acid-Schiff protein
(Chan & King, 2012a).
(2) The thick proteinaceous exudate causes bronchiolar occlusion,
poor respiratory compliance, and hypoxemia (Pedroso et al., 2007).
(3) Primary pathologic mechanism is likely related to GM-CSF de-
ficiency (Doerschuk, 2007; Uchida et al., 2009). In adults, it is
thought to be due to anti–GM-CSF antibodies (Bonella et al.,
2011; Carey & Trapnell, 2010).
b) Incidence: Rare
c) Risk factors (Inaba et al., 2008; Miyoshi, Daibata, Takemoto, Machi-
da, & Taguchi, 2005; Pamuk et al., 2003; Shoji et al., 2002)
(1) After HSCT (Ansari et al., 2012; Borie et al., 2011)
(2) Autoimmune disease or concomitant autoimmune pathologic
process (e.g., autoimmune hemolytic anemia, immune throm-
bocytopenia) is associated with > 90% of cases (Edwards, Prim-
hak, & Cohen, 2010; Inoue et al., 2008).
(3) Hematologic malignancies
(4) Myelodysplastic syndromes
(5) Profound neutropenia at the onset of the disorder
(6) Unclear whether disorder is caused by antineoplastic agents,
such as alkylating agents (Inaba et al., 2008) or imatinib, or
the underlying disease
(7) Infection with Acinetobacter, Pneumocystis, Nocardia, or Mycobac-
terium (Chan & King, 2012a; Edwards et al., 2010; Shattuck &
Bean, 2013)
d) Clinical manifestations
(1) Dyspnea, tachypnea, cough, and increased work of breathing
(2) Occurs over a few days with progressive worsening
(3) CT scan shows widespread air-space consolidation with “crazy-
paving” patterns, appearing like octagonal pavement stones
pieced together, with even bilateral distribution centrally lo-
cated and sparing the apices and costophrenic angle (Bonella
et al., 2011; Chan & King, 2012b; Guan et al., 2011; Shattuck
& Bean, 2013).
(4) 75% are diagnosed by bronchoscopy (Ishii et al., 2009).
(a) Lung biopsy specimens are positive for periodic acid-schiff
stain.
(b) Lavage specimens are cloudy, with alveolar macrophages
and eosinophils.
(c) A recent study showed the presence of myelin-like lamel-
lar bodies (Yi et al., 2012).
(5) Other markers include increased lactate dehydrogenase, car-
cinoembryonic antigen, and CA 19-9 (Chan & King, 2012a).
(6) The syndrome usually corrects itself when patients go into re-
mission or recover normal WBC counts.
(7) It may be fatal in patients with persistent disease or those who
fail to recover counts (Inaba et al., 2008).
e) Collaborative management (Inaba et al., 2008; Kim, Kim, & Kim,
2004; Pamuk et al., 2003)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 317
(1) Whole lung lavage: An operative procedure where single lung
ventilation is performed during warmed saline flushing of the
other lung; may require multiple procedures (Cai, Ye, Xu, &
Li, 2012; Luisetti et al., 2010)
(2) Antibiotics to treat causative organisms or prevent secondary
infections (Khan & Agarwal, 2011)
(3) Chest percussion
(4) Investigational use of GM-CSF subcutaneously or by inhalation
over 8–12 weeks (Khan & Agarwal, 2011; Khan, Agarwal, & Ag-
garwal, 2012; Satoh et al., 2012)
(5) Rituximab (Kavuru et al., 2011; Malur et al., 2012)
(6) Corticosteroids have been used to treat this disorder and have
a strong scientific basis validated by the inflammatory nature
of this disorder. Despite their extensive use, some authors be-
lieve them to be ineffective in altering the disease course (Chan
& King, 2012b).
(7) Hydration, sputum expectoration, and bronchodilators
9. Pulmonary VOD
a) Pathophysiology
(1) Endothelial wall damage is the proposed mechanism of injury
(Bunte, Patnaik, Pritzker, & Burns, 2008).
(2) Postcapillary pulmonary venular obstruction occurs with fibrous
tissue that becomes dense and sclerotic (Bunte et al., 2008).
(a) Calcium deposits in elastic fibers of venule walls
(b) Engorgement of alveolar capillaries
(c) Dilated lymphatics with interstitial edema
(d) Venous fibrosis
(3) The clinical result of this process is pulmonary hypertension
with right heart failure.
(4) Pulmonary VOD presents 40–60 days after HSCT as hypox-
emia, volume-dependent hypotension, atrial arrhythmias,
right bundle branch block, or hepatic congestion (Bunte
et al., 2008).
b) Incidence
(1) Infrequent manifestation of endothelial injury in < 2% of HSCT
recipients
(2) Likely underestimated because symptoms mimic other adverse
effects
(3) Possibly accounts for 5%–10% all cases of idiopathic pulmo-
nary hypertension (Montani, Price, et al., 2009; Palazzini &
Manes, 2008)
c) Risk factors (Bishop, Mauro, & Khouri, 2012; Bunte et al., 2008; Man-
del & Clardy, 2012; McKoy et al., 2007)
(1) HSCT: Especially matched unrelated transplant recipients and
those with GVHD
(2) High-dose alkylating agents: Busulfan, carmustine, other alkyl-
ating agents used for the preparative regimen for HSCT
(3) Other agents: Dasatinib, mitomycin
(4) Prior lung injury; familial pulmonary hypertension
(5) Viral illnesses (e.g., cytomegalovirus, Epstein-Barr virus)
(6) Thrombotic disorders
d) Clinical manifestations and assessment
(1) Subtle and vague symptoms: Dyspnea, fatigue
(2) Heart failure symptoms (Mandel & Clardy, 2012; Montani,
Kemp, et al., 2009)
(a) Right heart failure early: Elevated jugular venous pressure,
hepatomegaly, edema
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
318 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
(b) Left heart failure later: Crackles, heart murmurs and gal-
lops, subxiphoid retraction, oliguria
(3) Definitive diagnosis requires a right heart catheterization, but
risk of bleeding is high. Elevated right heart pressures on echo-
cardiogram may be suggestive of this disorder.
(4) CT demonstrates patchy, ground-glass, or nodular infiltrates
with perihilar distribution and engorgement of major central
pulmonary veins that are unique to pulmonary VOD, differen-
tiating pulmonary hypertension from other causes (Bunte et
al., 2008; Huertas et al., 2011).
(5) Bronchoscopic exam shows hyperemia of lobar and segmen-
tal bronchi with vascular engorgement (Huertas et al., 2011).
e) Collaborative management
(1) Correct etiologic factors (e.g., viral infections, DIC, offending
medications).
(2) Avoid calcium channel blockers and prostacyclins (usual treatments
for pulmonary hypertension), which can cause pulmonary ede-
ma in pulmonary VOD (Bishop et al., 2012; Huertas et al., 2011).
(3) Nitric oxide, prostanoids, endothelin-1 receptor antagonists,
and phosphodiesterase inhibitors have been used with limit-
ed success (Bishop et al., 2012; Huertas et al., 2011; Montani,
O’Callaghan, et al., 2009).
(4) If there is an autoimmune component (e.g., GVHD), cortico-
steroids may be beneficial (Bunte et al., 2008).
(5) Anticoagulant, antiplatelet, and fibrinolytic agents used with
hepatic VOD have not been proved effective and may increase
bleeding risk (Mandel & Clardy, 2012).
(6) Most documented cases have been fatal (Bunte et al., 2008).
(7) Differential diagnosis between pulmonary VOD and other eti-
ologies of pulmonary hypertension is essential to ensure appro-
priate treatment with minimization of adverse effects.
G. Hemorrhagic cystitis (HC) is the inflammation of the mucosal surface of the
bladder and/or ureters with the presence of sustained hematuria and low-
er urinary tract symptoms in the absence of other conditions such as infec-
tion and vaginal bleeding (Decker, Karam, & Wilcox, 2009).
1. Pathophysiology
a) Damage to the bladder wall can occur from toxins, drugs, disease, ra-
diation, and infection (Basler & Stanley, 2012).
(1) Chemotherapy-induced cystitis can arise from agents that are
directly instilled into the bladder or from toxic metabolites that
come in contact with the bladder.
(2) Radiation cystitis can occur when the bladder is within the ra-
diation port.
(3) Infectious cystitis can occur from bacterial, fungal, or parasit-
ic urinary infections.
(4) Gross hematuria can occur rarely from arteriovenous malforma-
tions, stones, primary bladder cancer, adjacent cancers (pros-
tate, uterus, cervix, or rectum), or metastatic disease that af-
fects the bladder.
b) Acrolein is a liver metabolite of cyclophosphamide and ifosfamide.
Eliminated through the urine, acrolein binds to the bladder mucosa,
resulting in ulceration, inflammation, necrosis, and hemorrhage. Al-
though the entire urinary tract can be affected, the bladder is more
likely to be affected because of prolonged contact (Basler & Stanley,
2012; Gerson, Bulgar, Weeks, & Chabner, 2011; Hassan, 2011; Lima,
Ferreira, Macedo, de Castro Brito, & Ribeiro, 2007).
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 319
2. Incidence
a) HC is reported more frequently following ifosfamide than cyclophos-
phamide. The incidence of HC after ifosfamide ranges from 18%–
40% (Lima et al., 2007).
b) When cyclophosphamide was used to treat non-Hodgkin lympho-
ma (NHL), the cumulative five-year incidence of HC was 12% (Le
Guenno, Mahr, Pagnoux, Dhote, & Guillevin, 2011).
c) HC occurs in about 2%–40% of patients treated with high-dose cyclo-
phosphamide (Levine & Ritchie, 1989; Marshall et al., 2012).
d) In the pediatric population following allogeneic stem cell transplan-
tation, the incidence of HC ranges from 10%–70% (Decker et al.,
2009; Hassan, 2011).
e) Severe cases are rare, but HC can be fatal up to 6% of cases (Mar-
shall et al., 2012).
3. Risk factors
a) HC can develop following treatment with oxazaphosphorines (cyclo-
phosphamide and ifosfamide). Cases have been reported with busul-
fan, cabazitaxel, high-dose therapy, and biologics such as gefitinib and
bevacizumab (Arakawa et al., 2010; Hassan, 2011).
b) Most patients who develop cyclophosphamide-induced HC have re-
ceived doses of approximately 150–200 g. HC is rarely seen after low-
dose cyclophosphamide (Marshall et al., 2012; Fairchild, Spence, Sol-
oman, & Gangai, 1979; Forni, Koss, & Geller, 1964).
c) HC is unlikely to occur with cumulative doses of oral cyclophospha-
mide lower than 100 g. Typical cumulative doses that can cause chronic
cystitis are 18–206 g over 10 months to 9 years (Hu et al., 2008; Mar-
shall et al., 2012).
d) Risk factors in the HSCT setting include male gender, age, allogene-
ic or myeloablative transplant, unrelated donor, presence of GVHD,
infection, and use of steroids (Hassan, 2011; Nadir & Brenner, 2007).
4. Clinical manifestations of HC
a) Usually occurs 24–48 hours after a single dose of high-dose cyclophos-
phamide and typically lasts four to five days (Marshall et al., 2012; Spi-
ers, 1963). Can occur at any time after repeated doses of ifosfamide
or lower-dose cyclophosphamide.
b) Symptoms may include dysuria, frequency, urgency, and lower ab-
dominal or suprapubic pain. In men, bladder spasms can produce se-
vere referred pain in the glans penis (Basler & Stanley, 2012; Camp-
Sorrell, 2011).
c) Clinical symptoms vary from asymptomatic microscopic hematuria
to frank hematuria with clot formation and urinary tract obstruc-
tion and may lead to acute renal failure (Basler & Stanley, 2012;
Hassan, 2011).
d) Rare adverse effects include bladder wall necrosis, bladder fibrosis
with loss of compliance, contracture or shrinkage of the bladder res-
ervoir volume, and vesicoureteral reflux (Basler & Stanley, 2012). Po-
tential exists for lifelong fibrosis, contracture of the bladder, and blad-
der cancer (Decker et al., 2009; Gerson et al., 2011).
e) Can deteriorate QOL and cause prolonged hospitalization (Hassan,
2011)
5. Assessment
a) Monitor for red-tinged urine or screen for hematuria with urine dip-
stick. Diagnosis is based on detection of microscopic or macroscop-
ic hematuria with or without symptoms of discomfort in the urinary
tract (Hassan, 2011).
b) Obtain history of past and present medications, as chemotherapy
agents can produce cystitis years after exposure.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
320 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
c) Laboratory analysis (Basler & Stanley, 2012; Decker et al., 2009; Has-
san, 2011)
(1) Obtain a baseline urinalysis and monitor as needed.
(2) Urine culture to screen for bacterial and viral infection. In grade
3 or 4 HC, it may be beneficial to follow the BK polyomavirus
titer because there is evidence linking BK virus and HC (Deck-
er et al., 2009; Hassan, 2011).
(3) CBC: Hgb is rarely below normal except in patients with chron-
ic HC. WBC count may be elevated with concurrent infections
or due to treatment of the underlying malignancy.
(4) Obtain basic metabolic panel to evaluate blood urea nitrogen
(BUN)/creatinine for renal failure.
(5) Assess coagulation parameters (prothrombin time [PT] and
partial thromboplastin time [PTT]).
d) Ultrasound of kidneys and bladder to characterize clotting within the
bladder and evaluate upper tract dilation
e) Cystoscopy to confirm diagnosis or for clot evacuation
f) Grading system (Decker et al., 2009; Droller, Saral, & Santos, 1982)
(1) Grade 0: No symptoms of bladder irritability or hemorrhage
(2) Grade I: Microscopic hematuria
(3) Grade II: Macroscopic hematuria
(4) Grade III: Macroscopic hematuria with small clots
(5) Grade IV: Gross hematuria with clots causing urinary tract ob-
struction requiring instrumentation for clot evacuation
6. Prevention strategies
a) Protective measures (Basler & Stanley, 2012; Camp-Sorrell, 2011;
Decker et al., 2009)
(1) Encourage increased fluid intake. Provide vigorous hydration
and diuresis as needed.
(2) Administer cyclophosphamide early in the day when feasible
to allow patients to drink fluids and void frequently without in-
terruption of sleep.
(3) Encourage patients to empty bladder frequently, including be-
fore sleeping at night.
(4) Monitor intake and output. Instruct patients and caregivers in
this process.
(5) Perform continuous bladder irrigation.
b) Mesna (2-mercaptoethane sulfonate) is the most effective agent for
preventing oxazaphosphorine-induced cystitis. By binding to acro-
lein, mesna neutralizes acrolein acid and serves as a uroprotectant
(Basler & Stanley, 2012; Decker et al., 2009; Gerson et al., 2011; Has-
san, 2011; Hensley et al., 2009). It usually is given in divided doses ev-
ery four hours (Gerson et al., 2011).
(1) Ifosfamide dose < 2.5 g/m2/day administered as a short infu-
sion: Mesna should be administered as three bolus doses giv-
en 15 minutes before and 4 and 8 hours after each dose of
ifosfamide.
(2) Ifosfamide dose over 2.5 g/m2/day: Insufficient evidence exists
on which to base a recommendation for use of mesna. ASCO
guidelines (Hensley et al., 2008) indicate that the efficacy of
mesna for urothelial protection with very-high-dose ifosfamide
has not been established.
(3) Ifosfamide as continuous infusion: Mesna may be administered
as a bolus dose equal to 20% of the total ifosfamide dose fol-
lowed by a continuous infusion of mesna equal to 40% of the
ifosfamide dose. Continue for 12–24 hours after completion of
ifosfamide infusion.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 321
(4) Mesna tablets: Administer IV mesna at a dose equal to 20% of the
ifosfamide dose at the time of ifosfamide administration. Then,
the oral dose of mesna is administered at 40% of the ifosfamide
dose at two and six hours after each dose of ifosfamide with the
total daily dose of mesna equaling 100% of the ifosfamide dose.
If the patient vomits within two hours after taking the oral mes-
na, repeat the dose or give the mesna IV. This same dosing sched-
ule should be followed each day the patient receives ifosfamide.
(5) Mesna with cyclophosphamide: In patients receiving high-dose
cyclophosphamide in the setting of HSCT, mesna plus saline
diuresis or forced saline diuresis is recommended to decrease
the incidence of urothelial toxicity.
7. Collaborative management
a) Management depends on etiology and severity of symptoms. No sin-
gle standardized, evidence-based approach to managing HC has
been adopted, and multiple therapeutic modalities often are neces-
sary (Decker et al., 2009).
b) Hematuria will subside in most patients if chemotherapy agents are
discontinued.
c) Microscopic hematuria with few or no clinical symptoms usually re-
solves spontaneously and does not require treatment other than hy-
dration (Hassan, 2011).
d) Early grade (grade 1–3): Interventions include intensive IV hydration,
forced diuresis, analgesia, and spasmolytic drugs (Decker et al., 2009).
e) Bladder irrigation: Continuous bladder irrigation through a three-
way Foley catheter is often the mainstay of management of HC in or-
der to prevent clot retention and renal insufficiency/failure (Deck-
er et al., 2009; Hassan, 2011).
f) Cystoscopy with clot evacuation is necessary when clot formation or
clot organization results in hydronephrosis and/or urinary bladder
tamponade (Decker et al., 2009; Hassan, 2011).
g) Intravesicular instillation of chemicals such as formalin, aluminum
potassium sulfate, prostaglandin, aminocaproic acid, or cidofovir may
be performed (Basler & Stanley, 2012; Decker et al., 2009; Hassan,
2011; Nadir & Brenner, 2007).
h) Administration of IV or oral aminocaproic acid can decrease clot-
ting (Hu et al., 2008).
i) Potential treatments include hyperbaric oxygen (Basler & Stanley,
2012; Nadir & Brenner, 2007), embolization or ligation of internal
iliac arteries, and endoscopic laser coagulation (Hu et al., 2008).
8. Patient education (Camp-Sorrell, 2011)
a) Teach patients and caregivers about the potential for HC following
administration of potential offending agents.
b) Instruct patients to drink plenty of fluids following treatment and to
void frequently.
c) Ensure that patients know how to identify and report urinary symptoms.
H. Hepatotoxicity
1. Pathophysiology (Aloia & Fahy, 2010; Camp-Sorrell, 2011; Floyd & Kerr,
2013; Medlin & Perry, 2008)
a) Hepatotoxicity can occur through the following mechanisms.
(1) Idiosyncratic hypersensitivity immune reactions
(2) Hepatocellular injury, necrosis; hepatocytes are at increased
risk if steatosis is present; some chemotherapy causes steatosis.
(3) Ductal injury with cholestasis
(4) Hepatic vascular lesions leading to thrombosis and occasion-
ally VOD
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
322 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
(5) Reactivation of dormant viruses such as hepatitis
b) Pediatric considerations (Chordas & Graham, 2010)
(1) Liver toxicity is commonly reported among children with the
use of antimetabolites.
(2) Hepatotoxicity from chemotherapy among pediatric pa-
tients is variable, and incidence and severity are increased
by concomitant supportive care medications such as anti-in-
flammatory agents, antimicrobials, and anticonvulsants. Fre-
quent monitoring of liver function tests (LFTs) is necessary
with the consideration of decreasing doses or discontinuing
drugs. Total parenteral nutrition should be avoided to de-
crease the potential for additional liver damage.
2. Incidence: See Table 37.
3. Risk factors
a) Child-Pugh class B or C score (Floyd & Kerr, 2013): Child-Pugh is a
grading system for cirrhosis that considers total bilirubin, albumin,
INR, ascites, and encephalopathy. Scores range from A–C, with a high-
er score indicating more hepatic dysfunction. It may be used for dose
modifications for chemotherapy, although it was originally designed
for predicting surgical mortality (Verbeeck, 2008).
b) Prior liver infection, damage, or disorder (e.g., cirrhosis, hepatitis,
Budd-Chiari syndrome)
c) Hepatotoxic chemotherapy drugs (risk increases with higher dosing)
d) Liposomal chemotherapy does not necessarily decrease hepatotoxic-
ity in children (Sieswerda, Kremer, Caron, & van Dalen, 2011).
e) Family history of hereditary liver diseases (e.g., alpha-1 antitrypsin
deficiency, hemochromatosis, Wilson disease)
f) Prior tumor involvement of the liver
g) Past medical history of transplantation (e.g., liver, kidney, bone mar-
row, peripheral blood stem cell): Cholestasis is present in 80% of pa-
tients with chronic GVHD; chronic hepatitis is seen in the majority
of HSCT survivors who experienced acute hepatitis.
h) Comorbidities such as HIV, diabetes mellitus, underlying liver dis-
ease, and obesity (Verma & Kaplowitz, 2009)
i) Prior radiation therapy to the liver or right side of abdomen
j) History of alcohol and illicit drug abuse, especially if liver is cirrhotic
k) Concurrent administration of noncytotoxic hepatotoxic drugs or
herbal products
l) Intrahepatic chemotherapy administration
m) Advancing age
n) Genetic factors, which may be different for each drug, leading to vari-
able reactions (de Beaumais et al., 2011; Verma & Kaplowitz, 2009)
4. Clinical manifestations (Roesser, in press)
a) Varying degrees of jaundice, from mild seen in the sclera to severe
seen in the tissue
b) Hyperpigmentation of the skin
c) Ascites and edema
d) Fatigue, malaise, and other flu-like symptoms
e) Anorexia and weight loss
f) Mild to severe nausea with varying degrees of emesis
g) Diarrhea, weight loss, dehydration, cachectic appearance
h) Right upper quadrant pain
i) Hepatosplenomegaly
j) Dark-orange urine, clay-colored stools
k) Pruritus
l) Elevated transaminases (aspartate aminotransferase, alanine amino-
transferase), prolonged PTT
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 37. Hepatotoxicity of Antineoplastic Agents
Route of
Classification Drug Administration Side Effects Nursing Considerations
Alkylating Busulfan PO, IV Increased ALT, hyperbilirubinemia, VOD (SCT: 11%– Monitor baseline LFTs, bilirubin, and alkaline phosphatase, and
agents 42%) (GlaxoSmithKline, 2008b; Otsuka America Phar- then every other day after BMT.
maceutical, Inc., 2011) Monitor for signs of VOD using Jones criteria: RUQ pain, weight
Hepatic VOD: High busulfan AUC values (> 1,500 mcM·min) gain, and increased bilirubin. If VOD is diagnosed, monitor LFTs
and baseline LFT elevations are associated with in- daily (Jones et al., 1987).
creased risk of hepatic VOD during conditioning for al-
logeneic BMT (Krivoy et al., 2008). Incidence of hepat-
ic VOD reported in the literature from randomized con-
trolled trials was 7.7%–12% (Otsuka America Pharma-
ceutical, Inc., 2011).
Dacarbazine IV Rare hepatic necrosis associated with venous thrombosis Monitor LFTs as clinically indicated.
has been reported (Teva Pharmaceuticals USA, 2007).
Increased LFTs
Procarbazine PO Hepatic dysfunction (Sigma-Tau Pharmaceuticals, Inc., Monitor LFTs prior to each cycle (Fesler et al., 2010).
2008)
Anthracycline Daunorubicin IV LFT elevations (Teva Pharmaceuticals USA, 2012a) Doses need to be modified for elevated LFTs.
antibiotics Monitor LFTs.
Doxorubicin IV, intravesicular, Increased bilirubin levels, hepatitis Hepatic impairment [U.S. Boxed Warning]: Use with caution in pa-
intraperitoneal tients with hepatic impairment; dosage adjustment is recom-
mended. Use with caution in patients with hepatobiliary dysfunc-
tion (Pfizer Inc., 2011a).
Drug is extensively metabolized in liver; reduce dose for T. bili >
1.2–3 mg/dl (Pfizer Inc., 2011a). Contraindicated in marked liver
Chapter 9. Side Effects of Cancer Therapy
function impairment.
Doxorubicin liposo- IV LFT elevations Monitor LFTs. Dose reduce for hepatic dysfunction (50% if T. bili
mal injection 1.2–3 mg/dl; 75% if T. bili > 3 mg/dl) (Janssen Products, LP,
2013).
Epirubicin IV – Dose reductions are recommended in patients with mild-to-mod-
erate hepatic impairment. Do not use in patients with severe he-
patic dysfunction (Pfizer Inc., 2013b). Monitor LFTs.
Mitoxantrone IV Transient elevation of liver enzymes, jaundice Consider dose adjustments in patients with severe hepatic dys-
function (T. bili > 3.4 mg/dl) (EMD Serono, Inc., 2012). Monitor
LFTs.
323
(Continued on next page)
324
Table 37. Hepatotoxicity of Antineoplastic Agents (Continued)
Route of
Classification Drug Administration Side Effects Nursing Considerations
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Antibiotic Dactinomycin IV Ascites, hepatic failure, hepatitis, hepatomegaly, LFT ab- Avoid dactinomycin use within 2 months of radiation treatment for
normality (Recordati Rare Diseases Inc., 2013) right-sided Wilms tumor, as it may increase the risk of hepato-
May cause hepatic VOD (increased risk in children < 4 toxicity (Recordati Rare Diseases Inc., 2013).
years of age); use with caution in patients with hepa-
tobiliary dysfunction (Recordati Rare Diseases Inc.,
2013).
Antimetabolites Eribulin mesylate IV Reversible elevations of ALT (Eisai Inc., 2013) Institute dose modifications and a lower starting dose for patients
with Child-Pugh A and Child-Pugh B hepatic impairment. Pa-
tients with Child-Pugh C hepatic impairment were not studied
(Eisai Inc., 2013).
Monitor LFTs at baseline and during treatment.
Among patients with grade 0 or 1 ALT levels at baseline, 18%
had grade 2 or greater elevations in ALT with eribulin mesylate,
which resolved and did not recur with re-exposure to the drug
(Eisai Inc., 2013).
6-Mercaptopurine PO Intrahepatic centrilobular necrosis can occur. Hyperbili- Clinically detectable jaundice usually occurs within 2 months
rubinemia, increased alkaline phosphatase and AST, of therapy, but may occur within 1 week or be delayed up to 8
jaundice, ascites, and encephalopathy; hepatotoxicity is years (Gate Pharmaceuticals, 2011). The majority of children
more common at doses > 2.5 mg/kg/day (Gate Pharma- who have developed portal hypertension continue to have it 10
ceuticals, 2011). years later (Rawat et al., 2011).
Antimetabolite: Methotrexate IM, IV, SC, intra- U.S. boxed warning: Methotrexate has been associated Monitor closely (with LFTs, including serum albumin) for liver tox-
Antifolates thecal with acute (elevated transaminases) and potentially fa- icities.
tal chronic (fibrosis, cirrhosis) hepatotoxicity. Risk is re- Use caution when drug is used with proton pump inhibitor therapy
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
lated to cumulative dose and prolonged exposure (Teva and other hepatotoxic agents (e.g., azathioprine, retinoids, sul-
Pharmaceuticals USA, 2012b). fasalazine).
Ethanol abuse, obesity, advanced age, and diabetes may Liver toxicity usually is transient and higher in patients treated on
increase the risk of hepatotoxic reactions (Teva Phar- a daily schedule (Camp-Sorrell, 2011).
maceuticals USA, 2012b).
Use caution in patients with preexisting liver impairment;
may require dosage reduction.
Pralatrexate IV 13% had elevated LFTs after treatment (Allos Therapeu- Monitor LFTs at baseline and prior to the start of the first and
tics, Inc., 2012). fourth dose of each cycle. Dose reductions are recommended
for elevated LFTs (Allos Therapeutics, Inc., 2012).
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 37. Hepatotoxicity of Antineoplastic Agents (Continued)
Route of
Classification Drug Administration Side Effects Nursing Considerations
Antimetabolite: Cytarabine IV, SC Transient elevations of liver enzymes, jaundice Dose adjustment may be needed in patients with liver failure be-
Purine High-dose cytarabine can cause intrahepatic cholestasis cause cytarabine is partially detoxified in the liver (Bedford Lab-
antagonist (Camp-Sorrell, 2011). oratories, 2008).
There is no FDA-approved hepatic dosing adjustment guideline; the
following guideline has been used by some clinicians (dose level
not specified): If bilirubin > 2 mg/dl, administer 50% of dose and
elevate subsequent doses with lack of toxicity (Koren et al., 1992).
Hepatic changes with cytarabine are usually reversible.
Antimetabolite: Capecitabine PO Increased bilirubin (22%–48%; grades 3–4: 11%–23%); Use with caution in patients with hepatic impairment.
Pyrimidine hepatic failure, hepatic fibrosis, hepatitis: < 1% (Genen- Institute dose modifications if T. bili > 1.5 × ULN (Genentech, Inc.,
antagonists tech, Inc., 2011) 2011).
Clofarabine IV Severe and fatal hepatotoxicity has occurred with clofar- Monitor LFTs at baseline and during treatment 2–3 times a week.
abine. Most often are transient in the first 15 days. Rare Educate patients to avoid other hepatotoxic drugs during the
cases of VOD have been reported (Genzyme Corp., five-day course (Dressel et al., 2011). Has not been studied in
2013; Hijiya et al., 2011). patients with baseline hepatic dysfunction. VOD has been re-
ported in patients who had a previous blood and marrow trans-
plant (Genzyme Corp., 2013).
Floxuridine Intra-arterial, IV Hepatocellular injury with increased aminotransferases, Use with caution in patients with hepatic impairment (Bedford
alkaline phosphatase, and serum bilirubin (hepatitis pat- Laboratories, 2000).
tern); stricture of the intrahepatic or extrahepatic bile
ducts (sclerosing cholangitis) accompanied by elevated
alkaline phosphatase and serum bilirubin (Bedford Lab-
oratories, 2000; Chang et al., 1987; Hohn et al., 1989)
Chapter 9. Side Effects of Cancer Therapy
Gemcitabine IV When used as a single agent: Increased transaminases Serious hepatotoxicity has been reported. Use caution in patients
(67%–68%; grades 3–4: 8%–10%), increased alkaline with hepatic impairment (history of cirrhosis, hepatitis, or alco-
phosphatase (55%; grades 3–4: 9%), increased bilirubin holism) or hepatic metastases; may lead to exacerbation of he-
(13%; grades 3–4: < 1%–2%) (Eli Lilly & Co., 2013) patic impairment. Monitor LFTs prior to initiation and periodical-
ly (Eli Lilly & Co., 2013).
Biotherapy IL-2; aldesleukin IV, SC Increased transaminases and alkaline phosphatase; jaun- Not recommended for patients with preexisting liver dysfunction;
agents dice dosing is typically delayed until resolution of hepatic dysfunction.
Signs of hepatic failure: encephalopathy, ascites, liver Monitor LFTs.
pain, hypoglycemia (Wilkes & Barton-Burke, 2012)
Pegylated interfer- SC Increased risk of hepatic decompensation and death in Contraindicated and must be discontinued in patients with moder-
on alfa-2b patients with cirrhosis (Schering Corp., 2012b) ate or severe hepatic dysfunction or history of autoimmune hep-
atitis. Monitor LFTs and LDH at baseline and at weeks 2, 4, 8,
and 12 and then at 6-week intervals following the initiation of
therapy (Schering Corp., 2012b).
325
(Continued on next page)
326
Table 37. Hepatotoxicity of Antineoplastic Agents (Continued)
Route of
Classification Drug Administration Side Effects Nursing Considerations
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Camptothecin Irinotecan IV Increased bilirubin (84%), increased alkaline phospha- Use with caution in patients with hepatic impairment.
tase (13%), increased AST (10%), ascites and/or jaun- Hyperbilirubinemia: Patients with even modest elevations in to-
dice (grades 3–4: 9%) (Pfizer Inc., 2012a) tal serum bilirubin levels (1–2 mg/dl) have a significantly greater
likelihood of experiencing first-course grade 3 or 4 neutropenia
than those with bilirubin levels < 1 mg/dl (Pfizer Inc., 2012a). Pa-
tients with abnormal glucuronidation of bilirubin, such as those
with Gilbert syndrome, may be at greater risk of myelosuppres-
sion when receiving therapy with irinotecan. Use caution when
treating patients with known hepatic dysfunction or hyperbiliru-
binemia; dose adjustments should be considered (Venook et al.,
2003).
Miscellaneous Abiraterone ac- PO – Monitor LFTs at baseline and every week for the first month, ev-
etate ery 2 weeks for the following 2 months, and monthly thereafter.
Reduce doses for Child-Pugh B at baseline and hold if T. bili > 3
× ULN or AST and/or ALT > 5 × ULN. Do not use in patients with
severe hepatic impairment (Janssen Biotech, Inc., 2012).
Asparaginase IM, IV, SC Increased transaminases, bilirubin, and alkaline phospha- Use with caution in patients with preexisting hepatic impairment;
tase (transient) (Lundbeck, 2013) may alter function.
Asparaginase Er- IM Elevated LFTs in 4%; rare hyperammonemia (1%) (EUSA Monitor LFTs, fibrinogen, PT, and PTT. Monitor ammonia level if
winia chrysanthemi Pharma [USA], Inc., 2011) signs and symptoms of encephalopathy develop.
Bexarotene Topical, PO Increased LDH and hepatic failure (with oral formulation) Extensive hepatic elimination
(Eisai Inc., 2011b) Monitor LFTs; consider stopping if values are > 3 × ULN (Eisai
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Inc., 2011b; Floyd & Kerr, 2013).
Monoclonal Denileukin diftitox IV Increase in ALT/AST from baseline occurred in 84% of Monitor LFTs.
antibodies patients, mostly occurring during either the first or sec-
ond cycle and resolving without medical intervention or
interruption of denileukin diftitox (Eisai Inc., 2011a).
Ipilimumab IV T-cell activation and proliferation leading to immune-medi- Monitor LFTs prior to each dose. Stop drug and treat immune re-
ated organ failure (Bristol-Myers Squibb Co., 2013) action with steroids for AST/ALT > 5 × ULN or T. bili > 3 × ULN
(Bristol-Myers Squibb Co., 2013).
Ofatumumab IV Hepatitis B reactivation (GlaxoSmithKline, 2011) Screen high-risk patients (GlaxoSmithKline, 2011).
Rituximab IV Hepatitis B reactivation with possible fulminant hepatitis, Screen high-risk patients and monitor hepatitis B carriers during
sometimes fatal (Biogen Idec, Inc., & Genentech, Inc., and several months after therapy (Biogen Idec, Inc., & Genen-
2013) tech, Inc., 2013).
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 37. Hepatotoxicity of Antineoplastic Agents (Continued)
Route of
Classification Drug Administration Side Effects Nursing Considerations
Nitrosourea Carmustine IV, wafer Reversible increases in bilirubin, alkaline phospha- Monitor LFTs (Bristol-Myers Squibb Co., 2011a).
tase, and AST occur in a small percentage of patients Dose adjustment may be required in hepatic impairment, but no
(Bristol-Myers Squibb Co., 2011a). guidelines are available.
Tyrosine kinase Axitinib PO 22% had ALT elevations of all grades; < 1% had severe Monitor LFTs at baseline and periodically. Dose adjust for pa-
inhibitors elevations (Pfizer Inc., 2012b). tients with prior Child-Pugh B hepatic impairment. Has not been
studied in patients with severe hepatic impairment (Pfizer Inc.,
2012b).
Crizotinib PO < 1% fatal hepatotoxicity has occurred (Pfizer Inc., Monitor LFTs at baseline and monthly; increase frequency if el-
2013c). Elevations in ALT/AST and T. bili can occur. evation occurs. Hold drug for elevated AST/ALT; discontinue if
concurrent rise in T. bili > 2 × ULN.
Imatinib mesylate PO Mild elevations in serum AST and ALT levels are very Use with caution in patients with hepatic impairment. Drug inter-
common and may be a hypersensitivity reaction (Novar- ruption is recommended for patients with AST/ALT > 5 × ULN
tis Pharmaceuticals Corp., 2013). or bilirubin > 3 × ULN. Steroids have been used to treat severe
hepatotoxicity. Advise patients to avoid alcohol and other hepa-
toxic drugs (Joensuu et al., 2011).
Pazopanib PO U.S. boxed warning: Severe fatal hepatotoxicity has been Monitor LFTs at baseline and once a week for the first 4 months
observed. LFT elevations can occur, usually in the first and then periodically. Institute dose modifications for patients
18 weeks (GlaxoSmithKline, 2013). with moderate hepatic impairment. Drug is not recommended in
patients with severe impairment.
Sunitinib PO U.S. boxed warning: Fatal hepatotoxicity has occurred. Monitor LFTs at baseline, during each cycle, and as clinically in-
Signs include jaundice, elevated transaminases and/or dicated. Drug interruption is instituted for patients with AST/ALT
hyperbilirubinemia, coagulopathy, encephalopathy, and/ > 5 × ULN.
Chapter 9. Side Effects of Cancer Therapy
or renal failure (Pfizer Inc., 2012c).
Vinca alkaloid; Vincristine IV – Metabolized extensively in the liver. Use with caution in patients
natural source with hepatic impairment; dose modification required (Hospira,
(plant) Inc., 2013).
derivative
ALT—alanine aminotransferase; AST—aspartate aminotransferase; AUC—area under the time-versus-concentration curve; BMT—bone marrow transplantation; FDA—U.S. Food and Drug Administration; IL-2—inter-
leukin-2; IM—intramuscular; IV—intravenous; LDH—lactate dehydrogenase; LFT—liver function test; PO—by mouth; PT—prothrombin time; PTT—partial thromboplastin time; RUQ—right upper quadrant; SC—subcu-
327
taneous; SCT—stem cell transplantation; T. bili—total bilirubin; ULN—upper limit of normal; VOD—veno-occlusive disease
328 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
m) Bruising and/or bleeding
n) Portal hypertension
o) Encephalopathy: Mental status changes ranging from subtle, such
as decrease in memory, mental fogginess, and mild confusion, to se-
vere, such as coma
p) Arthralgia/myalgia
5. Assessment (Khalili, Liao, & Nguyen, 2010; Roesser, in press)
a) Vital signs: Fever may suggest hepatitis.
b) Physical examination to find and document the preceding clinical
manifestations
(1) Integument: Assess for presence of jaundice, skin rash, ecchy-
mosis, and petechiae.
(2) Head, eyes, ears, nose, and throat examination: Assess for ic-
teric sclera.
(3) Neurologic examination: Assess level of orientation, mental sta-
tus, asterixis, and behavioral changes.
(4) Abdominal examination: Assess bowel sounds, liver/spleen, as-
cites, and venous distention.
(5) Assess for Charcot triad: jaundice, fever, and upper abdominal
pain, indicating gallstones.
(6) Cardiac and pulmonary exam: Assess for signs of CHF (e.g., pe-
ripheral edema, extra heart sounds, rales, jugular venous dis-
tention—may suggest hepatic congestion).
c) Baseline LFTs prior to initiation of therapy
d) History of hepatotoxic drug use
e) Past medical history: Organ transplant, hepatitis, exposure to infect-
ed individuals, comorbidities, drug and alcohol use, family history
of liver disease
6. Collaborative management: Few guidelines exist for the dosing of drugs
based on elevated LFTs.
a) Avoid using hepatotoxic drugs during the administration of hepato-
toxic chemotherapy and if LFT results are abnormal.
b) Consider adjusting the dose of chemotherapy in the presence of im-
paired hepatic function (Wilkes & Barton-Burke, 2012).
c) Monitor serum chemistries, CBC, and clotting factors. Institute bleed-
ing precautions if clotting factors are abnormal.
d) Instruct and assist patients in following a low-fat, high-glucose diet
containing vitamin B and C additives. Consult a dietitian and consid-
er decreasing dietary protein in patients with signs of liver dysfunc-
tion (Fisher & Brown, 2010).
e) Assess patients’ level of consciousness. If altered, monitor ammonia
levels and consider lactulose (McKinley, 2009).
f) Monitor for weakness, fatigue, and malaise. Encourage rest. If pa-
tients are confined to bed rest, elevate the head of the bed and pro-
mote deep breathing to prevent pneumonia. Assess and monitor fall
risk (McKinley, 2009).
g) Monitor subsequent LFT results. Consult a hepatologist for liver fail-
ure (Fleming & Abbass, 2010).
h) Rule out other causes of liver injury including infections, iron over-
load, and autoimmune hepatitis, and treat as indicated (Verma &
Kaplowitz, 2009).
i) Consider treating prolonged cholestasis with ursodeoxycholic acid
(Verma & Kaplowitz, 2009).
j) Monitor renal function and other electrolytes. Prevent hepatorenal
syndrome by optimizing fluid and sodium balance and avoiding neph-
rotoxic medications (Fleming & Abbass, 2010).
7. Patient and family education
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 329
a) If appropriate, inform patients and significant others that hepatotox-
icity is a possible side effect of the chemotherapy agent.
b) Instruct patients to avoid all alcoholic beverages if hepatotoxicity is
present.
c) Provide instruction on the signs and symptoms of liver failure (e.g.,
jaundice, liver tenderness, changes in color of urine or stool).
d) Promote rest.
e) Encourage use of soothing lotions and tepid showers to promote skin
comfort. Remind patients not to scratch.
f) Suggest that patients wear lightweight, loose clothing.
g) Encourage patients to continue eating a light (low-fat), high-glu-
cose diet.
h) Reinforce the importance of having lifelong annual follow-up assess-
ments performed by a healthcare provider familiar with their cancer
history, treatment, and risk of developing late effects (Rawat, Gillett,
Devadason, Wilson, & McKiernan, 2011).
i) Encourage patients to have periodic LFTs and to plan appropriate
follow-up.
j) For patients with signs of liver failure, provide education about infec-
tion prevention, bleeding precautions, and safety.
I. Nephrotoxicity
1. Pathophysiology: The kidneys clear metabolic waste products, control
fluid volume status, maintain electrolyte and acid-base balance, and as-
sist with endocrine function. Each kidney contains about 1 million neph-
rons, the functional unit of the kidney. The nephron includes the glom-
erulus, proximal tubule, loop of Henle, distal tubule, and collecting
duct (Trombetta & Foote, 2009). Chemotherapy can damage the prox-
imal tubule epithelial cells, leading to acute tubular necrosis. Renal im-
pairment often is reversible if the offending drug is discontinued early
(Naughton, 2008).
a) Tubulopathies: Drugs can cause injury to one or more segments of
the renal tubules, leading to salt wasting, magnesium wasting, syn-
drome of inappropriate antidiuretic hormone (SIADH), and Fanco-
ni syndrome (Perazella & Moeckel, 2010).
(1) SIADH is a disorder of water intoxication. The release of anti
diuretic hormone (ADH) causes the kidneys to reabsorb water,
leading to hyponatremia (Fairclough & Brown, 2010). Chemo-
therapy agents that can contribute to SIADH include cyclophos-
phamide, vincristine, cisplatin, docetaxel, melphalan, and ifos-
famide and regimens that require vigorous hydration (Kelly, Bil-
lemont, & Rixe, 2009; Perazella & Moeckel, 2010).
(a) ADH acts in the kidneys to conserve water by binding to
receptors in the distal or collecting renal tubules. This ac-
tion promotes reabsorption of water and excretion of a
lesser amount of concentrated urine. The reabsorbed wa-
ter dilutes the blood and reduces the serum osmolality to-
ward normal, with an increase in urine osmolarity causing
hyposmolality and dilutional hyponatremia (Fairclough &
Brown, 2010).
(b) Symptoms of SIADH depend on the absolute concentra-
tion of sodium in the serum (Fairclough & Brown, 2010;
Keenan, 2011).
i. Mild hyponatremia (serum sodium concentration of
125–135 mEq/L): Symptoms may be absent or non-
specific, such as thirst, anorexia, nausea, fatigue, weak-
ness, muscle cramps, or headache.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
330 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
ii. Moderate hyponatremia (serum sodium concentration
of 115–124 mEq/L): Symptoms include weight gain,
oliguria, and progressive neurologic deficits.
iii. Severe hyponatremia (serum sodium concentration
< 115 mEq/L): Considered an oncologic emergen-
cy. Symptoms of cerebral edema include papillede-
ma, delirium, hypoactive reflexes, ataxia, gait distur-
bance, seizures, coma, and death. Initiate seizure pre-
cautions for sodium levels < 120 mEq/L.
(c) Management of presenting symptoms may include fluid re-
striction, diuresis, demeclocycline, and hypertonic saline.
(2) Fanconi syndrome is characterized by urinary wasting of potas-
sium, phosphate, bicarbonate, uric acid, and glucose.
b) Acute kidney injury (AKI) has replaced the term acute renal failure and
is characterized by a rapid reduction in kidney function that results
in a failure to maintain fluid, electrolyte, and acid-base homeostasis
(Lewington & Kanagasundaram, 2011). Chemotherapy agents are a
common cause of AKI (Perazella & Moecke, 2010). Types of AKI in-
clude the following.
(1) Prerenal AKI occurs less commonly than the other types and
causes capillary leak syndrome. May be seen with IL-2 and de-
nileukin (Perazella & Moecke, 2010).
(2) Acute tubular injury (ATI) is the most common cause of AKI.
