ASCO

Metastatic Pancreatic Cancer: ASCO

Guideline Update
special articles
Davendra P.S. Sohal, MD, MPH1; Erin B. Kennedy, MHSc2; Pelin Cinar, MD, MS3; Thierry Conroy, MD4; Mehmet S. Copur, MD5;
Christopher H. Crane, MD6; Ignacio Garrido-Laguna, MD, PhD7; Michelle W. Lau, MD8; Tyler Johnson, MD9; Smitha Krishnamurthi, MD10;
Cassadie Moravek, BS11; Eileen M. O’Reilly, MD6; Philip A. Philip, MD, PhD12; Shubham Pant, MD13; Manish A. Shah, MD14;
Vaibhav Sahai, MBBS, MS15; Hope E. Uronis, MD, MHS16; Neeha Zaidi, MD17; and Daniel Laheru, MD18
abstract

PURPOSE The aim of this work was to provide an update to the ASCO guideline on metastatic pancreatic cancer
pertaining to recommendations for therapy options after first-line treatment.
METHODS ASCO convened an Expert Panel and conducted a systematic review to update guideline recom-
mendations for second-line therapy for metastatic pancreatic cancer.
RESULTS One randomized controlled trial of olaparib versus placebo, one report on phase I and II studies of
larotrectinib, and one report on phase I and II studies of entrectinib met the inclusion criteria and inform the
guideline update.
RECOMMENDATIONS New or updated recommendations for germline and somatic testing for microsatellite
instability high/mismatch repair deficiency, BRCA mutations, and TRK alterations are provided for all treatment-
eligible patients to select patients for recommended therapies, including pembrolizumab, olaparib, larotrectinib,
or entrectinib, or potential clinical trials. The Expert Panel continues to endorse the remaining recommendations
for second-line chemotherapy, as well as other recommendations related to treatment, follow-up, and palliative
care from the 2018 version of this guideline. Additional information is available at www.asco.org/gastrointestinal-
cancer-guidelines.
J Clin Oncol 38. © 2020 by American Society of Clinical Oncology
ASSOCIATED
CONTENT
Appendix INTRODUCTION progression or intolerable toxicity with first-line ther-
Data Supplement
There were an estimated 57,600 new cases and apy, including the addition of pembrolizumab as an
Author affiliations
47,050 deaths as a result of pancreatic cancer in the option for mismatch repair–deficient or microsatellite
and support instability–high tumors, as well as associated testing
information (if United States in 2020,1 and an estimated 460,000
new cases worldwide in 2018.2 A diagnosis of pan- recommendations.5
applicable) appear
at the end of this creatic ductal adenocarcinoma is associated with poor
article.
The previous version of this ASCO guideline, pub-
prognosis as a result of early micrometastatic spread,
Accepted on May 11,
lished in 2018, included 7 moderate-strength rec-
and the 5-year survival rate for metastatic pancreatic
2020 and published at ommendations for second-line therapy that were
cancer is approximately 2.9%.3
ascopubs.org/journal/ based on lower-quality evidence.5 This 2020 update
jco on August 5, The first ASCO guideline for clinical decision making of the 2018 recommendations was triggered by new
2020: DOI https://doi. for patients with metastatic pancreatic cancer was evidence for poly (ADP-ribose) polymerase (PARP)
org/10.1200/JCO.20.
01364
published in 2016 and included recommendations inhibitor olaparib as an option for maintenance
Clinical Practice
for initial assessment after diagnosis, first- and therapy after first-line treatment, as well as new
Guidelines second-line treatment options, palliative and sup- studies of tissue agnostic agents that target fusions of
Committee approval: portive care, and follow-up after treatment.4 ASCO the neurotrophin tyrosine receptor kinase (NTRK) 1/
April 22, 2020 guidelines are assessed annually for potential 2/3 genes. In addition, the Expert Panel considered
Reprint Requests: updating, or an update can be triggered whenever that these newer agents have been approved by the
2318 Mill Rd, Suite new potentially practice-changing evidence is US Food and Drug Administration (FDA) for use in the
800, Alexandria, VA
22314; e-mail:
published. In 2018, new evidence triggered a fo- target population.6-8 It is duly noted that overall evi-
guidelines@ cused update of the recommendations for second- dence was limited in terms of the number of studies
asco.org. line therapy for patients who had experienced and patients with pancreatic cancer in these studies,

1
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Copyright © 2020 American Society of Clinical Oncology. All rights reserved.
 Sohal et al