Proximal tubule cells are exposed to high levels of circulating
toxins, making them more vulnerable to the toxic effects of
drugs. ATI is dose related. Various tubulopathies may be per-
manent in 25%–44% of patients (Naughton, 2008; Perazella &
Moecke, 2010).
(3) Crystal nephropathy occurs when the insoluble crystals produced
by drugs precipitate, usually within the distal tubular lumen, ob-
structing urine flow. The likelihood of crystal precipitation de-
pends on drug concentration and the urinary pH. Patients at
highest risk are those with volume depletion and underlying re-
nal insufficiency (Naughton, 2008; Perazella & Moecke, 2010).
(a) Methotrexate is associated with production of crystals. The
parent drug and its metabolites precipitate within tubu-
lar lumens.
(b) Tumor lysis syndrome (TLS) is the massive and sudden re-
lease of cellular contents into the bloodstream following
the rapid lysis of tumor cells in large numbers. This release
results in abnormally high levels of potassium, phospho-
rus, and uric acid. Phosphorus binds to calcium, resulting
in hypocalcemia. Uric acid and calcium phosphate crystal
deposition occurs and leads to renal failure. Symptoms of
TLS include hypocalcemia, hyperkalemia, hyperuricemia,
and hyperphosphatemia. Because of the risk of life-threat-
ening complications, TLS is considered an oncologic emer-
gency (Fairclough & Brown, 2010; Givens & Crandall, 2010;
Lydon, 2011; Mackiewicz, 2012; Muslimani et al., 2011).
i. The incidence of TLS is unknown. Although it occurs
more frequently in aggressive hematologic malignan-
cies including Burkitt and other high-grade lympho-
mas, acute lymphoblastic leukemia, acute myeloid
leukemia, and multiple myeloma, TLS has been re-
ported in solid tumors including breast cancer, small
cell and non-small cell lung cancers, sarcoma, blad-
der cancer, and ovarian cancer. TLS can occur spon-
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 331
taneously but usually develops after the start of cyto-
toxic therapy, primarily chemotherapy.
ii. AKI may result from crystal formation due to hyper-
uricemia and hyperphosphatemia. Oliguria can lead
to volume overload, hypertension, and pulmonary
edema, and elevated BUN can result in pericarditis,
platelet dysfunction, and impaired cellular immuni-
ty. Cardiac arrhythmias can occur as a result of elec-
trolyte imbalances.
iii. Prevention is the goal of TLS management. Vigorous
hydration with 2–3 L of normal saline or 5% dextrose
solution is necessary to stimulate diuresis. Allopurinol
administration should begin one to three days before
chemotherapy and continue for three to seven days
after chemotherapy.
iv. For patients at high risk for TLS, including those
with a uric acid level > 7.5 mg/dl (Coiffier, Altman,
Pui, Younes, & Cairo, 2008), WBC count higher than
50,000/mcl, elevated lactate dehydrogenase or serum
creatinine (SCr), CHF, pulmonary edema, and those
unable to take oral medication, rasburicase is recom-
mended to decrease uric acid levels within four hours
of administration (sanofi-aventis U.S. LLC, 2011a).
Although the FDA-approved dose is 0.15–0.2 mg/kg
IV daily for five days (Coiffier et al., 2008), several
studies demonstrated that a single, 6 mg fixed dose
was effective and may be repeated if necessary, but
this is rarely required (Giraldez & Puto, 2010; Vines,
Shanholtz, & Thompson, 2010). Rasburicase should
not be administered to patients with glucose-6-phos-
phate dehydrogenase deficiency (sanofi-aventis U.S.
LLC, 2011a).
v. Urinary alkalinization is no longer recommended for
all patients at risk for TLS. Use should be individual-
ized and is recommended only in patients with met-
abolic acidosis.
vi. Nursing care involves monitoring for signs and symp-
toms of fluid and electrolyte abnormality and man-
agement of altered electrolyte levels as appropriate.
Monitor intake and output, and involve patients and
caregivers in prevention, early detection, and inter-
ventions.
(4) Thrombotic microangiopathy is damage with occlusion that oc-
curs in small vessels, most commonly within the kidneys, and
presents with hematuria and proteinuria or with isolated pro-
teinuria (Perazella & Moeckel, 2010).
c) Nephritic/nephrotic syndromes: Nephritic syndrome includes hema-
turia with the presence of RBC casts in the urine. It often includes
mild to moderate proteinuria, edema, hypertension, elevated SCr,
and oliguria. Nephrotic syndrome is characterized by proteinuria, hy-
poalbuminemia, hyperlipidemia, lipiduria, and hypercoagulabili-
ty (Firman, 2010). Drugs can cause inflammatory changes in the
glomerulus, renal tubular cells, and the surrounding interstitium,
which can lead to fibrosis and renal scarring (Kelly et al., 2009;
Naughton, 2008).
(1) Glomerulonephritis is an inflammatory condition primarily
caused by immune mechanisms and is often associated with
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
332 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
proteinuria, which may be mild and detected by dipstick. Im-
mune modulators associated with this mechanism of kidney
injury include IFN alfa, beta, and gamma.
(2) Acute interstitial nephritis can result from an allergic response
to a suspected drug, which may be individual and unrelated
to dose. Typical symptoms of hypersensitivity reaction such as
fever, rash, and eosinophilia are not always present. It can oc-
cur from numerous drugs, including allopurinol and acyclo-
vir. Chronic interstitial nephritis can progress to end-stage re-
nal disease.
d) Chronic kidney disease (CKD) may be associated with irreversible re-
nal injury, higher cumulative drug dose, combined treatment with
other nephrotoxins, and host risk factors such as diabetes and hyper-
tension. CKD includes chronic interstitial nephritis and glomerulo-
sclerosis (Perazella & Moeckel, 2010).
2. Incidence: See Table 38.
Table 38. Nephrotoxicity of Antineoplastic Agents
Drug Incidence of Nephrotoxicity Comments
Axitinib Proteinuria: 23%–70% Hypertension: 50%–100%
Azacitidine Transient elevation of SCr: 20% Magnesium wasting and sodium wasting
Bevacizumab Nephrotic-range proteinuria: 1%–2% Associated with TMA with associated side effects such as hypertension,
Proteinuria, any grade: 4%–36% proteinuria, and arterial thrombotic events
Hematuria: 6%; 6% with grade 3 cys- Bevacizumab administration may be associated with damage to the glo-
titis merular endothelium.
Renal damage induced by bevacizumab is a direct reduction of glomeru-
lar VEGF production.
Cetuximab Severe hypomagnesemia: 10%–15% Causes isolated urinary magnesium wasting
Renal failure in patients with colon
cancer: 1%
Cisplatin One-third of patients receiving cis Associated with chronic interstitial nephritis
platin develop AKI after one dose of Causes tubulopathies with FS, sodium and magnesium wasting
therapy. Chronic interstitial nephritis
Risk of AKI increases with higher cu- Nephrogenic diabetes insipidus
mulative dose. Associated with SIADH
Overall reported nephrotoxicity: 28%– Causes acute tubular necrosis: Usually causes proximal tubular inju-
36% ry caused by the pathway of renal excretion of cisplatin, and can cause
CKD
Conversion of cisplatin to toxic molecules is an important step in the in-
duction of nephrotoxicity.
Cisplatin is more nephrotoxic than carboplatin and oxaliplatin.
Cyclophospha- Hemorrhagic cystitis: 15% Associated with SIADH
mide
Cyclosporine Nephrotoxicity: 25%–38% Associated with chronic interstitial nephritis
Denileukin Capillary leak: 11.1%–32.5% Can cause prerenal AKI (capillary leak syndrome)
diftitox
Diaziquone – Causes acute tubular necrosis
Docetaxel – Associated with SIADH
Gefitinib – Promotes renal phosphate wasting and hypophosphatemia due to a par-
tial FS
Hemorrhagic cystitis has been reported.
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 333
Table 38. Nephrotoxicity of Antineoplastic Agents (Continued)
Drug Incidence of Nephrotoxicity Comments
Gemcitabine Hematuria: 13%–35% TMA
Proteinuria: 10%–45%
Elevated SCr: 2%–38%
Ifosfamide Hematuria without mesna: 44.1%; Associated with SIADH
hematuria with mesna: 21.3% Causes acute tubular necrosis
Can cause CKD
Can cause nephrogenic diabetes insipidus
Imatinib Acute renal failure: 0.1%–1% Promotes renal phosphate wasting and hypophosphatemia due to a par-
tial FS
Causes acute tubular necrosis
Interferon – Associated with minimal change disease
Associated with collapsing and noncollapsing focal segmental glomerulo-
sclerosis
Associated with membranoproliferative glomerulonephritis with proteinuria
that is often mild and reversible
Interleukin-2 Oliguria: 63% Can cause prerenal AKI (capillary leak syndrome)
Elevated SCr: 33%
Melphalan – Associated with SIADH
Methotrexate Overall incidence of AKI: 1.8% Associated with chronic interstitial nephritis
Causes crystal nephropathy when administered in high doses
Precipitation of the parent drug and its metabolites can occur within the
tubular lumens.
Initially an asymptomatic SCr increase develops with nonoliguria followed
by more severe AKI.
True or effective volume depletion and acidic urine are two major risk fac-
tors for AKI.
Drug-drug interaction may play a role in high-dose methotrexate–induced
AKI (e.g., methotrexate and piperacillin-tazobactam).
Another mechanism of methotrexate-mediated nephrotoxicity is hyperho-
mocysteinemia in patients with deficient folate metabolism.
Drug is retained in ascites and pleural effusions.
Avoid concurrent administration with NSAIDs.
Mithramycin – Causes acute tubular necrosis
Mitomycin C Approximately 10% of patients devel- Leads to TMA
op renal effects after 5–7 months of Higher cumulative dose (≥ 60 mg) increases risk for TMA.
mitomycin C.
Hemolytic uremic syndrome: < 10%
Nitrosoureas Kidney disease develops in approxi- Associated with chronic interstitial nephritis and glomerulosclerosis
mately 10% of patients who receive Nitrosoureas can cause slow, progressive CKD that occurs over a period
carmustine and lomustine. of 3–5 years.
Streptozocin and semustine are the Streptozocin causes AKI.
most nephrotoxic drugs, affecting > Can cause kidney injury that is manifested by an asymptomatic increase
75% of patients. in SCr, but tubular insufficiency can occur, resulting in clinically evident
FS.
In the majority of patients receiving 6 courses of nitrosoureas, irreversible
kidney damage that is chronic and progressive can occur.
Pamidronate Deteriorating renal function: 8.2% Associated with minimal change disease
Associated with focal segmental glomerulosclerosis, which is at least par-
tially reversible after discontinuation of pamidronate
Mechanism is at least partially related to podocyte apoptosis.
Causes acute tubular necrosis
(Continued on next page)
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334 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Table 38. Nephrotoxicity of Antineoplastic Agents (Continued)
Drug Incidence of Nephrotoxicity Comments
Panitumumab Hypomagnesemia: 36%; 3% with se- Associated with magnesium wasting
vere symptomatic hypomagnesemia
Pemetrexed Mild, transient renal dysfunction is re- Decreased GFR may occur.
ported in up to 20% of patients. Oc- Drug is retained in pleural effusions and ascites, leading to prolonged
casionally AKI is reported. drug exposure.
Pentostatin Renal failure: < 3% Causes acute tubular necrosis
Sorafenib Acute renal failure: < 1% Proteinuria has been reported in patients who have received sorafenib.
Other renal effects reported include hypophosphatemia, hyponatremia,
and hypocalcemia.
Sunitinib Creatinine elevation is reported in ap- Grade II–III hypertension has been reported.
proximately 14% of patients TMA has been reported.
Increased uric acid: 46%
Tacrolimus Nephrotoxicity: 36%–59% Associated with interstitial nephritis
Vincristine – Associated with SIADH
Zoledronic acid Nephrotoxicity: 11%–17% Acute renal failure
Elevated SCr: 1%–2.1%
AKI—acute kidney injury; CKD—chronic kidney disease; FS—Fanconi syndrome; GFR—glomerular filtration rate; NSAID—nonsteroidal anti-inflammato-
ry drug; SCr—serum creatinine; SIADH—syndrome of inappropriate antidiuretic hormone; TMA—thrombotic microangiopathy; VEGF—vascular endotheli-
al growth factor
Note. Based on information from Flombaum, 2011; Kelly et al., 2009; Launay-Vacher, 2011; Micromedex, 2013; Perazella & Moeckel, 2010.
3. Risk factors for chemotherapy-induced renal toxicity (Bhadauria & Agraw-
al, 2012; Camp-Sorrell, 2011; Naughton, 2008; Perazella & Moeckel, 2010;
Trombetta & Foote, 2009)
a) Older age
b) Female
c) History of nephrotic syndrome, acute or chronic kidney disease, ne-
phrectomy, ileal conduits
d) Cirrhosis or obstructive jaundice
e) Metabolic disturbances including diabetes mellitus, alkaline or acid-
ic urine pH, hypokalemia, hypomagnesemia, hypocalcemia, hyper-
calcemia.
f) History of hypertension, congestive heart failure
g) Hypovolemia
h) Administration of nephrotoxic drugs (e.g., aminoglycoside therapy,
amphotericin B, cyclosporine, NSAIDs)
i) Dehydration, poor nutritional status
j) Duration of cancer therapy
k) Malignancies associated with nephrotoxicity: Multiple myeloma, re-
nal infiltration by tumor, and urinary obstruction from malignancy
4. Clinical manifestations: See signs and symptoms listed previously for spe-
cific syndromes of SIADH and TLS. Signs and symptoms associated with
renal dysfunction that require attention include the following (Camp-
Sorrell, 2011; Perazella & Moeckel, 2010).
a) Oliguria
b) Azotemia
c) Increasing SCr
d) Declining creatinine clearance (CrCl)
e) Elevated BUN
f) Hypomagnesemia
g) Proteinuria
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Chapter 9. Side Effects of Cancer Therapy 335
h) Hematuria
i) Weight gain from fluid retention or edema
5. Collaborative management
a) Prior to therapy, assess for risk factors of nephrotoxicity. Evaluate for
comorbidities (e.g., diabetes, hypertension, nephrectomy) and pri-
or therapies that may contribute to renal toxicity (Kelly et al., 2009;
Naughton, 2008).
b) Physical assessment data (Camp-Sorrell, 2011; Kelly et al., 2009)
(1) Monitor vital signs.
(2) Monitor weight daily or as clinically indicated, especially in the
case of weight gain and edema.
(3) Monitor intake and output.
(4) Monitor for changes in mental status, level of consciousness,
or behavior.
c) Laboratory data
(1) SCr
(a) A rise in SCr usually indicates decreased GFR (Trombet-
ta & Foote, 2009).
(b) Monitor creatinine and discontinue offending agent if rise
is noted (Camp-Sorrell, 2011).
(c) Criteria that have been used for AKI include a 50% rise in
SCr over baseline, an increase of 0.5 mg/dl or more when
baseline SCr is < 2 mg/dl, or an increase of ≥ 1 mg/dl if
baseline SCr is > 2 mg/dl (Naughton, 2008).
(2) BUN (Trombetta & Foote, 2009)
(a) Provides an estimate of renal function
(b) Level may vary and should be used with other studies to
evaluate renal function.
(3) CrCl
(a) Most common method used to estimate GFR
(b) Level may be determined from a 24-hour urine collection,
the Cockcroft-Gault equation, or the Modification of Diet
in Renal Disease formula (Flombaum, 2011; Trombetta &
Foote, 2009).
(c) Most drugs that are renally excreted do not require dose
reduction until GFR is below 50 ml/min/1.73 m2 (Naugh-
ton, 2008).
(4) Urine protein: Proteinuria indicates damage to the tubular and
glomerular systems (Trombetta & Foote, 2009).
(5) Urine pH, osmolarity, and uric acid (Trombetta & Foote, 2009)
(6) Chemistry panel: Calcium, phosphorus, and magnesium (Giv-
ens & Crandall, 2010; Trombetta & Foote, 2009)
d) Preventive measures
(1) Correct metabolic abnormalities prior to treatment (e.g., hy-
pokalemia, hypomagnesemia) (Bhadauria & Agrawal, 2012).
(2) Hydrate patients with saline, approximately 3 L/day to prevent
or minimize renal damage, primarily with cisplatin and high-
dose methotrexate regimens (Camp-Sorrell, 2011).
(3) Assess for evidence of volume depletion such as orthostatic hy-
potension, blood pressure < 90/60 mm Hg, or decreased skin
turgor accompanied by a loss of > 5% of baseline body weight
(Launay-Vacher, Rey, Isnard-Bagnis, Deray, & Daouphars, 2008;
Naughton, 2008; Perazella & Moeckel, 2010).
(4) Adjust dose of medications for renal function. Most drugs that
are renally excreted do not require dose reduction until GFR
is below 50 ml/min/1.73 m2. Avoid nephrotoxic drug combi-
nations (Naughton, 2008).
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
336 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
e) Early intervention
(1) At the first sign of renal dysfunction, review patients’ medica-
tions to determine any potential agents that could be causing
the altered renal function. If more than one agent is renal tox-
ic and the patient is stable, discontinue the most recently add-
ed agent first (Naughton, 2008).
(2) Renal function generally returns to baseline if the impairment
is recognized early and the offending drug is discontinued
(Naughton, 2008).
(3) Treat hypertension. Encourage patients to monitor blood pres-
sure at home (Kelly et al., 2009).
f) Drug-specific measures
(1) Cisplatin administration may result in acute declines in renal
function, salt-wasting and magnesium-wasting nephropathy,
and SIADH. The nephrotoxicity can be cumulative and may
occur after intraperitoneal and regional intra-arterial delivery
(Flombaum, 2011).
(a) Assess renal function studies prior to administration (check
BUN, SCr, and 24-hour CrCl), and discuss abnormal results
with physician (Wilkes & Barton-Burke, 2012).
(b) Institute vigorous saline hydration before and after thera-
py. Urine output should be at least 100–150 ml/hr (Camp-
Sorrell, 2011; Wilkes & Barton-Burke, 2012).
(c) Mannitol may prevent renal damage from cisplatin. Loop
diuretics (furosemide) should be used with caution (Flom-
baum, 2011).
(d) Notify physician if CrCl < 50 mg/ml or if SCr is elevated.
Drug may be held until renal function improves (Flom-
baum, 2011).
(e) Monitor serum electrolytes and replace as ordered. Add
magnesium and potassium to IV hydration before and af-
ter cisplatin administration as ordered (Wilkes & Barton-
Burke, 2012).
(f) ASCO guidelines include the use of amifostine as a poten-
tial agent for the prevention of nephrotoxicity in patients
receiving cisplatin-based therapy (Hensley et al., 2009).
i. Amifostine is used to reduce the cumulative renal
toxicity experienced with multiple doses of cisplatin.
ii. Dose is 910 mg/m2 IV infused over 5–15 minutes after
antiemetics have been administered and the patient
has been hydrated with at least 1 L of fluid. Cisplatin
is administered 15 minutes after the amifostine is giv-
en (MedImmune Pharma B.V., 2013).
iii. Most common side effects are hypotension, nausea,
vomiting, flushing, chills, and dizziness (Vallerand &
Sanoski, 2012).
iv. Monitor blood pressure every five minutes through-
out infusion and then as clinically indicated. Treat
systolic hypotension with fluid administration and
Trendelenburg position (MedImmune Pharma
B.V., 2013).
(2) Methotrexate: Both the parent drug and its metabolite are high-
ly insoluble, especially in acidic and concentrated urine, lead-
ing to intratubular precipitation of the drug with large doses
(Flombaum, 2011).
(a) Check BUN and creatinine before, during, and after each
dose (Wilkes & Barton-Burke, 2012).
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 337
(b) Proper hydration (to ensure adequate urine volume) with
bicarbonate administration is needed to alkalinize the urine
before and after administration of high-dose (1–7.5 g/m2)
methotrexate to prevent urine crystallization.
(c) Monitor urine pH and maintain at > 7. Record intake and
output (Wilkes & Barton-Burke, 2012).
(d) Monitor methotrexate levels. To minimize systemic toxici-
ty, leucovorin must be administered on time (usually begin-
ning 24 hours after the start of methotrexate) and contin-
ued until serum methotrexate levels decrease below 0.05–
0.1 mcmol/L (Camp-Sorrell, 2011; Flombaum, 2011). Ad-
minister oral leucovorin with antacids, milk, or juice (Wilkes
& Barton-Burke, 2012).
(e) Ensure that patients do not take oral folic acid during meth-
otrexate therapy (Wilkes & Barton-Burke, 2012).
(f) Drugs that are protein-bound (e.g., aspirin, sulfonamides,
phenytoin) may increase toxicity and must be used
cautiously. Monitor patients closely (Wilkes & Barton-
Burke, 2012).
(g) Do not administer NSAIDs concurrently with methotrex-
ate. Drug levels may be increased and prolonged (Wilkes
& Barton-Burke, 2012).
(h) Methotrexate elimination is reduced in patients with im-
paired renal function, ascites, or pleural effusions. Such pa-
tients necessitate especially careful monitoring for toxicity
and require dose reduction or discontinuation of metho-
trexate (Flombaum, 2011).
6. Patient and family education (Camp-Sorrell, 2011; Fairclough & Brown,
2010; Wilkes & Barton-Burke, 2012)
a) Educate patients about the risk of nephrotoxicity with certain cyto-
toxic agents.
b) Provide patients with a list of drugs to avoid that can lead to renal
dysfunction.
c) Teach patients and family members the need for increased oral flu-
ids on discharge. Intake should be up to 3 L or more for five days af-
ter therapy.
d) Ensure that patients understand the reasons for changes in urine out-
put, electrolyte depletion, and increasing SCr and BUN.
e) Reinforce the importance of complying with preventive measures in-
cluding alkalinization of urine, allopurinol or amifostine treatment,
and the need to take leucovorin rescue as prescribed.
f) Instruct patients on when and how to notify the healthcare team, in-
cluding if
(1) Unable to make urine for more than 12 hours
(2) Only very small amounts of urine are produced
(3) Urine is dark, concentrated, pink, bloody, or cloudy
(4) Edema or weight gain occurs.
J. Neurotoxicity: Cancer therapy uses a combination of treatment modalities
such as surgery, radiation, and chemotherapy that may improve patient out-
comes (Butowski & Chang, 2005). However, combination therapy and ex-
tended survival often are associated with potential acute or delayed neuro-
toxicity. Neurotoxicity can arise as direct or indirect damage to the CNS, pe-
ripheral nervous system, cranial nerves (CNs), or any combination of the
three (Gilbert, 2008). Some drugs cause neurotoxicity at low doses, where-
as others cause neurotoxicity only during intensive therapy. Neurologic tox-
icity is a dose-limiting factor in several cancer treatments, such as radiation
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
338 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
therapy. Patients may suffer more from the toxicities than from the cancer
itself (Quasthoff & Hartung, 2002).
1. Pathophysiology
a) CN deficits: These deficits result from damage to one of the 12 CNs
arising from the brain stem. The result depends on which nerve is dam-
aged (Barker, 2008). Examples of CN deficits include the following.
(1) Olfactory (CN I): Loss or decrease of smell
(2) Optic (CN II): Loss of visual acuity, optic atrophy, altered vi-
sual field
(3) Oculomotor (CN III): Ptosis, dilated pupils, altered ocular mus-
cle function, nystagmus
(4) Trochlear (CN IV): Altered ocular muscle function causing
nystagmus
(5) Trigeminal (CN V): Numbness, poor blink reflex, weakened
chewing
(6) Abducens (CN VI): Altered ocular muscle function causing
nystagmus
(7) Facial (CN VII): Facial paralysis, drooping mouth, sagging low-
er eyelid, flat nasolabial fold
(8) Acoustic (CN VIII): Sensory neuronal hearing loss, vertigo, atax-
ia, nausea and/or vomiting
(9) Glossopharyngeal (CN IX): Altered sense of taste, altered throat
sensation
(10) Vagus (CN X): Hoarseness, altered gag reflex, altered swallow-
ing function
(11) Spinal accessory (CN XI): Tilting of head, weakness of shoul-
der muscles
(12) Hypoglossal (CN XII): Abnormal tongue movement
b) Peripheral nervous system deficits are a result of damage to sensory
and motor nerves outside the CNS, including the autonomic nerves.
Peripheral neuropathy is estimated to occur in 10%–20% of patients
with cancer. It is commonly associated with the use of platinum drugs,
taxanes, epothilones, vinca alkaloids, bortezomib, and lenalidomide
(Fernández-de-Las-Peñas et al., 2010). Peripheral neuropathy is caused
by chemotherapy injuring the sensory and motor axons. This results
in demyelination, which reduces nerve conduction velocity and leads
to loss of deep tendon reflexes. Disorders of one or more peripher-
al nerves cause signs and symptoms that correspond to the anatom-
ic distribution and normal function of the nerve. The distal branch-
es are most affected by axonal transport flow disruption, causing the
stocking-and-glove pattern of sensory loss (Stillman & Cata, 2006).
Signs and symptoms of a peripheral nerve disorder may include sen-
sory, motor, or autonomic disturbances (Hickey, 2009). The CTCAE
(NCI CTEP, 2010) is used to identify the severity of the neuropathy.
Grades range from 1 (mild symptoms) to 5 (death). See Table 39.
(1) Sensory nerve fibers: Decrease or loss of light touch and pin-
prick sensation along the involved dermatome. Tingling, numb-
ness, paresthesias, and dysesthesias are common. Paresthesias are
unusual sensations such as “pins and needles”; dysesthesias are
unpleasant sensations such as burning (Hickey, 2009). Cisplat-
in causes an axonal neuropathy that primarily affects large my-
elinated sensory fibers.
(2) Motor nerve fibers: Symmetric generalized motor weakness that
may cause decreased balance, strength, and activity level, foot
or wrist drop, myalgias, and muscle cramping (Armstrong, Al-
madrones, & Gilbert, 2005). Paclitaxel causes a motor neurop-
athy, which predominantly affects proximal muscles. A pacli-
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 339
Table 39. National Cancer Institute’s Common Terminology Criteria for Adverse Events: Neuropathies
Grade
Adverse Event 1 2 3 4 5
Cranial nerve disorder Asymptomatic; clinical Moderate symp- Severe symp- Life-threatening conse- Death
(cranial nerve specific) or diagnostic observa- toms; limiting in- toms; limiting quences; urgent interven-
tions only; intervention strumental ADL self-care ADL tion indicated
not indicated
Peripheral motor neu- Asymptomatic; clinical Moderate symp- Severe symp- Life-threatening conse- Death
ropathy or diagnostic observa- toms; limiting in- toms; limiting quences; urgent interven-
tions only; intervention strumental ADL self-care ADL; tion indicated
not indicated assistive device
indicated
Peripheral sensory neu- Asymptomatic; loss of Moderate symp- Severe symp- Life-threatening conse- Death
ropathy deep tendon reflexes toms; limiting in- toms; limiting quences; urgent interven-
or paresthesia strumental ADL self-care ADL tion indicated
ADL—activities of daily living
Note. From Common Terminology Criteria for Adverse Events [v.4.03], by National Cancer Institute Cancer Therapy Evaluation Program, 2010, Bethesda,
MD: National Cancer Institute.
taxel-associated pain syndrome can develop, which is character-
ized by severe arthralgias and myalgias (Loprinzi et al., 2011).
(3) Decreased or absent deep tendon reflexes are the two most com-
mon and earliest symptoms of peripheral neuropathy caused
by vincristine. The incidence of vincristine-induced areflexia is
57% (Armstrong et al., 2005).
(4) Autonomic nerves: Constipation, paralytic ileus (rare), urinary
retention, incontinence, erectile dysfunction, and orthostatic
hypotension. Autonomic symptoms commonly seen with bort-
ezomib include constipation and orthostatic hypotension; with
thalidomide, constipation, impotence, and bradycardia are com-
mon (Tariman, Love, McCullagh, & Sandifer, 2008).
c) CNS deficits: These deficits have multiple causes (e.g., metabolic im-
balances, intracranial hemorrhage, infection related to chemother-
apy-induced coagulopathy or myelosuppression, IT or intra-arterial
chemotherapy, high-dose therapy). Deficits depend on the area of
brain or brain stem affected (Gilbert, 2008).
(1) Acute or chronic encephalopathy: Symptoms of acute high-
dose methotrexate neurotoxicity include somnolence, leth-
argy, and confusion within 24 hours (Dietrich & Wen, 2008).
Methotrexate at a high dose in the CNS causes encephalopa-
thy or posterior reversible encephalopathy syndrome (PRES).
The main symptoms associated with PRES are encephalopathy
(92%), seizures (87%), headache (53%), and visual symptoms
(39%) (Hodnett, Coyle, O’Regan, Maher, & Fanning, 2009).
The pathogenesis of PRES is unclear, but it appears to be relat-
ed to disordered autoregulation and endothelial dysfunction.
This has become an increasingly recognized neurologic disor-
der (Hodnett et al., 2009). PRES has been associated with the
use of cisplatin, rituximab, bevacizumab, and immunosuppres-
sive therapy such as tacrolimus or cyclosporine (Seet & Rabin-
stein, 2012). PRES is a reversible condition that warrants either
dose reduction or withholding the causative agent, which re-
sults in a complete recovery for most patients (Aranas, Prabha-
karan, & Lee, 2009).
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
340 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
(2) Seizures: Can occur as a result of structural abnormalities of
the brain (brain metastasis), cerebrovascular disease, PRES,
and radiation toxicity (Pulzova, Bhide, & Andrej, 2009). The
following chemotherapy agents are known to cause seizures:
asparaginase, BCNU (carmustine), busulfan, cisplatin, cyclo-
phosphamide, dacarbazine, docetaxel, etoposide, 5-FU, gem-
citabine, IFN, ifosfamide, IL-2, suramin, temozolomide, tenipo-
side, thalidomide, and vinca alkaloids (Glantz & Batten, 2008).
(3) Cerebellar dysfunction: Truncal, limb, and gait ataxia; dysar-
thria (staggered gait and postural imbalance); difficulty speak-
ing; slow or irregular speech; nystagmus
(4) The blood-brain barrier contributes to the immune privilege of
the CNS; however, significant cross talk and bidirectional com-
munication occur between the CNS and the immune system
(Maier & Watkins, 2003). The release of proinflammatory cy-
tokines (e.g., IL-1, IL-6, TNF-α) in the peripheral blood leads
to penetration of the blood-brain barrier and production of
proinflammatory cytokines in the CNS (Myers, Pierce, & Paz-
dernik, 2008). The proinflammatory cytokines are associated
with a syndrome of behaviors and symptoms known as sickness be-
havior (Kronfol & Remick, 2000). Sickness behavior includes fe-
ver, fatigue, lethargy, muscle aches, decreased ability to concen-
trate, and decreased social interaction (Parnet, Kelley, Bluthé,
& Dantzer, 2002)
(5) Ifosfamide and some of its metabolites can cross the blood-brain
barrier (Verstappen, Heimans, Hoekman, & Postma, 2003). Ni-
trosoureas are alkylating agents that can cross the blood-brain
barrier and are used to treat brain tumors, melanoma, and
lymphomas. Concomitant administration of dexamethasone
or mannitol may reduce side effects of cerebral edema as a re-
sult of penetration of the blood-brain barrier (Wilkes & Barton-
Burke, 2013).
2. Incidence: Exact incidence is unknown, but as newer agents and targeted
therapies are being developed, the number and range of neurotoxicities
are increasing (Dropcho, 2010). Incidence is also increasing with great-
er use of high-dose chemotherapy, the use of more than one neurotox-
ic agent at a time or sequentially, and with increased detection because
of objective and subjective assessment (Dropcho, 2010) (see Table 40).
3. Risk factors
a) Regimens that include high-dose chemotherapy are associated with
blood-brain barrier penetration; most chemotherapeutic agents do
not cross the blood-brain barrier in standard doses (Saykin, Ahles, &
McDonald, 2003). Some exceptions are methotrexate, cisplatin, cy-
tarabine, ifosfamide, procarbazine, temozolomide, carmustine, lo-
mustine (Wilkes & Barton-Burke, 2013), and topotecan (Wong &
Berkenblit, 2004).
b) Route of administration: IT methotrexate and liposomal cytarabine
may be used to treat meningeal leukemia or lymphoma. Although
rare, toxicity to the spinal cord, which can be severe, can result from
IT drug administration (Schlegel, 2011). Methotrexate and liposo-
mal cytarabine can cause irritation of the spinal cord; patients can
experience transient pain that may progress to spinal cord dysfunc-
tion (Schlegel, 2011). High peripheral doses can cause neurotoxicity
(e.g., lethargy, somnolence) and cerebellar toxicity (e.g., nystagmus,
dysarthria, ataxia, slurred speech, decreased ability to make fine co-
ordinated movements) (Wilkes & Barton-Burke, 2013).
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 341
Table 40. Neurotoxicity of Antineoplastic Agents
Classification Drug Incidence of Neurotoxicity Characteristic Effects and Comments
Alkylating Busulfan Low at conventional dosing; high dosing can Administer seizure prophylaxis (e.g., phenyto-
agents cause seizures (Otsuka America Pharmaceu- in). Use caution when administering the rec-
tical, Inc., 2011). ommended dose of busulfan to patients with
a history of a seizure disorder or head trauma
or who are receiving other potentially epilep-
togenic drugs (Otsuka America Pharmaceuti-
cal, Inc., 2011).
Cisplatin Occurs with cumulative doses beyond 400 mg/ Numbness, paresthesia, and pain in toes and
m2 (van der Hoop et al., 1990) fingers spreading proximally to the arms and
Symptomatic hearing loss affects 15%–20% of legs; proprioception is impaired and reflexes
patients, and hearing impairment in more than are lost, but power is almost always spared
three-fourths of the patients (Oldenburg et al., (Hilkens et al., 1995).
2007). Radiation therapy to the normal cochlea or cra-
Genetic polymorphisms responsible for cisplatin nial nerve VIII with concurrent administration
metabolism may contribute to individual hear- of cisplatin results in ototoxicity (Low et al.,
ing loss (Oldenburg, 2007). 2006). Ototoxicity can be severe in children
(Li et al., 2004).
Lhermitte sign is a shock-like, nonpainful par-
esthesia radiating from the back to the feet
during neck flexion (Dietrich & Wen, 2008).
Ifosfamide Encephalopathy develops in 10%–20% of pa- Symptoms can occur during drug administra-
tients (David & Picus, 2005). tion and usually resolve within several days
Rare toxicities are seizures, ataxia, weakness, (David & Picus, 2005).
and neuropathies (Posner, 2001). Patients at risk for toxicities include those with
a prior history of ifosfamide-related encepha-
lopathy, renal dysfunction, or low serum albu-
min prior to treatment (Posner, 2001).
Oxaliplatin Acute symptoms were observed more frequent- Symptoms consist of striking paresthesias and
ly with doses > 130 mg/m2 than with doses < dysesthesias of the hands, feet, and perioral
85 mg/m2 and are dependent on infusion rate region with jaw tightness. Symptoms are of-
(Gamelin et al., 2002). However, a trial found ten induced or aggravated by the cold (Leh-
increasing neurotoxicity with a dose of 680 ky et al., 2004).
mg/m2 (Green et al., 2005).
Antimetabolites Capecitabine Paresthesias were common for less than 10% of Paresthesias, headaches, dizziness, or insom-
patients treated (Renouf & Gill, 2006). nia can occur. Cerebellar toxicity has been re-
ported (Renouf & Gill, 2006). Symptoms re-
solved after stopping the drug (Videnovic et
al., 2005).
Cytarabine Conventional doses cause little toxicity. High- Symptoms begin with somnolence and occa-
dose, 3 g/m2, every 12 hours for 6 doses can sionally encephalopathy. Immediately there-
cause an acute cerebellar syndrome in 10%– after, cerebellar signs are noted. Symptoms
25% of patients (Smith et al., 1997). range from mild ataxia to an inability to sit or
Patients older than age 50 with abnormal liver walk.
or renal function or who received a total dose No specific treatment, but cytarabine should be
> 30 g are likely to develop cerebellar toxicity stopped immediately. In some, the syndrome
(Smith et al., 1997). resolves immediately, but it is permanent in
others (Friedman & Shetty, 2001).
5-Fluoro- Rare side effects including encephalopathy, op- Symptoms of an acute onset of ataxia, dys-
uracil tic neuropathy, or seizures have been record- metria, and dysarthria can develop weeks to
ed (Pirzada et al., 2000). months after beginning treatment. Stop 5-flu-
orouracil in any patient with cerebellar toxici-
ty; with time, symptoms will resolve (Pirzada
et al., 2000).
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
342 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Table 40. Neurotoxicity of Antineoplastic Agents (Continued)
Classification Drug Incidence of Neurotoxicity Characteristic Effects and Comments
Antimetabolites Gemcitabine Up to 10% of patients experience mild paresthe- Acute inflammatory myopathy and asymmetric,
(cont.) sias during treatment, but severe peripheral painful, proximal muscle weakness can occur
and autonomic neuropathies can occur (Dor- (Ardavanis et al., 2005).
mann et al., 1998). Myositis can occur when gemcitabine is given
during or after radiation (radiation recall phe-
nomenon) (Friedlander et al., 2004).
Methotrexate Generalized or focal seizures have been report- Symptomatic patients were commonly noted to
ed among pediatric patients with acute lym- have leukoencephalopathy and/or microangi-
phocytic leukemia treated with intermediate- opathic calcifications on diagnostic imaging
dose IV methotrexate (1 g/m2) (Teva Pharma- studies (Teva Pharmaceuticals USA, 2012b).
ceuticals USA, 2012b). Symptoms such as somnolence, confusion,
Acute chemical arachnoiditis can occur after hemiparesis, transient blindness, seizures,
intrathecal methotrexate and presents with and coma may occur (Teva Pharmaceuti-
symptoms such as headache, back pain, nu- cals USA, 2012b); leucovorin administration
chal rigidity, and fever (Teva Pharmaceuticals should begin as promptly as possible. Moni-
USA, 2012b). toring of serum methotrexate concentration is
Acute neurotoxicity is most frequently seen after essential in determining optimal dose and du-
high-dose methotrexate and may develop in ration of leucovorin treatment (Teva Pharma-
the second or third week of therapy (Schmie- ceuticals USA, 2012b).
gelow, 2009).
Epothilone Ixabepilone Neurotoxicity is cumulative. Median time to on- Dose reduction of 20% is recommended for
set of grade 3–4 neuropathy was 4 cycles. patients with grade 2 (moderate) neuropa-
thy persisting ≥ 7 days (Bristol-Myers Squibb
Co., 2011c).
Interferons IFN alfa Low-dose toxicity causes tremors. High-dose Neurotoxicity tends to be dose related. High
(IFNs) toxicity is rare and includes oculomotor pal- doses can cause confusion, lethargy, halluci-
sy and sensory motor neuropathies (Rutkove, nations, and seizures (Meyers et al., 1991).
1997).
IFN alfa-2a, Incidence of neuropsychiatric depression and Motor weakness can be seen at high doses (>
IFN alfa-2b suicidal behavior was > 15% (Hensley et al., 100 million units) and reverses within days
2000). (Hensley et al., 2000).
Depression, anxiety, or emotional lability was All patients recovered upon withdrawal of drug.
seen in 4%–40% of patients (Hensley et al., Those with psychiatric history were more like-
2000). ly to develop neuropsychiatric toxicity (Hens-
ley et al., 2000).
Interleukin (IL) IL-2 Neuropsychiatric complications occur in 30%– Toxicity is dose dependent. Confusion may be
50% of patients (Denicoff et al., 1987). a dose-limiting effect of high-dose IL-2 (Pe-
trella et al., 2007).
Monoclonal Bevacizumab Posterior reverse encephalopathy syndrome Headache, seizure, lethargy, confusion, and
antibody (PRES) occurs infrequently (Seet & Rabin- blindness can occur. PRES associated with
stein, 2012). mild to moderate hypertension has been re-
ported. Symptoms can occur up to 1 year af-
ter therapy. Symptoms usually resolve after
stopping the bevacizumab and controlling hy-
pertension (Allen et al., 2006).
Protease Bortezomib Peripheral neuropathy is the main dose-limit- Peripheral neuropathy is length dependent and
inhibitors ing toxicity, and grade 1 or 2 peripheral neu- sensory rather than motor (Cata et al., 2007).
ropathies affect 33% of patients (Richardson Symptoms include reduced ankle reflexes,
et al., 2003). decreased vibration sensation, and impaired
heel-to-toe gait (Gidal, 2006). Symptoms can
improve or stabilize after patient stops or de-
creases the dose of the drug (Jagganath et
al., 2004).
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 343
Table 40. Neurotoxicity of Antineoplastic Agents (Continued)
Classification Drug Incidence of Neurotoxicity Characteristic Effects and Comments
Thalidomide Peripheral neuropathy develops in approximate- The neuropathy is partially reversible, and dose
ly 75% of patients who receive a prolonged reduction or cessation of treatment is re-
course of thalidomide (Cavaletti et al., 2004; quired in up to 60% of patients (Mileshkin et
Mileshkin et al., 2006; Tosi et al., 2005). al., 2006; Tosi et al., 2005).
Somnolence can occur and stops after a few Examine patients at monthly intervals for the
weeks on therapy. first 3 months to detect early signs of neu-
ropathy, which include numbness, tingling,
and pain in hands and feet (Celgene Corp.,
2013b).
Lenalidomide is less neurotoxic but still can
produce peripheral grade 2–3 neuropathy.
Plant alkaloids Docetaxel Sensory and motor neuropathies can occur. Treatment with docetaxel has been associat-
Grade 3 or 4 (National Cancer Institute Can- ed with the development of Lhermitte sign
cer Therapy Evaluation Program, 2006) neu- (Smith et al., 1997).
ropathies occur in less than 5% of patients
(Smith et al., 1997).
Paclitaxel Sensory and motor neuropathies are common Neuropathy with burning paresthesias of the
with paclitaxel. The incidence of grade 3 or 4 hands and feet can occur (Lee & Swain,
neuropathy occurs in patients receiving 250 2006). Paresthesias are dose dependent and
mg/m2 every 3 weeks compared to 5%–12% can be profound with numbness and a de-
with dosing of < 200 mg/m2 every 3 weeks crease in deep tendon reflexes (Postma &
(Lee & Swain, 2006). Heimans, 2000).
Vincristine Vincristine causes some degree of neuropathy. Symptoms include paresthesias of the finger-
The toxicity is severe in adults, dose dependent, tips and feet. Symptoms can occur with the
and more prominent with hepatic dysfunction first dose, may appear after the drug has been
(Donelli et al., 1998). stopped, and can progress before improving.
Autonomic neuropathy such as colicky abdom- Weakness can be mild, such as inability to walk
inal pain and constipation occurs in almost on heels or decreased strength in wrists, or
50% of patients; paralytic ileus may result more severe, such as foot drop and foot slap-
(Verstappen et al., 2005). ping when walking (Verstappen et al., 2005).
Purine analog Nelarabine In phase 2 studies, 40%–75% of patients had Peripheral neuropathy can mimic Guillain-Barré
neurotoxicity of any grade; 15%–20% were syndrome (Schiff et al., 2009). Seizures have
grade 3 (Cohen et al., 2006). been reported.
c) Concomitant cranial or spinal cord radiation therapy causes cells in
the CNS to replicate slowly or not at all. The brain and spinal cord,
and to a lesser degree the peripheral nerves, are susceptible to dam-
age by ionizing radiation that usually causes symptoms months or
years after completion of radiation treatment (Belka, Budach, Kort-
mann, & Bamberg, 2001). Radiation myelopathy may present as ear-
ly as four to six months or as late as one to two years after treatment.
Delayed radiation myopathy can occur even if the radiation dose is
considered safe or standard (Dropcho, 2010).
d) Age
(1) Cerebellar neurotoxicity of cytarabine and vincristine increases
with age. However, neurotoxicity varies with dose and route of
administration for both agents (Voss & Wilkes, 1999).
(2) Children are at higher risk than adults for ototoxicity because
children’s inner ears are not fully developed. Although chil-
dren may have a slightly greater capacity for improvement once
treatment is discontinued, profound hearing impairment can
interfere with subsequent speech and language development
(Knight, Kraemer, & Neuwelt, 2005).
(3) Older adults and pediatric patients receiving biologic agents
are at increased risk for neurotoxicity (Muehlbauer, 2011). The
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
344 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
risk and severity of chemotherapy-induced peripheral neurop-
athy appear to increase with age, and neuroprotective pharma-
cologic agents have had limited success (Visovsky, Collins, Ab-
bott, Aschenbrenner, & Hart, 2007). The drugs used to treat the
most common cancers (breast and lung) in older adults result in
neuropathy. This includes the taxanes, vinca alkaloids, platinum
complexes, thalidomide, and suramin (Malik & Stillman, 2008).
e) Acute renal injury or renal impairment can occur with high-dose
methotrexate and may be altered by drug excretion, which is related
to hydration and urinary alkalinization (Schmiegelow, 2009).
f) Steroids can lead to a variety of systemic and neurologic complica-
tions. Myopathy, which presents as skeletal muscle weakness and ten-
derness, is a common side effect associated with steroid therapy. My-
opathy may be so severe that it can impair mobility by causing in-
ability to lift arms and legs and preventing ambulation. Treatment is
dose reduction or taper with discontinuation (Owczarek, Jasińska, &
Orszulak-Michalak, 2005).
g) Preexisting neuropathy can be caused by concomitant medical con-
ditions (e.g., diabetes, vitamin B12 deficiency, thyroid dysfunction, ca-
chexia, Charcot-Marie-Tooth disease, hearing loss) (Armstrong & Gil-
bert, 2002). Peripheral neuropathy can have other etiologies includ-
ing alcoholism, HIV and other immunosuppressive illnesses, congen-
ital neuropathy, other neurotoxic medications, and exposure to cer-
tain toxins and metals (Hughes, 2002).
4. Assessment
a) Neurologic assessment enables determination of changes in the CNS,
peripheral nervous system, and CNs. The hallmark for optimal care
begins with assessment followed by documentation of findings (Bark-
er, 2008). Patient-reported symptoms as well as careful physical assess-
ment are critical in the detection of neurotoxicity.
b) Identify patients who are at increased risk for neurotoxicity based
on risk factors.
c) Perform a neurologic examination prior to each chemotherapy/bio-
therapy treatment and subsequent medical visits that includes evalua-
tion of level of consciousness, sensory and motor function, gait, range
of motion, CN function, and reflexes. Evaluation includes
(1) Peripheral neuropathy grading criteria scale (NCI CTEP, 2010)
(2) CNS deficits as described in Section 1.c
(3) CN assessment (see Table 41).
d) Assess pain. Despite a plethora of research and publications, pain con-
tinues to be common in adults with cancer (American Pain Society,
2005; NCCN, 2013a). A pathophysiologic approach to pain manage-
ment is required in patients with cancer. Such an approach includes
a patient history, physical examination, and dedicated testing to de-
termine whether pain is visceral, somatic, or neuropathic (de Leon-
Casasola & Lema, 2003). Patients describe visceral pain as gnawing,
cramping, aching, or sharp (NCCN, 2013a). Visceral pain is diffuse,
and many patients use a whole hand to describe where it hurts. With
somatic pain, patients can describe where it hurts with one finger.
Neuropathic pain usually is described as sharp, tingling, burning, or
shooting (NCCN, 2013a). Neuropathic pain caused by chemothera-
py is often distinguished by a cluster of symptoms: spontaneous pain
that is both constant and intermittent, loss of sensation, and motor
symptoms (Tofthagen, 2010). Pain is a nursing-sensitive outcome.
Nursing-sensitive outcomes are those that are attainable through or sig-
nificantly affected by interventions that are within the scope of nurs-
ing practice (Gobel, Beck, & O’Leary, 2006).
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 345
Table 41. Neurologic Assessment of the Cranial Nerves
Cranial Nerve Test Dysfunction
Olfactory I Check first for obstruction, mucus, and inflammation. Test one nostril at a time. Anosmia
Optic II Determine if patient wears glasses. Have patient read held-up fingers. Blind eye
Oculomotor III Test one eye at a time. Shine flashlight in eye; note brisk constriction. Nonreactive pupil, ptosis
Lids should not dip below top of iris (ptosis).
Ask patient to follow your finger/light as you move it up, down, and medially.
Trochlear IV Ability to move eyes down and in Inability to move eyes down
and in
Trigeminal V Patient closes eyes. Stroke three zones of face, comparing right to left. Blink reflex decreased or ab-
If awake, stroke cornea gently with cotton. Normal response is lid closure. sent
Abducens VI Ability to look out (abduct) Inability to look out
Facial VII Test all three zones; ask patient to close eyelids, wrinkle brow, raise eyebrows, Inability to close eyelids, raise
wiggle nose, pucker, show teeth, smile, and puff out cheek. eyebrows, wiggle nose, or
puff out cheeks
Acoustic VIII Ask patient to open eyelids and turn head side to side. Eyes will move to op- Eyes will not move when turn-
posite direction. ing head side to side.
Have patient close eyes, and test for sounds (tick of watch, rubbing fingers,
faint whisper).
Glossopharyngeal/ Assess patient’s gag, palate, swallow, and speech. Look for midline uvula. Palate sags on weak side.
vagus IX and X Note ability to give healthy cough. Uvula swings to strong side.
Decreased cough.
Spinal accesso- Have patient turn chin against resisting examiner’s hand. Push down on both Weakness
ry XI shoulders as patient elevates them.
Hypoglossal XII Ask patient to stick out tongue; note position and symmetry. Tongue deviates to weak side.
Ask patient to put tongue in cheek and push. Weakness
Note. From The Clinical Practice of Neurological and Neurosurgical Nursing (6th ed., p. 164), by J.V. Hickey, 2009, Philadelphia, PA: Lippincott Williams &
Wilkins. Copyright 2009 by Lippincott Williams & Wilkins. Adapted with permission.
e) Administer self-report questionnaires that assess neurologic function
and QOL at baseline and subsequent visits (Almadrones, McGuire,
Walczak, Florio, & Tian, 2004).
f) Assess hearing with audiogram prior to ototoxic chemotherapy (e.g.,
cisplatin, carboplatin) to establish baseline.
g) Older adults require different examination considerations.
(1) Use a quiet area and reduce background noise.
(2) Use a low-pitched, soft voice and address patients by surnames.
(3) Review medicines at every encounter.
(4) Always ask about pain.
(5) Do not expect a typical presentation of chronic or acute diseas-
es (Barker, 2008).
h) Assess patients’ environment to ensure safety with impaired function.
i) Assess patient and family coping.
5. Collaborative management
a) Use assessment guidelines for early detection and treatment.
b) Reduce drug dose, discontinue drug, or switch to a less neurotoxic drug
as ordered when neurologic deficits occur (Rose & Smrekar, 2003).
c) No proven pharmacologic intervention is currently available for neu-
rotoxicity prevention. Clinical trials using amifostine and glutamine
have been equivocal (Moore et al., 2003).
d) Manage concomitant medical conditions known to cause and increase
chemotherapy-related neurotoxicity (e.g., diabetes, vitamin B12 ca-
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
346 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
chexia, Charcot-Marie-Tooth disease) (Armstrong & Gilbert, 2002).
Chemotherapy-induced peripheral neuropathy is more likely to oc-
cur in individuals with baseline peripheral neuropathy (Chaudhry,
Chaudhry, Crawford, Simmons-O’Brien, & Griffin, 2003).
e) Use of vitamins and minerals to treat neurotoxic side effects
(1) Vitamin E is an antioxidant believed to protect against cellular
oxidative damage and side effects such as numbness, tingling,
burning, and pain in peripheral extremities produced by cispla-
tin and other cytotoxic drugs (Visovsky, Collins, Abbott, Aschen-
brenner, & Hart, 2007).
(2) Calcium and magnesium infusions were used in patients receiv-
ing oxaliplatin. Oxalate, an oxaliplatin metabolite, seeks and
binds to calcium and magnesium, which is responsible for the
neurotoxic effects of oxaliplatin therapy. Following infusion of
calcium and magnesium, patients experienced improvements
in pseudolaryngospasm and other clinical manifestations of
acute neurotoxicity (Gamelin et al., 2004).
(3) These studies were done with small samples and will need to
be tested further in larger randomized controlled clinical tri-
als. Other agents that are being investigated but need substan-
tiation include glutathione, N-acetylcysteine, oxcarbazepine,
and xaliproden (Fernández-de-Las-Peñas et al., 2010). More re-
cently, however, a trial was conducted in 353 patients with co-
lon cancer undergoing adjuvant therapy with FOLFOX (5-FU,
oxaliplatin, and leucovorin) who were randomized to receive
IV calcium and magnesium (1 g calcium gluconate, 1 g magne-
sium sulfate) or placebo before and after oxaliplatin (Loprinzi
et al., 2013). In a third arm in the trial, patients received calci-
um and magnesium before and placebo after the oxaliplatin.
The results showed no differences between the groups in either
acute neurotoxicity or cumulative sensory neurotoxicity, as as-
sessed both by patient and physician questionnaires.
f) Administer analgesic medications. The three most commonly used
are NSAIDs, opioids, and adjuvant agents such as tricyclic antidepres-
sants and corticosteroids (de Leon-Casasola & Lema, 2003).
g) Administer analgesics with coanalgesic medications. The effective-
ness of analgesics is variable, so drugs and dosing must be individ-
ualized. Coanalgesics were previously referred to as adjuvants. Indi-
vidualized categories of coanalgesics include anticonvulsants, antide-
pressants, and topical anesthetics. With many coanalgesics, the onset
of pain relief is delayed and analgesia may take weeks (Aiello-Laws et
al., 2009). Coanalgesics should be administered as a single agent for
management of neuropathic pain. First-line therapies include antide-
pressants, tricyclic antidepressants, selective serotonin-norepineph-
rine reuptake inhibitors, gabapentin, pregabalin, topical lidocaine,
and opioid analgesics (Dworkin et al., 2007).
h) Consider consultation with a neurologist; occupational, physical, or
speech therapist; or audiologist. Consider nerve function and mobility
tests over the course of the cancer treatment and refer patients to pre-
vent or rehabilitate nerve deficits (Hile, Fitzgerald, & Studenski, 2010).
i) Consider nonpharmacologic management (e.g., exercise, relaxation
techniques such as yoga, meditation, acupuncture, deep breathing,
and guided imagery) (Richardson, Sandman, & Vela, 2001). Neuro-
pathic pain usually does not respond to analgesics alone. In these pa-
tients, mind-body techniques may be especially worthwhile, as they may
alter the perception of pain (Deng & Cassileth, 2005). Physical activi-
ty and exercise interventions have not been studied in the prevention
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 347
or treatment of peripheral neuropathy in patients with cancer. Studies
with small sample sizes have examined progressive resistance exercise,
aerobic exercise, and stretching exercises in the treatment of diabet-
ic neuropathy and myotonic dystrophy. All three found significant im-
provements in outcomes such as stance and functional reach (Balduc-
ci et al., 2006). It has been demonstrated that acupuncture activates
both myelinated and unmyelinated nerve fibers (Zhao, 2008). Studies
of the use of acupuncture to help alleviate symptoms related to periph-
eral neuropathy have been conducted in patients with diabetes. Zhang,
Ma, and Yan (2010) reported effective treatment in both the treatment
and control group in a population of 65 patients with diabetic neurop-
athy treated with acupuncture. The study size was small, and further
randomized controlled clinical trials are needed in patients with can-
cer. Most studies to date have focused on outcomes at the impairment
level, but physical performance measures could be useful in deter-
mining functional limitations and restricted participation in response
to side effects such as neuropathy and fatigue (Gilchrist et al., 2009).
6. Patient and family education
a) Instruct patients and significant others that neurotoxicity is a possi-
ble side effect of selected cytotoxic agents. Teach strategies to manage
symptoms of autonomic dysfunction (postural hypotension, constipa-
tion, and urinary retention), such as dangling legs prior to standing,
increasing oral intake, and adding dietary fiber (Visovsky et al., 2007).
b) Emphasize patient safety issues and provide educational materials.
Teach clients strategies for managing personal safety, such as using vi-
sual input to compensate for loss of lower-extremity sensation in nav-
igating changing terrains, such as removing throw rugs and clearing
walkways of clutter (Visovsky et al., 2007). Currently, the only inter-
ventions that can be recommended for nursing practice are educa-
tion and support to preserve safety (Paice, 2007).
c) Provide information regarding signs and symptoms of neurotoxicity,
and instruct patients to report these symptoms to the physician and/
or nurse as soon as they or their families notice them.
d) Instruct patients about the risk for ischemic and thermal injuries re-
sulting from loss of sensation in the extremities. Patients should pro-
tect body parts from cold and hot temperature extremes (Visovsky et
al., 2007). Educate patients regarding foot care, including inspection
of the feet and importance of wearing properly fitted shoes.
e) Provide information about the potential side effects of medications that
can cause or change neurologic symptoms. Any changes in thinking or
behavior should be evaluated if they begin to affect the patient’s lifestyle.
f) Educate patients and significant others regarding any needed refer-
rals, support organizations, adaptations, and rehabilitative strategies.
Instruct patients to keep a notepad or diary and write down every-
thing that is important, keep a detailed calendar of events, and take
a friend or family member to doctor’s appointments.
g) Educate patients and families about seizures. Teach family members
to not restrain the person during a seizure, to turn the person’s head
to the side if vomiting with a seizure, and to avoid putting anything
in the person’s mouth during the seizure. Instruct patients to wear a
medical alert bracelet at all times. If patients have had a seizure, in-
struct them not to drive a car or operate any type of heavy machinery.
K. Cognitive impairment: Studies suggest that cancer and its treatments (i.e., sur-
gery, radiation therapy, chemotherapy, hormonal therapy, immunotherapy)
can cause changes in cognitive functioning (Joly, Rigal, Noal, & Giffard, 2011;
Khasraw & Posner, 2010; Wefel & Schagen, 2012). Cognitive function is a mul-
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
348 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
tidimensional concept that encompasses multiple domains (i.e., attention and
concentration, executive function, information processing speed, language,
motor function, visuospatial skill, learning, and memory) that are regulated
by the brain (Jansen, 2010). Cognitive impairment is a decline in function in
either one or multiple domains of cognitive function and may represent a sin-
gle highly specific deficit or a cluster of related deficits (Lezak, Howieson, Big-
ler, & Tranel, 2012; Von Ah, Jansen, Allen, Schiavone, & Wulff, 2011). Despite
heightened interest in cancer treatment–related cognitive impairment, it re-
mains the least understood toxicity. Identifying cognitive changes associated
with cancer treatments is challenging, as even patients with cancers outside of
the CNS may present with cognitive impairment prior to treatment (Jansen,
2010; Wefel & Schagen, 2012). Cognitive functioning is influenced by risk fac-
tors and confounding variables that are independent of cancer and/or cancer-
related treatment. The science defining the phenomena, potential mechanisms,
sensitive neuropsychological measures, and potential interventions is ongoing.
1. Pathophysiology: Although cancer therapies that have been associated
with cognitive changes include surgery, radiation therapy, chemothera-
py, hormonal therapy, and immunotherapy, the use of multimodal ther-
apy makes it difficult to determine the underlying mechanism for cogni-
tive impairment. In fact, the presence of cancer and tumor burden may
attribute to cognitive impairment prior to the initiation of treatment
(Wefel & Schagen, 2012). The mechanisms of cancer treatment–relat-
ed cognitive changes are thought to be multifactorial, and although an-
imal studies have elucidated many hypotheses, the actual mechanisms
for individual and multimodal treatments are still not fully understood
(Walker, 2010; Walker, Drew, Antoon, Kalueff, & Beckman, 2012). Sug-
gested mechanisms include the following.
a) Structural damage of the brain due to surgical removal of CNS tu-
mors (Jansen, 2010)
b) DNA damage due to chemotherapy or ionizing irradiation (Ahles &
Saykin, 2007; Aluise et al., 2010; Jansen, 2010)
c) Direct injury to neurons or other brain structures (including oligo-
dendrocytes, glial cells, and white matter tracts) may occur with che-
motherapy or radiation therapy (Jansen, 2010; Walker et al., 2012).
Neurotoxic effects can result in disruption of neural stem and pro-
genitor cells within the CNS, which appear to be more sensitive than
cancer cells to various chemotherapy agents (Dietrich, 2010; Dietri-
ch, Monje, Wefel, & Meyers, 2008; Vardy, Wefel, Ahles, Tannock, &
Schagen, 2008). Chemotherapy drugs shown to target neural progen-
itor cells in experimental studies include alkylating agents, carmus-
tine, cisplatin, cytarabine, 5-FU, ifosfamide, methotrexate, and thio-
tepa (Dietrich, 2010). Neural precursor cells are also sensitive to ra-
diation therapy (Fike, Rosi, & Limoli, 2009).
d) Oxidative damage: Various chemotherapy drugs, such as doxorubicin,
signal a cascade of oxidative stress that triggers cell membrane damage
and produces large amounts of free radicals (Aluise et al., 2010; Cardoso
et al., 2008; Joshi et al., 2007; Qin, He, Hai, Liang, & Liu, 2008). Oxida-
tive damage or inflammatory responses can occur with radiation thera-
py, are dose dependent, and may last weeks to months (Fike et al., 2009).
e) Telomeres are regions of repetitive nucleotide sequences at the end
of a chromosome. They are important for supporting chromosomal
stability and for cell division, such that increased telomere shorten-
ing due to oxidative stress can lead to cell death (Walker et al., 2012).
f) Hormone-mediated effects: Estrogen is thought to play a neuropro-
tective role in the brain by relieving oxidative stress (Ahles & Saykin,
2007). Chemotherapy often induces menopause and lowers estro-
gen levels, and aromatase inhibitors can decrease synthesis of estro-
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 349
gen in the peripheral tissues (Walker et al., 2012). Androgen recep-
tors are also present in the brain; therefore, the use of androgen de-
privation therapy can affect cognitive functioning (Grunfeld, Halli-
day, Martin, & Drudge-Coates, 2012; Jansen, 2010).
g) Cytokine dysregulation: Cytokines are proteins that have a role in neu-
ral function and repair and the metabolism of neurotransmitters. In-
creased levels of cytokines may activate a stress cascade that can affect
cognition (Myers, 2010). Although many chemotherapeutic agents are
not able to cross the blood-brain barrier, they can stimulate a release
of proinflammatory cytokines in response to cell injury. This release
leads to an elevation in circulating TNF-α that can cross the blood-
brain barrier and cause excessive levels of CNS cytokines, resulting in
cognitive impairment (Aluise et al., 2010; Konat, Kraszpulski, James,
Zhang, & Abraham, 2008; Raffa, 2011). One study found higher lev-
els of IL-6, IL-8, and monocyte chemotactic protein-1 in patients on
regimens containing doxorubicin with cyclophosphamide or cyclo-
phosphamide plus 5-FU compared to patients receiving cyclophos-
phamide, methotrexate, and 5-FU treatment (Janelsins et al., 2012).
h) Leukoencephalopathy: Structural alterations in cerebral white mat-
ter can occur with cranial irradiation (Ricard, Taillia, & Renard,
2009). White matter changes have also been reported with various
chemotherapy and targeted agents such as bevacizumab, bortezomib,
capecitabine, carmustine, cisplatin, cytarabine, docetaxel, erlotinib,
etoposide, 5-FU, fludarabine, gemcitabine, IFNs, L-asparaginase, le-
vamisole, melphalan, methotrexate, paclitaxel, procarbazine, ritux-
imab, sorafenib, sunitinib, thalidomide, and vincristine (Rinne, Lee,
& Wen, 2012; Wefel & Schagen, 2012).
i) Anemia: Insufficient brain oxygenation is associated with cognitive
problems in multiple domains such as attention and concentration,
executive functioning, motor function, and memory (Lezak et al.,
2012). In one study of patients with hematologic cancers who had
not received any previous or current treatment, an Hgb level ≤ 10
g/dl was associated with cognitive impairment, especially in the do-
mains of attention, motor function, and verbal memory (Wood et al.,
2011). Patients with cancer may experience anemia as a result of pri-
mary or metastatic cancer involvement of the bone marrow or bones
or because of cancer treatments such as chemotherapy and radiation
therapy (Jansen, 2010).
2. Incidence: The incidence of treatment-related cognitive changes is diffi-
cult to determine because many factors influence cognition. Many of the
earlier studies were limited by their cross-sectional study design, which
lacked baseline neuropsychological testing and consisted of small sam-
ple sizes. There is a growing evidence base for cancer and cancer treat-
ment–related cognitive changes that incorporates objective and subjec-
tive measures, as well as genetic and radiologic tests (see Table 42). It is
important to include predisposing factors and to evaluate for presence
of impairment prior to treatment, use of combination therapies, and dif-
ferences in sample characteristics to attempt to differentiate what cogni-
tive changes are truly treatment related.
a) Chemotherapy-related cognitive changes have been predominant-
ly studied in patients with breast cancer. Evidence to support wheth-
er chemotherapy-induced cognitive changes exist or are due solely
to chemotherapy is inconclusive. However, it is estimated that up to
75% of patients with cancer experience cognitive impairment dur-
ing or after cancer treatment (Janelsins et al., 2011).
b) Evidence of cognitive impairment prior to treatment has been found
(Wefel & Schagen, 2012).
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
350
Table 42. Evidence of Cancer Treatment–Related Cognitive Changes
Author Cognitive
Type of and Year Sample Characteristics Domains
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Cancer Published Treatment Specifics and Study Designs Assessed Results and Conclusions
Breast Abraham et Chemotherapy: AC, AC plus a N = 19; 10 with breast cancer, 9 healthy con- IPS There was a significant difference between groups
al., 2008 taxane trols in IPS (p = 0.005), with patients with poorer per-
Hormonal therapy: Anastrozole, Mean age (standard deviation): 49.8 (8.0) formance. Of note, patients had significantly more
tamoxifen breast cancer patients, 46.8 (6.8) controls anxiety (p = 0.36), which was correlated with IPS
Cognitive testing done at one time (an aver- (p < 0.05). Diffusion tensor imaging results of de-
age of 22 months since completion of che- creased cerebral white matter were also correlated
motherapy) with decreased IPS (p < 0.05). Findings are limited
in this pilot study because of a small sample, lack
of baseline data, and lack of a comparison group
that contained patients with breast cancer who did
not receive chemotherapy.
Ahles et al., Chemotherapy: AC, AC-T, CAF, N = 177; 60 chemotherapy patients, 72 AC, EF, IPS, Significant difference was found in L (p = 0.01) as
2010 CMF, FEC, TAC breast cancer controls, 45 healthy controls L, VerM, the control groups improved over time but the che-
Hormonal therapy: Anastrozole, Mean age (standard deviation): 51.7 (7.1) VisM, and motherapy group did not. Patients treated with
raloxifene, tamoxifen chemotherapy patients, 56.6 (8.3) breast a subjective tamoxifen performed worse than healthy controls in
cancer controls, 52.9 (10) healthy controls measure IPS (p = 0.16), L (p = 0.023), and VerM (p = 0.018).
Cognitive testing completed prior to the start There was a significant increase in cognitive com-
of chemotherapy and repeated at 1, 6, and plaints by chemotherapy patients compared to the
18 months after treatment two control groups (p < 0.05). Although there were
significant differences in anxiety (p = 0.002), de-
pression (p < 0.001), and fatigue (p = 0.011) be-
tween groups, these were not correlated with neu-
ropsychological test outcomes. There was a signifi-
cant difference in age (p = 0.003) between groups.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Of note, older patients with lower baseline cogni-
tive reserve who received chemotherapy had poor-
er performances in IPS than patients with breast
cancer (p = 0.003) and healthy controls (p < 0.001).
Study findings are limited by the focus on age and
cognitive reserve.
Breckenridge Hormonal therapy: Tamoxifen, N = 133; 77 exposed to endocrine therapy, AC, EF, MF, No differences were seen between the groups in
et al., 2012 aromatase inhibitor, combina- 56 controls and a subjec- objective measures. However, patients who re-
tion of both, or other not de- Mean age (standard deviation): 44.93 (9.99) tive measure ceived hormonal therapy reported significantly
fined endocrine group, 44.80 (8.88) controls of AC, EF, M, more perceived cognitive impairments (p < 0.05).
Cognitive testing done at one time; time since and VS Anxiety, depression, and fatigue significantly affect-
primary treatment ranged from 1–10 years ed perceptions of cognitive impairment but not ob-
for participants in both groups jective measures. Study results are difficult to inter-
pret because > 80% of patients in both groups had
received chemotherapy (regimens not defined).
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 42. Evidence of Cancer Treatment–Related Cognitive Changes (Continued)
Author Cognitive
Type of and Year Sample Characteristics Domains
Cancer Published Treatment Specifics and Study Designs Assessed Results and Conclusions
Breast (cont.) Collins et al., Chemotherapy: Various regi- N = 93; 53 receiving chemotherapy, 40 con- AC, EF, IPS, Significant decline was noted in patients on che-
2009a mens including AC, AC-T, AP, trols on hormonal therapy L, MF, VerM, motherapy compared to controls 1 month after che-
CEF, EC-T, FAC, FEC Mean age (standard deviation): 57.9 (3.7) VisM, VS motherapy (p = 0.02). However, no differences in
Hormonal therapy including chemotherapy patients, 57.6 (4.0) controls cognitive decline were found between groups at
tamoxifen, anastrozole, letro- Cognitive testing before chemotherapy and 1 the final testing. Of note, those who received che-
zole month and 1 year after completion of che- motherapy and hormonal therapy had significant-
motherapy ly decreased scores in IPS (p = 0.01) and VerM
(p = 0.01) than those who received chemotherapy
alone. Results are difficult to interpret because of
multiple chemotherapy regimens and attrition. Hor-
monal therapy may contribute to cognitive impair-
ments.
Collins et al., Hormonal therapy: Anastrozole N = 73; 14 on anastrozole, 31 on tamoxifen, AC, EF, IPS, Patients on hormonal therapy were more likely to
2009b or tamoxifen 28 healthy controls L, MF, VerM, show declines in cognitive functioning over time
Mean age (standard deviation): 57.8 (4.4) an- VisM, VS with deficits present in 64% in patients on anastro-
astrozole patients, 57.5 (4.0) tamoxifen pa- zole, 39% in those taking tamoxifen, and only 7% in
tients, 59.3 (4.2) controls healthy controls. Significant differences existed be-
Cognitive testing done after surgery and tween healthy controls and all patients on hormonal
around the time of the initiation of hormonal therapy in IPS (p = 0.02) and VerM (p = 0.003) for
therapy and repeated in 5–6 months patients on anastrozole. Results may be skewed as
some patients had already started hormonal thera-
py prior to baseline testing.
Debess et Chemotherapy: CEF N = 238; 120 patients with breast cancer (75 AC, EF, IPS, No differences were found in either objective or
Chapter 9. Side Effects of Cancer Therapy
al., 2010 Hormonal therapy: Tamoxifen who received chemotherapy, 26 hormonal VerM, VisM, perceived cognitive functioning between groups.
therapy, 19 with no treatment), 208 controls and a subjec- Study is limited by significant differences in age,
Mean age: 47.2 chemotherapy patients, 56.2 tive measure educational level, and menopausal status between
hormonal therapy patients, 49.7 breast can- of AC, mental groups. All of these factors are known to affect per-
cer controls, 48.1 healthy controls burden, vitali- formance on cognitive tests.
Cognitive testing done prior to chemotherapy ty, M, and CF
and after 6 months
351
(Continued on next page)
352
Table 42. Evidence of Cancer Treatment–Related Cognitive Changes (Continued)
Author Cognitive
Type of and Year Sample Characteristics Domains
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Cancer Published Treatment Specifics and Study Designs Assessed Results and Conclusions
Breast (cont.) Deprez et al., Chemotherapy: FEC or FEC-T N = 39; 14 post-chemotherapy patients, 10 AC, EF, IPS, Patients who had received chemotherapy per-
2011 Hormonal therapy: Tamoxifen breast cancer controls, 15 healthy controls L, MF, VerM, formed significantly worse in AC, IPS, and MF
Mean age (standard deviation): 45.4 (4.5) VisM, and (p < 0.001) than healthy controls. They also report-
chemotherapy patients, 42.9 (6.15) breast a subjec- ed cognitive problems with distraction (p = 0.02).
cancer controls, 45.1 (4.0) healthy controls tive measure Neuropsychological testing was not done for breast
Cognitive testing done in chemotherapy pa- of CF cancer controls. Significant decreases in white mat-
tients after completion of therapy (range ter integrity were found in chemotherapy patients
80–160 days) as well as in healthy controls compared to either control group (p < 0.05). In con-
Magnetic resonance diffusion tensor imaging trast, no differences were found between the two
done in all three groups to evaluate cere- control groups. Of note, self-reports of cognitive im-
bral white matter integrity pairment were significantly correlated with chang-
es in white matter integrity (p < 0.005). One limi-
tation of this study is the use of tamoxifen by pa-
tients in the chemotherapy and breast cancer con-
trol groups, which may have an effect on cognition.
In addition, the lack of baseline testing makes it dif-
ficult to ascertain whether cognitive impairments
can be directly attributed to treatment (either che-
motherapy or hormonal therapy).
Deprez et al., Chemotherapy: FEC or FEC-T N = 69; 34 chemotherapy patients, 16 breast AC, EF, IPS, Patients treated with chemotherapy performed sig-
2012 Hormonal therapy: Tamoxifen cancer controls, 19 healthy controls L, MF, VerM, nificantly worse in AC, IPS, and VerM in contrast to
Mean age (standard deviation): 43.7 (6.1) VisM, and control groups, which performed better over time
chemotherapy patients, 43.1 (5.7) breast a subjec- (p < 0.05). Significant decreases in white matter in-
cancer controls, 43.8 (4.9) healthy controls tive measure tegrity were found over time in frontal, parietal, and
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Cognitive testing done after surgery but prior of CF occipital white matter tracts of patients who re-
to the start of chemotherapy as well as 3–5 ceived chemotherapy (p < 0.05) but were not found
months after the completion of treatment in either control group. Of note, significant correla-
Magnetic resonance diffusion tensor imaging tions were found between cognitive complaints and
done in all three groups to evaluate cere- impairments in attention (p ≤ 0.05), verbal memory
bral white matter integrity (p = 0.026), and language (p = 0.02). One limita-
tion of this study is the use of tamoxifen by patients
in the chemotherapy and breast cancer control
groups, which may have an effect on cognition.
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 42. Evidence of Cancer Treatment–Related Cognitive Changes (Continued)
Author Cognitive
Type of and Year Sample Characteristics Domains
Cancer Published Treatment Specifics and Study Designs Assessed Results and Conclusions
Breast (cont.) Jansen et al., Chemotherapy: AC with or with- N = 71 AC, EF, L, 23% of patients had cognitive impairment prior to
2011 out a taxane Mean age (standard deviation): 50.3 (8.8) M, MF, VS, initiation of chemotherapy in L, VS, MF, immediate
Cognitive testing done prior to chemothera- and a subjec- M, and/or AC. No cognitive changes were found for
py and approximately 1 week after 4 cycles tive measure immediate M, L, or EF over time. However, a signifi-
of AC, 1 week after completing taxane, and of CF cant effect of time was found for AC (p = 0.022), VS
6 months after completing all chemotherapy (p < 0.001), delayed M (p = 0.006), MF (p = 0.043),
and the total cognitive score (p < 0.001). The trajec-
tory for most tests showed a general decline during
treatment followed by improvement within 6 months
after chemotherapy. However, VS did not improve to
baseline at that time. Cognitive changes were not
related to anemia, anxiety, depression, fatigue, or
patient perception of cognitive functioning. Howev-
er, self-reported cognitive problems were associ-
ated with anxiety, depression, and fatigue. Study is
limited by lack of a control group.
Kesler et al., Chemotherapy: Regimens in- N = 62; 25 chemotherapy patients, 19 breast EF, IPS, L, Significant reductions in prefrontal and premotor
2011 cluded AC, AC-D, AC-T, CAF, cancer controls, 18 healthy controls and a subjec- cortex activity were found in patients with breast
CEF-D, CMF, carboplatin + Mean age (standard deviation): 56.2 (7.2) tive measure cancer compared to healthy controls (p = 0.001).
docetaxel, or cyclophospha- chemotherapy patients, 58.1 (6.5) breast of EF Patients who received chemotherapy had signifi-
mide and either paclitaxel or cancer controls, 55.6 (9.4) healthy controls cantly poorer performances in EF than controls
docetaxel Cognitive testing done at one time (p = 0.02). Chemotherapy patients reported more
Hormonal therapy: 56% of che- difficulty with executive functioning (p = 0.001).
motherapy patients and 53% Findings are limited by lack of baseline testing and
Chapter 9. Side Effects of Cancer Therapy
of breast cancer controls on small sample size.
tamoxifen
Koppelmans Chemotherapy: CMF N = 1,705; 196 on chemotherapy, 1,509 con- EF, IPS, L, Women who received chemotherapy had signifi-
et al., 2012 trols MF, VerM, VS cantly poorer performance in EF (p = 0.013), IPS
Mean age (standard deviation): 64.1 (6.4) (p < 0.001), and motor speed (p = 0.001), as well
chemotherapy patients, 57.9 (5.4) controls as immediate (p = 0.015) and delayed VerM (p =
Cognitive testing done at one time (average 0.002). A limitation of this study is the lack of base-
time since treatment = 21 years) line testing prior to chemotherapy and a signifi-
cant difference in age (p < 0.001) between groups,
which may influence neuropsychological testing re-
sults.
353
(Continued on next page)
354
Table 42. Evidence of Cancer Treatment–Related Cognitive Changes (Continued)
Author Cognitive
Type of and Year Sample Characteristics Domains
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Cancer Published Treatment Specifics and Study Designs Assessed Results and Conclusions
Breast (cont.) Legault et al., Hormonal therapy: Tamoxifen or N = 1,498; 733 on tamoxifen, 765 on ralox- AC, L, MF, There were no differences between treatment
2009 raloxifene ifene VerM, VisM, groups. However, there were significant differenc-
Mean age (standard deviation): 70.1 (4.2) VS es over time in VS (p < 0.0001), VerM (p < 0.0001),
tamoxifen patients, 69.7 (4.2) raloxifene pa- VisM (p < 0.0001), and some measures of L
tients (p < 0.0001). A limitation of the study is the lack of
Cognitive testing started after initiation of a control group. In addition, only 273 patients had
therapy for most patients, then repeated 1 baseline testing done prior to the start of therapy.
and 2 years later
Mehlsen et Chemotherapy: CEF N = 58; 34 chemotherapy patients, 12 cardiac EF, IPS, L, No differences in cognitive functioning over time
al., 2009 Hormonal therapy: tamoxifen patients, 12 healthy controls VerM, VisM, were found. Additionally, there was no difference
(19 patients with cancer) Mean age (standard deviation): 48.6 (8.0) pa- VS and a in reliable decline or improvement in cognition be-
tients with cancer, 50.4 (9.1) cardiac pa- subjective tween groups. However, patients with cancer re-
tients, 39.3 (11.7) controls measure of ported significantly more negative changes in
Cognitive testing done prior to chemotherapy AC, M memory and concentration (p < 0.01). Findings are
and approximately 4–6 weeks after the last limited by small sample size.
cycle of treatment
Noal et al., Chemotherapy: FEC, FEC-D, N = 302; 161 receiving chemotherapy plus AC, EF, IPS, Cognitive impairment was found prior to the start of
2010 other not specified radiation, 141 receiving radiation therapy VerM radiation therapy in both groups. Interpretation of
Radiation therapy Median age: 53 chemotherapy patients, 58 results is difficult because of limited data reported
Hormonal therapy: Tamoxifen, radiation therapy–only patients and lack of a control group. Hormonal therapy may
aromatase inhibitor, or tamox- Cognitive testing done prior to the start of ra- have affected results.
ifen with luteinizing hormone- diation therapy, at 3 weeks, at the end of
releasing hormone treatment, and at 4 and 12 months after the
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
completion of radiation therapy
Phillips et al., Hormonal therapy: Tamoxifen, N = 120; 55 tamoxifen, 65 letrozole AC, L, MF, There was a significant difference with patients on
2010 letrozole Mean age (standard deviation): 64.15 (7.52) VerM, VisM letrozole with better overall cognitive function
tamoxifen patients, 63.25 (6.67) letrozole (p = 0.04). Findings are difficult to interpret be-
patients cause of lack of baseline testing prior to the start of
Cognitive testing done after completion of 5 therapy. Some of the participants were in arms that
years of treatment with hormonal therapy crossed over to the alternate hormonal agent after
two years.
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 42. Evidence of Cancer Treatment–Related Cognitive Changes (Continued)
Author Cognitive
Type of and Year Sample Characteristics Domains
Cancer Published Treatment Specifics and Study Designs Assessed Results and Conclusions
Breast (cont.) Phillips et al., Chemotherapy regimens: AC, N = 449; 96 receiving chemotherapy plus ra- AC, EF, IPS, There was a significant difference in the groups
2012 AC-D, AC-T, AD, CMF, FEC, diation therapy, 113 receiving radiation ther- VerM, VisM over time for IPS (p = 0.009) with controls improv-
FEC-T apy only, 240 controls ing over time. At each testing, controls performed
Hormonal therapy (48% of che- Mean age (standard deviation): 52.01 (8.84) better than patients who received treatment in EF
motherapy plus radiation ther- chemotherapy plus radiation therapy group, (p = 0.006). No differences were found between pa-
apy and 76% of radiation ther- 57.30 (8.57) radiation therapy–only group, tients who received hormonal therapy versus those
apy–only groups): Tamoxifen, 56.58 (8.60) healthy controls who did not.
anastrozole, toremifene, or le- Cognitive testing done 6 months after com-
trozole pleting radiation therapy and 36 months lat-
er
Quesnel et Chemotherapy regimens: AC, N = 126; 41 receiving chemotherapy, 40 re- AC, EF, IPS, Significant effects of time were found in VerM (p <
al., 2009 FEC, TAC ceiving radiation therapy only, 45 controls L, VerM, 0.01) for both patient groups. In contrast, a signif-
Hormonal therapy: Tamoxifen in Mean age (standard deviation): 50.3 (7.2) VisM, and icant group-by-time interaction was found only in
87.1% of chemotherapy and chemotherapy patients, 57.7 (4.9) radiation subjective patients receiving chemotherapy, signifying a de-
80.7% of radiation therapy pa- therapy–only controls measures of cline in L (p < 0.01). A significant effect of time was
tients; anastrozole in 12.9% of Cognitive testing done in patients prior to CF found in chemotherapy patients for reported cogni-
chemotherapy and 19.3% of therapy, immediately after their first treat- tive problems (p = 0.02). One limitation of this study
radiation therapy patients ment, and 3 months after completion of all is the use of hormonal therapy in several patients,
chemotherapy which might have influenced cognitive scores.
Reid-Arndt et Chemotherapy regimens: AC, N = 46 EF, IPS, L, As a group, there were no differences over time.
al., 2010 AC-D, AC-T Mean age (standard deviation): 53.38 (9.61) VerM Results must be interpreted with caution because
Hormonal therapy: 41% re- Cognitive testing done 1, 6, and 12 months improvement may have been due to practice ef-
ceived tamoxifen after chemotherapy fects. Study findings are limited by the lack of base-
Chapter 9. Side Effects of Cancer Therapy
line testing prior to the initiation of chemotherapy
and small sample size (especially with 28% dropout
rate). A control group would have been beneficial to
determine whether patients improved as much as
either healthy or nontreated controls.
Ribi et al., Hormonal therapy: Tamoxi- N = 100 AC, EF, IPS, No differences were found either between treat-
2012 fen, letrozole, or sequence of Mean age not reported VerM, VisM, ment groups or over time for subjective cognitive
tamoxifen and letrozole Cognitive testing done after completion of 5 and a subjec- measures. Objective and subjective measures of
Chemotherapy: Unclear how years of hormonal therapy and repeated 1 tive measure cognitive functioning were not correlated. A limita-
many patients received che- year later of CF tion of this study is the lack of baseline testing prior
motherapy prior to hormon- to the initiation of hormonal therapy as well the lack
al therapy of a non-treatment control group.
355
(Continued on next page)
356
Table 42. Evidence of Cancer Treatment–Related Cognitive Changes (Continued)
Author Cognitive
Type of and Year Sample Characteristics Domains
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Cancer Published Treatment Specifics and Study Designs Assessed Results and Conclusions
Breast (cont.) Scherling et Chemotherapy: AC, FEC-D, TC N = 46; 23 on chemotherapy, 23 healthy con- AC, EF, IPS, A significant decrease in white matter volume was
al., 2012 trols L, VerM, found in patients with cancer compared to controls
Mean age (standard deviation): 51 (8.5) che- VisM, and prior to initiation of chemotherapy. Neuropsycholog-
motherapy patients, 50 (9) controls magnetic res- ical test results were not reported. Whether these
Cognitive testing done prior to the start of onance im- findings are of importance would be determined
chemotherapy aging with follow-up after initiation of chemotherapy.
Schilder et Hormonal therapy: Tamoxifen N = 330; 92 patients with breast cancer on AC, EF, IPS, At baseline, patients had significantly lower cogni-
al., 2010 and exemestane tamoxifen, 114 receiving exemestane, 124 L, MF, VerM, tive scores (p = 0.03). Review of specific domains
controls VisM revealed significantly lower performance only in L
Age not reported (p < 0.01). Although differences were not found be-
Cognitive testing done after surgery but pri- tween patients on exemestane and controls, pa-
or to start of hormonal therapy and repeat- tients receiving tamoxifen had significant deficits
ed 1 year later on EF (p = 0.01) and VerM (p < 0.01) over time. In
addition, patients on tamoxifen scored lower than
those on exemestane on IPS (p = 0.02). A limitation
of this study is the short-term follow-up because
hormonal therapy is generally given for 5 years.
Schilder et Hormonal therapy: Tamoxifen N = 299; 80 on tamoxifen, 99 on exemestane, Subjective At baseline, healthy controls reported significant-
al., 2012 and exemestane 120 healthy controls measures of ly more cognitive problems on subjective measures
Age (standard deviation): 68.7 (7.6) tamox- CF (p = 0.004). However, there were no differences be-
ifen patients, 68.3 (6.8) exemestane pa- tween groups on prevalence of self-reported cogni-
tients, 66.2 (7.9) healthy controls tive complaints as measured by the interview ques-
Subjective cognitive measures done after tions. One year after baseline, healthy controls con-
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
surgery but prior to start of hormonal thera- tinued to report the highest frequency of cognitive
py and repeated 1 year later problems (p = 0.003). A limitation of this study is
the short-term follow-up because hormonal therapy
is generally given for 5 years. Objective measures
reported in another publication (see Schilder et al.,
2010 in previous row).
Small et al., Chemotherapy: AC, AC-D, AC-T, N = 334; 72 receiving chemotherapy, 58 re- AC, EF, L, Although differences were not found between can-
2011 CMF, CAF, CEF ceiving radiation therapy, 204 healthy con- MF, VerM, cer survivors and healthy controls, significant dif-
trols VisM ferences was found related to genotype, with cate-
Mean age (standard deviation): 51.22 (8.63) chol-O-methyltransferase (COMT)-Met homozygote
chemotherapy patients, 56.93 (9.01) radia- carriers outperforming COMT-Val carriers
tion therapy patients, 57.07 (9.52) healthy (p = 0.002).
controls
Cognitive testing done approximately 6
months after completion of chemotherapy
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 42. Evidence of Cancer Treatment–Related Cognitive Changes (Continued)
Author Cognitive
Type of and Year Sample Characteristics Domains
Cancer Published Treatment Specifics and Study Designs Assessed Results and Conclusions
Breast (cont.) Tager et al., Chemotherapy regimens: AC, N = 61; 30 on chemotherapy, 31 controls AC, EF, L, A significant time-by-treatment interaction was
2010 AC-T, CMF Mean age: 60.7 MF, VerM, found for MF (p = 0.007), revealing poorer perfor-
Hormonal therapies: Tamoxifen, Cognitive testing done prior to start of che- VisM, VS mance in those who received chemotherapy. How-
anastrozole motherapy and 6 and 12 months after treat- and a subjec- ever, these results may have been influenced by
ment tive measure peripheral neuropathy in those who received tax-
of CF anes. Although women reported memory prob-
lems at all time periods, these were related to anx-
iety and depression and not correlated with objec-
tive measures. A limitation of the study is the inclu-
sion of multiple chemotherapy regimens; some pa-
tients were also taking hormonal therapy at later
testing periods.
Vearncombe Chemotherapy regimens: AC, N = 159; 138 chemotherapy patients, 21 AC, EF, IPS, A significant effect of time was found for AC (p <
et al., 2009 AC-D, AC-T, CAF, CD, CMF, breast cancer controls L, MF, VerM, 0.001), IPS (p < 0.001), VerM (p < 0.001), and VisM
FEA, FEC, FEC-D Mean age (standard deviation): 49.38 (7.92) VisM (p < 0.01) only in the chemotherapy group. Signifi-
chemotherapy group, 53.98 (8.24) control cant differences between the two groups in meno-
group pausal status (p < 0.001) and time between testing
Cognitive testing done initially after surgery intervals (p < 0.001) may have affected results.
but prior to start of chemotherapy and re-
peated approximately 4 weeks after com-
pletion of chemotherapy
Vearncombe Chemotherapy regimens: AC, N = 121; 23 premenopausal patients, 43 pa- AC, EF, IPS, A significant effect of time was found for AC (p <
et al., 2011 FEC tients with chemotherapy-induced meno- L, MF, VerM, 0.001), one measure of EF (p < 0.001), and IPS
Chapter 9. Side Effects of Cancer Therapy
Hormonal therapy: Not specified pause, 55 postmenopausal patients VisM (p < 0.001), L (p = 0.002), VerM (p < 0.001), and
Mean age (standard deviation): 39.48 (4.96) VisM (p ≤ 0.001). These findings revealed a decline
premenopausal, 46.78 (3.68) chemothera- in cognitive functioning immediately after treatment
py-induced menopause, 55.77 (5.42) post- with subsequent improvement in performance over
menopausal time. A significant difference was found in EF over
Cognitive testing done at baseline after sur- time (p = 0.14) with improvement in pre- and post-
gery but prior to chemotherapy and approx- menopausal groups; however, there was no change
imately 1, 6, and 18 months after comple- in the chemotherapy-induced menopause group.
tion of chemotherapy Because estrogen levels were not measured, it is
difficult to determine definitively if patients had che-
motherapy-induced menopause.