THE BOTTOM LINE

Metastatic Pancreatic Cancer: ASCO Guideline Update
Guideline Question
The purpose of this focused update is to incorporate new evidence that is relevant to Clinical Question 3 from previous versions
of this guideline4,5: What is the appropriate therapy for patients with metastatic pancreatic cancer who experience either
disease progression or intolerable toxicity with prior regimens? For this guideline update, the Expert Panel also included studies
of maintenance treatment after first-line therapy.
Target Population
Patients with metastatic pancreatic adenocarcinoma
Target Audience
Medical oncologists, radiation oncologists, surgeons, gastroenterologists, and pathologists
Methods
An Expert Panel was convened to develop updated clinical practice guideline recommendations based on a focused sys-
tematic review of the medical literature related to second- or greater-line therapy. On the basis of a systematic evidence review,
recommendations 1.5, 3.1, and 3.3 were added. Minor modifications were made to recommendations 2.3, 3.5, and 3.7 based
on Expert Panel consensus. All other recommendations from the previous version (2018)5 of this guideline are endorsed for
this 2020 update. New recommendations or changes to the 2018 recommendations are denoted by bold, italicized text. The
full guideline text contains definitions of favorable and relatively favorable comorbidity profiles.
Recommendations
1. Initial Assessment
Recommendation 1.1. A multiphase computed tomography scan of the chest, abdomen, and pelvis should be performed
to assess the extent of disease. Other staging studies should be performed only as dictated by symptoms (Type:
evidence based, benefits outweigh harms; Evidence quality: intermediate; Strength of recommendation: strong).
Recommendation 1.2. The baseline performance status (PS), symptom burden, and comorbidity profile of a patient with
metastatic pancreatic cancer should be evaluated carefully (Type: evidence based, benefits outweigh harms; Evidence
quality: intermediate; Strength of recommendation: strong).
Recommendation 1.3. The goals of care (to include a discussion of an advance directive), patient preferences, and
support systems should be discussed with every patient with metastatic pancreatic cancer and his or her caregivers
(Type: evidence based, benefits outweigh harms; Evidence quality: intermediate; Strength of recommendation: strong).
Recommendation 1.4. Multidisciplinary collaboration to formulate treatment and care plans and disease management for
patients with metastatic pancreatic cancer should be the standard of care (Type: evidence based, benefits outweigh
harms; Evidence quality: intermediate; Strength of recommendation: strong).
Recommendation 1.5. Early testing for actionable genomic alterations is recommended for patients who are likely to be
potential candidates for additional treatment after first-line therapy. Both germline and tumor (somatic) testing are
recommended. This includes testing for microsatellite instability/mismatch repair deficiency, BRCA mutations (excluding
variants of unknown significance), and NTRK gene fusions. Results of testing can lead to therapies, such as poly (ADP-
ribose) polymerase inhibitors, programmed death-1 checkpoint inhibitor therapy, TRK fusion inhibitors, and clinical trials
of targeted therapies. Genomic testing is recommended as part of an initial assessment to ensure that the results of testing
are available at the time of treatment decision where applicable after first-line therapy (see 3. Treatment Options After
First-Line Therapy; Type: informal consensus; Strength of recommendation: strong).

Qualifying statement. The decision to test for actionable genomic alterations should involve a discussion between the patient
and physician regarding the frequency of actionable findings, treatment implications of testing results, and genetic counseling
related to germline testing. ASCO has previously developed a provisional clinical opinion on Evaluating Susceptibility to
Pancreatic Cancer that contains recommendations for germline genetic testing.10
Recommendation 1.6. Every patient with pancreatic cancer should be offered information about clinical trials, which
include therapeutic trials in all lines of treatment as well as palliative care, biorepository/biomarker, and observational
studies (Type: informal consensus, benefits outweigh harms; Evidence quality: intermediate; Strength of recom-
mendation: strong).
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2 © 2020 by American Society of Clinical Oncology

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 Metastatic Pancreatic Cancer

THE BOTTOM LINE (CONTINUED)

2. First-Line Treatment
Recommendation 2.1. FOLFIRINOX (leucovorin, fluorouracil, irinotecan, and oxaliplatin) is recommended for patients
who meet all of the following criteria: an Eastern Cooperative Oncology Group (ECOG) PS of 0 to 1, favorable comorbidity
profile, patient preference and a support system for aggressive medical therapy, and access to chemotherapy port and
infusion pump management services (Type: evidence based, benefits outweigh harms; Evidence quality: intermediate;
Strength of recommendation: strong).
Recommendation 2.2. Gemcitabine plus nab-paclitaxel is recommended for patients who meet all of the following criteria:
an ECOG PS of 0 to 1, a relatively favorable comorbidity profile, and patient preference and a support system for
relatively aggressive medical therapy (Type: evidence based, benefits outweigh harms; Evidence quality: intermediate;
Strength of recommendation: strong).
Recommendation 2.3. Gemcitabine alone is recommended for patients who have either an ECOG PS of 2 or a comorbidity
profile that precludes more aggressive regimens, and who wish to pursue cancer-directed therapy. The addition of nab-
paclitaxel or capecitabine or erlotinib to gemcitabine may be offered in this setting, with proactive dose and schedule
adjustments to minimize toxicities (Type: evidence based, benefits outweigh harms; Evidence quality: intermediate;
Strength of recommendation: moderate).
Recommendation 2.4. Patients with an ECOG PS of 3 or with poorly controlled comorbid conditions despite ongoing active
medical care should be offered cancer-directed therapy only on a case-by-case basis. Major emphasis should be on
optimizing supportive care measures (Type: evidence based, benefits outweigh harms; Evidence quality: intermediate;
Strength of recommendation: moderate).

3. Treatment Options After First-Line Therapy

Recommendation 3.1. In patients with tumors harboring NTRK fusions, treatment with larotrectinib or entrectinib is recommended
(Type: evidence based; benefits outweigh harms; Evidence quality: low; Strength of recommendation: moderate).
Recommendation 3.2. Programmed death-1 immune checkpoint inhibitor pembrolizumab is recommended as second-
line therapy for patients who have tested positive for mismatch repair deficiency or microsatellite instability high (Type:
evidence based; benefits outweigh harms; Evidence quality: high; Strength of recommendation: strong).
Recommendation 3.3. In patients who have a germline BRCA1 or BRCA2 mutation and who have received first-line platinum-
based chemotherapy without disease progression for at least 16 weeks, options for continued treatment include
chemotherapy or PARP inhibitor olaparib (Type: evidence based; benefits outweigh harms; Evidence quality: low;
Strength of recommendation: moderate).