357
(Continued on next page)
358
Table 42. Evidence of Cancer Treatment–Related Cognitive Changes (Continued)
Author Cognitive
Type of and Year Sample Characteristics Domains
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Cancer Published Treatment Specifics and Study Designs Assessed Results and Conclusions
Breast (cont.) Weis et al., Chemotherapy regimens: AC, N = 90 AC, IPS, At the final testing, 21% of patients met the au-
2009 AC-D, AC-T, CMF, CMF + ei- Mean age (standard deviation): 49.7 (7.6) VerM, VisM, thors’ criteria for clinically relevant cognitive deficits;
ther doxorubicin or epirubicin, Cognitive testing done at the start of inpatient and a subjec- however, this was based on objective or subjective
EC, EC-D, EC-T rehabilitation (shortly after conclusion of tive measure measures, or a combination of both. This study is
Hormonal therapy: Tamoxifen acute therapy), at the end of rehabilitation of CF limited by the lack of baseline testing prior to initia-
(average 26 days), and 6 months later tion of treatment, lack of a control group, and high
percentage of patients on hormonal therapy (72%),
which may contribute to test results. It is not clear
whether the rehabilitation program may have con-
tributed to improvement in cognitive functioning.
Central Correa et al., Chemotherapy: High-dose meth- N = 50; 24 received chemotherapy with AC, EF, L, The chemotherapy plus WBRT group was signif-
nervous 2012 otrexate plus a variety of oth- WBRT, 26 received chemotherapy alone MF, VerM, icantly younger (p ≤ 0.001) and tested at a lat-
system tumors er agents that included procar- Mean age (standard deviation): 53.5 (8.9) and a subjec- er date after completion of treatment (p < 0.0001).
bazine, vincristine, and high- chemotherapy with WBRT group, 70.6 (8.2) tive measure However, when controlling for age and time since
dose cytarabine chemotherapy-only group of CF treatment, patients receiving chemotherapy alone
Radiation therapy: WBRT Cognitive testing done after completion of were found to perform significantly better in some
treatment (50.3 [39.5] months for che- measures of attention (p < 0.04) and VerM (p <
motherapy plus WBRT group, 14.9 [12.5] 0.02). Follow-up testing revealed that patients who
months for chemotherapy-only group), and received chemotherapy alone still performed sig-
additional follow-up assessment in 33 pa- nificantly better on tests of attention (p = 0.04). Re-
tients (16.2 [18.3] months for the combined- sults are limited by small sample size, especially at
modality group, 14.1 [12.0] months for the follow-up testing. Another limitation is the lack
those on chemotherapy alone) of baseline testing prior to initiation of therapy.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Hahn et al., Radiation therapy: Partial brain N = 11 (only 6 patients completed all testing) AC, EF, VerM, Results indicated increases in relative blood flow
2009 irradiation Mean age: 48 VisM and a with increasing doses at 3 weeks (p = 0.037) and 6
Cognitive testing done prior to the initiation of subjective months (p = 0.072). No changes were found in AC,
radiation therapy, then repeated at 3 weeks measure of VerM, or VisM. However, decreased fluorodeoxy-
and 6 months. This was compared to cen- CF glucose uptake was correlated with EF (p = 0.037)
tral nervous system metabolism measured and increased symptoms on the subjective mea-
by positron-emission tomography. sure (p < 0.0001). Interpretation of results is difficult
because of the small sample size, especially at fol-
low-up. In addition, tumor location may have an im-
pact on testing deficits.
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 42. Evidence of Cancer Treatment–Related Cognitive Changes (Continued)
Author Cognitive
Type of and Year Sample Characteristics Domains
Cancer Published Treatment Specifics and Study Designs Assessed Results and Conclusions
Central Hilverda et Chemotherapy: Temozolomide N = 13 AC, EF, IPS, Eleven patients had cognitive impairment prior to
nervous al., 2010 Radiation therapy Mean age not reported MF, VerM the start of treatment. Although changes did occur
system tumors Cognitive testing done initially after surgery in individuals, overall cognitive impairment was sta-
(cont.) but before radiation therapy or chemothera- ble over time. However, it is difficult to make any
py, and repeated after 6 weeks of radiation conclusions because of the small sample size and
therapy with chemotherapy and after three lack of a control group.
cycles of adjuvant chemotherapy that was
given after radiation therapy
Colorectal Galica et al., Chemotherapy: 5-FU alone, or N = 74 (those who completed cognitive test- AC, EF, IPS, Although cognitive function was not the prima-
2012 with oxaliplatin or radiation, or ing); 16 prechemotherapy patients, 13 post- MF, VisM ry outcome, no group differences were found. This
capecitabine alone or with ox- surgery controls, 20 after completion of study is limited by lack of baseline testing in all
aliplatin chemotherapy, 15 six-months postsurgery groups, which may have affected results.
controls
Mean age not reported
Cognitive testing was done at the time based
on group assignment, then repeated at 6,
12, and 24 months. However, only baseline
data were presented in this publication.
Head and neck Gan et al., Radiation therapy alone or with N = 10; 5 underwent radiation therapy alone, AC, EF, IPS, Based on individual intelligence, cognitive perfor-
2011 chemotherapy (cisplatin) 5 received chemotherapy and radiation L, MF, VerM, mance was lower than expected for all cognitive do-
Mean age: 58.1 VisM, and a mains with the exception of language. However, pa-
Cognitive testing done at one time only with a subjective tients did not report cognitive problems. Interpreta-
mean time from the end of treatment of 20 measure of tion of results is difficult because of the small sam-
Chapter 9. Side Effects of Cancer Therapy
months (range 9–41) CF ple size, lack of baseline testing, and multiple co-
variates.
Hematologic Chang et al., Chemotherapy: Patients with N = 106; 91 with CML, 15 with MDS AC, EF, MF, Overall, significant time effects were found in VerM
2009 chronic myeloid leukemia Mean age (standard deviation): 45.2 (11.9) VerM (p < 0.0016) with improved scores at the final as-
(CML) treated with either ima- CML group, 64.8 (9.3) MDS group sessment regardless of treatment. Patients who un-
tinib mesylate, hydroxyurea, Cognitive testing done at baseline and re- derwent HSCT had worse MF than those who re-
or interferon; patients with my- peated 12 and 18 months after initial as- ceived other treatments (p = 0.05). Difficult to com-
elodysplastic syndrome (MDS) sessment pare groups by diagnosis because of the small
treated with hydroxyurea, number of patients with MDS.
5-azacitidine, or no chemo-
therapy
HSCT: Regimen not reported;
94% underwent TBI
359
(Continued on next page)
360
Table 42. Evidence of Cancer Treatment–Related Cognitive Changes (Continued)
Author Cognitive
Type of and Year Sample Characteristics Domains
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Cancer Published Treatment Specifics and Study Designs Assessed Results and Conclusions
Hematologic Jim et al., HSCT: Regimen not reported N = 278; 78% in group A, 13% in group B, AC, EF, MF, Patients with a greater number of risk factors had
(cont.) 2012 Chemotherapy treatment prior 9% in group C VerM, VisM poorer total cognitive functioning at baseline and at
to HSCT was variable (range Mean age (standard deviation): 50.5 (12.52) 6 months post HSCT, as well as less recovery over
of 0–7 regimens). In addition, Cognitive testing was done prior to HSCT time (p < 0.05). Study results may be skewed by
2% of patients received cranial and at 6 and 12 months after completion the high attrition rate (73%).
irradiation, 5% TBI, and 6% in- of HSCT. Patients in group A were tested
trathecal chemotherapy. at all three time periods, group B at 6 and
12 months after HSCT, and group C at 12
months after HSCT.
Syrjala et al., HSCT: Allogeneic regimens in- N = 158; 92 patients, 66 case-matched con- AC, EF, IPS, Overall survivors had improved cognitive function-
2011 cluded cyclophosphamide with trols L, MF, VerM ing over time (p < 0.001). Patients who had under-
TBI (52%), cyclophosphamide Mean age (standard deviation): 40.7 (9.2) gone HSCT showed persistent deficits in MF (p =
and busulfan (40%), other survivors, 46.6 (9.7) controls 0.017). A significant difference between survivors
chemotherapy (type not spec- Cognitive testing was done prior to HSCT and controls was found for MF (p < 0.001) only. Be-
ified) with TBI (7%), or other and 80 days, 1 year, and 5 years after cause controls were tested at only one time period
chemotherapy (type not speci- HSCT. Controls were tested at only one as compared to survivors, some of the results may
fied) alone (1%) time. be due to practice effects.
Chemotherapy treatment prior
to HSCT was not reported.
Lung Pesce et al., Radiation: WBRT N = 59; 16 on gefitinib, 43 on temozolomide EF and a No differences were found between groups. Study
2012 Chemotherapy: Gefitinib or te- Median age: 61 subjective results are limited by inability to meet accrual goal,
mozolomide Cognitive testing done prior to start of treat- measure of significant attrition (90%) over time, small sample
ment and on day 1 of cycles 2, 3, and 5 CF size, and lack of controlling for previous chemo-
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
therapy.
Sun et al., Radiation: PCI N = 340; 163 received PCI, 177 observation VerM and a Compared to patients who underwent observation,
2011 Age not reported subjective patients who received PCI showed significant de-
Cognitive testing done at baseline after de- measure of clines in VerM at all time periods. Study results are
finitive treatment (not defined), prior to PCI, CF limited by inability to meet accrual goal and signifi-
and repeated at 3, 6, and 12 months from cant attrition (72%) over time.
the original testing
Mixed cancer Kvale et al., Chemotherapy: Regimens not N = 76; 39 chemotherapy patients, 37 con- EF, IPS, VerM No differences were found; however, the study is
diagnoses 2010 reported; unclear if patients trols without cancer likely underpowered. Another limitation of the study
with cancer received any other Mean age: 76.0 patients with cancer, 75.8 is the inclusion of multiple cancer diagnoses with
treatments controls potentially variable chemotherapy regimens.
Cognitive testing done prior to treatment and
repeated annually for 4 years
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 42. Evidence of Cancer Treatment–Related Cognitive Changes (Continued)
Author Cognitive
Type of and Year Sample Characteristics Domains
Cancer Published Treatment Specifics and Study Designs Assessed Results and Conclusions
Ovarian Correa et al., Chemotherapy: Various regi- N = 48; 22 disease-free survivors, 26 survi- AC, EF, M Although no significant differences were seen be-
2010 mens including paclitaxel, car- vors who had at least one recurrence and tween the groups, 28% of those tested met crite-
boplatin, cisplatin, and others receiving active treatment ria for cognitive impairment. Cognitive scores were
not specified Mean age for entire group: 61 not significantly correlated with depression or age.
Concurrent hormonal therapy for Cognitive testing done at one time; all par- No baseline cognitive testing was done for either
five patients ticipants were 5–10 years from their origi- group.
nal diagnosis
Hess et al., Chemotherapy: Specified only N = 27 AC, IPS, and There was a significant group difference over time
2010 as platinum-based regimens Mean age: 59.3 a subjective in some measures of IPS (p < 0.0001). The authors
Cognitive testing done prior to chemotherapy measure of reported that almost half of the participants had im-
and repeated at cycles 3 and 6 AC, EF, VS, pairment compared to baseline. However, many of
and M the participants experienced neurotoxicity, which
may have been responsible for the decline in cogni-
tive measures.
Prostate Alibhai et al., ADT: Actual medications not N = 241; 77 receiving ADT, 82 prostate can- AC, EF, IPS, Although significant differences were found in a sin-
2010 stated cer controls, 82 healthy controls L, VerM, gle test for AC (p = 0.029), VS (p = 0.34), and EF
Mean age: 68.9 VisM, VS (p = 0.31), most measures did not show any differ-
Cognitive testing done prior to the start of ences between groups. The proportion of partici-
ADT and at 6 and 12 months after base- pants in each group who scored worse on any cog-
line testing nitive domain was similar, indicating that ADT does
not adversely affect cognitive function.
Cherrier et ADT: Intermittent therapy with N = 38; 19 receiving ADT, 19 controls AC, EF, L, A significant group-by-time interaction (p < 0.05)
Chapter 9. Side Effects of Cancer Therapy
al., 2009 leuprolide and flutamide Mean age (standard deviation): 62.05 (7.19) VerM, VisM, was found for cognitive function. Although declines
patients, 65.47 (7.99) controls VS in EF (p < 0.05) and VS (p < 0.05) were found three
Cognitive testing done prior to the start of months after initiation of ADT, these changes were
ADT and at 3, 9, and 12 months after base- not sustained and scores returned to baseline by
line testing subsequent testing.
Testicular Pedersen et Chemotherapy: BEP N = 72; 36 receiving chemotherapy, 36 un- EF, IPS, L, No differences were found between groups. The
al., 2009 dergoing surgery with or without radiation VerM, VisM, study may be underpowered but more important-
therapy VS ly is limited by lack of baseline cognitive testing pri-
Mean age (standard deviation): 38.3 (9.3) or to treatment.
chemotherapy group, 42.0 (9.8) controls
Cognitive testing done 2–7 years after com-
pletion of treatment
361
(Continued on next page)
362
Table 42. Evidence of Cancer Treatment–Related Cognitive Changes (Continued)
Author Cognitive
Type of and Year Sample Characteristics Domains
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Cancer Published Treatment Specifics and Study Designs Assessed Results and Conclusions
Testicular Skoogh et Chemotherapy: Platinum-based N = 960; 692 patients who received at least Subjective Patients who received ≥ 5 cycles of chemothera-
(cont.) al., 2012 regimens including BEP, BEP- one cycle of chemotherapy, 268 controls measure of py reported a greater incidence of language diffi-
if, CVB, PEI Mean age for all participants: 41 CF based on culties. Multiple limitations of the study, including
Cognitive functioning evaluated by a single earlier quali- the lack of an objective measure and cross-section-
study-specific questionnaire at a mean of tative results al design, make it difficult to determine the validity
11 years after diagnosis of the results.
Wefel, Vid- Surgery only N = 69 AC, EF, IPS, Prior to the initiation of chemotherapy, cognitive im-
rine, et al., Mean age (standard deviation): 31 (7.5) L, MF, VerM pairment was found in 46% of patients, especial-
2011 Cognitive testing performed after orchiecto- ly in VerM, EF, and MF (p < 0.001). Depression was
my and prior to starting chemotherapy associated with EF (p < 0.01), IPS (p < 0.01), and
VerM (p < 0.05). VerM was also associated with
anxiety (p < 0.05). Interpretation of results is diffi-
cult because of the lack of a control group and the
cross-sectional design.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Therapy: AC—doxorubicin and cyclophosphamide; AC-D—doxorubicin and cyclophosphamide followed by docetaxel; AC-T—doxorubicin and cyclophosphamide followed by paclitaxel; AD—doxorubicin and docetax-
el; ADT—androgen-deprivation therapy; AP—doxorubicin and cisplatin; BEP—bleomycin, etoposide, and cisplatin; BEP-if—bleomycin, etoposide, cisplatin, ifosfamide, and mesna; CAF—cyclophosphamide, doxorubi-
cin, and 5-FU; CD—cyclophosphamide and docetaxel; CEF—cyclophosphamide, epirubicin, and 5-FU; CEF-D—cyclophosphamide, epirubicin, and 5-FU followed by docetaxel; CMF—cyclophosphamide, methotrexate,
and 5-FU; CVB—cisplatin, vinblastine, and bleomycin; EC—epirubicin and cyclophosphamide; EC-D—epirubicin and cyclophosphamide followed by docetaxel; EC-T—epirubicin and cyclophosphamide followed by pa-
clitaxel; FAC—FU, doxorubicin, and cyclophosphamide; FEA—5-FU, epirubicin, and doxorubicin; FEC—5-FU, epirubicin, and cyclophosphamide; FEC-D—5-FU, epirubicin, and cyclophosphamide followed by docetax-
el; FEC-T—5-FU, epirubicin, and cyclophosphamide followed by paclitaxel; 5-FU—5-fluorouracil; HSCT—hematopoietic stem cell transplantation; PCI—prophylactic cranial irradiation; PEI—cisplatin, etoposide, ifos-
famide, and mesna; TAC—docetaxel, doxorubicin, and cyclophosphamide; TBI—total body irradiation; TC—docetaxel and cyclophosphamide; WBRT—whole brain radiation therapy
Cognitive domains: AC—attention/concentration; CF—cognitive function; EF—executive function; IPS—information processing speed; L—language; M—memory; MF—motor function; VerM—verbal memory; VisM—
visual memory; VS—visuospatial skill
Chapter 9. Side Effects of Cancer Therapy 363
c) Whether cognitive impairment starts before or after the cancer treat-
ment, cognitive problems are estimated to persist for months or years
following the completion of treatment in up to 35% of survivors
(Janelsins et al., 2011).
d) The duration of chemotherapy-related cognitive impairment remains
unknown. In one study of survivors, cognitive problems were the most
troublesome post-treatment symptom (Boykoff, Moieni, & Subrama-
nian, 2009). In other studies, survivors confirmed that cognitive issues
continued to have a negative impact on their workplace for at least
one if not many years after treatment (Calvio, Peugeot, Bruns, Todd,
& Feuerstein, 2010; Munir, Burrows, Yarker, Kalawsky, & Bains, 2010).
3. Risk factors
a) Predisposing factors that influence cognitive function are not consis-
tent; however, the following have been suggested.
(1) Gender: Women excel in language, information processing
speed, and motor function, whereas men perform better in vi-
suospatial skills and mathematics (Lezak et al., 2012).
(2) Age: Cognitive decline occurs with aging. However, normative
data for neuropsychological tests are based on age.
(3) Intelligence and educational levels: Intelligence and education-
al levels have strong, positive relationships with neuropsycho-
logical test performances and have been found to be protec-
tive against cognitive impairments associated with brain trau-
ma (Lezak et al., 2012).
(4) Genetics: Similar to other side effects, not all patients are
equally affected by the same regimen. Consequently, sever-
al genetic mutations are being evaluated to determine those
that might influence an individual’s risk of cognitive chang-
es during cancer and cancer treatments (Argyriou, Assimak-
opoulous, Iconomou, Giannakopoulou, & Kalofonos, 2011).
For example, the presence of the apolipoprotein E (APOE)
gene e4 variant has been associated with decreased cognitive
function, and several other candidate genes are being stud-
ied for their potential role in chemotherapy-induced cogni-
tive changes (Ahles & Saykin, 2007). In a study of breast cancer
survivors, participants who were catechol-O-methyltransferase-
Val carriers performed more poorly on tests of attention, ver-
bal fluency, and motor speed (Small et al., 2011). Other poly-
morphisms that have been proposed are those that influence
the efficiency of DNA repair mechanisms and drug efflux pump
systems (Fishel, Vasko, & Kelley, 2007).
(5) Psychological factors such as stress, anxiety, and depression can
affect performance on neuropsychological testing (Lezak et al.,
2012). However, in general, these psychological factors are not
correlated with objective measures in studies of patients with
cancer. In contrast, anxiety and depression often are correlat-
ed with subjective measures of cognitive functioning.
(a) Increased anxiety was found to predict overall cognitive
decline in one study (Vearncombe et al., 2009). Although
anxiety has not been consistently related to objective mea-
sures, it has been found to be significantly correlated to
perceived cognitive functioning (p < 0.05) in some studies
(Breckenridge, Bruns, Todd, & Feuerstein, 2012; Jansen,
Cooper, Dodd, & Miaskowski, 2011). In one study of em-
ployed survivors, anxiety was directly related to attention
and concentration (p < 0.01), executive functioning (p <
0.05), and memory (p < 0.05) (Breckenridge et al., 2012).
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
364 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
(b) Depression has been found to influence specific cognitive
domains such as attention (Vearncombe et al., 2009). One
study of employed survivors found depression to be corre-
lated with attention and concentration (p < 0.01), execu-
tive functioning (p < 0.05), and memory (p < 0.05) (Breck-
enridge et al., 2012).
(6) Fatigue can negatively affect cognitive function and was found
in several studies to cause impairments in specific domains, such
as attention, concentration, and executive function (Collins,
Mackenzie, Stewart, Bielajew, & Verma 2009a; Mehlsen, Ped-
ersen, Jensen, & Zacharieae, 2009; Vearncombe et al., 2009).
Fatigue is also related to subjective measures of cognitive func-
tioning (Breckenridge et al., 2012).
b) Factors related to cancer treatments
(1) Regimens: Because most patients receive multimodal therapy, it
is difficult to determine if specific drugs or regimens promote
higher incidences of cognitive changes.
(2) Dose intensity and cumulative effects: Cognitive changes in pa-
tients who receive cranial irradiation are related to the total
dose received (Khasraw & Posner, 2010; Rinne et al., 2012). Ex-
posure to higher doses of chemotherapy (or higher concentra-
tions due to impaired clearance), as well as the additive or syn-
ergistic effects of multiagent regimens, also may increase risk
(Wefel & Schagen, 2012).
c) Concomitant medications such as analgesics, antidepressants, anti-
epileptics, anxiolytics, antipsychotics, immunosuppressants, and ste-
roids (Allen et al., 2011)
4. Clinical manifestations: Although cognitive changes may be subtle, pa-
tients report that they impair their ability to concentrate, think clear-
ly, retain or learn new information, be efficient, manage responsibili-
ty, and cope with problems (Boykoff et al., 2009; Calvio et al., 2010; Mu-
nir et al., 2010).
5. Assessment: Many neuropsychological tests are available to measure cog-
nitive function. Imaging (e.g., MRI, PET) has been used to study struc-
tural and electrophysiologic outcomes related to cognitive impairment
(Raffa, 2010).
a) Factors in neuropsychological test selection (Lezak et al., 2012)
(1) Specific cognitive domain to be measured
(2) Appropriateness of test for the domain being studied
(3) Reliability and validity of the test and availability of normative data
(4) Sensitivity and specificity to measure cancer treatment–related
cognitive changes (Jansen, Miaskowski, Dodd, & Dowling, 2007)
(5) Availability of parallel forms or resistance to practice effects for
use with repeated measures
(6) Feasibility of instrument for clinical use (such as length of time
and ease of administration)
(7) Specific tests recommended by the International Cognition and
Cancer Task Force include the Hopkins Verbal Learning Test–
Revised, the Trail Making Test, and the Controlled Oral Word
Association Test to evaluate learning and memory, processing
speed, and executive function, which appear to be the most
vulnerable cognitive domains in patients with cancer (Wefel,
Vardy, Ahles, & Schagen, 2011).
b) Baseline neuropsychological assessment prior to the initiation of
treatment is necessary to determine if changes occur after treat-
ment. Changes may be difficult to assess because they may be sub-
tle (e.g., patients test within normal limits, but lower than non-
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 365
chemotherapy-treated patients), or preexisting risk factors may
influence results.
c) Although objective neuropsychological tests are the gold standard for
evaluating cognition, subjective measures may add valuable informa-
tion regarding patient complaints (e.g., inability to focus on tasks or
follow instructions; problems with concentration or memory).
d) Assess coexisting medical conditions (e.g., CVD, diabetes, neurolog-
ic conditions, psychiatric illness), current medications, and any po-
tential influencing factors such as anxiety, depression, fatigue, or
menopausal status.
6. Collaborative management: Currently, no evidence-based recommenda-
tions exist for the prevention or treatment of cognitive impairment. Al-
though the mechanisms of cancer treatment–related cognitive changes
are still unclear, several pharmacologic and nonpharmacologic interven-
tions have been studied. Many of these focus on preventing cognitive im-
pairment by targeting the potential mechanisms discussed earlier. Eryth-
ropoietin, although evaluated in several studies with mixed outcomes,
is not recommended because of FDA warnings regarding risks associat-
ed with its use (Allen et al., 2011). The effectiveness of other pharmaco-
logic (i.e., dexmethylphenidate methylphenidate, donepezil) and non-
pharmacologic (i.e., vitamin E, natural restorative environments, cogni-
tive training programs) interventions has not been established (Allen et
al., 2011; Von Ah et al., 2011). Further research is needed to determine
potential interventions for patients experiencing cognitive impairments.
7. Patient and family education: Patients should be informed that cognitive
changes are a possible side effect of treatment, but little information is
known. Studies elucidating this phenomenon, its mechanisms, and sub-
sequent interventions are ongoing.
a) Acknowledge, validate, and record patient reports of cognitive changes.
b) Advise patients that although studies have been done for various in-
terventions, not enough evidence is available to make treatment rec-
ommendations.
c) Although studies supporting the effectiveness of practical solutions
are lacking, patients have reported the following as helpful (Cheung
et al., 2012).
(1) Healthy lifestyle practices
(a) Ensure adequate sleep and rest.
(b) Eat a well-balanced diet.
(c) Engage in physical exercise.
(2) Intellectual activities (e.g., reading, learning new skills, solving
puzzles, working out math problems)
(3) Social activities (e.g., support groups)
(4) Practical management
(a) Use technology (e.g., smartphones, voice recorders).
(b) Keep a daily planner.
(c) Write reminders and use notes.
L. Ocular toxicity
1. Pathophysiology
a) The causes of ocular toxicity are not fully understood and may in-
clude the following.
(1) Damage to the eye or eye structures related directly to treatment
(e.g., distribution of cytotoxic drugs in tears, direct vascular injury
during intracarotid administration, direct nerve injury from che-
motherapy or radiation therapy, or the solubility characteristics
of the drug and its ability to gain access through barriers such as
the blood-ocular barrier) (DeAngelis, 2010; Palmer et al., 2008).
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
366 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
(2) EGFRIs: EGFR is a normal part of epidermal cells. EGFR is
widely distributed on the eye surface in the conjunctival and
corneal epithelium, as well as in the eyelid skin, lash folli-
cles, tear glands, and sebaceous and sweat glands (Burtness
et al., 2009). Inhibiting EGFR can lead to damage to the epi-
dermal cells found in the ocular region (eye and surround-
ing skin) (Garibaldi & Adler, 2007). Examples of EGFRI-
induced effects are tear film dysfunction and unusual hy-
per- or hypopigmentation (Zhang, Basti, & Jampol, 2007).
EGFRIs have led to dry eyes, inflammation of the lid mar-
gin (blepharitis), dysfunction of the sebaceous glands of the
eyelid (meibomitis), corneal erosion, and inversion or ever-
sion of the eyelid margin (Burtness et al., 2009). EGFR also
has a crucial role in the regulation of the hair growth cycle.
An EGFRI can hinder this cycle, leading to loss of eyelashes
and eyebrows (Robert et al., 2005; Zhang, Basti, et al., 2007)
or an accelerated growth and curling of the eyelashes, lead-
ing to tortuous eyelashes or eyelash trichomegaly (Robert et
al., 2005). Most ocular side effects are not vision threaten-
ing but should be followed by an ophthalmologist to quick-
ly treat the discomfort and prevent ocular injury (Burtness
et al., 2009). For symptom management for ocular toxicity
related to EGFRI medications, see Table 43.
(3) A secondary process related to treatment (e.g., eye irritation
caused by loss of eyelashes in the presence of neutropenia)
(4) A secondary process related to concurrent disease (e.g., diabe-
tes or Graves disease leading to diplopia or ptosis) (DeAngelis,
2010)
(5) Metastases to the eyes or CNS resulting in increased intracra-
nial pressure
(6) Factors unrelated to cytotoxic therapy (e.g., head trauma or
drug toxicity from narcotics or anticonvulsants leading to dip-
lopia) (DeAngelis, 2010)
b) A broad spectrum of disorders has been documented, including in-
flammatory conditions (e.g., uveitis, conjunctivitis, keratitis, blepha-
ritis, iritis), development of retinal opacities, cataract formation, lid
and lacrimation disorders, optic neuritis, and other neurologic inju-
ries (Fraunfelder, Fraunfelder, & Chambers, 2008). For site-specific
disorders, see Table 44.
c) With frequent use of combination therapy, determining which spe-
cific drug is causing complications may be difficult (Fraunfelder et
al., 2008).
d) Patients may experience toxicity-related visual impairment during
chemotherapy and up to two weeks after chemotherapy (Kende, Sir-
kin, Thomas, & Freeman, 1979). Neurologic damage to the eye has
occurred up to 43 days following chemotherapy (Warrell & Berman,
1986).
e) The toxic effect of certain drugs may be cumulative and dose depen-
dent (Palmer et al., 2008).
f) Ocular changes may go unnoticed until damage is irreversible.
g) Ocular signs and symptoms may precede the development of periph-
eral neuropathies and thus may be an important marker of neurolog-
ic status (Bobba & Klein, 2012).
h) The presence of ocular signs or symptoms may predict development
of GVHD in patients who have received allogeneic BMT (Kim et al.,
2002).
i) Ocular changes may be incorrectly attributed to the aging process.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 367
Table 43. Ocular Toxicity Symptom Management Related to EGFR Inhibitors
Adverse Event Symptoms Management Strategy
Corneal epithelial Significant eye pain, sensitivity to light Refer to an ophthalmologist.
defect
Eyelid skin Hyperemia, papulopustular rash, crusting Acute reactions: Warm compresses with a moist washcloth,
changes (i.e., Eyelids become sore and irritated, with discom- regular cleaning of the eyelid, artificial tears (Ouwerkerk &
squamous bleph- fort described as severe. The eyelid margins Boers-Doets, 2010)
aritis) may have mild redness to significant ede- Apply fluorometholone (0.1%) ointment to eyelid (both skin and
ma and soreness of the eyelid margin. Small lid margin) for 1 week. Do not use for > 2 weeks. An ophthal-
pustules at the base of the eyelashes may be mologist must examine patient within 4 weeks.
seen (Burtness et al., 2009). Chronic reactions: Apply tacrolimus 0.03% ointment or
pimecrolimus cream BID to skin of eyelid only. If treatment is
minimally effective or not effective at all, try tacrolimus 0.1%.
This treatment should not be used for > 6 months.
Iridocyclitis Sensitivity to light, sustained eye pain, de- Refer to an ophthalmologist.
crease in vision Treatment involves use of anti-inflammatory medications.
Meibomitis (mei- Fluctuations in vision (varying degrees), burn- Perform lid scrubs and apply warm compresses to the eyelid for
bomian gland ing sensation in the eye, some mucus dis- at least 5 minutes BID.
dysfunction) charge, eye redness (may occur only on If lid scrubs and warm compresses are ineffective, give doxycy-
awakening) cline 50 mg PO BID for 2 weeks followed by 50 mg every day
for 4 weeks.
Tear film chang- Fluctuating or mild decrease in vision, transient Mild symptoms: Apply supplemental tears 4–6 times a day.
es (dysfunctional eye pain, burning or foreign body sensation in Severe symptoms or no relief: Refer to an ophthalmologist
tear syndrome) the eye, eye fatigue (treatment may consist of punctal plugs and/or anti-inflamma-
tory medications).
Trichomegaly Lengthening of the eyelashes or eyebrows, Elongated or “patchy” lashes: No specific treatment. Will return
“patchy” lashes, misdirected lashes to normal after EGFR inhibitor is completed. While many re-
searchers (Braiteh et al., 2008; Eaby et al., 2008; Esper et
al., 2007) agree that for patients experiencing trichomegaly,
an ophthalmologist should be seen if eye irritations occur and
eyelashes may be carefully and safely trimmed, Basti (2007)
advises patients to not cut their lashes or have them cut.
Waxing or electrolysis may be recommended (Braiteh et al.,
2008; Segaert & Van Cutsem, 2005).
Misdirected lashes: This is infrequent. Refer to an ophthalmolo-
gist. Do not remove misdirected lashes.
BID—twice a daily; EGFR—epidermal growth factor receptor; PO—by mouth
Note. From “Ocular Toxicities of Epidermal Growth Factor Receptor Inhibitors and Their Management,” by S. Basti, 2007, Cancer Nursing, 30(Suppl. 4), p.
S14. Copyright 2007 by Lippincott Williams & Wilkins. Adapted with permission.
2. Incidence
a) Incidence varies according to drug classification, dose, and route of
administration (see Table 45).
b) Ophthalmologic effects of chemotherapy occur less frequently and
tend to be less severe than other chemotherapy-related side effects.
Most ocular side effects tend to improve or even resolve completely
upon discontinuation of the drug. Sequelae are often minimized by
early detection (Teitelbaum, 2011)
3. Risk factors: Causal relationships between agents and ocular toxicities
are difficult to establish. Risk factors are equally difficult to establish.
4. Clinical manifestations: See Table 45.
5. Assessment: Ask patients about a history of any eye disturbance. In addi-
tion, assess the following (Bickley, 2013).
a) Visual acuity: Use a Snellen eye chart if possible. Position the patient
20 feet from the chart. Have the patient wear glasses or contacts for
the examination if the corrective lenses are normally used other than
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
368 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Table 44. Specific Ocular Toxicities by Anatomic Site
Site Ocular Toxicity
Orbit Arteriovenous shunts, cavernous sinus syndrome, edema, exo
phthalmos, pallor, pain
Lids Cicatricial ectropion, ankyloblepharon, increased lid necrosis
after cryotherapy, hyperpigmentation
Lacrimal drainage Tear duct fibrosis and punctal occlusion
Lacrimal gland Keratoconjunctivitis sicca
Conjunctiva Conjunctivitis
Sclera Discoloration
Cornea Keratopathy, keratitis
Pupil Pinpoint pupils, internal ophthalmoplegia
Uvea Uveitis
Trabecular meshwork and/ Increased intraocular pressure
or ciliary body
Lens Cataract
Retina Toxic retinopathy
Vitreous Opacification
Optic nerve Disc edema, optic neuritis, optic atrophy
Cranial nerves III, IV, V, VI Ptosis, paresis with or without diplopia, corneal hypesthesia
Extraocular muscles Fibrosis
Central nervous system Cortical blindness, internuclear ophthalmoplegia, blepharo-
spasm
Note. Based on information from Palmer et al., 2008.
for reading. Ask the patient to cover one eye with a card and to read
the smallest line possible. Have the patient repeat with the other eye.
Acuity can be assessed using a near-vision card held at arm’s length;
patients who wear glasses or contact lenses should remove them. Re-
cord any visual disturbances.
b) Visual fields: Sit or stand in front of the patient and have the patient
look with both eyes into your eyes. While the patient gazes into your
eyes, place your hands two feet apart, lateral to the patient’s ears. In-
struct the patient to point to your fingers as soon as they are seen.
Slowly move your fingers along an imaginary bowl and toward the
line of gaze until the patient identifies them. Repeat this pattern in
upper and lower temporal quadrants.
c) Position of eyes, eyebrows, and eyelids: While standing or sitting in
front of the patient, observe the eyes for position and alignment with
each other. Inspect the eyebrows, noting their quantity and distribu-
tion and any flaking of the underlying skin. Survey the eyelids, ob-
serving and palpating for signs of erythema and edema. Assess for
signs of exudates, crusting, and presence of ptosis. Observe condi-
tion of lashes.
d) Lacrimation: Note dryness, foreign-body sensation, excessive tearing,
or swelling of the lacrimal sac.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 45. Ocular Toxicities of Antineoplastic Agents
Classification Drug Ocular Toxicity Comments
Alkylating agents Busulfan Long-standing reports of cataract formation and blurred vision (Bobba & Klein, 2012; Toxic effects are believed to act on proliferating lens epithelial
Palmer et al., 2008; Singh & Singh, 2012); rare cases of keratoconjunctivitis sicca cells (Bobba & Klein, 2012).
(Palmer et al., 2008; Sidi et al., 1977; Singh & Singh, 2012)
Carboplatin IV: Rare cases of blurred vision, eye pain (Al-Tweigeri et al., 1996); reports of mac- –
ulopathy and optic neuropathy with transient cortical blindness when given to pa-
tients with renal dysfunction (O’Brien et al., 1992; Singh & Singh, 2012)
Intracarotid: Reports of severe ocular and orbital toxicity in ipsilateral eye following in-
tracarotid injection (Watanabe et al., 2002)
Chlorambucil Keratitis, diplopia, bilateral papilledema, retinal hemorrhages (Bobba & Klein, 2012); Ocular toxicity is rare (Bobba & Klein, 2012).
oculomotor disturbance, disc edema, retinopathy (Palmer et al., 2008)
Cisplatin IV: Blurred vision, altered color perception, papilledema, decreased visual acuity, ret- –
robulbar neuritis, transient cortical blindness, disc edema, retinopathy, electroret-
inogram abnormalities, cavernous sinus syndrome, color blindness (Becher et al.,
1980; Palmer et al., 2008; Prager et al., 1998)
Intracarotid: Ipsilateral visual loss (15%–60%) from retinal or optic nerve ischemia, pos-
sibly prevented by infusion distal to ophthalmic artery (Palmer et al., 2008); optic neu-
ropathy, unilateral vision loss (Bobba & Klein, 2012); retinal pigment disturbances, al-
tered color perception, cotton wool spots, intraretinal hemorrhages (Kwan et al., 2006)
Cyclophospha- Blurred vision (reversible), keratoconjunctivitis sicca, pinpoint pupils (Jack & Hicks, –
mide 1981; Kende et al., 1979; Palmer et al., 2008; Singh & Singh, 2012)
Ifosfamide Blurred vision (reversible), conjunctivitis (Bobba & Klein, 2012; Choonara et al., 1987; –
Singh & Singh, 2012)
Chapter 9. Side Effects of Cancer Therapy
Mechloretha- Intracarotid: Rare reports of ipsilateral necrotizing uveitis and necrotizing vasculitis of No reports exist of ocular toxicity with IV administration (Bob-
mine choroids (Bobba & Klein, 2012) ba & Klein, 2012).
Oxaliplatin Mild changes: Dry eyes, excessive tearing, severe ocular irritation, conjunctivitis, ab- Look for patients complaining of blurred vision, visual loss,
normal lacrimation (Mesquida et al., 2010; OncUView, 2011b; Singh & Singh, 2012) tunnel vision, or altered color vision. Most changes are
Severe changes: Retinal damages, visual field cuts (Mesquida et al., 2010; Singh & transient and reversible once treatment is stopped (Mesqui-
Singh, 2012) da et al., 2010).
Antimetabolites Capecitabine Ocular irritation, decreased vision, corneal deposits (Singh & Singh, 2012; Walkhom –
et al., 2000)
Cytarabine IV: Keratitis and conjunctivitis most common (Haddadin & Perry, 2012); blurred vision Hydrocortisone or dexamethasone eye drops may prevent
with evidence of bilateral conjunctival hyperemia, ocular pain, photophobia, and for- keratitis. It is recommended to start eye drops the evening
eign body sensation at high doses (Al-Tweigeri et al., 1996; Bobba & Klein, 2012); before therapy begins (Cleri & Haywood, 2002; Higa et al.,
case reports of corneal toxicity with low dose of cytarabine (Lochhead et al., 2003) 1991).
Intrathecal: Optic neuropathy leading to severe visual loss (may be potentiated by
cranial radiation therapy) (Hopen et al., 1981; Margileth et al., 1977)
369
(Continued on next page)
370
Table 45. Ocular Toxicities of Antineoplastic Agents (Continued)
Classification Drug Ocular Toxicity Comments
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Antimetabolites 5-Fluorouracil Conjunctivitis (Christophidis et al., 1979; Singh & Singh, 2012), excessive lacrima- Loprinzi et al. (1994) studied the use of ice packs to de-
(cont.) tion (Hamersley et al., 1973; Singh & Singh, 2012), tear duct fibrosis (Haidak et crease ocular irritation; effectiveness was reinforced by
al., 1978), and blepharitis (Fraunfelder et al., 2008). Other ocular toxicities include North Central Cancer Treatment Group (ice applied for
keratoconjunctivitis, cicatricial ectropion, ankyloblepharon, blepharospasm, punc- 30 minutes, starting 5 minutes before infusion). The use
tal occlusion, oculomotor disturbances, blurred vision, photophobia, nystagmus, in- of dexamethasone eye drops decreased ocular toxicities
creased lid necrosis after cryotherapy, ocular pain, circumorbital edemas (Jansman (Jansman et al., 2001).
et al., 2001; Palmer et al., 2008; Singh & Singh, 2012), dry eyes, and excessive
tearing (OncUView, 2011b)
Fludarabine Decreased visual acuity (most common presenting sign before development of pro- Effects are dose dependent (Bobba & Klein, 2012).
gressive encephalopathy); rare cases of diplopia, photophobia, and optic neuri-
tis (Al-Tweigeri et al., 1996; Chun et al., 1986; Palmer et al., 2008; Singh & Singh,
2012; Warrell & Berman, 1986)
Methotrexate IV: Blepharitis, conjunctival hyperemia, increased lacrimation, periorbital edema, pho- Up to 25% of patients may develop ocular toxicity (Palmer et
tophobia, optic pain (Palmer et al., 2008; Singh & Singh, 2012) al., 2008). Toxicity is more common with higher doses (Bob-
Intrathecal: With concurrent radiation, case reports of bilateral ophthalmoplegia with ba & Klein, 2012).
exotropia; optic nerve atrophy (Bobba & Klein, 2012) Drug is found in tears (Fraunfelder et al., 2008).
Intra-arterial: Retinal changes in ipsilateral eye (Fraunfelder et al., 2008; Singh &
Singh, 2012)
Pentostatin Conjunctivitis, photophobia, diplopia (Haddadin & Perry, 2012); abnormal vision, am- –
blyopia, conjunctivitis, dry eye, problems with lacrimation, photophobia, retinopathy,
watery eyes (Singh & Singh, 2012)
Antitumor Doxorubicin Conjunctivitis, increased lacrimation (Bobba & Klein, 2012; Curran & Luce, 1989; Serious ocular side effects are rare (Bobba & Klein, 2012).
antibiotics Singh & Singh, 2012); increased lacrimation in up to 25% of patients receiving
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
doxorubicin (Blum, 1975; Singh & Singh, 2012)
Mitomycin C IV: Blurred vision (Al-Tweigeri et al., 1996; Palmer et al., 2008; Singh & Singh, 2012) Other than blurred vision, keratoconjunctivitis was report-
Topical: Keratoconjunctivitis (Bobba & Klein, 2012) ed after topical use in ophthalmologic surgeries (Bobba &
Klein, 2012; Singh & Singh, 2012).
Mitoxantrone Conjunctivitis, discoloration of sclera (Karch, 2014) Drug is secreted in tears.
Biotherapy BCG live vac- Uveitis, conjunctivitis, iritis, keratitis, granulomatous chorioretinitis (Palmer et al., Ocular side effects rare and are more common in patients
agents cine 2008; Sanofi Pasteur Inc., 2012) who are positive for HLA-B27 (Sanofi Pasteur Inc., 2012).
G-CSF, Case report of acute iritis in healthy stem cell donor taking G-CSF (Parkkali et al., –
GM-CSF 1996); marginal keratitis and mild uveitis in healthy stem cell donor following both
G-CSF and GM-CSF (Esmaeli et al., 2002)
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 45. Ocular Toxicities of Antineoplastic Agents (Continued)
Classification Drug Ocular Toxicity Comments
Biotherapy IFN alfa, Retinopathy, primarily retinal hemorrhages; cotton wool spots (Esmaeli, Koller, et al., Risk is increased in patients with hypertension or diabe-
agents (cont.) IFN beta, 2001; Wilson, 2004); disc edema (Palmer et al., 2008) tes and those receiving higher doses. Effects may occur
IFN gamma Changes in vision, nonspecific conjunctivitis, and ocular pain are most frequent re- as soon as 15 minutes after initial exposure or take many
ported ocular side effects (Teitelbaum, 2011). months to be seen. Less than 1% of patients receiving IFN
develop ocular toxicities (Teitelbaum, 2011).
IL-2 Neuro-ophthalmic effects including scotoma, diplopia, transient blindness, and visual –
hallucinations (Teitelbaum, 2011)
Retinoid Blepharoconjunctivitis, corneal opacities, papilledema, pseudotumor cerebri, night Avoid concurrent use of tetracyclines and drugs causing in-
blindness (Al-Tweigeri et al., 1996) tracranial hypertension (Fraunfelder et al., 2008).
Miscellaneous Bisphospho- Conjunctivitis, uveitis, scleritis (Fraunfelder et al., 2008), episcleritis, eyelid edema, Bisphosphonates must be discontinued for symptoms to re-
nates optic neuritis, periorbital edema (Renouf et al., 2012) solve (Fraunfelder et al., 2008).
Most reports describe the onset of symptoms within 48 hours
of the initial infusion along with symptoms such as flu-like,
fever, or myalgia (Renouf et al., 2012).