Qualifying statement. For the group of platinum-sensitive patients included in Recommendation 3.3, the decision to continue
treatment with chemotherapy or proceed to maintenance therapy with olaparib should be based on a discussion between the
patient and the oncologist, including consideration of whether a maximum response and plateau in response to chemotherapy
have been achieved, the level of cumulative toxicities associated with chemotherapy treatment, patient preference, conve-
nience, toxicity, goals of care, cost, and clinical evidence, including a lack of overall survival benefit demonstrated in the POLO
randomized controlled trial11
Recommendation 3.4. Gemcitabine plus nab-paclitaxel may be offered as second-line therapy to patients who meet all of
the following criteria: first-line treatment with FOLFIRINOX, an ECOG PS of 0 to 1, a relatively favorable comorbidity
profile, and patient preference and a support system for aggressive medical therapy (Type: informal consensus,
benefits outweigh harms; Evidence quality: low; Strength of recommendation: moderate).
Recommendation 3.5. Fluorouracil plus nanoliposomal irinotecan, or fluorouracil plus irinotecan where the former
combination is unavailable, is preferred as a second-line therapy for patients who meet all of the following criteria: first-
line treatment with a gemcitabine-based regimen, an ECOG PS of 0 to 1, a relatively favorable comorbidity profile, patient
preference and a support system for aggressive medical therapy, and access to chemotherapy port and infusion pump
management services (Type: informal consensus, benefits outweigh harms; Evidence quality: low; Strength of rec-
ommendation: moderate).
Recommendation 3.6. Fluorouracil plus oxaliplatin may be considered as second-line therapy for patients who meet all of
the following criteria: first-line treatment with gemcitabine plus nab-paclitaxel, an ECOG PS of 0 to 1, a relatively
favorable comorbidity profile, patient preference and a support system for aggressive medical therapy, and access to
chemotherapy port and infusion pump management services (Type: informal consensus, benefits outweigh harms;
Evidence quality: low; Strength of recommendation: moderate).
(continued on following page)

Journal of Clinical Oncology 3

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 Sohal et al

THE BOTTOM LINE (CONTINUED)

Qualifying statement. A phase III trial comparing mFOLFOX6 (infusional fluorouracil, leucovorin, and oxaliplatin) with
fluorouracil plus leucovorin demonstrated a higher rate of grade 3 or 4 adverse events and significantly reduced overall survival
within the mFOLFOX6 arm of the trial12; however, previous phase III data have demonstrated a benefit with the OFF
(oxaliplatin, folinic acid, and fluorouracil) regimen compared with fluorouracil plus leucovorin.5,13 Considering the in-
consistency of these results, although fluorouracil plus nanoliposomal irinotecan is preferred, the Expert Panel continues to
support the use of fluorouracil plus oxaliplatin as an option when availability of fluorouracil plus nanoliposomal irinotecan is
limited or when residual toxicity from first-line therapy or comorbidities preclude the use of fluorouracil plus nanoliposomal
irinotecan.
Recommendation 3.7. Gemcitabine or fluorouracil can be considered as second-line therapy for patients who have either
an ECOG PS of 2 or a comorbidity profile that precludes more aggressive regimens and who wish to pursue cancer-
directed therapy (the addition of nab-paclitaxel to gemcitabine or nanoliposomal irinotecan to fluorouracil may be offered
in this setting, with proactive dose and schedule adjustments to minimize toxicities). (Type: informal consensus, benefits
outweigh harms; Evidence quality: low; Strength of recommendation: moderate).
Recommendation 3.8. No data are available to recommend third-line or greater therapy with a cytotoxic agent. Clinical trial
participation is encouraged (Type: informal consensus, benefits outweigh harms; Evidence quality: low; Strength of
recommendation: moderate).

4. Palliative Care
Recommendation 4.1. Patients with metastatic pancreatic cancer should have a full assessment of symptom burden,
psychological status, and social support as early as possible, preferably at the first visit. In most cases, this assessment
will indicate a need for a formal palliative care consultation and services (Type: evidence based, benefits outweigh
harms; Evidence quality: intermediate; Strength of recommendation: strong).

5. Treatment of Pain and Symptoms

Recommendation 5.1. Patients with metastatic pancreatic cancer should be offered aggressive treatment of the pain and
symptoms of the cancer and/or cancer-directed therapy (Type: evidence based, benefits outweigh harms; Evidence
quality: intermediate; Strength of recommendation: strong).

6. Follow-Up and Surveillance

Recommendation 6.1. For patients on active cancer-directed therapy outside of a clinical trial, imaging to assess first
response should be offered at 2 to 3 months from the initiation of therapy. Computed tomography scans with contrast
are the preferred modality. Thereafter, clinical assessment, conducted frequently during visits for cancer-directed
therapy, should supplant imaging assessment. Routine use of positron emission tomography scans for the man-
agement of patients with pancreatic cancer is not recommended. CA19-9 is not considered an optimal substitute for
imaging for the assessment of treatment response (Type: informal consensus, benefits outweigh harms; Evidence
quality: low; Strength of recommendation: strong).
Recommendation 6.2. No data exist on the duration of cancer-directed therapy. An ongoing discussion of the goals of care
and assessment of treatment response and tolerability should guide decisions to continue or to hold or terminate
cancer-directed therapy (Type: informal consensus, benefits outweigh harms; Evidence quality: low; Strength of
recommendation: strong).

Additional Resources
More information, including a supplement with additional evidence tables, slide sets, and clinical tools and resources, is
available at www.asco.org/gastrointestinal-cancer-guidelines. The Methodology Manual (available at www.asco.org/guideline-
methodology) provides additional information about the methods used to develop this guideline.
ASCO believes that cancer clinical trials are vital to inform medical decisions and improve cancer care, and that all patients
should have the opportunity to participate.

along with the fact that 2 of the 3 included studies were endorse previous ASCO recommendations on first-line
nonrandomized trials. As the signals approach9 did not therapy, palliative and supportive care, and follow-up. A
identify any new information relevant to the other topics summary of all current recommendations is contained in
included in this guideline, the Expert Panel continues to the Bottom Line Box.