Corticosteroids Posterior subcapsular cataracts, glaucoma, retinal hemorrhage (Loredo et al., 1972); –
opportunistic eye infections, visual field defects, blurred vision, diplopia, exophthal-
mos, scleral discoloration (Palmer et al., 2008)
Increased intraocular pressure and subsequent glaucoma have been noted with
long-term use (Teitelbaum, 2011).
Cyclosporine A Optic neuropathy (Mejico et al., 2000); blurred vision, retinopathy, case reports of cor- Combination of cyclosporine A and TBI may increase sus-
tical blindness (Palmer et al., 2008) ceptibility to develop radiation-induced optic neuropathy;
patients’ symptoms improved to some extent when cyclo-
sporine was discontinued (Mejico et al., 2000).
Chapter 9. Side Effects of Cancer Therapy
Deferoxamine Night blindness, visual field constriction, cataracts, pigmentary retinopathy, optic neu- Ocular side effects occurred related to prolonged use and
mesylate/ ropathy (Arora et al., 2004); blurring vision, decreased visual acuity, vision loss, vi- high doses or in patients with low ferritin levels; ocular dis-
desferriox- sual defects, scotoma, impaired peripheral, color, and night vision, optic neuritis, turbances were reversible upon cessation of treatment
amine corneal opacities (Novartis Pharmaceuticals Corp., 2011) (Arora et al., 2004; Novartis Pharmaceuticals Corp., 2011).
Ethambutol Decreased visual acuity, color blindness, visual defect, possible irreversible blind- Ocular toxicity can happen at any dose but is increased at
hydrochloride ness, optic neuritis (STI Pharma, LLC, 2012) doses > 50 mg/kg (Donald et al., 2006); change in visual
acuity can be unilateral or bilateral. Testing for visual acuity
should be performed before treatment begins and periodi-
cally during treatment, unless dose is > 15 mg/kg/day, then
monthly testing is needed (STI Pharma, LLC, 2012).
371
(Continued on next page)
372
Table 45. Ocular Toxicities of Antineoplastic Agents (Continued)
Classification Drug Ocular Toxicity Comments
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Miscellaneous Mannitol Blurred vision (Baxter Healthcare Corp., 2009b) Because of fluid and electrolyte shift, side effects can be pre-
(cont.) vented with close monitoring and test dose to evaluate de-
gree of renal failure when indicated (Baxter Healthcare
Corp., 2009b).
Mitotane Visual blurring, diplopia, lens opacity, toxic retinopathy (Bristol-Myers Squibb Co., Ocular side effects are infrequent (Bristol-Myers Squibb Co.,
2010b; Palmer et al., 2008) 2010b).
Procarbazine Retinal hemorrhage, papilledema, photophobia, diplopia, inability to focus (Sigma- Ophthalmic side effects are rare (Cleri & Haywood, 2002).
hydrochloride Tau Pharmaceuticals, Inc., 2008)
Radiation ther- Xerophthalmia, keratoconjunctivitis (dry eye syndrome), pain, sensation of a foreign Xerophthalmia is caused by the radiation effect on the lac-
apy body in the eye, corneal ulceration (Brigden & McKenzie, 2000) rimal and other adnexal glands that contribute to tear pro-
duction. Lubricants and an ophthalmologic consultation are
helpful (Brigden & McKenzie, 2000).
Tacrolimus Optic neuropathy (Mejico et al., 2000) –
(FK506)
Tamoxifen Cataracts and decreased color vision; increased risk with doses > 20 mg/day (Singh A baseline ophthalmic examination is recommended with-
& Singh, 2012); retinal toxicity (small refractile or crystalline dot-like yellowish de- in the first year (Gorin et al., 1998). Visual acuity along with
posits in the area surrounding the macula, in the nerve, and in plexiform layers) macular edema may improve with tamoxifen withdrawal, but
(Gianni et al., 2006; Lazzaroni et al., 1998; Singh & Singh, 2012; Tsai et al., 2003); retinal deposits often do not (Gianni et al., 2006).
corneal opacities, retinopathy (Palmer et al., 2008; Singh & Singh, 2012)
Nitrosoureas Carmustine, Optic neuritis and atrophy, hyperemia, orbital pain, retinopathy, corneal opacities and –
lomustine edema, orbital IV shunts, secondary glaucoma, internal ophthalmoplegia, blurred
vision, vitreous opacification, extraocular muscle fibrosis, diplopia (Palmer et al.,
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
2008; Singh & Singh, 2012)
IV: Rare reports of delayed blurred vision and loss of depth perception (Bobba &
Klein, 2012; Singh & Singh, 2012)
Intracarotid: Severe, ipsilateral occurrences including arterial narrowing, disc edema,
and intraretinal hemorrhages (Greenberg et al., 1984; Shingleton et al., 1982; Singh
& Singh, 2012)
(Continued on next page)
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Table 45. Ocular Toxicities of Antineoplastic Agents (Continued)
Classification Drug Ocular Toxicity Comments
Targeted Cetuximab Blurred vision, eye pain, visual field cuts (OncUView, 2011b); blepharitis (Ramírez- Ocular side effects occured in < 20% of patients and resolved
therapies Soria et al., 2008); eyelid dermatitis, conjunctivitis, poliosis (whitening of the eye- after treatment was discontinued (OncUView, 2011b).
lashes), corneal erosions, punctate keratitis (Renouf et al., 2012) Blepharitis was treated with oxytetracycline cream TID for 20
Relatively common: Loss of eyelashes/eyebrows (madarosis) and/or cicatricial ec- days (Ramírez-Soria et al., 2008)
tropion, loss of color of the skin around the eye with weekly infusions (Garibaldi & Madarosis and cicatricial ectropion resolved after discontinu-
Adler, 2007), trichomegaly (Basti, 2007; Robert et al., 2005) ation of cetuximab (Garibaldi & Adler, 2007).
Very rare: Bilateral ocular discomfort with itchiness around both eyelids, foreign body Ocular discomfort cleared up with topical antibiotics and
sensation, tearing associated with exfoliated skin, oil secretions, crusty scaling (To- holding therapy (Tonini et al., 2005). While many research-
nini et al., 2005) ers (Braiteh et al., 2008; Eaby et al., 2008; Esper et al.,
2007) agree that for patients experiencing trichomegaly,
an ophthalmologist should be seen if eye irritations occur
and eyelashes may be carefully and safely trimmed, Basti
(2007) advises patients to not cut their lashes or have them
cut. Waxing or electrolysis may be recommended (Braiteh
et al., 2008; Segaert & Van Cutsem, 2005).
Erlotinib Periorbital rash, conjunctivitis, eyelid ectropion (Methvin & Gausas, 2007; Singh & Side effects resolved within 6 weeks after treatment was
Singh, 2012); eyelash trichomegaly (Robert et al., 2005) stopped (Methvin & Gausas, 2007; Renouf et al., 2012).
Episcleritis and corneal abrasion related to infectious keratitis (Renouf et al., 2012) See cetuximab for comments regarding trichomegaly.
Imatinib Periorbital edema (Robert et al., 2005), dry eyes, visual disorders such as blurred vi- Symptoms resolve after EGFR inhibitor treatment is stopped.
sion, reduced visual acuity, and visual disturbances (Singh & Singh, 2012), epipho- Periorbital edema is the most common side effect, occurring
ra, optic neuritis, cystoid macular edema (Renouf et al., 2012) in 30% (Renouf et al., 2012).
Ipilimumab Uveitis, iritis, papillitis; rare (< 1%) conjunctivitis, scleritis, episcleritis, blepharitis, and Uveitis, iritis, and papillitis were successfully treated with top-
temporal arteritis (Renouf et al., 2012) ical corticosteroid drops (Renouf et al., 2012).
Panitumumab Keratitis and ulcerative keratitis, conjunctivitis, ocular hyperemia, increased lacri- Onset of ocular symptoms is 14–15 days after first dose of
Chapter 9. Side Effects of Cancer Therapy
mation, eye/eyelid irritation, growth of eyelashes (Amgen Inc., 2013b; OncUView, panitumumab. Symptoms resolve after panitumumab is
2011b; Singh & Singh, 2012) stopped. Median time of resolution is 84 days (Amgen Inc.,
2013b).
Rituximab Conjunctivitis, transient ocular edema, burning sensation, transient visual changes or –
permanent and severe loss of visual acuity (Singh & Singh, 2012)
Sunitinib Periorbital edema (Robert et al., 2005), neurosensory retinal detachment (Renouf et Effects resolve after EGFR inhibitor treatment is stopped
al., 2012) (Renouf et al., 2012; Robert et al., 2005).
Taxanes Docetaxel Epiphora, canalicular stenosis (Esmaeli, Valero, et al., 2001); conjunctivitis, punctal Drug is secreted in tears (Esmaeli et al., 2002).
stenosis (Singh & Singh, 2012) Successful treatment is achieved with bicanalicular silicone
intubation (Ahmadi & Esmaeli, 2001).
373
(Continued on next page)
374
Table 45. Ocular Toxicities of Antineoplastic Agents (Continued)
Classification Drug Ocular Toxicity Comments
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Taxanes (cont.) Paclitaxel Scintillating scotomas or “shooting lights” in 20% of cases, which resolved spontane- Scotomas usually occur toward the end of the 3-hour infusion
ously (Bobba & Klein, 2012); transient scintillating scotoma, visual impairment, pho- (Bobba & Klein, 2012).
topsia, possible ischemic optic neuropathy (Singh & Singh, 2012)
Vinca alkaloids Etoposide Intracarotid: Optic neuritis, transient cortical blindness (Lauer et al., 1999) Effects occur when etoposide is given in combination with
carboplatin (Lauer et al., 1999).
Vinblastine Extraocular muscle palsies (Fraunfelder & Fraunfelder, 2004), cranial nerve palsies, –
optic neuropathy, optic atrophy, cortical blindness, night blindness (Singh & Singh,
2012)
Vincristine Cranial nerve palsies, optic neuropathy, optic atrophy, case reports of transient cor- Effects usually are reversible after discontinuation of vincris-
tical blindness, night blindness (Bobba & Klein, 2012; Palmer et al., 2008; Singh & tine (Bobba & Klein, 2012).
Singh, 2012)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
BCG—bacillus Calmette-Guérin; EGFR—epidermal growth factor receptor; G-CSF—granulocyte–colony-stimulating factor; GM-CSF—granulocyte macrophage–colony-stimulating factor; HLA—human leukocyte anti-
gen; IFN—interferon; IL—interleukin; IV—intravenous; TBI—total body irradiation; TID—three times daily
Chapter 9. Side Effects of Cancer Therapy 375
e) Conjunctiva and sclera: Ask the patient to look up as you depress
both lower lids with your thumbs, exposing the sclera and conjuncti-
va. Inspect both for color, vascular pattern, discharge, and any nod-
ules or swelling.
f) Cornea, lens, iris, and pupils: Observe the cornea and lens for smooth
appearance, clarity, and any opacities in the lens. Test corneal reflex
by gently touching a cotton swab to corneal surface. Observe iris and
pupils. Margins should be clearly identified. Observe the pupils for
size, shape, and symmetry. If the pupils are > 5 mm or < 3 mm, then
measure the pupils with a pupil guide (a card or pen light with black
circles of varying sizes). Test the pupils for light reaction, observing
for direct reaction (pupillary constriction in the same eye) and con-
sensual reaction (pupillary constriction in the opposite eye). Note
pain and photophobia.
g) Extraocular muscles (CNs): Observe for light reflex (shining a
light in the patient’s eyes and inspecting the reflections in the cor-
neas) and extraocular movement by having the patient follow fin-
ger movements in six planes and convergence. Note any unilateral
movement, lack of movement, nystagmus, lid lag, or other abnor-
mal movements.
6. Collaborative management
a) Refer to an ophthalmologist for further evaluation and treatment.
b) Symptoms that necessitate a referral (Ouwerkerk & Boers-Doets, 2010)
(1) Persistent ocular pain, significant loss of vision, or decreased
acuity of vision
(2) Severe redness of the eye or light sensitivity
(3) Trichomegaly
(4) Failure to respond to treatment within one week of initiation
of treatment for squamous blepharitis, meibomitis, or dysfunc-
tional tear syndrome
c) Instruct patients to use pharmacologic management as appropriate
(e.g., antibiotics, steroids, artificial tears).
d) Prevent further damage: Discontinue causative agent and promote
symptom management.
e) Surgical interventions may be necessary (e.g., cataract surgery, dila-
tion for punctal stenosis, enucleation).
7. Patient and family education
a) Teach patients self-examination techniques, emphasizing the impor-
tance of close monitoring and prompt reporting of any structural
changes in eyelids or eyelashes or changes in vision.
b) Emphasize the importance of careful hygiene and hand-washing tech-
niques to minimize cross-contamination.
c) Demonstrate the proper use of eye drops and lubricants.
d) Encourage patients to schedule regular eye examinations.
M. Pancreatitis: Inflammation of the pancreas
1. Pathophysiology (Andris, 2010; Hruban & Iacobuzio-Donahue, 2010)
a) Inflammation that can lead to parenchymal necrosis and alteration
of pancreatic exocrine cells that produce digestive enzymes such as
amylase and lipase and endocrine cells that produce insulin, gluca-
gon, and somatostatin, secondary infection with gram-negative bac-
teria commonly occurs.
b) Secondary to ductal obstruction, possible ductal rupture, and pre-
mature activation of pancreatic enzymes leading to pancreatic au-
todigestion
2. Risk factors (Andris, 2010; Hruban & Iacobuzio-Donahue, 2010; Stock
et al., 2011)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
376 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
a) Pegylated and natural asparaginase: Causes pancreatitis in 5%–18%
of patients (5% in adults), with a 2% incidence of grade 3 or 4 acute
pancreatitis (per CTCAE version 4.0). Pancreatitis associated with as-
paraginase usually occurs with the first three to five doses.
b) Other agents: Mercaptopurine, ATRA in case reports (Hoshino, Hat-
sumi, Takada, Sakura, & Miyawaki, 2008), arsenic in case reports (Con-
nelly, Zancosky, & Farah, 2011), cytosine arabinoside, and tamoxifen
c) Obstructions of the duct system including periampullary neoplasms,
cholelithiasis, and congenital alterations in the ductal system such as
pancreas divisum
d) Hypertriglyceridemia, hypercalcemia
e) Diabetes
f) TLS
g) Post–endoscopic retrograde cholangiopancreatography
h) Alcohol abuse
i) Illicit drug use
j) Pediatrics: Post-BMT
k) Infection
l) Genetic mutations of cationic trypsinogen (PRSS1) and trypsin in-
hibitor (SPINK1) genes
3. Three main clinical manifestations (Brenner & Krenzer, 2010)
a) Sudden onset of severe epigastric, periumbilical, or left or right
upper abdominal pain that radiates to the back: Pain lasts > 72
hours and usually is exacerbated by sitting up and alleviated by
fetal position.
b) Increased serum levels of pancreatic enzymes: Amylase rises within
two hours of symptoms to two or more times the upper limit of nor-
mal and decreases within 36 hours. Serum lipase is elevated within
4–8 hours of symptoms and decreases after 14 days.
c) CT positive for signs of pancreatic inflammation
4. Other clinical findings
a) Fever
b) Tachycardia and hypovolemia
c) Hypoxemia in 40%–70% of patients (Werner, Feuerbach, Uhl, &
Büchler, 2005)
d) Anorexia and severe nausea and vomiting
e) Jaundice
f) Hypoactive bowel sounds, ileus
g) Elevated LFTs
h) Hyperglycemia, especially related to steroids
i) Frequently elevated WBC count
j) Hemorrhagic pancreatitis manifested by a bluish discoloration around
the umbilicus (Cullen sign) or a reddish-brown discoloration along
the flanks (Grey Turner sign)
k) Later complications include hemorrhage, sepsis, and multiple sys-
tem organ failure.
5. Assessment
a) Perform physical examination to find and document the preceding
clinical manifestations.
b) Anticipate orders for diagnostic imaging of the abdomen (e.g., ab-
dominal flat plate and upright to detect ileus and rule out other eti-
ologies such as bowel perforation or obstruction; ultrasound to visu-
alize gallbladder and biliary tree for stones, edema, and dilation; CT
scan to image pancreas).
6. Collaborative management (Andris, 2010; Forsmark & Baillie, 2007):
Treatment is aimed at correcting underlying predisposing conditions,
managing complications, and decreasing pancreatic inflammation.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 377
a) Holding or discontinuing any agent that may be the cause of the con-
dition is the primary treatment. Pancreatitis associated with aspara-
ginase tends to respond after the drug is discontinued and aggres-
sive treatment is initiated (Stock et al., 2011; Treepongkaruna et al.,
2009) and will most likely recur if the drug is used again (Kearney et
al., 2009; Stock et al., 2011; Tokimasa & Yamato, 2012). Because re-
duced asparaginase exposure is related to a decreased cure rate in
acute lymphoblastic leukemia, the drug should not be stopped unless
pancreatitis is diagnosed. Asparaginase is contraindicated in patients
with a history of severe pancreatitis (EUSA Pharma [USA], Inc., 2011).
b) Insert a nasogastric tube if patients have nausea and vomiting or ile-
us to rest the gut and the pancreas during the acute phase.
c) If patients are unable to eat, consider enteral nutrition through a
feeding tube to prevent malnutrition (McClave et al., 2009).
d) Administer vigorous hydration with electrolyte monitoring and re-
placement (e.g., calcium, potassium, magnesium) as indicated.
e) Monitor serum lipase, amylase, glucose, electrolytes, and LFTs.
f) Treat hyperglycemia as indicated.
g) Provide effective pain control and monitor for increasing pain, which
may indicate progression of pancreatitis.
h) Administer antibiotic therapy.
i) Some studies show severe pancreatitis can be managed with prote-
ase inhibitors, such as nafamostat mesylate, or octreotide therapy
(Stock et al., 2011).
j) Monitor patients’ vital signs, oxygen saturation, level of conscious-
ness, and condition carefully for signs of hypovolemic shock. Hy-
potension occurs because of sequestration of protein-rich fluids in
the pancreas, retroperitoneal space, and abdominal cavity in severe
acute pancreatitis.
k) When food is reintroduced, provide a lipid-restricted diet.
7. Patient and family education
a) Instruct patients to use analgesics for pain control.
b) Implement oral and nasal care while patients are NPO (nothing by
mouth) with a nasogastric tube.
c) Ensure that patients know the importance of adherence to dietary,
pharmacologic, and lifestyle recommendations.
d) Ensure that patients and significant others can recognize the early
symptoms of pancreatitis such as abdominal pain, especially associ-
ated with vomiting, and instruct them to seek medical intervention
when these occur.
N. Fatigue: “Cancer-related fatigue is a distressing, persistent, subjective
sense of physical, emotional, or cognitive tiredness or exhaustion relat-
ed to cancer or cancer treatment that is not proportional to recent activ-
ity and interferes with usual functioning” (NCCN, 2012, p. FT-1). Mul-
tiple factors contribute to this complex syndrome in patients with can-
cer, making it difficult to identify a clear underlying cause (Johnson Ar-
min, & Matzo, 2012). Fatigue is underreported, underdiagnosed, and
undertreated. Cancer-related fatigue is the most common and distress-
ing side effect of cancer treatment and has a profound effect on individ-
uals’ ability to carry out usual functions of daily living (Berger, Gerber,
& Mayer, 2012). NCCN (2012) guidelines recommend that all patients
be screened for fatigue at their initial visit and at regular intervals dur-
ing the cancer treatment continuum and that fatigue should be treated
promptly in both children and adults.
1. Pathophysiology: Exact mechanisms are unknown. Clinical studies have
focused on understanding the factors that contribute to cancer-related
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
378 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
fatigue. Factors include the tumor itself, treatments, and comorbid con-
ditions (Wang, 2008) (see Figure 36).
a) Underlying causes of cancer-related fatigue are believed to involve
several physiologic and biochemical systems (Wang, 2008).
(1) 5-HT neurotransmitter dysregulation
(2) Vagal afferent activation
(3) Alterations in muscle and ATP metabolism
(4) Anemia
(5) Proinflammatory cytokines
(a) Hypothalamic-pituitary-adrenal axis and cortisol dysfunction
(b) Circadian rhythm disruption
(c) Cytokine dysregulation
(d) Growth factor modulation
(e) Depression
(f) Cachexia
b) Treatment-related causes: Direct effects of chemotherapy, hormone
therapy, radiation therapy, and combined-modality therapies have
Figure 36. Proposed Potential Causes of Cancer-Related Fatigue
EGFR—epidermal growth factor receptor; 5-HT—5-hydroxytryptamine; HPA—hypothalamic-pituitary-adrenal; VEGF—vascular endothelial growth factor
Note. From “Pathophysiology of Cancer-Related Fatigue,” by X.S. Wang, 2008, Clinical Journal of Oncology Nursing, 12(Suppl. 5), p. 12. doi:10.1188/08.
CJON.S2.11-20. Copyright 2008 by the Oncology Nursing Society. Reprinted with permission.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 379
all been implicated as contributors to the intensity of fatigue in pa-
tients with cancer (Bruera & Yennurajalingam, 2010). Travel to and
from a clinic for treatment adds to a patient’s fatigue, as well as the
therapy itself.
c) Disease process and comorbid conditions including metabolic dis-
orders
(1) Hypothyroidism
(2) Electrolyte imbalances
(3) Infection
(4) Insulin sensitivity: Insulin resistance causes abnormal uptake of
glucose by muscle and increases body fat, contributing to can-
cer-related fatigue (Berger et al., 2012).
d) Uncontrolled pain, nausea, and vomiting
e) Anxiety and stress
f) Sleep disturbances (NCCN, 2012)
(1) Obstructive sleep apnea
(2) Restless legs syndrome
(3) Narcolepsy
(4) Insomnia
(5) Hypersomnia
g) Mood disturbances
h) Anemia: A relationship clearly exists between Hgb and fatigue. A de-
crease in RBCs increases hypoxia-related compromise in organ func-
tion, which contributes to fatigue (Wang, 2008).
i) Nutritional deficiencies: Reduced caloric intake and imbalances in se-
rum levels of sodium, potassium, calcium, and magnesium may con-
tribute to fatigue and affect QOL (NCCN, 2012; Sauer & Voss, 2012).
j) Physical deconditioning and activity level: Direct effects of the tumor
or side effects of the treatment regimen often contribute to fatigue
through reduced physical activity, debilitation, and reduced muscle
strength (Winters-Stone, Bennett, Nail, & Schwartz, 2008).
k) Stress
l) Depression: Depression may occur concurrently or independently of
fatigue and has a different pattern of expression over time. Depres-
sion often decreases over the course of treatment, whereas fatigue
increases (NCCN, 2012).
m) Phenotypes/genotypes: Underlying genetic variants and pathways may
produce a cancer-related fatigue phenotype (Piper & Cella, 2010).
2. Incidence: Fatigue is one of the most commonly reported symptoms
experienced by patients receiving treatment for cancer, and it often
persists beyond the conclusion of active treatment. Depending upon
how cancer-related fatigue is defined and measured, prevalence es-
timates across the disease trajectory range from 25%–99% (Mitch-
ell, 2010b).
3. Assessment: Oncology nurses can ensure that cancer-related fatigue is
routinely assessed, managed, and documented. Multiple cancer-related
fatigue assessment and screening tools are available (Piper et al., 2008).
a) Single-item, single-dimension measures are easy to administer. These
include a 0–10 scale, a visual analog scale, or Likert scales (Piper et
al., 2008).
(1) On a 0–10 scale (0 = no fatigue, and 10 = worst fatigue imag-
inable), mild fatigue is given a score of 1–3; moderate fatigue,
4–6; and severe fatigue, 7–10.
(2) Fatigue measurement in children is simplified. Young children
(age < 6) may just be asked if they are “tired” or “not tired.” Val-
id and reliable instruments are available to measure fatigue in
children and adolescents (NCCN, 2012).
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
380 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
(3) If mild levels (1–3) are determined, patients and family mem-
bers should receive education about fatigue and common strat-
egies for management.
(4) When fatigue is rated as moderate to severe (4–10), a more fo-
cused history and physical examination should be conducted as
part of the primary evaluation phase. Multi-item, single-dimen-
sion measures, multidimensional measures, and fatigue mea-
sures embedded in other scales are available with limitations.
Most have been validated as reliable but have not been tested
in practice settings. More studies are needed to evaluate wheth-
er these scales are useful for treatment planning.
b) Disease status
c) Disease recurrence or progression
d) Current medications or medication changes that may contribute to
fatigue
(1) Polypharmacy is common in patients with cancer. Many drugs
alone (e.g., antihistamines, beta-blockers) or in combination
can contribute to fatigue (Breitbart & Alici, 2008).
(2) Tricyclic antidepressants, opioids, antiemetic medications, and
sleep aids all can cause sedation. Combined use of these agents
can cause prolonged sedation, leading to limited activity and
overall fatigue.
e) Complete review of systems
f) Onset, pattern, and duration of fatigue
g) Nutritional and metabolic evaluation: Improving dietary intake, with
appropriate caloric intake, often can improve fatigue symptoms.
(1) A dietitian can design a patient-specific plan to improve nutri-
tional status. Fluids and electrolytes should be assessed. Specif-
ically, imbalances in sodium, potassium, calcium, and magne-
sium can be reversed with appropriate supplementation, which
may improve fatigue (NCCN, 2012).
(2) Nausea and vomiting, taste changes, and bowel changes (e.g.,
obstruction, constipation, diarrhea) will interfere with nutri-
tional intake and affect fatigue level.
h) Activity level
i) Associated or alleviating factors (e.g., rest, energy conservation, bal-
ancing activities with rest periods)
4. Collaborative management
a) General
(1) Energy conservation: The goal of energy conservation as de-
fined by NCCN (2012) “is to maintain a balance between rest
and activity during times of high fatigue so that valued activi-
ties can be maintained” (p. MS-16). This is a learned process for
each patient and is dictated by the patient’s disease experience.
(2) Instruct patients to delegate activities, pace themselves, take ex-
tra rest periods, plan high-energy activities at times of peak en-
ergy, and conserve energy for valued activities (NCCN, 2012).
(3) Recommend energy-saving devices (e.g., raised toilet seats, grab-
ber tools, seated walkers, wheelchairs).
b) Pharmacologic: Because the exact pathophysiology of cancer-related
fatigue is obscure, pharmacotherapy is empiric or geared toward re-
versing possible contributing factors such as anemia, poor nutrition,
or depression (Minton, Richardson, Sharpe, Hotopf, & Stone, 2008).
(1) ESAs (Epogen®, Procrit®, and Aranesp®) have been under in-
tense scrutiny. These agents, when used appropriately, reduce
transfusion requirements and improve anemia. However, safe-
ty concerns, including increased risk of thrombotic events, hy-
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 381
pertension, red cell aplasia, and decreased locoregional disease
control and survival outcomes, limit their use in clinical prac-
tice. Current recommendations for use are for treatment of ane-
mia related to myelosuppressive chemotherapy without cura-
tive intent (Mitchell, 2010b; Minton et al., 2008; NCCN, 2012).
(2) Antidepressants have been recommended as treatment for fa-
tigue because depression was suggested as a causal factor. In
particular, paroxetine, bupropion, and venlafaxine are used.
(a) Although these drugs are helpful in alleviating depression,
studies have not demonstrated a benefit compared to place-
bo in cancer-related fatigue, and they are not recommend-
ed to lessen fatigue (Mitchell, 2010b; Minton, Richardson,
Sharpe, Hotopf, & Stone, 2010; NCCN, 2012).
(b) Antidepressants might have a greater effect on cancer sur-
vivors, in whom fatigue and depression are prevalent and
often coexist (Johnson et al., 2012).
(3) Psychostimulants
(a) Methylphenidate: Studies have reported mixed results us-
ing methylphenidate to reduce fatigue (Portela, Rubiales,
& Centeno, 2011). Side effects of headache, insomnia, agi-
tation, anorexia, nausea, vomiting, and dry mouth are com-
mon (Minton et al., 2008; Mitchell, 2010b; NCCN, 2012).
The most recent randomized controlled trial conducted
by the North Central Cancer Treatment Group was unable
to demonstrate that the chosen long-acting methylpheni-
date product would decrease cancer-related fatigue (Mo-
raska et al., 2010).
(b) Dexmethylphenidate has a longer duration of action com-
pared to methylphenidate. Trials have demonstrated im-
provement in fatigue outcomes in patients with breast and
ovarian cancers but no improvement in those with primary
or metastatic brain tumors (Breitbart & Alici, 2008; Mitch-
ell, 2010b).
(c) Modafinil is a wakefulness-promoting agent. It is indicated
for narcolepsy. Data from a large randomized controlled
trial observed improvement in fatigue in patients with se-
vere fatigue but not in those with mild or moderate fatigue
(NCCN, 2012).
(4) Glucocorticoids
(a) Corticosteroids (prednisone and dexamethasone) have
been used in providing short-term relief for cancer-related
fatigue. Given the detrimental side effects of muscle wast-
ing with long-term use, steroids are restricted to the termi-
nally ill (Breitbart & Alici, 2008; NCCN, 2012).
(b) Megestrol acetate is widely used for appetite improvement,
and its safety and efficacy have been confirmed in treating
cancer cachexia. However, meta-analysis of the four trials
that compared progestational steroids with placebo found
no difference in the two arms for reducing cancer-related
fatigue (Breitbart & Alici, 2008; Chan, 2011; NCCN, 2012).
(5) The supplement L-carnitine has been examined in several open-
label studies and has shown improvement in cancer-related fa-
tigue. Carnitine is a micronutrient important in the processing
of long-chain fatty acids and energy production in mammalian
cells. Carnitine supplements may prove beneficial for fatigue
management (Breitbart & Alici, 2008; Mitchell, 2010b).
(6) CAM therapies
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
382 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
(a) Limited studies of herbal supplements have been conduct-
ed with regard to fatigue in patients with cancer. A trend
toward improvement in fatigue was seen with ginseng at
greater dose levels (Homeber, Fischer, Dimeo, Rüffer, &
Weis, 2012; Mitchell, 2010b). Current data are insufficient
to warrant recommendation of many of these substances.
(b) Mistletoe extract demonstrated some positive effect on
cancer-related fatigue in an observational cohort analysis
(Mitchell, 2010b).
(7) Nonpharmacologic interventions
(a) Exercise (activity enhancement): Cumulative evidence is
strong in support of exercise as an intervention to manage
cancer-related fatigue (NCCN, 2012). All patients with can-
cer should be encouraged to maintain an optimum level of
physical activity during and following cancer treatment. Ex-
ercise improves aerobic capacity, prevents muscle loss and
deconditioning, and helps to manage cancer-related fatigue
during and after treatment even in older cancer survivors
(Brown, Huedo-Medina, et al., 2011; Mishra et al., 2012;
Mitchell, 2010b; Puetz & Herring, 2012).
i. Exercise intensity, frequency, and type of activity need
further study to determine the most beneficial pro-
gram for each individual and stage of disease. Refer-
ral for exercise rehabilitation can be helpful (Mitch-
ell, 2010b; NCCN, 2012).
ii. Exercise programs must be undertaken with caution
for patients with bone metastasis, immunosuppression
or neutropenia, fever, thrombocytopenia, anemia, or
other treatment complications.
iii. Programs should be initiated slowly to assess the pa-
tient’s tolerance and can be modified as the patient’s
condition changes (NCCN, 2012). Walking, cycling,
swimming, resistance training, and a combination of
these have been evaluated and are reasonable modal-
ities for patients to choose.
(b) Complementary therapies: In cases in which exercise or
medication is prohibited, evidence is emerging in sup-
port of complementary therapies. Yoga, progressive mus-
cle relaxation, polarity therapy, hypnosis, medical Qigong,
healing touch, Reiki, and massage have demonstrated im-
provement in cancer-related fatigue in small trials (Mitch-
ell, 2010b; NCCN, 2012). Boehm, Ostermann, Milazzo, and
Büssing (2012), in a meta-analysis of the effects of yoga on
fatigue in patients with cancer, found the intervention to
be limited. However, the authors concluded that the studies
were not well designed and that the treatment benefit from
this generally safe, therapeutic intervention may be more
powerful than reported. Although patients frequently use
complementary therapies to reduce distress from cancer
treatment side effects, efficacy related to benefit for cancer-
related fatigue needs to be confirmed in further random-
ized controlled studies (Wanchai, Armer, & Stewart, 2011).
Psychosocial and educational interventions that teach pa-
tients to recognize cancer-related fatigue and manage it
through energy conservation activities have demonstrated
some benefit (Bennett et al., 2009; Goedendorp, Gielissen,
Verhagen, & Bleijenberg, 2009).
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 383
(c) Sleep therapy: Cognitive-behavioral therapies to optimize
sleep quality have been shown to decrease cancer-related
fatigue (NCCN, 2012; Wanchai et al., 2011).
i. Stimulus control: Maintain a consistent bedtime ritu-
al and wake time.
ii. Sleep restriction: Limit the amount of time in bed,
including naps.
iii. Sleep hygiene: Avoid caffeine late in the day and pro-
vide a comfortable sleep environment to promote a
good night’s sleep.
5. Patient and family education
a) Management of fatigue originates with the primary oncology team with
assessment of fatigue as a symptom related to treatment and disease sta-
tus. This begins with the initial screening and then expands to a more fo-
cused evaluation for moderate to higher levels of fatigue (NCCN, 2012).
b) Inform patients and family members that fatigue is a major symptom
related to the disease and treatment process and that patterns are vari-
able and not necessarily an indication of treatment failure or disease
progression. Daily self-monitoring of fatigue levels in a log or diary
can be helpful (NCCN, 2012). Verbal encouragement from health-
care providers and other patients with cancer to maintain physical ac-
tivity may enhance self-efficacy and mediate the effect of cancer-relat-
ed fatigue on activity enhancement (Haas, B.K., 2011).
c) Supportive expressive therapies, including in-person or online sup-
port groups, counseling, and journal writing, may serve as an emo-
tional outlet as well as an avenue for support and encouragement
(NCCN, 2012). Oncology nurses frequently provide this one-on-one
education for the patient.
d) Nutritional consults with a registered dietitian will identify nutrition-
al deficits and inform patients and caregivers of the best strategies to
improve dietary intake. Maintaining adequate hydration and electro-
lyte balance is essential in preventing and managing cancer-related
fatigue (NCCN, 2012; Sauer & Voss, 2012).
O. Alterations in sexuality
1. Pathophysiology
a) Female: Ovarian function is affected by chemotherapy.
(1) Altered production of female sex hormones (estrogen, progester-
one, and testosterone) (Nappi, Albani, Strada, & Jannini, 2011)
(2) Varying effects on sexuality (Krebs, 2012)
(3) No association found between specific androgen levels and low
sexual function (Davis, Davison, Donath, & Bell, 2005)
b) Male
(1) Testosterone is involved in
(a) Development of secondary sex characteristics
(b) Development of sperm
(c) Secretion of fluid from the prostate gland, seminal vesicles,
and Cowper glands.
(2) Prolactin is secreted by the pituitary gland.
(a) Maintains the production of testosterone
(b) At high levels, suppresses production in a negative feed-
back loop (Deneris & Huether, 2010)
2. Incidence: Almost all cancer survivors report ongoing problems with sex-
ual functioning. These issues are global and reflect changes in body im-
age, sexual self-image, and reentering life as a cancer survivor and may
persist for many years after completion of treatment (Harrington, Han-
sen, Moskowitz, Todd, & Feuerstein, 2010).
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
384 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
a) Females
(1) Desire: Decrease in desire ranges from 31%–56%, although
this may be underreported (Rellini, Farmer, & Golden, 2011).
(2) Dyspareunia: Painful intercourse is a common complaint caused
by vaginal dryness as a result of reduced estrogen levels or radi-
ation damage to the pelvis (Goldfinger & Pukall, 2011).
(3) Arousal and orgasm: 36% of women report problems with arous-
al and pleasure, and 46% report decreased lubrication follow-
ing cancer diagnosis and treatment (Huyghe, Sui, Odensky, &
Schover, 2009).
b) Males
(1) 90% of men experience profound loss of sexual desire while on
androgen deprivation therapy (DiBlasio et al., 2008).
(2) Up to 80% of men experience permanent erectile problems af-
ter any treatment for prostate cancer (Hoffman et al., 2006).
3. Chemotherapy agents that affect sexual function: There is very little in-
formation in the literature directly related to the effects of chemother-
apy on sexual functioning beyond agents that are known to target the
gonads. Much of what is known comes from anecdotal evidence from
qualitative studies where participants may mention alterations in sexu-
al functioning while on chemotherapy. All of the following agents are
used in various combinations; thus, the side effects may be cumulative
(Lubejko & Ashley, 1998).
a) Alkylating agents (e.g., busulfan, cyclophosphamide, ifosfamide, ni-
trogen mustard) cause nausea and vomiting, which significantly de-
creases desire.
b) Antimetabolites (e.g., cladribine, cytarabine, hydroxyurea, methotrex-
ate) cause general malaise, mucositis, nausea, and vomiting.
c) Antitumor antibiotics (e.g., daunorubicin, doxorubicin, mitoxan-
trone) cause nausea, vomiting, and mucositis.
d) Plant alkaloids (e.g., vincristine) cause peripheral neuropathy, which may
affect sensation in the hands and fingers (Schwartz & Plawecki, 2002).
e) Hair loss is a common side effect of chemotherapy. The loss of hair
makes both men and women feel less attractive.
4. Biologic agents: Many of these agents cause fatigue, flu-like symptoms,
and changes to body image (Rothaermel & Baum, 2009).
5. Targeted therapies: There is no evidence about direct sexual effects, but
these agents cause fatigue, diarrhea, and rash with the potential to affect
body image (Remer, 2009).
6. Contributing factors
a) Chemotherapy-induced menopause: Symptoms of chemically induced
menopause are dramatic.
(1) Menstrual cycle changes with eventual cessation
(2) Hot flashes, insomnia
(3) Vaginal dryness
(4) Dyspareunia
(5) Weight gain (Deniz et al., 2007)
b) Severity
(1) Symptoms may be worse for women who are premenopausal
when diagnosed (Rogers & Kristjanson, 2002).
(2) Postmenopausal women also suffer severe symptoms (Crandall,
Petersen, Ganz, & Greendale, 2004).
c) Treatment: Women experiencing chemotherapy-induced menopause
benefit from a coordinated, multidisciplinary approach to manag-
ing symptoms.
(1) Hormonal: No consensus exists on the safety of hormone ther-
apy for women with breast cancer, especially if it is estrogen
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 385
receptor–positive (Hickey, Saunders, & Stuckey, 2005, 2007;
Ponzone et al., 2005). Those with hormone-dependent cancer
should make a decision based on consultation with an oncolo-
gist (North American Menopause Society, 2007).
(a) Local estrogen therapy for vaginal atrophy
i. The use of vaginal estrogen creams, pessaries, or rings
can significantly reduce vaginal dryness.
ii. Systemic absorption is minimal (Ponzone et al., 2005).
(b) Systemic therapy: Three to five years of hormone replace-
ment therapy may be considered if menopausal symptoms
are refractory to other treatments (Xydakis, Sakkas, & Mas-
torakos, 2006).
(2) Nonhormonal
(a) Clonidine (an antihypertensive) and gabapentin (an anti-
convulsant) may reduce the severity and frequency of hot
flashes (Molina, Barton, & Loprinzi, 2005).
(b) Selective serotonin reuptake inhibitors
i. These agents have been effective in reducing the fre-
quency and severity of hot flashes (Hickey et al., 2007).
ii. Venlafaxine and paroxetine have been suggested as
the most effective nonhormonal treatments for wom-
en with breast cancer (Bordeleau, Pritchard, Good-
win, & Loprinzi, 2007).
iii. Safety of selective serotonin reuptake inhibitors in
women with cancer is not yet established. Recent evi-
dence suggests that these drugs may decrease the ef-
fectiveness of tamoxifen (Antoine, Liebens, Carly, Pas-
tijn, & Rozenberg, 2007).
(c) Vitamin E may be effective in reducing hot flashes (Hick-
ey et al., 2007).
(d) Vaginal moisturizers such as Replens® may help women
who are experiencing vaginal dryness (Davis, Zinkand, &
Fitch, 2000).
(3) Complementary therapies
(a) Phytoestrogens: Long-term effectiveness has not been es-
tablished (Hickey et al., 2007).
(b) Acupuncture may reduce the severity but not the frequency
of hot flashes (Nir, Huang, Schnyer, Chen, & Manber, 2007).
(c) Relaxation exercises are effective in reducing hot flashes
(Zaborowska et al., 2007).
d) Endocrine manipulation
(1) Tamoxifen
(a) Side effects appear to be most severe in premenopausal
women.
(b) Postmenopausal women experience negative side effects
of this drug to a lesser degree (Ganz, Rowland, Desmond,
Meyerowitz, & Wyatt, 1998).
(c) Decrease in libido has been reported.
(d) Tamoxifen produces mildly estrogenic effects on the vagi-
na. Some women find relief from the vaginal dryness expe-
rienced as a result of chemotherapy-induced atrophy (Rog-
ers & Kristjanson, 2002), whereas others think that the dry-
ness has resulted from tamoxifen use (Hunter et al., 2004).
(2) Aromatase inhibitors cause vaginal dryness leading to dyspareu-
nia (Mok, Juraskova, & Friedlander, 2008)
e) Body image changes related to ability to engage in sexually pleasur-
able activities: A woman’s comfort with her body after treatment; the
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
386 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
reaction of her sexual partner to her body and weight gain (Garru-
si & Faezee, 2008).
7. Clinical manifestations
a) Females: Alterations in sexual functioning can occur at all stages
of the sexual response cycle for women treated for cancer. Fatigue,
weight gain, and altered sexuality occur as a cluster of symptoms,
which magnifies the impact of each more than if they occurred indi-
vidually (Wilmoth, Coleman, Smith, & Davis, 2004).
(1) Dyspareunia leading to vaginismus (Goldfinger & Pukall, 2011)
(2) Urinary tract infections after attempts at sexual intercourse
(Ponzone et al., 2005); this can create a negative feedback loop
with decreased interest in sex if the result is a painful infection.
(3) Mucositis manifested as vaginal irritation or vaginitis, vulvar ir-
ritation, itching, discharge, soreness, bleeding, and odor; this
usually occurs 3–5 days after chemotherapy administration and
lasts for up to 10 days.
(4) Other factors contributing to decreased sexual desire
(a) Depressed mood, fatigue, and nausea (Taylor, Basen-
Engquist, Shinn, & Bodurka, 2004)
(b) Loss of hair, particularly pubic hair (Fitch, 2003)
(c) Distress at role inadequacy (Lammers, Schaefer, Ladd, &
Echenberg, 2000)
(d) Fear that lack of sexual activity may cause problems in the
relationship (Sun et al., 2005)
b) Males
(1) Effects of androgen deprivation therapy
(a) Absence of sexual dreams; cessation of fantasies
(b) Lack of interest in anything sexual
(c) Cessation of any sexual pleasure (Navon & Morag, 2003)
(d) Changes in body image and perception of masculinity
(e) Alterations in spousal/partner relationships (Wittmann
et al., 2009)
(f) Erectile dysfunction
(g) Feminization
(h) Gynecomastia (increase in volume of breast tissue) (An-
derson, 2001)
(i) Genital shrinkage, which is very distressing (Higano, 2003)
(2) Treatment for testicular cancer: More than one-third of men
experience loss of libido, orgasmic and ejaculatory problems,
and a subsequent decrease in sexual activity (Dahl et al., 2007).
These problems may persist for two years after completion of
treatment (Wiechno, Demkow, Kubiak, Sadowska, & Kamińska,
2007). Inability to perform sexually can affect the man’s con-
fidence in himself as a sexual partner and may have psycho-
logical consequences that last for a significant period of time.
8. Collaborative management
a) Females
(1) Provision of anticipatory guidance at all stages of the disease
trajectory (Rustøen & Begnum, 2000)
(a) 68% of women with breast cancer wanted information
about all aspects of sexual functioning (Ussher, Perz, &
Gilbert, 2013).
(b) A great deal of information is given at the time of diagno-
sis, when patients cannot assimilate and integrate the new
information (Koinberg, Holmberg, & Fridlund, 2001).
(c) Only a small proportion of women with breast cancer discussed
sexual issues with their physician (Barni & Mondin, 1997).
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 387
(d) Most women have never been asked if sexual problems oc-
curred as a result of treatment (Young-McCaughan, 1996).
(e) Less than half of women were satisfied with their discus-
sion with their oncologist or family physician compared to
almost 60% who were satisfied with their discussion with a
breast care nurse (Ussher et al., 2013)
(f) Women have reported that their physicians were not un-
derstanding or helpful when sexual dysfunction was iden-
tified as a problem (Wilmoth & Ross, 1997).
(g) Older women may be more reluctant than younger wom-
en to state their needs for information (Gray, Goel, Fitch,
Franssen, & Labrecque, 2002).
(2) A modified form of sensate focus exercises can help the woman
and her partner to learn a new way of dealing with the changes
from treatment. Refer patients to a sexuality counselor or sex
therapist for assistance.