4 © 2020 by American Society of Clinical Oncology

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Copyright © 2020 American Society of Clinical Oncology. All rights reserved.
 Metastatic Pancreatic Cancer

GUIDELINE QUESTIONS • Population: adult patients with metastatic pancreatic

This clinical practice guideline update addresses the fol- cancer, or patients with cancer of any site who have
lowing clinical question: After first-line therapy, what is the tested positive for actionable genetic mutations, in-
appropriate maintenance therapy or second-line therapy cluding BRCA1, BRCA2, NTRK 1/2/3, or mismatch
for patients with metastatic pancreatic cancer? Specific repair deficiency or microsatellite instability high, and
populations of interest for this focused guideline update who have undergone first-line therapy. Studies with
include patients who have a germline BRCA mutation or a combination of adult and pediatric patients were
somatic NTRK mutation. considered eligible for inclusion.
• Interventions: systemic therapy, including chemo-
therapy, PARP inhibitor olaparib, pembrolizumab, or
METHODS TRK inhibitors larotrectinib and entrectinib.
Guideline Development Process • Comparisons: other systemic therapy and placebo; no
This systematic review-based guideline product was de- comparison group.
veloped by a multidisciplinary Expert Panel, which included • Outcomes: rates of overall survival (OS), progression-
a patient representative and an ASCO guidelines staff free survival (PFS), objective response, adverse
member with health research methodology expertise events, discontinuation of trial agent, dose reductions,
(Appendix Table A1, online only). The Expert Panel met in and dose modifications.
person and via teleconference and/or webinar and corre- Articles were excluded from the systematic review if they
sponded through e-mail. Based on a consideration of the were meeting abstracts not subsequently published in
evidence, the authors were asked to contribute to the peer-reviewed journals; editorials, commentaries, letters,
development of the guideline, provide critical review, and news articles, case reports, and narrative reviews; and/or
finalize the guideline recommendations. Guideline recom- published in a non-English language. The complete search
mendations were sent for an open comment period of 2 strategy is provided in the Data Supplement.
weeks, allowing the public to review and comment on the
recommendations after submitting a confidentiality agree- Certainty of the evidence (ie, evidence quality) for each
ment. These comments were taken into consideration while outcome was assessed using the Cochrane Risk of Bias
finalizing the recommendations. Members of the Expert tool14 and elements of the GRADE quality assessment and
Panel were responsible for reviewing and approving the recommendations development process.15 To facilitate
penultimate version of the guideline, which was then cir- quality assessment ratings, MAGICApp guideline devel-
culated for external review and submitted to Journal of opment software was used. Within this framework, out-
Clinical Oncology for editorial review and consideration for comes from observational—nonrandomized—studies are
publication. All ASCO guidelines are ultimately reviewed and rated low quality and can subsequently be downgraded or
approved by the Expert Panel and the ASCO Clinical Practice upgraded if factors that affect quality (ie, certainty) are
Guidelines Committee before publication. All funding for the identified.15 GRADE quality assessment labels (ie, high,
administration of the project was provided by ASCO. moderate, low, very low) were assigned for each outcome
by the project methodologist in collaboration with the Expert
A search of PubMed was conducted to capture studies of Panel co-chairs, and reviewed by the full Expert Panel.
systemic therapy published after the last guideline update
(January 2018) to December 31, 2019. For agents that Guideline recommendations are crafted, in part, using
were not included in the 2018 update search, the search the Guidelines into Decision Support methodology and
was conducted from July 2015 (final search date of the accompanying BRIDGE-Wiz software.16 In addition, a
original guideline) to December 31, 2019—these agents guideline implementability review is conducted. Based on
include PARP inhibitor olaparib and the NTRK inhibitors the implementability review, revisions were made to the
larotrectinib and entrectinib. Eligible study designs in- draft to clarify recommended actions for clinical practice.
cluded phase III randomized controlled trials (RCTs) for Ratings for the type and strength of recommendation,
studies of systemic therapy and olaparib, and phase I to III evidence, and potential bias are provided with each
trials for studies of larotrectinib and entrectinib. Studies for recommendation.
which the sole purpose was determination of optimal ther-
The ASCO Expert Panel and guidelines staff will work with
apeutic dose were excluded. The Expert Panel also planned
co-chairs to keep abreast of any substantive updates to the
to examine the testing methods used in the included studies
guideline. Based on formal review of the emerging litera-
to inform a potential update of informal consensus-based
ture, ASCO will determine the need for subsequent up-
Recommendation 3.1 for biomarker testing.
dates. The ASCO Guidelines Methodology Manual (available
In summary, the PICO (population, interventions, com- at www.asco.org/guideline-methodology) provides additional
parisons, outcomes) elements that informed the search information about the guideline update process. This is the
strategy were as follows: most recent information as of the publication date.

Journal of Clinical Oncology 5

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Copyright © 2020 American Society of Clinical Oncology. All rights reserved.
 Sohal et al

Definitions assumes no responsibility for any injury or damage to

A favorable comorbidity profile is loosely defined as he- persons or property arising out of or related to any use of
moglobin $ 10 g/dL and platelet count $ 100,000/mL this information, or for any errors or omissions.
without transfusion support; absolute neutrophil count Guideline and Conflicts of Interest
$ 1,500/mL; bilirubin and international normalized ratio
# 1.5 times the upper limit of normal; albumin $ 3 g/dL; The Expert Panel was assembled in accordance with
creatinine clearance $ 60 mL/min/1.73 m2; and absence ASCO’s Conflict of Interest Policy Implementation for
of comorbid conditions that require ongoing active medical Clinical Practice Guidelines (“Policy,” found at http://
care, such as congestive heart failure, chronic obstructive www.asco.org/rwc). All members of the Expert Panel
pulmonary disease, uncontrolled diabetes mellitus, and completed ASCO’s disclosure form, which requires dis-
neurologic disorders. A relatively favorable comorbidity closure of financial and other interests, including re-
profile is loosely defined as hemoglobin $ 9 g/dL and lationships with commercial entities that are reasonably
platelet count $ 75,000/mL without transfusion support; likely to experience direct regulatory or commercial impact
absolute neutrophil count $ 1,500/mL; bilirubin and in- as a result of promulgation of the guideline. Categories for
ternational normalized ratio # 1.5 times the upper limit of disclosure include employment; leadership; stock or other
normal; albumin $ 3 g/dL; creatinine clearance $ 60 mL/min/ ownership; honoraria, consulting or advisory role; speaker’s
1.73m2; and absence of poorly controlled comorbid bureau; research funding; patents, royalties, other in-
conditions, such as congestive heart failure, chronic tellectual property; expert testimony; travel, accommoda-
obstructive pulmonary disease, uncontrolled diabetes tions, expenses; and other relationships. In accordance
mellitus, and neurologic disorders. with the Policy, the majority of the members of the Expert
Panel did not disclose any relationships constituting
Guideline Disclaimer a conflict under the Policy.
The Clinical Practice Guidelines and other guidance
published herein are provided by the American Society of RESULTS
Clinical Oncology, Inc. (ASCO) to assist providers in clinical
decision making. The information herein should not be Characteristics of Included Studies
relied upon as being complete or accurate, nor should it be Three studies met eligibility criteria and form the evidentiary
considered as inclusive of all proper treatments or methods basis for this focused guideline update. Nonrandomized
of care or as a statement of the standard of care. With the studies include Drilon et al,17 which is a basket trial of 55
rapid development of scientific knowledge, new evidence patients with TRK fusion-positive cancers from 3 phase I or
may emerge between the time information is developed phase II single-arm studies of larotrectinib across multiple
and when it is published or read. The information is not disease sites, and a report by Doebele et al18 of 55 patients
continually updated and may not reflect the most recent from the ALKA-372-001 and STARTRK-1 phase I and
evidence. The information addresses only the topics spe- STARTRK-2 phase II trials of entrectinib. These 2 studies
cifically identified therein and is not applicable to other included 1 and 3 patients with pancreatic cancer, re-
interventions, diseases, or stages of diseases. This in- spectively. The POLO phase III RCT of olaparib compared
formation does not mandate any particular course of with placebo11 was conducted in 154 patients with met-
medical care. Further, the information is not intended to astatic pancreatic adenocarcinoma who had undergone at
substitute for the independent professional judgment of the least 16 weeks of platinum-based chemotherapy and who
treating provider, as the information does not account for had tested positive for a germline BRCA1 or BRCA2 mu-
individual variation among patients. Recommendations tation. Key characteristics of these studies are included
reflect high, moderate, or low confidence that the rec- in Table 1, and additional description is included in the
ommendation reflects the net effect of a given course of Recommendations section.
action. The use of words like “must,” “must not,” “should,”
and “should not” indicates that a course of action is rec- Assessment of Data Quality
ommended or not recommended for either most or many Outcomes from the included RCTs were initially rated as
patients, but there is latitude for the treating physician to high quality and downgraded as quality issues were
select other courses of action in individual cases. In all identified. Phase I or II trials, as a result of the non-
cases, the selected course of action should be considered randomized study design, were initially rated as low quality,
by the treating provider in the context of treating the in- and quality was downgraded for such issues as small study
dividual patient. Use of the information is voluntary. ASCO size and industry funding. Where appropriate, evidence
provides this information on an “as is” basis and makes no quality was upgraded because of a large magnitude of
warranty, express or implied, regarding the information. effect. More details regarding the reasons for quality (ie,
ASCO specifically disclaims any warranties of merchant- certainty) ratings for the evidence are included in the
ability or fitness for a particular use or purpose. ASCO footnotes to Tables 2 to 4.

6 © 2020 by American Society of Clinical Oncology

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 Journal of Clinical Oncology
TABLE 1. Characteristics of Included Studies
Primary Study End
Study Study Population No. of Patients Intervention Comparator Point(s) Biomarker Testing Method(s)
17
Drilon et al (phase I/II Locally advanced or metastatic 55 (8 adults and 12 pediatric Larotrectinib (orally, 100 mg No comparator Overall (complete and TRK fusions were identified using
study) NTRK fusion-positive tumors patients from the phase I twice daily for adults or partial) response rate NGS (50 patients) or FISH (5
(age 4 months to 76 years) trial; 35 adults and children with a BSA $ patients) as routinely obtained
previously treated with therapy adolescents from the 1 m2) by each participating site
other than kinase inhibitors phase II trial); 1 patient
(where available); ECOG PS 0- with pancreatic cancer
2 (ECOG PS 0-3 were eligible)
Doebele et al18 ALKA- Locally advanced or metastatic 54 patients with advanced or Entrectinib (orally, at least No comparator Objective response rate Patients enrolled on the basis of
372-001 (phase I), NTRK fusion-positive solid metastatic NTRK fusion- 600 mg once per day in and median duration local testing, including FISH,
STARTRK-1 (phase I), tumors; ECOG PS 0-2; positive solid tumors (6%; capsule form) of response quantitative PCR, or DNA-
STARTRK-2 (phase II minimum life expectancy of 3 patients with pancreatic based or RNA-based NGS;
global basket study) 3 months (ALKA or STARTRK- cancer); 51 patients from STARTRK-2 phase II study
1) or 4 weeks (STARTRK-2) STARTRK-2; 2 patients patients required to provide
and adequate organ function from STARTRK-1; 1 tumor tissue for NGS
patient from ALKA-372-
001
Golan et al11 (phase III Patients with platinum-sensitive 154 patients Maintenance therapy with Placebo Progression-free survival “[D]etection of a germline BRCA
POLO trial, 119 sites, metastatic pancreatic cancer olaparib tablets (300 mg mutation by central testing
12 countries) and germline BRCA1 or twice daily) with the use of the
Metastatic Pancreatic Cancer

BRCA2 mutations who BRACAnalysis CDx text

received at least 16 weeks of (Myriad Genetic Laboratories)
platinum-based or by local testing with
chemotherapy (therapy subsequent confirmation with
continued as long as there was the use of BRACAnalysis CDx
no evidence of disease test after randomization”
progression)

Copyright © 2020 American Society of Clinical Oncology. All rights reserved.

Abbreviations: BSA, body surface area; ECOG PS, Eastern Cooperative Oncology Group performance status; FISH, fluorescence in situ hybridization; NGS, next-generation sequencing; PCR, polymerase

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chain reaction.