(3) Instruct patients to prevent or manage vaginitis or vulvar irri-
tation.
(a) Focus on prevention, including avoidance of tight-fitting
pants and pantyhose.
(b) Wear cotton underwear.
(c) Employ fastidious personal hygiene; use a mild soap with
water for cleansing.
(d) Avoid bubble baths, douching, and chemical irritants such
as genital deodorant sprays.
(e) Use cool sitz baths and warm compresses to provide lo-
cal relief.
(f) Treat concomitant bacterial infections such as Candida al-
bicans or Trichomonas vaginitis, if present.
(4) Lubricants are available to help women feel more comfortable
with sexual activity.
(a) Water- and glycerin- or silicone-based lubricants are the
safest to use.
(b) Lubricants that are dye and perfume free are less irritating.
(c) Instruct patients to avoid the use of oil-based products or
anything that is colored, scented, or not designed specifi-
cally for sexual activity, such as hand lotion.
b) Males: A thorough assessment of prediagnosis and pretreatment sex-
ual functioning is important to establish the man’s current level of
functioning.
(1) It is common for men age 75 and older who have prostate can-
cer to have diminished levels of sexual interest and function-
ing before treatment begins.
(2) Other men may have erectile difficulties before the diagnosis
of cancer as a result of cardiac disease, diabetes, and medica-
tions (Clayton & Ramamurthy, 2008).
(3) Obtaining an accurate description of pretreatment erectile func-
tioning and sexual activity is crucial so that the patient has re-
alistic expectations of what treatment can do.
(4) Treatment of erectile dysfunction includes oral therapies (phos-
phodiesterase-5 [PDE5] inhibitors), vacuum devices, alprostadil
intraurethral pellets (MUSE®), alprostadil intracorporeal injec-
tions (Caverject®), and penile implants. Each has benefits and
disadvantages. All require a prescription, extensive patient ed-
ucation, and varied degrees of motivation on the part of both
the man and his partner. Only 10% of men who used erectile
aids after surgery (PDE5 inhibitors such as sildenafil, tadalafil,
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
388 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
or vardenafil, or vacuum devices) reported satisfaction with
their sex lives (Miller et al., 2006).
9. Patient/couple education: A number of models are helpful in commu-
nicating with patients about sexuality. The most frequently used model
is the PLISSIT model (Annon, 1974). A more recent model specifical-
ly designed for the oncology population is the BETTER model (Mick,
Hughes, & Cohen, 2003).
a) PLISSIT
(1) The first level in this model involves giving the patient or client
permission to talk about sexual issues.
(2) The second level, limited information, refers to factual information
given to the patient in response to a question or observation.
(3) The third level involves making a specific suggestion to the cli-
ent or patient.
(4) The fourth level refers to intensive therapy needed for severe or
more long-standing sexual problems.
b) BETTER
(1) The first level of intervention involves bringing up the topic.
(2) The second level involves explaining that sexuality is part of
QOL, and patients should be aware that they can talk about
this with the nurse.
(3) Care providers should then tell patients that appropriate re-
sources will be found to address their concerns.
(4) Care providers should state that while the timing may not be
appropriate now, patients can ask for information at any time.
(5) Patients should be educated about the sexual side effects of their
treatment.
(6) Finally, a record should be made in the patient’s medical record
to report that this topic has been discussed.
c) Sexual intercourse is not always the end goal of sexual touch. Encour-
age patients and their partners to find other ways of sexual pleasuring
that are not fatigue- or nausea-provoking for patients and that satisfy
both individuals’ needs and desires for intimate touch.
d) Patients should avoid intercourse when neutrophil and platelet counts
are low (Vachani, 2011). Recommend use of condoms to prevent trans-
mission of infection and exposure of the partner to chemotherapeutic
agents in the body fluids of the patient. Caution should be used in the
type of condom chosen, as those that are lubricated usually contain non-
oxynol-9, which can be irritating to vaginal tissue (Burke et al., 2010).
P. Reproductive alterations
1. Pathophysiology
a) Females (Knobf, 2006)
(1) Effects of chemotherapy
(a) Damage to ovarian follicles
(b) Decreased ovarian volume
(c) Ovarian fibrosis
(2) Manifestations
(a) Amenorrhea (permanent or reversible)
(b) Menopausal symptoms
(c) Eventual bone loss
(3) Associated factors
(a) Age
(b) Dosage and duration of treatment
b) Males: Effects of chemotherapy (Maltaris et al., 2006)
(1) Primary or secondary hormonal changes from damage to the
hypothalamic-pituitary axis
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 389
(2) Damage to germinal stem cells in the testes
2. Incidence
a) Females
(1) Women older than age 30: Risk of permanent amenorrhea in-
creases.
(2) Breast cancer: 15% of premenopausal women treated with an
alkylating agent developed long-term amenorrhea (Fornier,
Modi, Panageas, Norton, & Hudis, 2005).
(3) Childhood cancer survivors: Less than 20% will develop prema-
ture ovarian failure (Larsen, Müller, Schmiegelow, Rechnitzer,
& Andersen, 2006).
b) Males: Testicular cancer
(1) Decreased sperm production is present at the time of diagno-
sis (Rives et al., 2012).
(2) 70% of patients who have retroperitoneal lymph node dissec-
tion will be unable to ejaculate and will notice a decrease in se-
men volume or experience a “dry ejaculate” (Arai, Kawakita,
Okada, & Yoshida, 1997).
3. Agents
a) Alkylating agents (e.g., cyclophosphamide, cisplatin, chlorambucil,
melphalan, busulfan, nitrogen mustard, dacarbazine, ifosfamide, pro-
carbazine) (Marhhom & Cohen, 2007) have the greatest effect on
both female and male fertility (Maltaris et al., 2006).
b) Nitrosoureas (e.g., carmustine, lomustine) affect the ovaries (Blatt, 1999).
c) Anthracycline antibiotics affect fertility.
d) Vinca alkaloids affect fertility (Maltaris et al., 2007).
e) Taxanes increase the risk of chemotherapy-induced amenorrhea
(Tham et al., 2007).
4. Contributing factors
a) Age
(1) Older women are more likely to experience complete ovarian
failure and permanent infertility (Maltaris et al., 2007).
(2) The adult testis is more susceptible than the testis of the prepu-
bescent boy (Tomao, Miele, Spinelli, & Tomao, 2006).
b) Combination therapy: The addition of radiation to the treatment
regimen significantly increases the risk of permanent infertility (Da-
vis, V.J., 2006).
c) Preexisting disease: Men with cancer commonly have reduced
fertility before diagnosis and treatment. This reduced fertility is
thought to be a result of anatomic or endocrine changes (Maltar-
is et al., 2006).
d) Treatment effect: Lymph node or tumor resection results in retro-
grade ejaculation, which affects fertility (Spermon et al., 2003).
5. Clinical manifestations
a) Females
(1) Amenorrhea (permanent or temporary)
(2) Signs of premature menopause in younger women: These may
be more severe than in naturally menopausal women.
(a) Hot flashes
(b) Urogenital atrophy
(c) Osteoporosis (late-stage symptom)
(3) Psychosocial distress: 57% of young women in one study identi-
fied significant concerns about infertility (Partridge et al., 2004).
b) Males: Alterations in spermatogenesis (Maltaris et al., 2006)
(1) Low sperm counts
(2) Poor sperm motility
(3) Altered morphology
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
390 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
6. Collaborative management
a) Females
(1) Cryopreservation of embryos
(a) Most effective intervention in terms of successful preg-
nancies
(b) May result in a delay of two to six weeks in starting chemo-
therapy (Oktay, 2005)
(c) Requires ovarian stimulation; may be contraindicated with
estrogen-sensitive cancers (Marhhom & Cohen, 2007)
(d) Tamoxifen and letrozole may be used to stimulate ovaries
with estrogen-sensitive tumors. Tamoxifen cannot be used for
women with endometrial cancer (Marhhom & Cohen, 2007).
(2) Oocyte cryopreservation (surgical)
(a) Regarded as experimental
(b) May be offered to single women with no male partner
(c) Low pregnancy rates (Marhhom & Cohen, 2007).
(3) Cryopreservation of ovarian tissue (surgical)
(a) New experimental technique that may offer some hope to
women who do not have the time for ovarian stimulation
(b) Concerns about introducing malignant cells when the pre-
served ovarian tissue is transplanted back into the woman
(4) Nonsurgical: Monthly injections of gonadotropin analogs (e.g.,
leuprolide) to reduce the rate of ovarian follicle atresia (Da-
vis, M., 2006)
(5) The return of menstrual periods does not necessarily indicate
good ovarian function, and in turn, lack of menstruation does
not mean that ovarian function has ceased (Del Mastro, Catzed-
du, & Venturini, 2006).
b) Males
(1) Cryopreservation: Sperm cryopreservation before treatment is
highly effective, as sperm remain viable after freezing and can
be used to fertilize ovum.
(2) New reproductive technologies may be useful in causing preg-
nancy (Stensvold, Magelssen, & Oskam, 2011).
(a) Testicular sperm extraction
(b) In vitro fertilization
(c) Intracytoplasmic sperm injection
7. Patient and family education: Decisions about treatments that affect fer-
tility have to be made when the patient is trying to cope with the diag-
nosis of cancer; priorities may change over time. It is important to edu-
cate patients honestly and directly, as they may assume that modern re-
productive technologies will result in a future pregnancy.
a) Parents of a child with cancer may have to make decisions about treat-
ment for their child and may not be capable of discussing sperm bank-
ing or ovarian preservation with their child or healthcare providers,
as their priority is to save the life of their child.
b) Males: Because of the average young age of those affected with tes-
ticular cancer, many will not be in a relationship at the time of diag-
nosis, and thoughts of parenthood may be remote and not a priority.
(1) Men who are young, unmarried, and childless experience more
infertility-related distress than those who have fathered chil-
dren and are in a supportive relationship. This needs to be tak-
en into consideration when informing patients of the conse-
quences of treatment.
(2) Sperm samples can be obtained with 24–48 hours between col-
lections (Brown, 2003), which allows for minimal delay of che-
motherapy treatment.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 9. Side Effects of Cancer Therapy 391
(3) Men should be counseled honestly and directly that cryopreser-
vation does not guarantee success despite advances in technique
(Schmidt et al., 2004).
c) Females: Women older than age 18 want information about fertili-
ty and are frustrated by their lack of choice or control over fertility
(Gorman, Bailey, Pierce, & Su, 2012).
(1) Many do not recall being told about the potential for alterations
to reproductive health (Duffy, Allen, & Clark, 2005).
(2) Women who have been treated for cancer have lower live birth
rates with in vitro fertilization than women without cancer un-
dergoing in vitro fertilization (Barton, Missmer, Berry, & Gins-
burg, 2012).
8. Access to fertility services
a) A multidisciplinary approach is regarded as optimal to address the
complex ethical and psychological issues (Treves, Grynberg, Hesters,
& Frydman, 2011).
b) Disparity in access to fertility services is related to age (older than
35), previous children, ethnicity, and sexual orientation (Letour-
neau et al., 2012).
9. Ethical issues
a) Concerns exist about whether teens can make decisions about fertil-
ity; however, they are interested in future fertility and want to be in-
volved in decisions (Quinn et al., 2011).
b) Patients have concerns about insurance coverage, even though threat
to future fertility is iatrogenic (Shah, Goldman, & Fisseha, 2011).
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Chapter 9. Side Effects of Cancer Therapy 435
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Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 10
Post-Treatment Care
A. Overview: Over the past 30 years, the number of cancer survivors in the Unit-
ed States has increased from 3 million to 13 million (NCI, 2011). Early diag-
nosis and advances in cancer treatment have led to improved five-year relative
survival rates for all cancers from 50% in the 1970s to 68% during 2007–2008
(Siegel, Naishadham, & Jemal, 2013). Childhood cancers are now often cured;
83% of children and adolescents survive a cancer diagnosis (Siegel et al., 2013).
However, long-term cancer survivors are at risk for adverse effects from their
lifesaving treatment. Research suggests that more than 60% of survivors of
childhood cancers have one or more treatment- or disease-related long-term
effects (Oeffinger et al., 2006). Late treatment effects include impairment in
the function of specific organs, second malignant neoplasms (SMNs), cognitive
impairments, and psychosocial concerns. COG (2008) developed long-term
follow-up guidelines for screening and management of late effects in survi-
vors of childhood cancer. These guidelines are available at www.survivorship
guidelines.org. The Childhood Cancer Survivor Study has followed more
than 14,000 childhood cancer survivors to observe the type and incidence
of the late effects of cancer treatment. This study provides important infor-
mation about late effects of cancer treatment in childhood cancer survivors
and can be accessed at http://ccss.stjude.org.
1. Because more than 60% of cancer survivors are older than age 60, re-
search efforts are under way to better understand the long-term effects
of cancer treatment for adult cancers (COG, 2008).
2. Nurses have an important role in the continuing care of survivors, in-
cluding monitoring, assessing, and treating children and adult survivors
for the effects of treatment that emerge long after completion of thera-
py. Nurses are vital in teaching survivors about leading a healthy lifestyle
to minimize the potential effects of cancer treatment.
B. Survivorship care
1. Cancer survivor: “An individual is considered a cancer survivor from the
time of cancer diagnosis, through the balance of his or her life, regard-
less of the ultimate cause of death.” This definition was first published
by Fitzhugh Mullan in his seminal 1985 article and has been adopted by
the National Coalition for Cancer Survivorship, NCI, and other survivor-
ship organizations (Mullan, 1985; NCI, 2012).
2. Cancer survivors require follow-up care annually for life.
3. Early follow-up care may be more frequent and emphasizes surveillance
and detection of disease recurrence. Long-term follow-up care transi-
tions to a focus on identifying and anticipating chronic or late effects
of the disease or treatment, as well as continued surveillance for disease
recurrence.
4. Essential components of survivorship care (Hewitt, Greenfield, & Stovall,
2005)
a) Prevention of recurrent and new cancers and of other late effects
b) Surveillance for cancer recurrence, metastasis, or second cancers
c) Assessment of medical and psychosocial late effects 437
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
438 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
d) Intervention for consequences of cancer and its treatment, includ-
ing medical problems such as lymphedema and sexual dysfunction;
symptoms including pain and fatigue; psychosocial distress experi-
enced by cancer survivors and their caregivers; and concerns related
to employment, insurance, and disability
e) Coordination among specialists and primary care providers to ensure
that all of the survivor’s health needs are met
C. Late effects of cancer treatment: SMNs and CVD are among the most seri-
ous and life-threatening late adverse effects of cancer treatment.
1. Incidence
a) Cancer survivors have a 14% greater risk of developing another ma-
lignancy than the general population with 25 years of follow-up (Cur-
tis et al., 2006).
b) The 30-year cumulative incidence of SMNs among survivors of child-
hood malignancies is 20.5% including nonmelanoma skin cancer and
7.9%, excluding nonmelanoma skin cancer (Friedman et al., 2010).
2. Therapy-related risk factors
a) Chemotherapy
(1) Chemotherapy is associated with a risk of SMN, primarily treat-
ment-related leukemia, and to a lesser extent, solid tumors
(Cowell & Austin, 2012; Ng & Travis, 2008; Travis et al., 2010).
(2) Type of chemotherapy: Alkylating agents are associated with the
greatest incidence of late effects.
(3) Dose
(a) Higher cumulative dose increases the risk of treatment-
related leukemia (Leone, Fianchi, & Voso, 2011; Travis et
al., 2010).
(b) Higher cumulative doses of alkylating agents are associ-
ated with an increased risk of multiple health conditions
(Oeffinger et al., 2006).
(4) Agents with known carcinogenic potential (see Table 12)
(a) Alkylating agents
(b) Heavy metals
i. Cisplatin
ii. Carboplatin
(c) Topoisomerase II inhibitors
i. Epipodophyllotoxins (etoposide, teniposide)
ii. Anthracyclines
(d) Nonclassical alkylating agents
i. Dacarbazine
ii. Temozolomide
b) Radiation-associated solid tumors: The most common type of SMN
(Ng, Kenney, Gilbert, & Travis, 2010)
(1) Radiation is associated with a risk of solid tumors that develop
within or near the radiation fields and have a latency period of
5–10 years (Ng & Travis, 2008; Travis et al., 2012).
(2) The risk of an SMN from radiation increases with the dose of ra-
diation and the extent of the radiation field (Travis et al., 2012).
(a) Advances in imaging have resulted in three-dimension-
al views of the tumor to accurately identify tumor vol-
ume, allowing reduction of the radiation field (Travis
et al., 2012).
(b) Advances in radiation technology allow for more precise
delivery of radiation to the tumor so that increased doses
can be delivered to the tumor while sparing healthy tissue
(Travis et al., 2012).
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 10. Post-Treatment Care 439
(c) Treatment with 35 gray (Gy) involved-field radiation ther-
apy (IFRT): Compared to 35 Gy mantle radiation therapy,
35 Gy IFRT is estimated to reduce the risk for female breast
and lung cancer by approximately 65% and the risk for male
lung cancer by approximately 35%. Reducing the dose of
IFRT from 35 Gy to 20 Gy is estimated to reduce the risk
approximately 40% more (Koh et al., 2007).
(3) Combination chemotherapy and radiation
(a) The combination of radiation and alkylating agents is as-
sociated with increased risk of secondary malignancies (Al-
lan & Travis, 2005; Oeffinger et al., 2006).
(b) Exposure to one of five specific combinations is associat-
ed with a risk of having a severe health condition that is at
least 10 times the expected risk (Oeffinger et al., 2006).
i. Chest irradiation plus bleomycin
ii. Chest irradiation plus an anthracycline
iii. Chest irradiation plus abdominal or pelvic irradiation
iv. Anthracycline plus an alkylating agent
v. Abdominal or pelvic irradiation plus an alkylating agent
c) Patient-related risk factors
(1) Age
(a) Younger age at cancer diagnosis increases the risk of devel-
oping an SMN (van den Belt-Dusebout et al., 2007). The
risk of developing a subsequent cancer is sixfold in child-
hood cancer survivors, two- to threefold in patients diag-
nosed at ages 18–39, and 1.2–1.6-fold in patients diagnosed
at ages 40–59 (Curtis et al., 2006).
(b) Developing organs in younger patients may be especially
vulnerable to the effects of medication and radiation (Ng,
Kenney, et al., 2010). Older patients who experience ad-
verse effects from their disease or its treatment may be un-
able to compensate for lost function.
(c) The cumulative incidence of a chronic health condition
in childhood cancer survivors is more than 70% within 30
years of the cancer diagnosis, and more than 40% of these
conditions will be severe, disabling, or fatal (Oeffinger et
al., 2006).
(2) Gender
(a) Female childhood cancer survivors are more likely than
male survivors to have one or more chronic health condi-
tions (Oeffinger et al., 2006).
(b) Overall, women have a slightly higher risk of secondary
malignancies than men (Curtis et al., 2006; Friedman et
al., 2010).
(3) Exposures
(a) Tobacco and alcohol exposure increase the risk of devel-
oping a secondary malignancy in all cancer survivors to ap-
proximately 35% (Curtis et al., 2006).
(b) Infections such as HPV, HIV, human herpes virus-8, Epstein-
Barr virus, hepatitis B and C, and Helicobacter pylori may in-
crease the risk of SMNs (Ng & Travis, 2008).
(c) Sun exposure (Ng & Travis, 2008)
(4) Diet and exercise: Caloric excess, a diet low in fruits and vege-
tables, obesity, and physical inactivity contribute to the risk of
SMNs involving the upper aerodigestive tract, colon cancer,
breast cancer, and cancers of the female reproductive organs
(Curtis et al., 2006; Ng & Travis, 2008).
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
440 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
(5) Immunodeficiency increases the risk of secondary malignan-
cies. Immune dysregulation may be associated with primary
cancers such as leukemia and lymphoma or with immunosup-
pressive treatment.
(6) Genetic predisposition: Patients with genetic phenotypes that
contributed to the development of their original cancer are
at increased risk for a secondary cancer. Examples of genetic
cancer syndromes that increase the susceptibility to a prima-
ry or secondary cancer include Fanconi anemia, Cowden dis-
ease, BRCA1- or BRCA2-related cancer, hereditary nonpolyposis
colorectal cancer, Bloom syndrome, xeroderma pigmentosum,
and Li-Fraumeni syndrome (Ng & Travis, 2008).
D. Types of late effects
1. Nonmalignant physical effects (Miller & Triano, 2008): See Table 46.
a) Cardiac: Cardiomyopathy, subclinical left ventricular dysfunction,
coronary artery disease, valvular heart disease, pericardial disease,
and arrhythmias
(1) The risk of developing anthracycline-associated cardiotoxicity
increases with the total cumulative dose of doxorubicin: 1%–
5% up to 550 mg/m2; 30% at 600 mg/m2; and 50% at 1,000
mg/m2 (Carver et al., 2007).
(2) Approximately 60% of children treated for childhood cancers
received an anthracycline; subsequently, there is a 0%–16% risk
of heart failure and 0%–57% risk of subclinical cardiomyopa-
thy (Dickerman, 2007).
(3) Cardiac toxicity may have a latency period of 25 years, and the
risk increases with time (Carver et al., 2007).
(4) Cisplatin is associated with an increased risk of cardiovascular
risk factors such as obesity, lipid abnormalities (decreased high-
density lipoprotein and elevated low-density lipoprotein), and
hypertension (Carver et al., 2007).
b) Pulmonary: Pulmonary fibrosis, restrictive/obstructive lung disease,
and delayed ILD
c) Renal: Nephropathy, CKD
d) Musculoskeletal: Osteopenia, osteoporosis, avascular necrosis
e) Endocrine: Hypothyroidism, growth hormone deficiency, gonadal
failure, panhypopituitarism, adrenal insufficiency, diabetes mellitus
f) CNS: Cognitive impairment, peripheral neuropathy, leukoencepha-
lopathy, cataracts, hearing loss, visual changes
2. SMNs (see Table 47)
a) Definition: A second malignant neoplasm is a new cancer that is distinct
from the original malignancy and does not represent metastatic dis-
ease from the primary tumor (Allan & Travis, 2005).
b) Pathophysiology
(1) Chemotherapy and radiation therapy cause DNA damage, which is
the mechanism that leads to cell death. However, if nonlethal DNA
damage occurs, DNA repair is critical to prevent the development
of a secondary cancer (Allan & Travis, 2005; Cowell & Austin, 2012).
(2) Alkylating agents transfer an alkyl group to DNA, causing
DNA mismatch and inhibition of DNA replication and tran-
scription. A DNA mismatch repair mechanism is responsible
for repairing this cell damage; otherwise, apoptosis occurs. If
cells survive with a dysfunctional DNA mismatch repair or ge-
nomic instability, this may lead to malignancy (Allan & Tra-
vis, 2005; Cowell & Austin, 2012; Tward, Glenn, Pulsipher, Bar-
nette, & Gaffney, 2007).
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 46. Potential Late Effects of Selected Cancer Treatments by Organ System With Associated Monitoring
Therapeutic Exposures
Radiation
Organ System Chemotherapy Therapy Surgery HSCT Potential Late Effect(s) Screening
Psychosocial Any Any Any Any Depression, anxiety, post-traumatic stress disorder, Psychosocial as-
limitations in health care access, alterations in body sessment
image
Ocular Corticosteroids Head/brain Neurosurgery Chronic GVHD Cataracts, glaucoma Ophthalmology
Busulfan TBI Crystal deposition of the retina—tamoxifen evaluation
Tamoxifen Retinopathy, optic nerve injury/atrophy
Ocular nerve palsy (surgery)
Xerophthalmia (radiation, GVHD)
Auditory Platinum chemotherapy Head/brain – – Tinnitus Audiological eval-
Sensorineural hearing loss uation
Conductive hearing loss
Eustachian tube dysfunction
Vestibular dysfunction/balance problems
Dental – Head/brain – Chronic GVHD Xerostomia Dental exams
Neck Periodontal disease
Dental caries
Cardiovascular Anthracyclines Thorax – – Congestive cardiomyopathy ECG
Trastuzumab Congestive heart failure Echocardiogram
High-dose cyclophos- Electrical/conductive system disease MUGA scan
phamide Pericardial disease/restrictive cardiomyopathy
Mitomycin Coronary artery disease
Platinum agents Valvular heart disease
Dyslipidemia (related to platinum agents)
Chapter 10. Post-Treatment Care
Respiratory Bleomycin Head/neck Head/neck surgery Chronic GVHD Upper airway sequelae PFT
Busulfan Thorax Pulmonary lobec- Pulmonary fibrosis CXR
Nitrosoureas TBI tomy Interstitial pneumonitis
Restrictive/obstructive lung disease
Fatigue
Breast – Thorax – – Radiation-induced breast cancer Mammogram
Axilla Breast MRI
TBI
441
(Continued on next page)
442
Table 46. Potential Late Effects of Selected Cancer Treatments by Organ System With Associated Monitoring (Continued)
Therapeutic Exposures
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Radiation
Organ System Chemotherapy Therapy Surgery HSCT Potential Late Effect(s) Screening
Gastrointestinal – Head/neck Head/neck surgery HSCT with Chronic enterocolitis Colonoscopy
Abdominal Laparotomy chronic GVHD Diarrhea
Pelvic Colorectal surgery GI tract strictures/fibrosis/vasculitis
Ostomy Adhesions/fistulae/obstruction/perforation/hernia
Pelvic/spinal sur- Impaired swallowing
gery Anorexia
Impaired nutritional intake
Impaired gastrointestinal motility
Vomiting
Constipation
Impaired absorption of nutrients
Fecal incontinence
Subsequent malignancy (e.g., colon)
Hepatic Antimetabolites Abdominal – HSCT Hepatic dysfunction Liver function tests
VOD Ferritin
Hepatic fibrosis, cirrhosis Hepatitis serologies
Cholelithiasis
Iron overload (HSCT)
Hepatitis (related to blood product transfusions)
Renal Platinum agents Abdominal (in- Nephrectomy HSCT with Glomerular toxicity Renal function tests
Ifosfamide cluding kidney) GVHD Tubular dysfunction Urinalysis
Methotrexate TBI Acute kidney injury
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Bisphosphonates Hypertension
Nitrosoureas Radiation nephritis
Calcineurin inhibitors Chronic kidney disease
(for GVHD)
Bladder Cyclophosphamide Pelvic (including Spinal surgery – Hemorrhagic cystitis Urinalysis
prostate and Cystectomy Bladder fibrosis
bladder) Prostatectomy Dysfunctional voiding
Lumbar-sacral Incontinence
spine Neurogenic bladder
Bladder malignancy
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 46. Potential Late Effects of Selected Cancer Treatments by Organ System With Associated Monitoring (Continued)
Therapeutic Exposures
Radiation
Organ System Chemotherapy Therapy Surgery HSCT Potential Late Effect(s) Screening
Sexual/reproduc- Alkylating agents Hypothalamic- Pelvic/spinal sur- – Hypogonadism FSH, LH
tive (males) Androgen deprivation pituitary gery Infertility Testosterone
(hormonal) therapy Pelvic Orchiectomy Erectile/ejaculatory dysfunction Semen analysis
Prostate Prostatectomy
Testicular
TBI
Sexual/reproduc- Alkylating agents Hypothalamic- Oophorectomy Chronic GVHD Premature menopause FSH, LH
tive (females) Tamoxifen pituitary Infertility Estradiol
Aromatase inhibitors Pelvic Uterine vascular insufficiency
Lupron Ovarian Vaginal fibrosis/stenosis
Lumbar-sacral Sexual dysfunction
spine
TBI
Endocrine/ Corticosteroids Hypothalamic- Thyroidectomy – Hypothyroidism Free T4
metabolic pituitary Surgery involving Adrenal insufficiency TSH
Neck (thyroid) the hypothalamus Growth hormone deficiency 8 am serum cortisol
Pancreas or pituitary Impaired glucose tolerance
Surgery involving Thyroid nodules/cancer
the pancreas High radiation doses
Hyperprolactinemia
Central adrenal insufficiency
Gonadotropin deficiency
Hyperthyroidism
Neurocognitive Methotrexate (high- Head/brain Neurosurgery – Neurocognitive deficits (executive function, atten- Neurocognitive
dose IV, IT) TBI tion, memory, processing speed, visual motor inte- testing
Chapter 10. Post-Treatment Care
Cytarabine (high-dose gration)
IV)
Adjuvant chemotherapy
for breast cancer
Central nervous Methotrexate (high- High radiation Neurosurgery – Leukoencephalopathy –
system dose IV, IT) doses to head/ Motor and sensory deficits
Cytarabine (high-dose brain/neck Cerebrovascular complications (stroke, moyamoya
IV) disease [certain arteries in the brain are constrict-
ed], occlusive cerebral vasculopathy)
Radiation-induced brain tumor
Seizures
443
(Continued on next page)
444
Table 46. Potential Late Effects of Selected Cancer Treatments by Organ System With Associated Monitoring (Continued)
Therapeutic Exposures
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Radiation
Organ System Chemotherapy Therapy Surgery HSCT Potential Late Effect(s) Screening
Peripheral Vincristine High-dose radia- Spinal surgery – Peripheral sensory neuropathy (e.g., paresthesias, –
nervous system Vinblastine tion to brachial dysesthesias, sensory loss)
Platinum agents or lumbosacral Peripheral motor neuropathy (e.g., weakness, foot
Taxanes plexus drop)
Bortezomib Plexopathies
Thalidomide
Oxaliplatin
Lymphatic – Radiation involv- Breast cancer sur- – Lymphedema –
ing lymphatic gery
channels Melanoma excision
Pelvic lymph node
dissection
Axillary lymph
node dissection
Musculoskeletal Corticosteroids Pelvic/gonadal Surgical castration HSCT Osteopenia/osteoporosis DEXA scan
Methotrexate Bilateral oophorec-
Androgen deprivation tomy
therapy Gastrectomy
Aromatase inhibitors
– – Amputation – Functional changes –
Limb-sparing pro- Postsurgical phantom pain
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
cedures
– – – HSCT with Joint contractures –
chronic GVHD
Corticosteroids High-dose radia- – HSCT Osteonecrosis MRI of affected
Bisphosphonates tion to jaw Myopathy (proximal muscle weakness) area
Chemotherapy for – – – Post-chemotherapy rheumatism syndrome –
breast and ovarian
cancers
– All fields – – Atrophy, deformity, fibrosis, fractures X-ray of affected
Secondary benign or malignant neoplasms area
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Table 46. Potential Late Effects of Selected Cancer Treatments by Organ System With Associated Monitoring (Continued)
Therapeutic Exposures
Radiation
Organ System Chemotherapy Therapy Surgery HSCT Potential Late Effect(s) Screening
Dermatologic – All areas – Chronic GVHD Dysplastic nevi –
Vitiligo
Scleroderma
Nail dysplasia
Alopecia
Skin cancer
Hematologic Anthracyclines – – Autologous Acute myeloid leukemia CBC with differ-
Epipodophyllotoxins HSCT for non- Myelodysplastic syndrome (associated with alkylat- ential
Alkylating agents Hodgkin lym- ing agents)
Stem cell priming with phoma
etoposide
Immunologic – Abdomen, left Splenectomy Chronic active Life-threatening infection related to functional or ana- –
upper quadrant, GVHD tomic asplenia
spleen (high
doses)
Chapter 10. Post-Treatment Care
CBC—complete blood count; CXR—chest x-ray; DEXA—dual energy x-ray absorptiometry; ECG—electrocardiogram; FSH—follicle-stimulating hormone; GI—gastrointestinal; GVHD—graft-versus-host disease;
HSCT—hematopoietic stem cell transplant; IT—intrathecal; IV—intravenous; LH—luteinizing hormone; MRI—magnetic resonance imaging; MUGA—multigated acquisition; PFT—pulmonary function testing; TBI—total
body irradiation; T4—thyroxine; TSH—thyroid-stimulating hormone; VOD—veno-occlusive disease
Note. Based on information from Aziz, 2007; Children’s Oncology Group, 2008; Ganz, 2006; Miller & Triano, 2008; Stricker & Jacobs, 2008; Tichelli & Socié, 2005.
From “Late Effects of Cancer Treatment” (pp. 1757–1761), by W. Landier and S. Smith in C.H. Yarbro, D. Wujcik, and B.H. Gobel (Eds.), Cancer Nursing: Principles and Practice (7th ed.), 2011, Burlington, MA: Jones
445
and Bartlett. Copyright 2011 by Jones and Bartlett. Reprinted with permission.
446 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
(3) Topoisomerase II inhibitors cause double-stranded DNA breaks,
which lead to apoptosis. If the cell survives, these DNA breaks
may cause chromosomal translocations of the mixed lineage
leukemia (MLL) gene or other crucial transforming genes that
can lead to leukemia (Allan & Travis, 2005; Cowell & Austin,
2012; Tward et al., 2007).
(4) Radiation therapy deposits energy in or near DNA, which results
in genetic or epigenetic changes that cause cell death. If radi-
ation induces mutations in the DNA and the cells do not die,
the DNA mutations are passed on to cellular progeny and over
time may lead to malignant transformation (Travis et al., 2012).
(5) Chemotherapy and radiation therapy interact with other fac-
tors such as tobacco exposure, genetic makeup, hormonal sta-
tus, and immune function, which may contribute to the risk
of developing a secondary cancer (Allan & Travis, 2005; Tra-
vis et al., 2012).
c) Types of SMNs: The two major types of SMNs are acute myeloid neo-
plasms and solid neoplasms. The relative risk of treatment-related
leukemia is generally greatest during the first five years after thera-
py, whereas solid tumors occur at least 5–10 years after treatment with
the risk tending to increase over time (Ng & Travis, 2008). The over-
all risk of developing an SMN is small compared to the risk of dying
from the primary malignancy.
(1) Treatment-related acute myeloid leukemia/myelodysplastic syn-
drome (AML/MDS) generally presents within five years of che-
motherapy and is most commonly associated with the use of al-
kylating agents or topoisomerase inhibitors.
Table 47. Second Malignant Neoplasms
Primary
Malignancy Second Malignant Neoplasm Risk Factors
ALL • CNS malignancy Cranial irradiation at doses of 18–24 Gy
–– Risk is 17-fold after 5 years.
• Melanoma > 10 years old (p < 0.001)
–– Cumulative incidence: 0.43% Family history of cancer (p = 0.01)
• Thyroid cancer RT
Breast cancer • Any SMN Age < 40 at diagnosis
–– Elevated risk for women diagnosed at younger Risk of leukemia associated with alkylating agents
than age 40 (SIR: 1.81) but not for women di- Risk of solid tumors associated with radiation therapy
agnosed after age 40
–– Increased risk of salivary gland, esophagus,
stomach, colon, breast, uterine corpus, ova-
ry, thyroid, soft tissues, melanoma, and acute
nonlymphocytic leukemia
• Leukemia –
–– Cumulative incidence: < 0.5% at 8–10 years
after anthracycline-cyclophosphamide chemo-
therapy
• Endometrial Tamoxifen
–– Associated with 35% increased risk
• Sarcoma RT
–– SIR: 3–6
–– Latency: 5–10 years
Cervical cancer • Urogenital cancer RT
–– 10 to > 40 years after treatment
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 10. Post-Treatment Care 447
Table 47. Second Malignant Neoplasms (Continued)
Primary
Malignancy Second Malignant Neoplasm Risk Factors
CLL/SLL • HL Age < 70 at time of CLL/SLL diagnosis
–– SIR: 15.11 Chemotherapy
Risk higher in CLL than SLL
• Lung cancer Patients diagnosed before age 55 had higher SIR: 2.32.
–– SIR: 1.44
• Melanoma
–– SIR: 1.92
CML • Breast cancer (in CML Ph+)
–– SIR: 0.24
• Endocrine cancer (in CML Ph+)
–– SIR: 3.0
• Gastrointestinal cancer (in CML Ph+)
–– SIR: 0.38
• Stomach cancer
–– SIR: 2.76
• Colorectal cancer
–– SIR: 1.12
• Head and neck cancer
–– Buccal cavity, SIR: 1.27
• Lymphoid leukemia
–– SIR: 5.53
• Myeloid leukemia
–– SIR: 12.32
• Melanoma
–– SIR: 1.4
–– SIR: 3.0 (CML Ph+)
• NHL
–– SIR: 2.17
• Prostate cancer
–– SIR: 1.38
• Renal cancer
–– SIR: 1.5 (CML Ph+)
• Skin (nonmelanoma)
–– SIR: 5.36
• Urogenital cancer
–– SIR: 1.61
HL • Breast Occurs 10–15 years after chest irradiation
–– 20-year cumulative risk after mantle RT: 23% Highest risk occurs in women treated with chest irradiation
(median dose 40 Gy) at age 35 or younger; risk increases with younger age.
–– RR: 6.1 for patients diagnosed at age 30 and Risk increases with dose of radiation.
survived to ≥ 40 Risk increases with TBI use pretransplantation.
RT-related premature menopause is associated with de-
creased risk.
• Leukemia MOPP
–– Peaks 3–7 years after treatment Risk is 7 times greater in patients who received > 20 Gy irra-
–– Up to 10% risk diation to bone marrow than in those who received a less-
er dose.
HCT
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
448 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Table 47. Second Malignant Neoplasms (Continued)
Primary
Malignancy Second Malignant Neoplasm Risk Factors
• Lung cancer Thoracic irradiation
–– RR: 7.0 Risk increases with dose of radiation.
–– Chemotherapy-associated lung cancer occurs Alkylating agents
1–4 years after therapy up to 15 years. Radiation dose and therapy with alkylating agents has a
–– Radiation-associated lung cancer risk is ele- combined additive risk.
vated for 5–9 years after therapy and can last RT and smoking significantly increases risk (p < 0.001)
for more than 20 years.
• Pleura
–– RR: 19.5
• Melanoma May be related to immunosuppression associated with HL
–– 1–4 years after treatment
–– RR: 5.5
• NHL Immunosuppression associated with the HL or with com-
–– Within 5 years of treatment, then risk remains bined chemoradiation treatment
constant or increases over lifetime
–– 25-year cumulative risk: 3.5%
–– RR: 21.5
• Thyroid cancer RT
–– RR: 15.2
• Colorectal cancer Risk increases with dose of radiation.
• Mesothelioma –
–– RR is 20-fold for patients diagnosed at age 30
and survived to ≥ age 40.
Multiple • 17% at 50 months Alkylating agents
myeloma
NHL • Bladder cancer Cyclophosphamide > 20 g
–– Cyclophosphamide: Risk increases with RT use.
** 20–49 g, RR: 6.0
** > 50 g, RR: 14.5
• Leukemia CHOP (RR: 14.2)
–– Overall RR: 8.8 ACVBP
–– Occurs within 15 years Carmustine
–– Male, RR: 5.65 Procarbazine
–– Female, RR: 19.89 Mechlorethamine (RR: 13.0)
Chlorambucil > 1,300 mg (RR: 6.5)
Risk of acute leukemia increases with RT use, especially
TBI pretransplantation.
• Lung cancer Male gender
–– SIR: 1.6–2.45 Smoking is dose-related with higher risk in those who
smoked at diagnosis and continue to smoke after therapy.
Alkylating agents
• Melanoma > 10 years old (p < 0.001)
–– Cumulative incidence: 0.55% Family history of cancer (p = 0.01)
• Mesothelioma Risk increases with RT use.
DLBCL • AML Chemotherapy
–– SIR: 4.96 Age < 55
Female
• HL –
–– SIR: 9.02
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 10. Post-Treatment Care 449
Table 47. Second Malignant Neoplasms (Continued)
Primary
Malignancy Second Malignant Neoplasm Risk Factors
Follicular lym- • AML Chemotherapy
phoma –– SIR: 5.96 Age < 55
• HL –
–– SIR: 6.78
• Lung cancer Patients diagnosed before age 55 had higher SIR: 2.01.
–– SIR: 1.28
• Melanoma –
–– SIR: 1.6
Lung cancer • Leukemia Increased risk due to use of alkylating agents
• Small cell, SIR: 6.57
• Non-small cell, SIR: 1.47
Mycosis fun- • Bladder cancer
goides/Sézary –– SIR: 1.71
syndrome • HL
–– SIR: 1.71
• Lung cancer
–– SIR: 1.42
• Melanoma
–– SIR: 2.60
• NHL
–– SIR: 5.08
• Renal cancer
–– SIR: 1.71
Ovarian cancer • Leukemia Alkylating agents, including cyclophosphamide and melpha-
–– Occurs up to 10 years after therapy lan
Platinum-containing regimens
Polycythemia • CML
vera –– SIR: 1.6
• Myeloid leukemia:
–– SIR: 8.5 at 1–2 years
–– SIR: 14.6 at 2–4 years
–– SIR: 18.6 at 5 years
• Lung cancer
–– SIR: 1.8
• NHL
–– SIR: 1.8
Testicular can- • Leukemia Etoposide (Risk appears to be increasing since PEB chemo-
cer –– SIR: 1.6–6.7 therapy became standard in the 1990s.)
–– Median time to occurrence: 4.5 years
• Gastrointestinal cancer RT
–– SIR: 1.27–2.1
• Bladder cancer RT including the iliac lymph nodes (This risk will likely de-
–– SIR: 3.9 crease because from the mid-1980s, RT has been directed
–– Median time to occurrence: 20 years to the para-aortic lymph nodes only.)
No study noted increased risk of bladder cancer after che-
motherapy alone; however, because PEB is carcinogen-
ic to humans, and platinum is excreted in urine up to 20
years after treatment with PEB chemotherapy, prolonged
platinum exposure may play a role in bladder cancer de-
velopment.
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
450 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Table 47. Second Malignant Neoplasms (Continued)
Primary
Malignancy Second Malignant Neoplasm Risk Factors
Waldenström • AML
macroglobulin- –– SIR: 5.3
emia • Colorectal cancer
–– SIR: 2.2
• Lung cancer
–– SIR: 1.6
• Melanoma
–– SIR: 1.6
• Multiple myeloma
–– SIR: 4.4
• NHL
–– SIR: 4.9
• Prostate cancer
–– SIR: 1.2
• Renal cancer
–– SIR: 1.4
• Uterine cancer
–– SIR: 2.2
SIR: Standardized incidence ratio or relative risk (observed cases/expected cases) compares actual cases observed with the number of expected cases in
the general population to determine increased (> 1.0) or decreased (< 1.0) risk (Curtis et al., 2006; Ojha & Thertulien, 2012; Verma et al., 2011).
ACVBP—doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone; ALL—acute lymphocytic leukemia; AML—acute myeloid leukemia; CHOP—cy-
clophosphamide, doxorubicin, vincristine, prednisone; CLL—chronic lymphocytic leukemia; CML—chronic myeloid leukemia; CNS—central nervous system;
DLBCL—diffuse large B-cell lymphoma; Gy—gray; HCT—hematopoietic cell transplantation; HL—Hodgkin lymphoma; MOPP—mechlorethamine, vincristine,
procarbazine, prednisone; NHL—non-Hodgkin lymphoma; PEB—cisplatin, etoposide, bleomycin; Ph+—Philadelphia chromosome positive; RR—relative risk;
RT—radiation therapy; SIR—standardized incidence ratio; SLL—small lymphocytic lymphoma; SMN—second malignant neoplasm; TBI—total body irradiation
Note. Based on information from André et al., 2004; Chaturvedi et al., 2007; Curtis et al., 2006; Forman & Nakamura, 2011; Frederiksen et al., 2011; Hodg-
son, 2011; Hodgson et al., 2007; Huang et al., 2007; International Agency for Research on Cancer, 2012a, 2012b; Morton et al., 2010; Ng et al., 2011; Ojha
& Thertulien, 2012; Rebora et al., 2010; Richiardi et al., 2007; Travis et al., 2012; Tward et al., 2007; van den Belt-Dusebout et al., 2007; van Leeuwen et al.,
2000; van Leeuwen & Travis, 2001; Verma et al., 2011.
From “Management of the Complications of Hematologic Malignancy and Treatment,” by C.H. Erb and W.H. Vogel in M. Olsen and L.J. Zitella (Eds.), Hema-
tologic Malignancies in Adults (pp. 629–633), 2013, Pittsburgh: PA: Oncology Nursing Society. Copyright 2013 by the Oncology Nursing Society. Adapted
with permission.
(2) Two types of treatment-related leukemia (Cowell & Austin, 2012)
(a) “Classic” alkylating agent–induced AML (Cowell & Aus-
tin, 2012)
i. Associated with alkylating agents such as cyclo-
phosphamide, melphalan, chlorambucil, and ni-
trosoureas
ii. Usually occurs two to eight years after treatment
iii. More than half present as MDS, which typically pro-
gresses to AML within a year.
iv. Development is associated with chromosome 5 and
7 aberrations.
(b) Topoisomerase II inhibitor–induced acute leukemia (Cow-
ell & Austin, 2012)
i. Associated with topoisomerase II inhibitors such as et-
oposide, teniposide, mitoxantrone, and anthracyclines
ii. Risk begins shortly after completion of therapy, and
disease usually occurs within two years of treatment.
iii. It is not associated with preceding MDS.
iv. Development is associated with chromosomal trans-
locations 11q23 (MLL gene), t(15;17) (PML-RARA),
and t(8;21) (AML-ETO).
d) Radiation-induced solid tumors, such as sarcomas, breast, lung, skin,
and thyroid, are observed at least 5–10 years after treatment, and the
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 10. Post-Treatment Care 451
risk persists for decades (Ng & Travis, 2008; Travis et al., 2012). Ra-
diation-induced SMNs tend to occur within or at the margins of the
radiation field, and the risk increases with the volume of tissue irra-
diated and the dose of radiation (Ng & Travis, 2008).
3. Psychosocial effects (Hewitt et al., 2005; Stein, Syrjala, & Andrykowski,
2008)
a) Psychosocial disorders: Social withdrawal, educational problems, and
relationship, body image, and sexuality issues
b) Mental health disorders: Depression, anxiety, post-traumatic stress
c) Political and vocational issues: Employment, access to health care, in-
surance, and educational assistance
E. Risk of late effects for patients with select primary cancers
1. HL
a) The leading causes of death in HL survivors are SMNs and CVD (Ng,
LaCasce, & Travis, 2011).
(1) Patients treated with radiation are at greater risk of SMNs and CVD
than those treated with chemotherapy alone (Ng et al., 2011).
(2) SMNs: HL survivors are at risk for leukemia and solid tumors,
particularly lung and breast cancer (Ng et al., 2011).
(a) Solid tumors account for 70%–80% of all SMNs following
treatment for HL, and the risk is greatly increased with ra-
diation (Ng, Costine, et al., 2010).
i. Cumulative risk of SMN following treatment with 40–
45 Gy of extended-field or mantle radiation therapy
is approximately 30% at 30 years (Hodgson, 2011).
ii. Modern radiation therapy for HL uses IFRT, which
treats only the lymph node regions that are initially
involved. Prescribed radiation doses range from 20–
30 Gy. This reduces the volume of healthy tissue ex-
posed to radiation and significantly decreases the risk
of SMNs (Hodgson, 2011).
(b) Breast cancer: Risk of breast cancer in HL survivors is signif-
icantly increased, particularly for women who were treated
with chest irradiation before age 35 (Hodgson, 2011; Ng et
al., 2011). The latency period is 10–15 years following treat-
ment (Ng, Costine, et al., 2010). The risk of breast cancer
appears to be decreased in patients who experienced treat-
ment-related premature menopause (Hodgson, 2011; Ng,
Costine, et al., 2010).
(c) Lung cancer: The risk of lung cancer is associated with ra-
diation therapy, alkylating agents, and smoking (Hodg-
son, 2011).
(3) CVD: HL survivors have a three- to fivefold increased risk of
CVD, which generally manifests 10 years after therapy and per-
sists more than 25 years after therapy (Ng et al., 2011)
(a) Coronary artery disease is the most common form of cardio-
vascular toxicity among HL survivors, accounting for approxi-
mately 40%–50% of adverse cardiac events (Hodgson, 2011).
(b) Valvular disease is less common, typically has a late onset
(10 years after radiation therapy), and is related to higher
doses (30 Gy) or young age at treatment (Hodgson, 2011).
(c) Acute pericarditis is uncommon but may occur following radi-
ation that includes a large cardiac volume (Hodgson, 2011).
(d) HL survivors treated with mantle radiation therapy at dos-
es of 35–45 Gy are estimated to have a two- to fourfold in-
creased risk of cardiac morbidity. The cumulative risks of
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
452 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
significant heart disease among survivors of adult HL are
approximately 5%–10% at 15 years, 16% at 20 years, and
34% at 30 years (Hodgson, 2011).
b) Pulmonary toxicity: HL survivors have a risk of treatment-related pul-
monary toxicity including radiation pneumonitis and bleomycin tox-
icity (Ng et al., 2011)
2. NHL
a) Relative risk of a secondary cancer in NHL survivors is increased 1.14–
1.47 over the general population (Tward et al., 2007).
b) Patients are at increased risk for AML, sarcomas, bladder cancer, can-
cers of the head and neck, melanoma, lung cancer, GI cancer, kidney
cancer, HL, and thyroid cancer (Tward et al., 2007).
(1) Chemotherapy increases the risk of AML, lung cancer, and blad-
der cancer (Tward et al., 2007).
(2) Radiation therapy increases the risk of sarcomas, breast cancer,
and mesothelioma (Tward et al., 2007).
c) Survivors of NHL have an overall significantly decreased risk of breast
cancer, prostate cancer, and myeloma (Tward et al., 2007).
3. Breast cancer: Breast cancer survivors are at risk for SMNs, cardiac toxic-
ity from anthracyclines and/or trastuzumab, chemotherapy-induced pre-
mature menopause, osteoporosis, chemotherapy-induced cognitive im-
pairment, sexual dysfunction, and taxane-related neuropathy (Azim, de
Azambuja, Colozza, Bines, & Piccart, 2011; Ganz & Hahn, 2008).
a) SMNs: Breast cancer survivors are at increased risk for sarcoma,
melanoma, AML, and cancers of the salivary gland, esophagus,
stomach, colon, breast, uterine corpus, ovary, and thyroid (Cur-
tis et al., 2006).
b) Risk of SMN is greater in breast cancer survivors who carry a genet-
ic predisposition (e.g., BRCA2 and TP53), were treated with radia-
tion therapy (e.g., risk for secondary lung and esophageal cancer),
or were treated with hormonal therapy (e.g., risk for uterine cancer
secondary to tamoxifen) (Azim et al., 2011).
c) Radiation to the breast increases the risk of lung cancer, esophageal
cancer, and sarcoma in all patients, as well as the risk of the contra-
lateral breast cancer in patients younger than 40–45 years of age (Ng,
Kenney, et al., 2010; Travis et al., 2012).
4. Prostate cancer: Prostate cancer survivors are at increased risk for subse-
quent melanoma, small intestine, soft tissue, bladder, thyroid, and thy-
mus cancer (Curtis et al., 2006; Ng, Kenney, et al., 2010).
5. Testicular cancer
a) Testicular cancer survivors are at risk for SMNs, CVD, neurotoxicity,
nephrotoxicity, pulmonary toxicity, hypogonadism, decreased fertility,
psychosocial disorders, and cognitive impairment (Travis et al., 2010).
b) SMNs
(1) Among 10-year testicular cancer survivors, there are statistically
significant increased risks of malignant melanoma and cancers
of the lung (relative risk [RR] = 1.5, 95% confidence interval
[CI] [1.2, 1.7]); thyroid, esophagus, pleura, and stomach (RR
= 4.0, 95% CI [3.2, 4.8]); and pancreas, colon, rectum, kidney,
bladder, and connective tissue (RR = 4.0, 95% CI [2.3, 6.3])
(Travis et al., 2005, 2012).
(2) Chemotherapy increases the risk of radiation-associated SMNs
(van den Belt-Dusebout et al., 2007).
(3) The risk of SMN increases with younger age at time of treat-
ment (van den Belt-Dusebout et al., 2007).
(4) The median time to occurrence of SMN is 20 years (van den
Belt-Dusebout et al., 2007).
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 10. Post-Treatment Care 453
(5) Etoposide and cisplatin chemotherapy increase the risk of treat-
ment-related leukemia in a dose-related fashion (Travis et al.,
2010).
c) Cardiac toxicity: Increased risk of cardiac toxicity, including
myocardial infarction, coronary artery disease, hyperlipidemia,
and metabolic syndrome (Carver et al., 2007; Ng, 2011; Travis
et al., 2010)
d) Neurotoxicity: Increased risk of sensory peripheral neuropathy and
cisplatin-induced ototoxicity (Travis et al., 2010)
e) Nephrotoxicity: Increased risk of cisplatin-induced chronic renal dys-
function (Travis et al., 2010)
f) Pulmonary toxicity: Increased risk of bleomycin-induced pneumoni-
tis and increased risk of mortality related to respiratory disease (Tra-
vis et al., 2010)
6. Cervical cancer (Chaturvedi et al., 2007)
a) Cervical cancer survivors have an increased risk for HPV-related can-
cers (of the pharynx, genital sites, and rectum/anus) and smoking-
related cancers (of the pharynx, trachea/bronchus/lung, pancreas,
and urinary bladder).
b) Patients with cervical cancer treated with radiation were at increased
risk for all SMNs at heavily irradiated sites (colon, rectum/anus, uri-
nary bladder, ovary, and genital sites) beyond 40 years of follow-up
compared with women in the general population (Curtis et al., 2006;
Travis et al., 2012).
c) The 40-year cumulative risk of any secondary cancer was 22% among
women diagnosed with cervical cancer before age 50 and 16% for
those diagnosed after age 50.
7. Pediatric malignancies
a) The cumulative incidence of SMNs in five-year survivors of childhood
cancer treated from 1970–1986 at 30 years after diagnosis was 20.5%
(95% CI [19.1%, 21.8%]) and was higher for patients who received
radiation therapy than for those who did not (approximately 25%
versus 10%) (Friedman et al., 2010).
b) The most frequent SMNs were nonmelanoma skin cancer and breast
cancer, with 30-year cumulative incidences of 9.1% and 5%, respec-
tively (Friedman et al., 2010). SMNs with a 30-year cumulative inci-
dence < 1% included bone cancer, soft tissue sarcoma, leukemia, lym-
phoma, CNS tumors, head and neck cancer, GI cancer, lung cancer,
and thyroid cancer (Friedman et al., 2010).
c) The risk of SMNs among childhood cancer survivors is associated
with radiation therapy, chemotherapy, and genetic predisposition
(Travis et al., 2012).
d) The median latency period for development of an SMN was 17.8 years
(range 5–35.2 years) (Friedman et al., 2010).
8. HSCT recipients: HSCT recipients are at risk for secondary solid tumors,
treatment-related leukemia/MDS, and post-transplant lymphoprolifer-
ative disorders
a) In patients who underwent autologous HSCT for lymphoma, the cu-
mulative incidence of secondary myelodysplasia/acute leukemia was
3.09% at 5 years and 4.52% at 10 years. The cumulative incidence of
solid tumors was 2.54% at 5 years and 6.79% at 10 years. The risk of
solid tumors was associated with advanced age and radiation thera-
py (Tarella et al., 2011).
b) Allogeneic HCT recipients were twice as likely to develop a solid tu-
mor than the general population. Risk was related to younger age
at the time of transplantation (age < 30) and exposure to radiation
(Rizzo et al., 2009).
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
454 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
c) The risk of a post-transplant malignancy increases with younger age
at time of transplant, especially for those younger than 10 years (Bak-
er et al., 2003; Bhatia et al., 2001).
d) Relative risk of thyroid carcinoma is 3.26 overall, with a significantly
increased risk associated with age < 10 years, radiation, female gen-
der, and chronic GVHD (Cohen et al., 2007).
F. Collaborative management
1. Elements of comprehensive survivorship care (Hewitt et al., 2005; Rech-
is, Beckjord, Arvey, Reynold, & McGoldrick, 2011)
a) Essential elements
(1) Survivorship care plan, psychosocial care plan, and treatment
summary
(2) Screening for new cancers and surveillance for recurrence
(3) Care coordination strategy, which addresses care coordination
with primary care physicians and primary oncologists
(4) Health promotion education
(5) Symptom management and palliative care
b) Highly recommended elements
(1) Late effects education
(2) Psychosocial assessment and care
(3) Comprehensive medical assessment
(4) Nutrition services, physical activity services, and weight man-
agement
(5) Transition visit and cancer-specific transition visit
(6) Rehabilitation for late effects
(7) Family and caregiver support
(8) Patient navigation
(9) Educational information about survivorship and program of-
ferings
c) Other services
(1) Self-advocacy skills training
(2) Counseling for practical issues
(3) Ongoing quality improvement activities
(4) Referral to specialty care
(5) Continuing medical education for healthcare providers
2. Survivorship care plan: Patients completing primary treatment should
be provided with a comprehensive care summary and follow-up plan that
is clearly and effectively explained. This survivorship care plan should
be written by the principal provider(s) who coordinated oncology treat-
ment. The plan should summarize critical information needed for the
survivor’s long-term care (Hewitt et al., 2005).
a) Summary of cancer treatment
(1) Date of diagnosis
(2) Survivor’s age at diagnosis
(3) Names of all chemotherapy agents and doses received
(4) All radiation field(s) and total radiation dose (in Gy) to each
field (For chest, thoracic spine, and upper abdominal radia-
tion, include age at first dose.)
(5) Names of all relevant surgical procedures
(6) Names of all other therapeutic modalities
(7) Complications related to cancer treatment
b) Potential long-term effects of cancer treatment
c) Specific information about the timing and content of recommend-
ed follow-up
d) Recommendations regarding preventive practices and how to main-
tain health and well-being
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 10. Post-Treatment Care 455
e) Information on legal protections regarding employment and access
to health insurance
f) Availability of psychosocial services in the community
3. Models of survivorship care (Oeffinger & McCabe, 2006)
a) Consultative model: Primary oncology team refers survivor for a one-
time visit in long-term follow-up clinic, where a comprehensive survi-
vorship care plan is developed.
b) Nurse practitioner (NP)-led survivor clinic: Survivors are transitioned
to the care of an NP who shares care of the survivor with the prima-
ry care physician. The NP and primary care physician communicate
regularly, and the NP provides details of the patient’s cancer history
and patient-specific recommendations for follow-up care.
c) Specialty multidisciplinary clinic: Modeled after pediatric long-term
follow-up clinics, these clinics employ a team consisting of physicians,
oncology NPs, social workers, psychologists, administrators, and a
network of consulting physicians trained in the care of cancer survi-
vors. NPs play a central role in the coordination and delivery of care.
G. Nursing assessment
1. Obtain history.
a) Chemotherapy, surgery, and radiation received
b) Toxicities experienced during therapy
c) Physical and psychosocial systems
d) Preexisting diseases that may exacerbate effects or contribute to syn-
ergistic effects of long-term effects or secondary malignancies
2. Perform physical examination.
3. Review results of laboratory tests including CBC, blood chemistry pan-
el, and urinalysis.
4. Review results of imaging studies as indicated (e.g., chest x-ray, bone
densitometry).
5. Review results of pulmonary function tests, echocardiogram, and ECG
as indicated.
H. Preventive screening recommendations and follow-up care
1. Survivors should follow adult cancer screening recommendations. This
is especially important for childhood cancer survivors who have addi-
tional risk for premature development of adult cancers.
2. Irradiated skin and soft tissues should be thoroughly evaluated and re-
assessed for the life of the patient.
3. Women who have been treated with mantle-field irradiation should per-
form breast self-examination on a monthly basis beginning at the time
of puberty, and medical breast examination should be performed an-
nually. Annual mammograms should begin eight years after irradiation
(Ng, Costine, et al., 2010).
4. Discuss weight management and exercise regimens with all cancer sur-
vivors. Physical activity and a healthy diet reduce the risk of cancer re-
currences and decrease overall mortality in multiple cancer survivor
groups, including breast, colorectal, prostate, and ovarian cancer (Amer-
ican Cancer Society, 2013).
a) Eating a diet high in fruits, vegetables, and whole grains and low in
red and processed meat appears to protect against cancer progres-
sion, risk of recurrence, and overall mortality for a variety of cancers.
b) Regular exercise appears to be associated with a lower risk for recur-
rence and improved survival following treatment for breast, prostate,
ovarian, and colorectal cancers.
c) Cancer survivors who are overweight or obese may benefit from in-
tentional weight loss following treatment.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
456 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
d) Cancer survivors should obtain the nutrients they need from foods
instead of supplements or vitamins because preliminary evidence has
shown that supplements may do more harm than good.
5. Patients should be counseled regarding smoking cessation (Curtis et
al., 2006).
6. Bone density studies are indicated for breast cancer survivors age 65 or
older, age 60–64 with risk factors (family history, prior nontraumatic frac-
ture), postmenopausal patients on an aromatase inhibitor, and patients
with chemotherapy-induced early menopause (Ganz & Hahn, 2008).
I. Patient and family education
1. Provide information about the treatment and potential late effects relat-
ed to disease and treatment received (see Table 48).
2. Explain the risks of SMNs, the typical time to onset, cancer screening
recommendations, and the importance of follow-up visits.
3. Promote healthy lifestyle practices.
a) Diet
(1) A diet high in fruits, vegetables, and whole grains is associated
with a lower risk of death than one that contains a high intake
of processed and red meat, refined grains, sugar, and high-fat
dairy products.
(2) Avoid vitamin supplements, and obtain nutrients from food.
b) Regular physical activity
c) Smoking cessation
d) Sun safety practices
J. Professional education
1. Educate primary care professionals who may be working with survivors
after the survivors are no longer followed by an oncologist. A survivor-
Table 48. Key Resources for Cancer Survivorship Information
Organization and Website Description
Centers for Disease Control and Prevention: Comprehensive cancer survivorship information for patients and caregivers
Cancer Survivorship
www.cdc.gov/cancer/survivorship
National Coalition for Cancer Survivorship Comprehensive cancer survivorship information for patients, caregivers, and
www.canceradvocacy.org healthcare professionals
http://journeyforward.org Resources include
• Patient education
• Cancer Survivor Toolbox®, a free, self-learning audio program to help patients/
survivors acquire knowledge and skills to face common issues during the can-
cer journey.
Downloadable software
• Medical History Builder (http://journeyforward.org/patients/medical-history-
builder)
• Journey Forward’s Survivorship Care Plan Builder (http://journeyforward.org/
professionals/survivorship-care-plan-builder)
–– Designed for oncology professionals to create custom Survivorship Care
Plans for patients with cancer and their physicians.
–– Includes forms that expedite the preparation of treatment summaries and fol-
low-up care plans
–– Contains utilities such as a built-in regimen library, body surface area and
body mass index calculators, and various checklists
–– Provides support for breast cancer, colon cancer, lymphoma, and other
types of cancer
–– Ability to customize survivorship care plans with custom practice logo
–– Ability to expand care plans with information on symptoms to watch for, ef-
fects of treatment, support resources, and more
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 10. Post-Treatment Care 457
ship plan that includes potential long-term effects of treatment and rec-
ommended follow-up is helpful for primary providers who may be unfa-
miliar with cancer and its treatments.
2. Ensure that healthcare providers have the same information about SMNs
as do patients and that they are aware of recommended follow-up (see
Table 48).
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Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 11
Competence in
Chemotherapy
Administration
A. Professional education: To ensure a safe level of care for individuals receiv-
ing chemotherapy and biotherapy agents, each institution or supporting
agency ensures that RNs receive specialized education and preparation con-
sisting of didactic learning followed by successful completion of a clinical
practicum (ONS, 2011).
1. Didactic content is comprehensive, current, and evidence-based. At
the conclusion of the didactic course, the nurse demonstrates an un-
derstanding of the following as identified in the ONS (2011) posi-
tion Education of the Nurse Who Administers Chemotherapy and Biotherapy.
a) Principles of cancer chemotherapy and biotherapy
b) Types, classifications, and routes of administration of chemotherapy
and biotherapy agents
c) Pharmacology of cytotoxic and immunologic agents in cancer care
d) Chemotherapy and biotherapy indications in cancer care
e) Molecular biomarkers pertinent to chemotherapy and biotherapy
f) Chemotherapy and radiotherapy protectants
g) Principles of safe preparation, administration, storage, labeling, trans-
portation, and disposal of chemotherapy and biology agents
h) Appropriate use and disposal of PPE
i) Administration procedures, including administration schedule, dose,
and route; patient consent; and appropriate documentation in the
medical record
j) Process to ensure patient safety
k) Assessment, monitoring, and management of patients receiving che-
motherapy and biotherapy in all care settings
l) Patient and family education on chemotherapy and biotherapy side
effects and related symptom management and appropriate documen-
tation in the medical record
m) Assessment of, education about, and management of post-treat-
ment care, including urgent follow-up care procedures, late or long-
term side effects, and physical and psychosocial aspects of survivor-
ship
2. The clinical practicum allows the nurse to apply the knowledge gained
in the didactic component to direct patient care situations. Emphasis is
placed on the clinical skills that a nurse must demonstrate prior to be-
ing considered competent to administer chemotherapy and biotherapy
(see Appendices 3 and 4). At the completion of the clinical practicum,
the nurse will be able to
a) Demonstrate proficiency regarding the safe preparation, storage,
transport, handling, spill management, administration, and disposal
of chemotherapy drugs and equipment. 461
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
462 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
b) Identify appropriate physical and laboratory assessments for specif-
ic chemotherapy agents.
c) Demonstrate skill in venipuncture, including vein selection and sterile
technique and care of the site during and after drug administration.
d) Demonstrate skill in the care and use of various VADs.
e) Identify patient and family education needs in relation to specific
chemotherapy agents.
f) Identify acute local or systemic reactions as a result of extravasation
or anaphylaxis in association with specific chemotherapy drugs, and
identify appropriate interventions.
g) Demonstrate proficiency in the safe administration of chemotherapy
and disposal of chemotherapy waste and equipment.
h) Verbalize knowledge of institutional policies and procedures regard-
ing chemotherapy administration.
i) Document pertinent information in the medical record.
3. Clinical activities
a) The nurse should be supervised by a qualified preceptor to ensure
safe practice.
b) The preceptor and the nurse should establish specific objectives at
the beginning of the clinical practicum. Ideally, the nurse and pre-
ceptor should select a specific population of patients, and the nurse
should assume responsibility for planning the care for these patients
with supervision by the preceptor.
c) The length of time spent in the supervised clinical practicum should
be individualized depending on the nurse’s ability and skill in meet-
ing the specific objectives and institutional standards.
d) After the nurse becomes proficient and independent in administer-
ing nonvesicants, progression to vesicant administration can occur.
e) The nurse should verbalize to the preceptor potential adverse reac-
tions, side effects, toxicities, and measures to prevent and/or man-
age these reactions.
f) Various clinical settings can be used for the nurse to demonstrate
competence in chemotherapy administration. It may not be realistic
for all settings or agencies to provide on-site chemotherapy education
and training. Alternative methods should be used, such as
(1) Contracting with larger institutions to credential nurses for spe-
cific needs (e.g., vesicant, nonvesicant, IV push, short infusion,
continuous infusion)
(2) Creating a simulated laboratory to substitute for the clinical
component when patients are not available.
4. Evaluation: An evaluation tool based on the course objectives should be
used to determine
a) The nurse’s knowledge of chemotherapy drugs and the associated
nursing implications
b) The nurse’s knowledge of the necessary technical skills required for
the administration of chemotherapy agents (e.g., venipuncture, VAD
access and management, indwelling catheter management)
c) The nurse’s knowledge of patient and family education, which should
be initiated based on the chemotherapy administered
d) The nurse’s knowledge of steps to be taken in the event of an unto
ward response following chemotherapy administration (e.g., anaphy-
laxis, hypersensitivity reaction, extravasation).
5. Following successful completion of the clinical practicum, the nurse
should complete a skills inventory to demonstrate his or her ability to
perform the four criteria described herein. This can be done in a simu-
lated setting (e.g., skills laboratory) or as a precepted experience in the
clinical setting. It is recommended that the learner administer at least
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Chapter 11. Competence in Chemotherapy Administration 463
three chemotherapy agents under the supervision of trained personnel.
Two should be administered by IV push—the first should be a nonvesi-
cant agent, the second should be a vesicant agent.
6. Annual education and competency evaluation is recommended. Educa-
tional content should, at a minimum, emphasize any new information avail-
able. Methods for evaluation may include but are not limited to clinical
observation, quality improvement studies, chart audits, competency check-
list, attendance at an educational program, literature review, and testing.
B. Policies and procedures
1. Policies help to promote standardization of practice within an institu-
tion. They provide an operational framework for organizational goals
and objectives and may be required by regulatory or accrediting agen-
cies. Procedures commonly outline the steps needed to accomplish a
task (Scott & Harris, 2011).
2. Once a policy is implemented, it is imperative that it is enforced and fol-
lowed by staff. Individuals can be held liable if patient harm results from
failure to follow a policy; institutions are liable if a policy is not followed
by their staff. Consider staff in units outside of hematology/oncology.
Are nurses administering HDs in obstetrics/gynecology or rheumatolo-
gy? How is this addressed in institutional policy?
3. Interdisciplinary staff involvement is recommended when creating anti-
neoplastic policies and procedures. Input from pharmacy, medicine, nurs-
ing, and other departments will result in a more comprehensive policy.
4. Topics that may be included in an antineoplastic policy are drug ad-
ministration, safety checks, disposal, home care, medical surveillance
for staff, mixing, medication orders (e.g., who can write them, round-
ing volumes, format), PPE, linen handling, spill management, staff ex-
posure to HDs, staff education, extravasation, documentation, storage,
and transportation.
5. To maintain safety, it is important to accurately identify the patient prior
to antineoplastic administration. Unique patient identifiers to be used
are frequently standardized by the institution and may include the indi-
vidual’s name; date of birth; medical record number; account, visit, or
admission number; photograph; and social security number. Many insti-
tutions incorporate this data on a wristband that may be read or scanned
electronically. Caution should be used when verifying patient identifica-
tion with an identifier that can be easily changed, such as bed or chair
number or a phone number.
6. Antineoplastic medications administered outside the oncology areas: It
is the position of ONS that all RNs who administer and/or care for pa-
tients receiving chemotherapy receive specialized education, including
a didactic component and a practicum. Refer to the ONS position titled
Education of the Nurse Who Administers Chemotherapy and Biotherapy, avail-
able at www.ons.org/about-ons/ons-position-statements. This position
applies to antineoplastic drugs regardless of route, indication, or setting.
a) All nurses should be knowledgeable about the drugs they administer:
the mode of action, side effects, and toxicity; dosage range, rate, and
route of excretion; potential responses; and interactions with other
medications and foods.
b) Institutional policy should address the antineoplastic medication ed-
ucational plan for nurses working within the facility. Some staff may
require drug- or disease-specific education, whereas others will re-
quire comprehensive education for all antineoplastic medications.
C. Sample documentation tools
1. Consent document (see Appendix 5)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
464 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
2. Extravasation flow sheet (see Appendix 6)
3. Competency checklist (see Appendices 3 and 4)
References
Oncology Nursing Society. (2011). Oncology Nursing Society position on the education of the nurse
who administers chemotherapy and biotherapy. Retrieved from http://www.ons.org/about-ons/
ons-position-statements/education-certification-and-role-delineation/education-rn-who
Scott, M.L., & Harris, J.Y. (2011). Organizational design and structure. In M.M. Gullatte (Ed.), Nurs-
ing management: Principles and practice (2nd ed., pp. 97–113). Pittsburgh, PA: Oncology Nursing So-
ciety.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Appendices
465
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
466 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Appendix 1. Safe Management of Chemotherapy in the Home
You are getting medicine used to treat cancer (chemotherapy, or “chemo”). You must be careful to make sure other people do not acci-
dentally touch the drugs or your body waste for a time after treatment. This form teaches you and your family how to protect others from
the chemo and how to handle the waste from the chemo in your home.
Chemo Drugs Are Dangerous
Chemo drugs are strong chemicals. Only patients who need chemo for treatment should take or touch the drugs. Items that touch the
medicines (such as syringes and needles) are contaminated with chemo. Regardless of how you take the medicines, chemo remains in
your body for many hours and sometimes days after your treatment. Your body will get rid of the drugs in your urine or stool. Traces of
chemo also may be present in vomit.
Disposal of Chemo
Dispose of items contaminated with chemo separately from other trash. If required, the company supplying your medicines and equip-
ment will give you a hard plastic container labeled with “Chemotherapy Waste” or a similar warning. Place equipment and gloves that
have touched chemo into this container after use. If the waste is too large to fit in the plastic container, place it in a separate plastic bag
and seal it tightly with rubber bands. Place sharp objects in the hard plastic container. The company will tell you who will pick up the dis-
posal container.
Body Waste
You may use the toilet (septic tank or sewer) as usual. Flush twice with the lid closed for 48 hours after receiving chemo. Wash your
hands well with soap and water afterward, and wash your skin if urine or stool gets on it. Pregnant women, children, and pets should
avoid touching chemo or contaminated waste.
Laundry
Wash your clothing or linen normally unless they become soiled with chemo. If that happens, put on disposable gloves and handle the
laundry carefully to avoid getting chemo on your skin. If you do not have a washer, place soiled items in a plastic bag until they can be
washed.
Skin Care
Chemo spilled on skin may be irritating. If this happens, thoroughly wash the area with soap and water, then dry. If redness lasts for
more than one hour or if a rash occurs, call your doctor. To prevent chemo from being absorbed through the skin, wear gloves when
working with chemo, chemo-soiled equipment, or waste.
Eye Care
If any chemo splashes into your eyes, flush them with water for 10–15 minutes and notify your doctor.
Questions and Answers
Is it safe for family members to have contact with me during my chemo treatment?
Yes. Eating together, enjoying favorite activities, hugging, and kissing are all safe.
Is it safe for my family to use the same toilet as I do?
Yes. As long as you clean any chemo waste from the toilet seat, sharing is safe.
What should I do if I do not have control of my bladder or bowels?
Use a disposable, plastic-backed pad, diaper, or sheet to soak up urine or stool. Change immediately when soiled, and wash skin with
soap and water. If you have an ostomy, your caregiver should wear gloves when emptying or changing the bags. Discard disposable os-
tomy supplies in the chemo waste container.
What if I use a bedpan, urinal, or commode?
Your caregiver should wear gloves when emptying body wastes. Rinse the container with water after each use, and wash it with soap
and water at least once a day.
What if I vomit?
Your caregiver should wear gloves when emptying the basin. Rinse the container with water after each use, and wash it with soap and
water at least once a day.
Is it safe to be sexually active during my treatment?
Ask your doctor or your nurse this question. Traces of chemo may be present in vaginal fluid and semen for up to 48 hours after treat-
ment. Special precautions may be necessary.
How should I store chemo at home?
You should store chemo and equipment in a safe place, out of reach of children and pets. Do not store chemo in the bathroom, as high
humidity may damage the drugs. Check medicine labels to see if your chemo should be kept in the refrigerator or away from light. Be
sure all medicines have complete labels.
(Continued on next page)
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Appendices 467
Appendix 1. Safe Management of Chemotherapy in the Home (Continued)
Is it safe to dispose of chemo in the trash?
No. Chemo waste is dangerous and requires separate handling. If you are receiving IV chemo at home, you should have a special
waste container for the chemo and equipment. This includes used syringes, needles, tubing, bags, cassettes, and vials. This container
should be hard plastic and labeled with “Chemotherapy Waste” or a similar warning.
Can I travel with my chemo?
Yes. Usually, traveling is no problem. Some chemo requires special storage (such as refrigeration), so you may need to make special ar-
rangements. Check with your nurse, doctor, or medicine supplier for further instructions. Regardless of your means of travel (airplane,
car, or other), always seal your chemo drugs in a plastic bag.
What should I do if I spill some chemotherapy?
You will have a spill kit if you are receiving IV chemo at home. In the event of a chemo spill, open the spill kit and put on two pairs of
gloves, the mask, gown, and goggles. Absorb the spill with the disposable sponge. Clean the area with soap and water. Dispose of all
the materials—including gloves, mask, gown, and goggles—in the chemo waste container.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
468 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Appendix 2. Extravasation
Photo 1. Erythema of site of port extravasation of doxorubicin Photo 2. Skin necrosis begins (February 28).
(February 14)
Photo 3. Area of extravasation following debridement (March 18) Photo 4. Outer areas of debrided area are granulating (June 5).
Photo 5. Ten months following extravasation, the area has healed Photo 6. Severe tissue necrosis secondary to vesicant extravasa-
and scars have formed (December 10). tion
Note. Photos 1–5 from “Chemotherapy Extravasation From Implanted Ports,” by L. Schulmeister and D. Camp-Sorrell, 2000, Oncology Nursing Forum, 27,
p. 534. Copyright 2000 by the Oncology Nursing Society. Reprinted with permission. Photo 6 courtesy of Rita Wickham, RN, PhD, AOCN®. Used with per-
mission.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Appendices 469
Appendix 3. Clinical Practicum Evaluation: Part I
Chemotherapy Administration Competency Record
Employee Name _______________________________________________________________________________
Chemotherapy-competent RN evaluators must observe practice and validate that the nurse meets all of the following criteria. Adminis-
ter at least one vesicant under supervision.
RN Evaluators Date Drugs Administered
PRIOR TO ADMINISTRATION Initials
1. Coordinates time of administration with pharmacy and others as needed.
2. Verifies signed consent for treatment.
3. Verifies laboratory values are within acceptable parameters and reports results to provider as
needed.
4. Performs independent double check of original orders with a second RN for accuracy of
• Protocol or regimen
• Agents
• Recalculated body surface area
• Patient dose
• Schedule
• Route
5. Verifies that patient education, premedication, prehydration, and other preparations are completed.
ADMINISTRATION
1. Compares original order to dispensed drug label at the bedside or chairside with another RN.
2. Verifies patient identification.
3. Applies gloves and gown and uses safe handling precautions.
4. Verifies adequacy of venous access and appropriate IV site selection.
5. Checks IV patency and flushes line with 5–10 ml normal saline.
6. Demonstrates safe administration:
• Pushes through side arm or at hub closest to patient; checks patency every 2–5 ml (every 2–3
ml for pediatric patients).
• Verifies appropriate rate of administration.
7. Demonstrates appropriate monitoring/observation for specific acute drug effects.
8. Verbalizes appropriate action in the event of extravasation.
9. Verbalizes appropriate action in the event of hypersensitivity reaction.
AFTER ADMINISTRATION
1. Flushes line with enough fluid to clear IV tubing of drug.
2. Removes peripheral IV device or flushes/maintains vascular access device.
3. Disposes of chemotherapy waste according to policy.
4. Documents medications, education, and patient response.
5. Communicates post-treatment considerations to the patient, caregivers, and appropriate personnel.
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
470 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Appendix 4. Clinical Practicum Evaluation: Part II
Check the appropriate column to indicate whether the nurse performs the listed activities satisfactorily. If the nurse has not had the op-
portunity to perform an activity, check the N/A (not applicable) column. Under Comments, provide examples of how the nurse met each
objective or performed each activity. Include plans for remediation for all activities for which “No” is indicated.
Yes No N/A
1. Participates in interdisciplinary care planning with physicians, nurses, and other healthcare professionals
(e.g., home care or dietary workers).
Comments:
2. Anticipates complications of chemotherapy and takes action to prevent or minimize the complications.
Comments:
3. Involves patients and caregivers in care planning and provides interventions specific to individual patient
needs.
Comments:
4. Instructs patients about hair, scalp, and skin care and takes measures to preserve body image.
Comments:
5. Reviews laboratory values and provides patients with information about myelosuppression, prevention of in-
fection, fatigue, and prevention of bleeding according to ONS Putting Evidence Into Practice (PEP) evidence.
Comments:
6. Identifies patients at risk for oral mucositis and provides education regarding oral hygiene according to ONS
PEP evidence.
Comments:
7. Demonstrates knowledge of interventions (drug therapy and nonpharmacologic) for prevention and manage-
ment of nausea and vomiting according to ONS PEP evidence.
Comments:
8. Instructs patients about the prevention and management of gastrointestinal complications (e.g., constipa-
tion, diarrhea, anorexia) according to ONS PEP evidence.
Comments:
9. Identifies and takes nursing action to prevent or manage potential or actual hypersensitivity and anaphylac-
tic reactions.
Comments:
10. Uses appropriate safe handling precautions in the preparation, handling, and disposal of hazardous drugs.
Comments:
11. Demonstrates knowledge and skill in the assessment, management, and follow-up care of extravasations.
Comments:
12. Assesses patients for the most appropriate type of venous access device (peripheral or central) based on
type and duration of intended therapy.
Comments:
13. Demonstrates knowledge of research trials by participating in data collection, drug administration, patient
education, and follow-up.
Comments:
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Appendices 471
Appendix 5. Consent for Chemotherapy Treatment
Patient Name: Date:
Diagnosis:
Medications:
Possible side effects may include any of the following or a combination of the following:
Allergic and allergic-like reactions Skin and nail darkening Risk of infection
Anemia Skin ulceration at injection site Menopausal symptoms
Fatigue Skin rash Menstrual irregularities
Constipation Light and temperature sensitivity Sterility
Diarrhea Numbness or tingling Dizziness
Loss of appetite Hearing loss Forgetfulness
Mouth sores Heart damage Cognitive impairments
Nausea or vomiting Kidney damage Secondary malignancy
Weight gain or loss Low platelet count causing bleeding Muscle aching or weakness
Liver damage Low white blood cell count
Hair loss
Unexpected side effects may occur in addition to those noted above. In rare instances, cancer treatment can cause life-threat-
ening complications and death.
Chemotherapy can be harmful to an unborn child. It is important to tell the doctor if I think I may be pregnant. It is important for both
men and women who are being treated with chemotherapy and who are sexually active and fertile and who have a fertile partner to use
a reliable form of birth control (birth control pills, a reliable barrier method, or a hormonal implant as recommended by your physician). I
have discussed possible ways of preserving my fertility with my doctor, if applicable.
_________ (Patient Initials) A healthcare professional has provided and reviewed with me written information on the drugs I
will receive. I HAVE HAD THE CHANCE TO ASK ANY QUESTIONS ABOUT THE DRUGS I WILL RECEIVE AND AM SATISFIED
WITH THE INFORMATION PROVIDED.
My healthcare team has explained my treatment plan in detail. My doctor has discussed with me other methods of treating this disease
and the risks and benefits of treatment. There is no guarantee that this treatment will give me the same results that other patients have
received. If I change my mind and decide to stop treatment at any time, my doctor will continue to provide for my care in the future.
I have read the above information. I understand the possible risks and benefits of the recommended treatment plan. I agree to
accept the treatment and authorize Dr. _______________________ and his/her healthcare team to carry out the treatment plan.
Patient signature: Date:
I have explained the expected response, side effects, and possibility of risks of the listed drugs to the above named patient.
Physician signature:
Witness:
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
472 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Appendix 6. Extravasation Record
Vesicant Drug Extravasation Record
Patient: Date of infiltration: Time:
Today’s date:
Drug: Dilution (mg/ml):
Estimated amount infiltrated:
Vascular access Infusion method Pretreatment assessment
Peripheral IV IV push via side-arm of free-flow- Location:
Location: ing IV
PICC Direct IV push Type and size of needle/catheter:
Implanted port Minibag infusion
Needle size and length: Continuous infusion
Tunneled catheter Description and quality of blood return:
Other Infusion pump used?
Yes No
Comments:
**Attach timed and dated photograph of site, if re-
quested**
Description
Include topical cooling/heating applied, treatments, antidotes used, measurements of site, edema, and/or redness.
Assess extremity for range of motion and discomfort with movement.
Situation:
Background:
Assessment (include photos):
Recommendations:
Physician notified:
Patient/Caregiver Instructions:
Comments:
Consultations: Follow-up:
Plastic Surgery Date: Include return appointments, patient instructions on
Physical Therapy Date: skin assessment, temperature monitoring, and report-
Other: ing of pain.
Notes:
Signature: Date:
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Index
The letter f after a page number indicates that relevant content appears in a figure; the letter t, in a table.
A alemtuzumab
cardiotoxicity of, 264t
androgen inhibitors, cardio-
toxicity of, 257t
abiraterone acetate nausea/vomiting from, 195t anemia
cardiotoxicity of, 257t pulmonary toxicity of, 300t adverse outcomes of, 183,
hepatotoxicity of, 326t alimentary tract mucositis, 277, 349
absolute neutrophil count 213, 217–218 classification of, 182t
(ANC), 171 alkylating agents, 27t–31t, 158t. clinical manifestations of,
calculation of, 177 See also specific drugs 183, 184t
ACE inhibitors, for cardiomy- affecting sexuality, 384 definition of, 171
opathy, 284 cardiotoxicity of, 256t and fatigue, 379
acneform eruptions, 235t, 243f hepatotoxicity of, 323t incidence of, 181
acquired drug resistance, 13 neurotoxicity of, 341t lab assessment of, 184t
acral erythema, 238t, 251f ocular toxicity of, 369t management of, 183–184,
actinomycin, nausea/vomiting pulmonary toxicity of, 292t– 184t–187t
from, 194t 293t pathophysiology of, 181
acupressure wristbands, for allergies, 130. See also hyper- risk factors for, 181–183
nausea/vomiting, 204– sensitivity angiogenesis, 93–94
205 alopecia, 232t, 244, 250–251, angiogenic switch, 94
acupuncture, for nausea/vom- 384 anorexia, 222
iting, 205 clinical manifestations of, assessment of, 222t, 224
acute infusion reactions, 163– 253–254 clinical manifestations of,
167 grading of, 253 224
pathophysiology of, 163 incidence of, 251 incidence of, 223
preadministration guide- management of, 256 management of, 224–225
lines, 164–165 pathophysiology of, 251 pathophysiology of, 222–223
risk factors for, 163–164, risk factors for, 251–253, risk factors for, 223–224
164f 253t anthracyclines, 38t–40t. See also
acute kidney injury (AKI), support/resources for, 255 specific drugs
330–331 time frame/pattern of, 253– cardiotoxicity of, 257t–259t,
acute nausea/vomiting, 193– 254 278, 280–281
196, 198–203 alpha particles, 58–59 extravasation of, 159t
acute renal failure. See acute alprazolam, for nausea/vomit- antiangiogenic agents, 93–94.
kidney injury ing, 199t See also biotherapeutic
acute tubular injury (ATI), 330 altered immunogenicity, 55 agents
acyclovir, for mucositis, 220t alternative therapies. See com- pulmonary toxicity of, 300t
adaptive immunity, 52t, 52– plementary and alterna- antibodies, 55
54, 53f tive medicine anticipatory nausea/vomiting,
adherence, to therapy, 129– altretamine, 27t 192–193, 204
130 alveolar hemorrhage, 311–312 antidepressants, for fatigue
adjuvant therapy, 5 amifostine, for GI mucositis, management, 381
adotrastuzumab emtansine, 217–218, 219t antidiarrheal medications,
78t anagen effluvium, 251. See also 211t
aldesleukin (IL-2), 65t alopecia antiemetic therapy, 198, 199t–
hepatotoxicity of, 325t anaphylaxis, 163. See also acute 202t
nausea/vomiting from, infusion reactions antigen modulation, 55
194t–195t clinical manifestations of, antigen-presenting cells, 54
nephrotoxicity of, 333t 165 antimetabolites, 32t–36t. See
neurotoxicity of, 342t emergency treatment of, also specific drugs
ocular toxicity of, 371t 165–167, 166t affecting sexuality, 384
pulmonary toxicity of, 294t grading of, 167t cardiotoxicity of, 260t–261t
473
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
474 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
hepatotoxicity of, 324t beta particles, 59 brentuximab vedotin, 58, 70t cell cycle, 25, 26f
neurotoxicity of, 341t–342t BETTER model, of communica- pulmonary toxicity of, 299t cell cycle–nonspecific drugs,
ocular toxicity of, 369t–370t tion on sexuality, 388 bronchospasm, 290 26, 48
pulmonary toxicity of, 294t– bevacizumab, 58, 70t bulk-forming laxatives, 228 cell cycle–specific drugs, 26
296t cardiotoxicity of, 264t busulfan, 27t cell-mediated immunity, 53, 53f
antitumor antibiotics, 37t–40t. nausea/vomiting from, 195t hepatotoxicity of, 323t cell signaling, 60, 92–93
See also specific drugs nephrotoxicity of, 332t nausea/vomiting from, 194t central nervous system (CNS)
affecting sexuality, 384 neurotoxicity of, 342t neurotoxicity of, 341t deficits, 339–340
cardiotoxicity of, 257t–259t, pulmonary toxicity of, 300t ocular toxicity of, 369t as late effects, 443t
261t bexarotene, hepatotoxicity of, pulmonary toxicity of, 290– central nervous system (CNS)
discovery of, 3t 326t 291, 292t tumors, cognitive impair-
extravasation of, 159t biologic response modifiers, ment with, 358t–359t
hepatotoxicity of, 324t 68t–69t central venous catheters (CVCs),
ocular toxicity of, 370t biologic safety cabinets (BSCs), C 127–128
pulmonary toxicity of, 296t– 107–108, 113–114 cerebellar dysfunction, 340
297t biotherapeutic agents, 5. See also cabazitaxel, 45t cervical cancer, secondary malig-
APL differentiation syndrome, specific drugs nausea/vomiting from, 195t nancies following, 453
287–288, 312–314 accidental exposure to, 104– cabozantinib, 80t cetuximab, 58, 71t
aprepitant, 191 105 cachexia. See anorexia cardiotoxicity of, 264t
drug interactions with, 145 characteristics/therapeutic Calvert formula, 148, 148f diarrhea from, 208
for nausea/vomiting, 200t, uses of, 60, 61t–67t, 93f camptothecins, 44t nausea/vomiting from, 195t
203 hepatotoxicity of, 325t cancer nephrotoxicity of, 332t
arsenic trioxide, 40t ocular toxicity of, 370t–371t definition of, 1–2 ocular toxicity of, 373t
cardiotoxicity of, 263t supportive uses for, 60 factors causing, 1–2 pulmonary toxicity of, 300t
nausea/vomiting from, 194t biotherapy genetic alterations in, 1, 2f rash from, 244. See also rash
pulmonary toxicity of, 298t cardiac assessment before, grading/staging of, 2–3 chemokines, 55
arterial access devices, 125–126 283 history of therapy, 3t–4t, 3–5 chemoprevention, 7
ASCO/ONS Chemotherapy categories of, 56–60 therapy goals, 1–27 chemoreceptor trigger zone
Administration Safety definition/overview of, 56 treatment approaches, 5–6 (CTZ), 190–191, 191f
Standards, 100 strategies of, 60–93, 68t–91t, treatment strategies, 6 chemotactic cytokines, 55
asparaginase, 40t 92f cancer cachexia, 222, 223f. See chemotherapeutic agents. See
hepatotoxicity of, 326t bisphosphonates, ocular toxici- also anorexia also specific drugs
nausea/vomiting from, 195t ty of, 371t cancer-related fatigue. See fa- cell cycle–nonspecific, 26, 48
asparaginase Erwinia chrysanthe- bleomycin, 37t tigue cell cycle–specific, 26
mi, 41t cardiotoxicity of, 261t capecitabine, 32t characteristics of, 27t–47t
hepatotoxicity of, 326t nausea/vomiting from, 195t cardiotoxicity of, 260t history of, 3t–4t
assessment, pretreatment, 130– pulmonary toxicity of, 290– hepatotoxicity of, 325t chemotherapy
133 291, 296t–297t nausea/vomiting from, 197t for cancer treatment, 5
ATRA, pulmonary toxicity of, blistering, 236t neurotoxicity of, 341t dosing of, 6–7
298t, 312–314 blistering agents. See vesicants ocular toxicity of, 369t chemotherapy-induced nausea
atropine, for diarrhea, 211t blood-brain barrier, 340 pulmonary toxicity of, 294t and vomiting (CINV), 190.