7
 Sohal et al

TABLE 2. Study Outcomes: Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children
Certainty of the
Evidence (quality of
Outcome Study Results evidence) Plain Text Summary
Overall response rate ORR: 75%a (95% CI, 61% to 85%; pre-established lower Low (1, 2) Larotrectinib may improve overall
(primary outcome)a boundary of 30% ruled out); 13% complete response response for patients with TRK
(95% CI, 6% to 25%); 62% partial response (95% CI, fusion-positive tumors
49% to 75%); 13% stable disease (95% CI, 6% to 25%);
9% progressive disease (95% CI, 3% to 20%); 4% early
withdrawal because of clinical deterioration (95% CI,
0.5% to 13.5%)
Progression-free 55% progression-free at 1 year (95% CI, 42% to 67%) Low (1, 2) Larotrectinib may improve progression-
survival free survival for patients with TRK
fusion-positive tumors
Most common grade 3-4 1,038 events occurred among 55 patients (93% grade 1 or 2; Very low (1) Larotrectinib may result in adverse
adverse events 7% grade 3 or 4): events for patients with TRK fusion-
positive tumors
Anemia (11%)
Increased level of ALT or AST (7%)
Weight increase (7%)
Decreased neutrophil count (7%)
Drug reductions or 15% had dose reductions related to adverse events; no Very low (1) Larotrectinib may result in dose
discontinuations discontinuations as a result of drug-related adverse events reductions for patients with TRK
were recorded fusion-positive tumors

NOTE. Results from Drilon et al.17 (1) Downgrade: commercially funded; indirectness: locally advanced included. (2) Upgrade: large magnitude of effect.
Population: Fifty-five patients with TRK fusion-positive locally advanced or metastatic tumors, including 1 patient with pancreatic cancer. Intervention:
Larotrectinib (20 patients treated in dose-escalation study and 35 treated at a therapeutic dose of 100 mg orally twice daily). Comparator: no comparator arm.
ALT, alanine aminotransferase; AST, aspartate aminotransferase.
a
Independently assessed according to the RECIST version 1.1.19 Overall response rate: sum of complete and partial responses.19

2020 NEW OR UPDATED RECOMMENDATIONS genetic counseling related to germline testing. ASCO has
The following section contains a summary of new or previously developed a provisional clinical opinion (PCO),
substantially updated recommendations, incorporating the Evaluating Susceptibility to Pancreatic Cancer, which
results of the literature that met the inclusion criteria of the contains recommendations for germline genetic testing.10
systematic review. Literature review update and analysis. This recommenda-
Recommendation 1.5 tion is based on informal consensus of the Expert Panel.
Because a proportion of patients, albeit small, with meta-
Early testing for actionable genomic alterations is recom- static pancreatic cancer have targetable genomic alter-
mended for patients who are likely to be potential candi- ations, the Expert Panel recognizes the need for biomarker
dates for additional treatment after first-line therapy. Both testing to identify appropriate candidates for targeted
germline testing and tumor (somatic) testing are recom- therapies included in Recommendations 3.1 to 3.3. Ad-
mended. This includes testing for microsatellite instability/ ditional guidance for evaluating susceptibility to pancreatic
mismatch repair deficiency, BRCA mutations (excluding cancer with germline genetic testing is available in a sep-
variants of unknown significance), and NTRK gene fusions. arate ASCO PCO.10
Results of testing can lead to therapies, such as PARP
inhibitors, programmed death-1 checkpoint inhibitor Recommendation 3.1
therapy, TRK fusion inhibitors, and clinical trials of targeted In patients with tumors harboring NTRK fusions, treatment
therapies. Genomic testing is recommended as part of an with larotrectinib or entrectinib is recommended (Type:
initial assessment to ensure that the results of testing are evidence based; benefits outweigh harms; Evidence
available at the time of treatment decision where applicable quality: low; Strength of recommendation: moderate).
after first-line therapy (see 3. Treatment Options After First-
Literature review and analysis. Larotrectinib in TRK
line Therapy; Type: informal consensus; Strength of rec-
fusion-positive cancers. Drilon et al17 studied TRK fusion
ommendation: strong).
inhibitor larotrectinib in 55 patients age 4 months to
Qualifying statement. The decision to test for actionable 76 years with TRK fusion-positive locally advanced or
genomic alterations should involve a discussion between the metastatic tumors who had received treatment with therapy
patient and physician regarding the frequency of actionable other than kinase inhibitors (where available). Twelve dif-
findings, treatment implications of testing results, and ferent tumor disease sites were represented, including 1

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 Metastatic Pancreatic Cancer

TABLE 3. Study Outcomes: Entrectinib in Patients With Advanced or Metastatic NTRK Fusion-Positive Solid Tumors: Integrated Analysis of Three Phase I-II
Trials
Certainty of the
Evidence (quality of
Outcome/Timeframe Study Results the evidence) Plain Text Summary
ORR (coprimary end point) ORR: 31 of 54 (57%; 95% CI, 43.2% to 70.8%), 4 CR Moderate (1, 2) Entrectinib may improve ORR
median follow-up, 12.9 months (7%), 27 PR (50%), 9 SD (17%); 2 of 3 patients with (coprimary end point)
pancreatic cancer experienced PR by RECIST v1.1
(67%; 95% CI, 9% to 99%)
Median duration of response By blinded independent review: 10.4 months (95% CI, Low (1) Entrectinib may improve duration
(coprimary end point) 7.1 months to not estimable) of response (coprimary end
point)
Median progression-free survival Median PFS: 11.2 months (95% CI, 8.0 to 14.9 months) Low (1) Entrectinib may improve
progression-free survival
Median overall survival 21 months (95% CI, 14.9 months to not estimable) Low (1) Entrectinib may improve overall
survival
Most common grade 3-4 adverse Anemia (12%), increased weight (10%), fatigue (7%) Very low (1) Entrectinib may worsen adverse
events in NTRK fusion-positive events
safety population
Dose modifications Treatment discontinuations (4%), dose interruptions Very low (1) Entrectinib may result in dose
(31%), dose reductions as a result of treatment-related modifications, interruptions,
adverse events (40%); the latter were most commonly and reductions
because of anemia (7%), increased blood creatinine
levels (6%), and fatigue (6%)

NOTE. Results from Doebele et al.18 (1) Downgrade: risk of bias, population dissimilarity (locally advanced included), low number of patients (3 of 54
patients with pancreatic cancer), commercially funded. (2) Upgrade: large magnitude of effect. Population: 54 patients with NTRK fusion-positive patients
with solid tumors, including 3 patients with pancreatic cancer. Intervention: entrectinib (600 mg orally daily). Comparator: no comparator.
Abbreviations: CR, complete response; ORR, objective response rate; PR, partial response; SD, stable disease.

patient with pancreatic cancer, and 51% of patients had rate, the primary end point, was 57% (95% CI, 43.2% to
received at least 2 prior systemic chemotherapies. Genes 70.8%), including 4 complete responses and 27 partial
included NTRK1 (45%), NTRK2 (2%), and NTRK3 (53%). responses. Two of 3 patients with pancreatic cancer
TRK fusions were identified using next-generation se- achieved a partial response. The outcome in the overall
quencing (50 patients) or fluorescence in situ hybridization study population exceeded the prespecified lower clinically
(5 patients) as routinely obtained by each participating site. meaningful boundary of 30%. The second primary end
The primary study outcome was overall rate of response, point, median duration of response, was 10 months. Me-
which was 75% (95% CI, 61% to 85%) and exceeded dian PFS and OS were 11 months (95% CI, 8.0 months to
a pre-established lower boundary of 30%. Thirteen percent 14.9 months) and 21 months (95% CI, 14.9 months to not
of patients experienced complete response and 62% ex- estimable), respectively. Analyses were also conducted in
perienced partial response (Table 2). The patient with a safety population that included 68 NTRK fusion-positive
pancreatic cancer achieved a partial response. In addition, patients who had received at least 1 dose of entrectinib.
73% of patients were progression free at 6 months and Within this population, most treatment-related adverse
55% were progression free at 1 year. Adverse events were events were grade 1 and 2 and reversible; 10% of patients
most commonly grade 1 or 2. The most frequent grade 3 reported serious adverse events. In addition, results were
adverse event was anemia (15%). reported for a larger safety population that included patients
with any gene rearrangement and tumor type and at least 1
Entrectinib in patients with advanced or metastatic NTRK dose of entrectinib. Overall, the results in this larger safety
fusion-positive solid tumors. Data from 3 patients in the population were consistent with the safety profile of NTRK
STARTRK-1 and ALKA-1-372-011 trials who had solid fusion-positive safety population.
tumors, NTRK molecular alterations, and were considered
phase II eligible—that is, solid tumors, RECIST measurable Clinical interpretation. Several quality considerations were
disease, no prior tyrosine kinase inhibitor treatment tar- identified for the outcomes of studies of larotrectinib and
geting the fusion of interest, and treatment consistent with entrectinib, which resulted in the downgrading of study
the established phase II dose of 600 mg/m2 of entrectinib quality. These included the small overall study sample sizes
daily—were combined in an analysis with 51 patients from and even fewer patients with pancreatic cancer, inclusion
the STARTRK-2 phase II trial (Table 3). Objective response of locally advanced patients, and risk of bias associated with

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 Sohal et al

TABLE 4. Study Outcomes: Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer
Absolute Effect
Estimate Certainty of the
Study Results and Evidence (quality of
Outcome/Timeframe Measurements Placebo Olaparib evidence) Plain Text Summary
Progression-free survival Hazard ratio, 0.53 (95% CI, 904 per 711 per Moderate (1, 4) Olaparib probably improves progression-
(primary outcome) 0.35 to 0.82) 1,000 1,000 free survival (primary outcome)
Based on data from 154 Difference: 193 fewer
patients in 1 study; follow-up, per 1,000 (95% CI,
24 months 344 fewer to 50
fewer)
Overall survival Hazard ratio, 0.91 (95% CI, 640 per 605 per Moderate (1, 2) Olaparib may have little or no difference
0.56 to 1.46) 1,000 1,000 on overall survival
Based on data from 154 Difference: 35 fewer
patients in 1 study Follow-up per 1,000 (95% CI,
24 months 204 fewer to 81
more)
Response rate Odds Ratio: 2.3 (95% CI, 0.89 100 per 204 per Very low (1, 3) Olaparib may have little or no difference
to 6.76) 1000 1,000 on response rate
Based on data from 154 Difference: 104 more
patients in 1 study per 1,000 (95% CI,
10 fewer to 329
more)
Serious adverse events Relative risk, 1.56 (95% CI, 150 per 234 per Low (1) Olaparib may worsen serious adverse
0.76 to 3.16) 1,000 1,000 events
Based on data from 151 Difference: 84 more
patients in 1 study per 1,000 (95% CI,
36 fewer to 324
more)
Discontinuation of trial agent Relative risk, 3.3 (95% CI, 0.39 17 per 56 per Very low (1, 3) Olaparib may increase the risk of
as a result of adverse events to 27.5) 1,000 1,000 discontinuation of trial agent because
of adverse events
Based on data from 151 Difference: 39 more
patients in 1 study per 1,000 (95% CI,
10 fewer to 451
more)

NOTE. Results from Golan et al.11 (1) Downgrade: only one study, commercially funded. (2) Based on an interim analysis; however, Expert Panel members
agreed that this result can be considered moderately certain to be corroborated by final study results. (3) Imprecision: wide confidence interval. (4) Upgrade:
large magnitude of effect. Population: platinum-sensitive patients with metastatic pancreatic adenocarcinoma and a germline BRCA1 or BRCA2 mutation.
Intervention: poly (ADP-ribose) polymerase inhibitor olaparib as maintenance therapy for disease that has not progressed during first-line platinum-based
therapy. Comparator: placebo.