AUC calculations, 148–149 blood components, life spans of, capillary leak syndrome, 272 See also nausea/vomiting
autologous cellular immuno- 174t, 181 carboplatin, 27t–28t chemotherapy-induced neutro-
therapy, 67t B lymphocytes, 55 AUC-based dosing of, 148– penia (CIN), 172. See also
autonomic nerve deficits, 339 body fluids, safe handling of, 149, 149f neutropenia
axitinib, 78t 110 nausea/vomiting from, 194t chest CT, 309
cardiotoxicity of, 267t body surface area (BSA) dosing, ocular toxicity of, 369t chest x-ray, 287, 308–309
hepatotoxicity of, 327t 144–148, 147f cardiac failure/cardiomyopa- Children’s Cancer Group, 3t
nephrotoxicity of, 332t bone marrow, 174 thy, 277 Children’s Oncology Group
azacitidine, 32t bortezomib, 79t assessment of, 282–283 (COG), 4t, 19
cardiotoxicity of, 259t inadvertent IT administration clinical manifestations of, chimeric mAbs, 57, 57f
nausea/vomiting from, 194t of, 102, 103f 282 chlorambucil, 28t
nephrotoxicity of, 332t nausea/vomiting from, 195t incidence of, 280 nausea/vomiting from, 197t
neurotoxicity of, 342t management of, 283–285 ocular toxicity of, 369t
pulmonary toxicity of, 300t pathophysiology of, 277–278 pulmonary toxicity of, 292t
B bosutinib, 79t risk factors for, 280–282 chlorhexidine, for oral mucosi-
cardiotoxicity of, 265t types of, 278–280 tis, 217, 219t
band neutrophils, 172, 177 bradycardia. See conduction cardiovascular toxicity, 255, chronic kidney disease (CKD),
BCG live vaccine, ocular toxici- pathway disorders 256t–269t. See also specific 332
ty of, 370t brain natriuretic peptide levels, disorders cisplatin, 28t
BCNU. See carmustine 283–284 as late effect, 441t cardiotoxicity of, 256t
Beau lines, 233t breakthrough nausea/vomit- carfilzomib, 80t nausea/vomiting from, 194t
bendamustine, 27t ing, 204 carmustine, 43t nephrotoxicity of, 332t, 336
as irritant, 162 breast cancer hepatotoxicity of, 323t neurotoxicity of, 341t
nausea/vomiting from, 194t cognitive impairment with, nausea/vomiting from, 194t ocular toxicity of, 369t
benzodiazepines, for anticipato- 350t–358t ocular toxicity of, 372t cladribine, 32t
ry nausea/vomiting, 204 as late effect, 441t pulmonary toxicity of, 290, cardiotoxicity of, 261t
benzydamine, for mucositis, secondary malignancies fol- 302t nausea/vomiting from, 195t
220t lowing, 452 catheters, 125, 127–128 clinical trials, 17–23
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Index 475
nurses’ role in, 20–23 risk factors for, 270–271
congestive heart failure (CHF),
D nausea/vomiting from, 195t
nephrotoxicity of, 332t
nursing core competencies
for, 22, 22t 284 dacarbazine, 29t neurotoxicity of, 343t
pediatric patient involvement conjugated antibodies, 58 hepatotoxicity of, 323t ocular toxicity of, 373t
in, 19–20 conjunctivitis, 244 nausea/vomiting from, 194t pulmonary toxicity of, 303t,
phases of, 18t–19t constipation, 225–226 dactinomycin, 37t 307
regulation of, 17–19 assessment of, 227 extravasation of, 159t documentation, 99–100, 112
resources for, 20 consequences of, 226 hepatotoxicity of, 324t of extravasation, 160, 161f,
clofarabine, 33t incidence of, 226 nausea/vomiting from, 194t 472
hepatotoxicity of, 325t management of, 228–230 darbepoetin, 61t of patient education, 138–139
nausea/vomiting from, 194t pathophysiology of, 226 dasatinib, 81t dolasetron, for nausea/vomit-
clonidine, for hot flashes, 385 risk factors for, 226–227 cardiotoxicity of, 268t ing, 201t
clot formation, 184–188. See also continuity of care, 142 pulmonary toxicity of, 305t dose calculation, 146–149
thrombocytopenia continuous IV infusion, 128–129 daunorubicin, 38t verification of, 146, 150–151
cluster of differentiation (CD) control, as treatment goal, 7 cardiotoxicity of, 257t, 283 dose capping, 149, 149f
markers, 54 coronary artery disease, 275–277 extravasation of, 159t dose density, 6, 140–141
Cockcroft-Gault formula, 148, corticosteroids hepatotoxicity of, 323t dose intensity, 7, 140–141
149f for anorexia, 224–225 nausea/vomiting from, 194t dose modifications, verification
cognitive impairment, 347–348 for fatigue management, 381 daunorubicin citrate liposo- of, 144–145
assessment of, 364–365 for mucositis, 220t mal, 38t dosimeters, 110
by cancer site, 350t–362t for nausea/vomiting, 199t, cardiotoxicity of, 257t dosing, of chemotherapy, 6–7
clinical manifestations of, 364 2023 decitabine, 34t doxorubicin, 39t
incidence of, 349, 363 ocular toxicity of, 371t nausea/vomiting from, 195t cardiotoxicity of, 258t, 283
as late effect, 443t cranial nerve deficits, 338, 339t, deep tendon reflexes, 339 extravasation of, 159t
management of, 365 345t deferoxamine, ocular toxicity flare reaction with, 163
pathophysiology of, 348–349 crizotinib, 81t, 92 of, 371t hepatotoxicity of, 323t
risk factors for, 363–364 cardiotoxicity of, 268t delayed nausea/vomiting, 191, nausea/vomiting from, 194t–
Coley, William, 3t hepatotoxicity of, 327t 196, 204 195t
colony-stimulating factors pulmonary toxicity of, 305t denileukin diftitox, 68t ocular toxicity of, 370t
(CSFs), 61t–64t. See also fil- cryotherapy, oral (ice chips), cardiotoxicity of, 262t doxorubicin liposomal, 39t
grastim; pegfilgrastim; sar- 216, 221t hepatotoxicity of, 326t cardiotoxicity of, 258t
gramostim cryptogenic organizing pneumo- nausea/vomiting from, 195t hepatotoxicity of, 323t
for anemia, 185t–187t nia, 290 nephrotoxicity of, 332t dronabinol, for nausea/vomit-
for neutropenia, 178 crystal nephropathy, 330–331 denosumab, 72t ing, 199t
colorectal cancer, cognitive im- cure, as treatment goal, 7 depigmentation, 240t drug interactions, 145
pairment with, 359t cutaneous effects. See skin tox- detergent laxatives, 228 drug resistance, 12–13, 92
combination chemotherapy icities dexamethasone, for nausea/ dysesthesias, 338
first used, 4t cyclin–cyclin-dependent kinase vomiting, 199t dyspnea, 290. See also pulmonary
vs. single-agent, 6 (CDK) complexes, 25 dexmethylphenidate, for fatigue toxicities
Common Terminology Criteria cyclophosphamide, 28t management, 381 dysrhythmias. See conduction
for Adverse Events cardiotoxicity of, 256t, 278, dexrazoxane, 284 pathway disorders
(CTCAE) 281 diapedesis, 174 dystrophy (nail), 233t
for diarrhea, 209 nausea/vomiting from, 194t, diarrhea, 206
for nausea/vomiting, 198t 197t assessment of, 208–210, 209t
for neuropathies, 339t nephrotoxicity of, 332t chemotherapeutic/biotherapy E
for oral mucositis, 216, 218t ocular toxicity of, 369t agents causing, 206–207
for skin toxicities, 245t pulmonary toxicity of, 290, clinical manifestations/conse- Eastern Cooperative Oncology
competence 292t, 307 quences of, 207 Group (ECOG) scale, 10,
for chemotherapy administra- cyclosporine incidence of, 207 11t
tion, 461–464, 469–470 nephrotoxicity of, 332t management of, 210, 211t, echocardiography, 283, 287
for clinical trial nursing, 22, 22t ocular toxicity of, 371t 212f eculizumab, 72t
complementary and alternative cytarabine, 33t pathophysiology of, 206 electroacupuncture, for nausea/
medicine (CAM), 97–98 hepatotoxicity of, 325t patient education on, 210–213 vomiting, 205
assessment of, 130 nausea/vomiting from, 194t– risk factors for, 208 electrocardiogram (ECG), 283,
for fatigue management, 381– 195t diaziquone, nephrotoxicity of, 287
382 neurotoxicity of, 341t 332t electrolyte replacement, 210
for sexuality alterations, 385 ocular toxicity of, 369t dietary interventions emergent drug resistance, 13
complete response (CR), 8, 8t pulmonary toxicity of, 295t for constipation, 229 emesis. See nausea/vomiting
compounding aseptic contain- cytarabine liposomal, 33t for nausea/vomiting, 205 emetogenicity, of antineoplastic
ment isolators (CACIs), cytokine-release syndrome, 163– for neutropenia, 177 drugs, 194t–197t
107–108, 113–114 165, 164f, 167, 167t diffusing capacity of lung encephalopathy, 339
conditioning therapy, 5–6 cytokines, 55–57 for carbon monoxide energy conservation, 380
conduction pathway disorders, cardiotoxicity of, 261t (DLCO), 310 enteral nutrition, for anorex-
255 pulmonary toxicity of, 294t diphenoxylate, for diarrhea, ia, 225
assessment of, 271 cytopenia, definition of, 171 211t epidermal growth factor (EGF),
clinical manifestations of, 271 cytosine arabinoside, pulmonary distress, 130–131 93
incidence of, 270 toxicity of, 290, 307 docetaxel, 45t epidermal growth factor recep-
management of, 271 cytotoxic T-lymphoctye antigen cardiotoxicity of, 267t tor inhibitors (EGFRIs)
pathophysiology of, 255, 270 4 (CTLA-4), 54–55 extravasation of, 160t ocular toxicity of, 366, 367t
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
476 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
pulmonary toxicity of, 307 management of, 157–160,
158t–160t
G safe compounding of, 107–
rash with, 231, 242–246, 247f. 109
See also rash pathophysiology of, 155 gabapentin, for hot flashes, 385 spill management of, 112f,
epidermal growth factor recep- risk factors for, 155–156 gamma rays, 59 112–114, 114f
tors (EGFRs), 93, 231 signs/symptoms of, 156–157, gefitinib storage/labeling of, 107
epipodophyllotoxins, 44t–45t 157t, 470 nausea/vomiting from, 197t transporting, 109
epirubicin, 39t exudative diarrhea, 206 nephrotoxicity of, 332t head and neck cancer, cognitive
cardiotoxicity of, 259t, 283 eye damage. See ocular toxicity pulmonary toxicity of, 306t impairment with, 359t
extravasation of, 159t eye exposure, to hazardous gemcitabine, 34t hematologic cancer
hepatotoxicity of, 323t drugs, 111 cardiotoxicity of, 261t cognitive impairment with,
nausea/vomiting from, 194t eye protection, 106 hepatotoxicity of, 325t 359t–360t
epoetin alfa, 61t nausea/vomiting from, 195t secondary, 445t
eribulin, 42t nephrotoxicity of, 333t hematopoiesis, 172, 173f
cardiotoxicity of, 263t F neurotoxicity of, 342t hematopoietic stem cell mobi-
hepatotoxicity of, 324t pulmonary toxicity of, 290, lizers, 66t
nausea/vomiting from, 195t face protection, 106 295t–296t hematopoietic stem cells
erlotinib, 81t–82t, 92 fatigue, 377 genetic alterations, 1, 2f (HSCs), 172
nausea/vomiting from, 197t assessment of, 379–380 GI mucositis, 213, 217–218 hemorrhagic cystitis (HC)
ocular toxicity of, 373t incidence of, 379 glomerular filtration rate (GFR), assessment of, 319–320
pulmonary toxicity of, 305t management of, 380–383 148–149, 149f clinical manifestations of, 319
rash from, 244. See also rash nonpharmacologic interven- glomerulonephritis, 331–332 incidence/risk factors of, 319
erythema multiforme, 235t–236t tions, 382–383 gloves, 106 management of, 321
erythema, transient, 240t pathophysiology of, 377–379, glucose analog tracer, 10 pathophysiology of, 318
erythrocytes, normal physiology 378f goals of cancer therapy, 7 prevention of, 320–321
of, 180–181 febrile neutropenia, 175f, 175– gowns, 106 hemorrhagic pneumonitis, 289
erythropoiesis, 180 176, 178. See also neutro- grading hepatitis B vaccine, 60
erythropoiesis-stimulating penia of alopecia, 253 hepatotoxicity
agents (ESAs), 184, 185t– management of, 179–180 of anaphylaxis, 167t assessment of, 328
187t fertility services, 391. See also re- of cancer, 2–3 clinical manifestations of,
for fatigue management, 380– productive alterations of rash, 244, 245t 322–328
381 fever, 175–176, 178–180. See also granisetron, for nausea/vomit- as late effect, 442t
erythropoietin (EPO), 180–181 neutropenia ing, 201t management of, 328
ESA APPRISE Oncology fiber intake, for constipation, 229 granulocyte–colony-stimulating pathophysiology of, 321–322
Program, 61t, 184 filgrastim (G-CSF), 62t factor (G-CSF). See also fil- risk factors for, 322
esophagitis. See GI mucositis for anemia, 186t grastim; pegfilgrastim HERA (HERceptin Adjuvant)
estramustine, cardiotoxicity of, development of, 4t for mucositis, 220t clinical trial, 280
256t for neutropenia, 178 for neutropenia, 178 hexamethylmelamine, nausea/
estrogen receptors (ERs), 12 film badges, 110 ocular toxicity of, 370t vomiting from, 197t
estrogen therapy, 385 fissures, in skin, 236t–237t, 250f granulocyte macrophage–colo- high-dose chemotherapy, 144,
ethambutol, ocular toxicity of, 5-HT3 receptor antagonists ny-stimulating factor (GM- 194t
371t development of, 4t CSF). See also sargramos- cardiotoxicity of, 256t, 281–
ethical issues for nausea/vomiting, 201t– tim 282
in cancer therapy, 97–98 202t, 203 for mucositis, 220t high-output failure, 277
with reproductive chang- fixed dosing, 146 for neutropenia, 178 hirsutism, 232t
es, 391 flare reaction, 155, 157t, 163 ocular toxicity of, 370t Hodgkin lymphoma (HL), 451–
ethical principles, 98t floxuridine, 34t growth factors, 60, 92–93 452
etoposide, 44t hepatotoxicity of, 325t growth fraction, of tumor, 11–12 hormone receptor status, 12
nausea/vomiting from, 194t– fludarabine, 34t guided imagery, for nausea/ HPV vaccine, 60
195t, 197t nausea/vomiting from, 196t– vomiting, 205 HSCT, secondary malignancies
ocular toxicity of, 374t 197t following, 453–454
pulmonary toxicity of, 303t– ocular toxicity of, 370t humanized mAbs, 57, 57f
304t
everolimus, 81t–82t
pulmonary toxicity of, 295t H human mAbs, 57, 57f
humoral immunity, 53, 53f
fluid replacement
nausea/vomiting from, 197t for constipation, 229 hair changes, 232t hydrogen peroxide, for mucosi-
pulmonary toxicity of, 290, for diarrhea, 210 haloperidol, for nausea/vomit- tis, 220t
304t fluorine-18 fluorodeoxyglucose ing, 199t hydroxyurea, 41t
exercise (18F-FDG), 10 hand-foot syndrome, 239t, 252f nausea/vomiting from, 196t–
for constipation, 229 fluorouracil (5-FU), 34t hand hygiene, 177, 179 197t
for fatigue management, 382 cardiotoxicity of, 260t hazardous drugs hyperpigmentation, 233t, 250f
for nausea/vomiting, 204 diarrhea from, 208 definition of, 102–103 hypersensitivity, 163–165, 164f,
expedited approval programs, nausea/vomiting from, 195t disposal of, 111 166t, 167, 167t. See also
for new drugs, 23 neurotoxicity of, 341t occupational exposure to, acute infusion reactions
extracellular matrix components ocular toxicity of, 370t 103–105, 104t, 111–112 hypersensitivity pneumonitis,
(ECM), 94 forced expiratory volume in one policy requirements for, 114– 289–290, 307
extravasation, 155 second (FEV1), 310 115 hypertension, 273–274
documentation of, 160, 161f, forced vital capacity (FVC), 310 routes of exposure to, 105 hypertrichosis, 232t
472 fosaprepitant dimeglumine, for safe administration of, 109, hypoxia, 183–184
factors affecting, 155 nausea/vomiting, 200t– 128–129, 131–133, 142– hypoxia-inducible factor-1
follow-up after, 160–161 201t, 203 143, 145, 466–467 (HIF-1) complex, 94
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Index 477
I interstitial lung disease (ILD),
288
of cancer treatment, 438–440 cardiotoxicity of, 256t
nonmalignant, 440, 441t–445t as irritant, 162
ibritumomab tiuxetan, 58, 73t assessment of, 308–309 types of, 440–451, 441t–450t nausea/vomiting from, 194t,
idarubicin, 40t clinical manifestations of, 308 laxatives, 228 197t
cardiotoxicity of, 259t, 283 incidence of, 290 L-carnitine, for fatigue manage- nephrotoxicity of, 333t
extravasation of, 159t management of, 309–310 ment, 381 pulmonary toxicity of, 293t
nausea/vomiting from, 194t pathophysiology of, 288–290 legal issues, in cancer therapy, memory T cells (TM cells), 54
IFN alfa-2b, 64t risk factors for, 290–307, 99–100 menopause, chemotherapy-in-
IFN gamma, 65t 292t–306t lenalidomide, 68t duced, 384–385
ifosfamide, 29t intra-arterial infusion, 125–126 cardiotoxicity of, 269t mercaptopurine (6-MP), 3t, 35t
cardiotoxicity of, 256t intramuscular (IM) injection, nausea/vomiting from, 197t hepatotoxicity of, 324t
nausea/vomiting from, 194t 122 pulmonary toxicity of, 299t nausea/vomiting from, 195t
nephrotoxicity of, 333t intraperitoneal (IP) chemother- leucovorin, diarrhea from, 208 mesna, for cystitis prevention,
neurotoxicity of, 340, 341t apy, 122–123 leucovorin rescue, 144 320–321
ocular toxicity of, 369t intrapleural administration, leukocyte growth factor, for ane- metamyelocytes, 172
pulmonary toxicity of, 293t 124–125 mia, 187t methotrexate, 35t
imatinib, 83t, 92 intrathecal (IT) administration, leukoencephalopathy, 349 hepatotoxicity of, 324t
diarrhea from, 208 123–124 linens, safe handling of, 110– nausea/vomiting from, 194t–
hepatotoxicity of, 327t inadvertent, 102, 103f, 124 111 197t
nausea/vomiting from, 197t intravenous (IV) administration, liver toxicity. See hepatotoxicity nephrotoxicity of, 333t, 336–
nephrotoxicity of, 333t 126–127 lomustine, 43t 337
ocular toxicity of, 373t intravesicular administration, nausea/vomiting from, 194t neurotoxicity of, 339, 342t
pulmonary toxicity of, 306t 125 ocular toxicity of, 372t ocular toxicity of, 370t
immune response, types of, 51– investigational regimens, 143 pulmonary toxicity of, 291, pulmonary toxicity of, 290,
54, 52t, 52f–53f involved-field radiation therapy 303t 296t, 307
immune suppression, 55 (IFRT), 439 “Look Good Feel Better” pro- methylnaltrexone, for constipa-
immune system, 51, 51f iodine-131 tositumomab, 58 gram, 255 tion, 229
cells of, 54f, 54–55 ipilimumab, 58, 73t loperamide, for diarrhea, 210, methylphenidate, for fatigue
immunoglobulins, 55 cardiotoxicity of, 264t 211t management, 381
immunosenescence, 56 hepatotoxicity of, 326t lorazepam, for nausea/vomit- metoclopramide, for nausea/
immunosuppressive therapy, 6 nausea/vomiting from, 195t ing, 199t vomiting, 200t
immunosurveillance, 56, 60 ocular toxicity of, 373t low-level laser therapy, for oral metoprolol, for cardiomyopa-
immunotoxins, 68t irinotecan, 44t mucositis, 218 thy, 284
implanted arterial ports, 125 diarrhea from, 208 L-phenylalanine, nausea/vomit- microcytic anemia, 182t
implanted arterial pumps, 126 hepatotoxicity of, 326t ing from, 197t minoxidil, for alopecia, 254
individualized protocols, 143– nausea/vomiting from, 194t lubricant laxatives, 228 mithramycin, nephrotoxicity
144 iron-chelating agents, 284 lung cancer, cognitive impair- of, 333t
informed consent (IC), 20–22, iron, for RBC production, 181 ment with, 360t mitomycin, 37t– 38t
21t, 100, 131, 471 irritants, 161. See also venous ir- extravasation of, 159t
infusion complications, 155. See ritation nausea/vomiting from, 195t
also acute infusion reac- with vesicant properties, 161– M nephrotoxicity of, 333t
tions; extravasation; flare 162 ocular toxicity of, 370t
reaction; venous irritation itching, 241t macrocytic anemia, 182t pulmonary toxicity of, 290–
Infusion Nursing Standards of IV push, 129 major histocompatibility com- 291, 297t
Practice, 99 ixabepilone, 43t plex (MHC), 55 mitotane, 41t
infusion reaction, 163–167 nausea/vomiting from, 195t malnutrition, and cardiotoxic- ocular toxicity of, 372t
inhalation exposure, to hazard- neurotoxicity of, 342t ity, 282 mitoxantrone, 38t
ous drugs, 112 mammalian target of rapamycin cardiotoxicity of, 259t
innate immunity, 51–52, 52f, 52t (mTOR) kinase, 92 extravasation of, 158t
institutional review boards K mannitol, ocular toxicity of, 372t hepatotoxicity of, 324t
(IRBs), 19 marginated cells, 174 nausea/vomiting from, 195t
interferon alfa Karnofsky Performance Status matrix metalloproteinases ocular toxicity of, 370t
cardiotoxicity of, 261t (KPS) scale, 10, 11t (MMPs), 94 pulmonary toxicity of, 297t
hepatotoxicity of, 325t keratinocyte growth factors, for MDA classification, of tumor re- modafinil, for fatigue manage-
nausea/vomiting from, 194t– oral mucositis, 217 sponse, 10 ment, 381
195t keratoconjunctivitis sicca, 244 mechlorethamine, 29t monoclonal antibodies (mAbs),
neurotoxicity of, 342t extravasation of, 158t 57f, 57–58. See also specif-
ocular toxicity of, 371t nausea/vomiting from, 194t ic drugs
interferons (IFNs), 64t–65t L ocular toxicity of, 369t cardiotoxicity of, 264t–265t
discovery of, 3t medical records, 99–100 characteristics of, 70t–78t, 93f
nephrotoxicity of, 333t labyrinthitis, 191 medication errors, 100–102, hepatotoxicity of, 326t
neurotoxicity of, 342t lacrimation, 244, 368. See also oc- 103f neurotoxicity of, 343t
ocular toxicity of, 371t ular toxicity medication sequence, verifica- pulmonary toxicity of, 300t–
pulmonary toxicity of, 294t Lansky Performance Scale, 10, tion of, 150 302t
interleukins (ILs), 65t–66t. See 11t megakaryocytes, 188 MOPP chemotherapy, first
also aldesleukin lapatinib, 84t megestrol acetate used, 4t
cardiotoxicity of, 262t cardiotoxicity of, 265t for anorexia, 225 Mosteller equation, 147f
neurotoxicity of, 342t nausea/vomiting from, 197t for fatigue management, 381 motion sickness, 191
pulmonary toxicity of, 307 late effects melphalan, 30t motor neuropathy, 338, 339t
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
478 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
mTOR inhibitors, pulmonary neovascularization, 94. See also as late effect, 441t nausea/vomiting from, 195t
toxicity of, 304t–305t, 307 angiogenesis management of, 375 neurotoxicity of, 343t
mucositis, 213–222. See also oral nephritic/nephrotic syndromes, pathophysiology of, 365–366 ocular toxicity of, 374t
mucositis 331–332 ofatumumab, 73t pulmonary toxicity of, 304t,
MUGA scans, 283, 285 nephrotoxicity, 332t–334t hepatotoxicity of, 326t 307
multidrug resistance (MDR), clinical manifestations of, nausea/vomiting from, 196t paclitaxel protein-bound/albu-
12–13 334–335 Office for Human Research min-bound, 46t
murine mAbs, 57, 57f management of, 335–337 Protections (OHRP), 17 extravasation of, 160t
music therapy, for nausea/vom- pathophysiology of, 329–332 olanzapine, for nausea/vomit- nausea/vomiting from, 195t
iting, 204 risk factors for, 334 ing, 199t pain, with neuropathies, 344–
myeloablation, 5–6 neuropathic pain, 344 older adults 345
myeloblasts, 172 neuroreceptors, 192f cardiotoxicity in, 282 palifermin, 63t
myelocytes, 172 neurotoxicity, 337–338 neurotoxicity in, 344 palliative cancer care, 7
myelosuppression, 171–190. See assessment of, 344–345 omacetaxine, 43t palmar-plantar erythrodysesthe-
also anemia; neutropenia; incidence of, 340 omeprazole, for GI mucosi- sia, 239t, 252f
thrombocytopenia as late effect, 443t tis, 217 palonosetron, for nausea/vomit-
myocardial muscle dysfunc- management of, 345–347 Oncology Nursing Society ing, 201t, 203
tion, 277 pain with, 344–345 (ONS) pamidronate, nephrotoxicity
pathophysiology of, 338–340 on nursing scope and stan- of, 333t
risk factors for, 340–344 dards, 99 pancreatitis, 375–377
N neutropenia, 171–172 on role of clinical trials nurs- pancytopenia, definition of, 171
clinical manifestations of, es, 22 panitumumab, 74t
nabilone, for nausea/vomit- 176–177 ondansetron diarrhea from, 208
ing, 199t management of, 177–180 development of, 4t nephrotoxicity of, 334t
nadir pathophysiology of, 174–175 for nausea/vomiting, 201t ocular toxicity of, 373t
in children, 175 prevention of, 179 onycholysis, 233t pulmonary toxicity of, 301t
definition of, 171–172 risk factors for, 175f, 175–176 oprelvekin, 66t papulopustular rash, 235t, 242–
WBC, 174–175 neutropenic diet, 177 for anemia, 187t 244, 245t, 246
nail changes, 233t neutrophils pulmonary toxicity of, 294t parenteral nutrition, for anorex-
National Cancer Act (1937), 3t locations of, 174 Oral Assessment Guide, 216, ia, 225
National Cancer Act (1971), 4t normal physiology of, 172– 217t paresthesias, 338
National Cancer Institute (NCI), 174 oral care, 216, 218–222 paronychia of nail, 232t, 245t,
3t pathophysiology of, 174–175. oral cryotherapy (ice chips), 250f
Cancer Therapy Evaluation See also neutropenia 216, 221t paroxetine, 385
Program (CTEP), 17 nilotinib, 84t–85t oral mucositis, 213 partial response (PR), 8, 8t
Common Terminology nitrogen mustard. See mechlor- assessment of, 216 patient education
Criteria for Adverse ethamine clinical manifestations of, on alopecia, 254–255
Events (CTCAE). See nitrosoureas, 43t–44t 215–216 on anorexia, 225
Common Terminology hepatotoxicity of, 323t incidence of, 214 barriers to, 138
Criteria for Adverse nephrotoxicity of, 333t phases of, 214 on cardiomyopathy, 285–286
Events ocular toxicity of, 372t prevention of, 216–217 on cognitive impairment, 365
National Chemotherapy pulmonary toxicity of, 302t– risk factors for, 214–215 on constipation, 229
Program, 3t 303t treatment for, 218, 219t–221t on coronary artery disease,
natural killer (NK) cells, 52, 55 NK1 antagonists, for nausea/ oral route of administration, 277
natural killer T (NKT) cells, vomiting, 200t–201t, 203 121–122 on cystitis, 321
52, 55 NK1 receptors, 191 order sets, 143 definition of, 137
nausea, definition of, 190 non-Hodgkin lymphoma orthochromatic normoblasts, documentation of, 138–139
nausea/vomiting, 190 (NHL), 452 181 on dysrhythmias, 271–272
acute, 193–196, 198–203 nonmyeloablative therapy, 6 osmotic diarrhea, 206 factors affecting, 137
anticipatory, 192–193, 204 nonspecific immunity, 51–52, osmotic laxatives, 228 on fatigue management, 383
antineoplastic drugs causing, 52f, 52t ovarian cancer, cognitive impair- on hepatotoxicities, 328
194t–196t normocytic anemia, 182t ment with, 361t on infusion reactions, 167–
assessment of, 196–197, 198t Notch receptor pathway, 94 oxaliplatin, 30t– 31t 168
breakthrough, 204 nurse practice acts, 99 as irritant, 161–162 on mucositis, 218–222
complications of, 197–198 nursing-sensitive outcomes, 344 nausea/vomiting from, 195t on nausea/vomiting, 205–206
delayed, 191, 196, 204 neurotoxicity of, 341t on nephrotoxicities, 337
management of, 198–204, ocular toxicity of, 369t on neurotoxicities, 347
199t–202t O pulmonary toxicity of, 290, on ocular toxicities, 375
nonpharmalogic interven- 293t outcomes of, 137–138
tions for, 204–205 occupational exposure oxidative damage, cognitive im- on perirectal cellulitis, 231
pathophysiology of, 190–196, hazard controls hierarchy, pairment from, 348 on pulmonary toxicities, 310
191f–192f 105 on reproductive changes,
patient education on, 205– to hazardous drugs, 103–110, 380–381
206 104t P for self-administration of oral
risk factors for, 196 octreotide, for diarrhea, 210, therapy, 121–122
nelarabine, 35t 211t paclitaxel, 46t on sexuality alterations, 388
nausea/vomiting from, 196t ocular toxicity, 244, 367t–368t cardiotoxicity of, 267t, 280 on skin toxicities, 248
neurotoxicity of, 343t assessment of, 367–375 development of, 4t during survivorship care, 456
neoadjuvant therapy, 5, 8 incidence/risk factors, 367 extravasation of, 160t on thrombocytopenia, 189
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
Index 479
patient safety, 100–102, 103f, polymorphonuclear neutro-
phils, 177
Q S
131–133, 142–143, 145,
466–467. See also hazard- polypharmacy, 145 quality of life (QOL), measure- safe handling/disposal, of haz-
ous drugs pomalidomide, 69t ment of, 10 ardous drugs, 102–115
pazopanib, 85t Positron Emission Tomography safety standards, for antineoplas-
cardiotoxicity of, 268t Response Criteria in Solid tic administration, 100,
hepatotoxicity of, 327t
pediatric cancers, secondary ma-
Tumors (PERCIST), 10
positron-emission tomography
R 103f. See also patient safety
saline laxatives, 228
lignancies following, 453 (PET) scans, 10, 309 radiation enhancement, 248 sargramostim (GM-CSF), 64t
pediatric patients posterior reversible encephalopa- radiation monitoring devic- for anemia, 187t
in clinical trials, 19–20 thy syndrome (PRES), 339 es, 110 for neutropenia, 178
dose modifications for, 144– pralatrexate, 36t radiation recall, 248 scalp hypothermia, for alope-
145 hepatotoxicity of, 324t radiation safety officer (RSO), cia, 254
neurotoxicity in, 343 nausea/vomiting from, 195t 109 Scope and Standards of Oncology
safe administration to, 145 preclinical studies, 17 radiation therapy Nursing Practice (ONS), 99
pegaspargase, 41t pregnancy, cancer treatment for cancer treatment, 5 secondary cancers, 437–440,
nausea/vomiting from, 196t during, 131. See also repro- late effects of, 438–439, 446 446t–450t, 451
pegfilgrastim (PEG-G-CSF), 63t ductive alterations ocular toxicity of, 372t prevention of, 7
for anemia, 186t primary cancer prevention, 7 pulmonary toxicities from, risk factors for, 439–440
and dose-dense chemother- primary engineering control 291 types of, 446–450, 446t–450t
apy, 6 (PEC), 107–108 skin toxicities from, 248 secondary infections, with skin
for neutropenia, 178 probiotics, for diarrhea, 210 radioisotope (RIT) treatment, toxicities, 246–247
peginterferon, nausea/vomiting procarbazine, 41t 58–60 secretory diarrhea, 206
from, 196t hepatotoxicity of, 323t safety precautions for, 109– segmented neutrophils, 177
pemetrexed, 36t nausea/vomiting from, 194t, 111 seizures, 340
nausea/vomiting from, 195t 197t ranitidine, for GI mucositis, 217 selective serotonin reuptake in-
nephrotoxicity of, 334t ocular toxicity of, 372t rasburicase, 331 hibitors, 385
pulmonary toxicity of, 296t prochlorperazine, for nausea/ rash, 232t–241t, 242, 243f sensory neuropathy, 338, 339t
pentostatin, 36t vomiting, 200t grading of, 244, 245t septic shock, 177. See also neu-
nausea/vomiting from, 195t professional education, 456– incidence of, 243–244 tropenia
nephrotoxicity of, 334t 457, 461–464 Raynaud phenomenon, 272–273 serotonin antagonists, for nau-
ocular toxicity of, 370t progesterone receptors (PRs), 12 RBC production, 180–181. See sea/vomiting, 201t–202t
pericardial effusions, 286–287 progestins, for anorexia, 224– also anemia sexuality, alterations in
peripheral nervous system defi- 225 record keeping. See documen- agents causing, 384
cits, 338–339, 339t progressive disease (PD), 8, 8t tation clinical manifestations of,
as late effects, 444t progressive muscle relaxation, regorafenib, 86t 386
peripheral venous access, 126–127 for nausea/vomiting, 205 regulatory T cells (Treg), 53–54 incidence of, 383–384
perirectal cellulitis, 230–231 prokinetic agents, for constipa- relapse, 8 as late effect, 443t
personal protective equipment tion, 228 relative dose intensity (RDI), 7, management of, 386–388
(PPE), 104–107 promegakaryocytes, 188 140–141 pathophysiology of, 383
pertuzumab, 74t promyelocytes, 172 reproductive alterations, 388– short-term infusion, 125, 128
cardiotoxicity of, 262t pronormoblasts, 180 391, 443t signal transduction, and tar-
photosensitivity, 239t prostate cancer respirators, 106 geted therapies, 60, 92f,
physical activity. See exercise cognitive impairment with, Response Evaluation Criteria in 92–93
plant alkaloids, 44t–47t 361t Solid Tumors (RECIST) sipuleucel-T, 60, 67t
affecting sexuality, 384 secondary malignancies fol- guidelines, 8, 8t, 9–10 skin exposure, to hazardous
cardiotoxicity of, 266t–267t lowing, 452 retching. See also nausea/vom- drugs, 111
extravasation of, 159t–160t pruritus, 241t, 245t iting skin toxicities, 231, 232t–241t,
hepatotoxicity of, 327t psychosocial issues definition of, 190 250f–252f. See also rash;
neurotoxicity of, 343t as late effects, 441t reticulocytes, 181, 182t toxic erythema of chemo-
pulmonary toxicity of, 303t– with skin toxicities, 247–248 retinoic acid syndrome, 287– therapy
304t psychostimulants, for fatigue 288, 312–314 from chemoradiation, 248
plants/flowers, neutropenic pa- management, 381 risk evaluation and mitigation grading of, 244, 245t
tients and, 178 pulmonary alveolar proteinosis/ strategy (REMS), 184 incidence of, 243–244
platelets, normal physiology of, phospholipoproteinosis, rituximab, 58, 75t as late effects, 445t
184–188 316–317 cardiotoxicity of, 264t management of, 232t–241t,
plerixafor, 66t pulmonary edema, 289–290, hepatotoxicity of, 326t 245–246
pleural effusions, 314–316 307 nausea/vomiting from, 196t nursing interventions, 244–
plicamycin, nausea/vomiting pulmonary function tests, 309– ocular toxicity of, 373t 246
from, 194t 310 pulmonary toxicity of, 290, pathophysiology of, 231–242
PLISSIT model, of communica- pulmonary toxicities, 287–288, 301t psychosocial issues with, 247–
tion on sexuality, 388 292t–306t. See also alveo- romidepsin, 42t 248
pluripotent stem cells, 172 lar hemorrhage; intersti- cardiotoxicity of, 263t and response/survival, 247
polychromatophilic erythro- tial lung disease; pleural nausea/vomiting from, 195t and secondary infections,
cytes, 181 effusions routes of administration, 121– 246–247
polychromatophilic normo- as late effect, 441t 129 small molecule inhibitors, 78t–
blasts, 180 pulmonary veno-occlusive dis- and neurotoxicity, 340 91t
polyethylene glycol (PEG), for ease (VOD), 288, 317– rubricytes, 180 somatic pain, 344
constipation, 228 318 ruxolitinib, 86t–87t sorafenib, 87t, 92
Copyright © 2014 by the Oncology Nursing Society. All rights reserved.
480 Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
cardiotoxicity of, 265t taxanes, 45t–46t. See also specif- treatment plan, 7, 131–132, verification of orders, 142–143
diarrhea from, 208 ic drugs 139–140 vesicants. See also extravasation
nausea/vomiting from, 197t cardiotoxicity of, 267t nurses’ role in, 141–142 IV administration of, 128–
specific immunity, 52t, 52–54, extravasation of, 160t patient understanding of, 142 129, 155
53f ocular toxicity of, 373t–374t trichomegaly, 232t, 244, 250f vinblastine, 47t
spill management, 112f, 112– tbo-filgrastim, 62t tubulopathies, 329 cardiotoxicity of, 266t
114, 114f for anemia, 187t tumor burden, 11 extravasation of, 159t
stable disease (SD), 8, 8t T cells, 54–55 tumor doubling time, 11–12 nausea/vomiting from, 196t
staging, of cancer, 2–3 tegafur-uracil, nausea/vomiting tumor escape mechanisms, 55– ocular toxicity of, 374t
standards of practice, 99 from, 197t 56 vinca alkaloids, 47t. See also plant
standard treatment regimens, telangiectasia, 237t tumor lysis syndrome (TLS), alkaloids; specific drugs
143 telogen effluvium, 251. See also 330–331 ocular toxicity of, 374t
Stevens-Johnson syndrome alopecia tumor, node, metastasis (TNM) vincristine, 47t
(SJS), 237t telomeres, 348 staging system, 3 cardiotoxicity of, 267t
stimulant laxatives, 228 temozolomide, 31t tumor response extravasation of, 159t
stomatitis, 213 nausea/vomiting from, 195t, factors affecting, 10–13 hepatotoxicity of, 327t
streptozocin, 44t 197t measurement of, 7–10, 8t inadvertent IT administration
nausea/vomiting from, 194t pulmonary toxicity of, 293t 2-chlorodeoxyadenosine, nau- of, 102, 103f
subcutaneous (SC) injection, temsirolimus, 88t, 92 sea/vomiting from, 195t nausea/vomiting from, 196t
122 nausea/vomiting from, 196t tyrosine kinase inhibitors, 93f. nephrotoxicity of, 334t
substance P, 191 pulmonary toxicity of, 305t See also specific drugs neurotoxicity of, 339, 343t
sun exposure, 246 teniposide, 45t cardiotoxicity of, 267t–268t ocular toxicity of, 374t
sunitinib, 87t, 92 nausea/vomiting from, 196t diarrhea from, 208 vindesine, extravasation of, 159t
cardiotoxicity of, 266t tertiary cancer prevention, 7 hepatotoxicity of, 327t vinorelbine, 47t
diarrhea from, 208 testicular cancer pulmonary toxicity of, 307 cardiotoxicity of, 266t
hepatotoxicity of, 327t cognitive impairment with, tyrosine kinase receptors, 60, 92 extravasation of, 159t
nausea/vomiting from, 197t 361t–362t as irritant, 162
nephrotoxicity of, 334t secondary malignancies fol- nausea/vomiting from, 196t–
ocular toxicity of, 373t lowing, 452–453 U 197t
suppositories, for constipation, thalidomide, 69t pulmonary toxicity of, 304t
228 cardiotoxicity of, 269t unconjugated antibodies, 58 visceral pain, 344
suppressor T cells (Ts), 53–54 nausea/vomiting from, 197t urinary alkalinization, 331 vismodegib, 90t
surgery, for cancer treatment, 5 neurotoxicity of, 342t urticaria, transient, 240t vomiting. See also nausea/vom-
survivorship care, 437–438 pulmonary toxicity of, 299t U.S. Food and Drug iting
elements of, 454 thioguanine, 3t, 36t Administration (FDA), definition of, 190
follow-ups during, 455–456 nausea/vomiting from, 197t 19, 23 vomiting center (VC), 190, 191f
models of, 455 thiotepa, 31t vorinostat, 42t
nursing assessment in, 455 nausea/vomiting from, 195t cardiotoxicity of, 263t
plan for, 454 thrombocytopenia V
resources for, 456t clinical manifestations of, 189
syndrome of inappropriate definition of, 171 vaccines, 59–60 W
antidiuretic hormone management of, 189–190 vagus nerve, 190
(SIADH), 329–330 risk factors for, 188–189 valrubicin, 40t weight-based dosing, 146
thrombopoiesis, 184–188 nausea/vomiting from, 196t wigs, 255
thrombopoietic growth factor, vandetanib, 89t World Health Organization
T for anemia, 187t vascular abnormalities, 272–275 (WHO)
thrombotic microangiopathy, vascular access devices (VADs), oral assessment guide, 216
tacrolimus 331 infection from, 176–177, patient response scale, 10, 11t
nephrotoxicity of, 334t topotecan, 44t 179–180. See also neutro- tumor response criteria,
ocular toxicity of, 372t nausea/vomiting from, 195t penia 7–9, 8t
tamoxifen pulmonary toxicity of, 306t vascular endothelial growth fac-
cardiotoxicity of, 263t tositumomab, 76t tor (VEGF), 93–94
first used, 4t toxic epidermal necrolysis vascular endothelial growth fac- X
ocular toxicity of, 372t (TEN), 238t tor (VEGF) inhibitors. See
pulmonary toxicity of, 290 toxic erythema of chemotherapy also specific drugs xerosis, 236t, 245t
sexuality alterations with, 385 (TEC), 249, 249f cardiotoxicity of, 269t
targeted therapies. See also bio- toxin-conjugated molecules, 59 vascular endothelial growth fac-
therapeutic agents; bio- transient erythema/urticar- tor receptor (VEGFR), 93 Z
therapy ia, 240t vemurafenib, 90t, 92
characteristics of, 60, 68t– trastuzumab, 58, 77t venlafaxine, 385 ziv-aflibercept, 91t
91t, 93f cardiotoxicity of, 265t, 280, venous irritation, 155–163, 157t cardiotoxicity of, 263t
ocular toxicity of, 373t 285, 285t venous thromboembolism zoledronic acid, nephrotoxici-
pulmonary toxicity of, 304t– nausea/vomiting from, 196t (VTE), 274–275 ty of, 334t
306t pulmonary toxicity of, 301t ventricular dilation, 277 Zubrod scale, 10, 11t
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