commercial sponsorship. Despite the limitations in quality without experiencing disease progression for at least 16
and certainty of the evidence, the primary outcomes for both weeks, options for continued treatment include chemo-
studies exceeded a prespecified clinically meaningful therapy or PARP inhibitor olaparib (Type: evidence based;
30% threshold for objective response rate by a large margin benefits outweigh harms; Evidence quality: low; Strength of
(75% [95% CI, 61% to 85%] and 57% [95% CI, 43% to recommendation: moderate).
71%] for larotrectinib and entrectinib, respectively). In ad-
dition, results for PFS and/or OS in these studies compared Qualifying statement. For the group of platinum-sensitive
favorably with results published in previous trials, including patients included in Recommendation 3.3, the decision to
a meta-analysis that demonstrated OS of 6 months with continue treatment with chemotherapy or to proceed to
chemotherapy and 2.8 months with best supportive maintenance therapy with olaparib should be based on
care.4,5,20 The adverse events profiles associated with these a discussion between the patient and oncologist, including
agents were found to be manageable (Tables 2 and 3). consideration of whether a maximum response and plateau
in response to chemotherapy have been achieved, level of
Recommendation 3.3 cumulative toxicities associated with chemotherapy treat-
In patients who have a germline BRCA1 or BRCA2 mutation ment, patient preference, convenience, toxicity, goals of
and have received first-line platinum-based chemotherapy care, cost, and clinical evidence, including a lack of OS

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 Metastatic Pancreatic Cancer

benefit demonstrated in the POLO randomized controlled Results for therapy options larotrectinib and entrectinib
trial.11 have been incorporated in this update. Larotrectinib was
Literature review and analysis. The phase III POLO RCT approved in November 2018 by the FDA as a disease-site
included patients with metastatic pancreatic cancer and agnostic option for solid tumors with NTRK fusions.6
a germline BRCA1 or BRCA2 mutation, which were Entrectinib was also approved by the FDA in August 2019
identified via central testing with the use of the BRACA- for this indication, as well as for ROS1-positive metastatic
nalysis CDx test or by local testing and confirmation of non–small-cell lung cancer when no other effective treat-
positive results using BRACAnalysis. Maintenance olaparib ment options are available and for which first-line therapy
was initiated 4 to 8 weeks after the completion of at least has not been effective.7 These approvals were based on
16 weeks of continuous first-line platinum-based chemo- evidence from basket trials in which efficacy of treatment of
therapy without evidence of disease progression or dis- a specific genomic alteration is evaluated regardless of tumor
continuation because of toxicity (the platinum component site.21 These trials did not include a comparator group, and
of therapy could be discontinued as a result of toxicity after recommendations for these interventions are based on the
16 weeks).11 Nearly one half of patients (49.4%) achieved large magnitude of the objective response rate for laro-
a complete or partial response to first-line platinum-based trectinib (75%)17 and entrectinib (57%),18 which exceeded
therapy. Radiologic disease progression was determined the predetermined minimum response rate of 30% that
using modified RECIST version 1.1.19 The primary outcome investigators agreed would indicate a clinically meaningful
was PFS, and OS, response rates, and adverse events were benefit. In addition, adverse events were largely grade 1 and
also evaluated. PFS was significantly better for patients 2 and manageable with dose modifications. Doebele et al18
assigned to olaparib compared with placebo (hazard ratio, note that comparisons between trials of larotrectinib and
0.53 [95% CI, 0.35 to 0.82]). There were no significant entrectinib are difficult because of differences between
differences between groups for OS, response rate, rate of patient populations and study design, and acknowledge that
serious adverse events, or discontinuation of therapy as some tumor types are less responsive and that more of these
a result of adverse events; however, the quality of these were included in the entrectinib trials, which could account
outcomes was rated as low to very low (ie, high uncertainty; for the lower objective response rate.
Table 1). PARP inhibitor olaparib is a recommended treatment op-
Clinical interpretation. The POLO phase III RCT demon- tion as maintenance therapy, based on a statistically sig-
strated a statistically significant improvement in the primary nificant benefit in PFS compared with placebo. Olaparib
study outcome of PFS. There was no difference in OS was approved by the FDA on December 27, 2019, for the
between groups in an analysis that was performed at data maintenance treatment of adult patients with germline
maturity of 46%. Patients receiving olaparib were more BRCA mutations and metastatic pancreatic adenocarci-
likely to experience serious adverse events and/or dis- noma whose disease has not progressed on at least
continue participation in the trial because of adverse events 16 weeks of first-line platinum-based chemotherapy.8
compared with placebo; however, these differences were In addition, while this targeted update considered only new
not statistically significant. Based on the large magnitude of evidence for recommendations for treatment after first-line
PFS benefit, the Expert Panel concluded that olaparib may therapy, the Expert Panel is aware of new evidence in the
be recommended as an option for maintenance therapy for first-line setting, such as data from the FRAGRANCE trial of
patients with metastatic pancreatic cancer and an identi- the efficacy and safety of nab-paclitaxel in combination with
fied germline BRCA mutation. No head-to-head compari- gemcitabine in patients with Eastern Cooperative Oncology
son of chemotherapy and PARP inhibitors was available to Group performance status of 2.22 In response to this, minor
inform a recommendation for a preferred option; therefore, modifications to Recommendations 2.3, 3.7, and 3.9 were
clinicians are advised to engage in shared decision making also included, based on the consensus of the Expert Panel
with patients, considering the factors outlined in the members.
qualifying statement after Recommendation 3.3.
Biomarker Testing
DISCUSSION In conjunction with the recommendation for these newer
This focused update to the ASCO Metastatic Pancreatic agents, this guideline update includes a modification to the
Cancer guideline includes new evidence for targeted recommendation for molecular testing to include testing for
therapy options after first-line therapy for disease that has biomarkers used to select patients for therapy. This rec-
progressed, intolerable toxicity, or as maintenance therapy ommendation was consensus based. In the case of the
after a response. Since the time of previous update of this recommendation for the treatment of NTRK fusion positive
guideline in 2018, new evidence has been published for cancers, the Expert Panel acknowledged the low preva-
targeted agents that may provide clinical benefit to this lence of NTRK fusions (ie, approximately 0.34% in patients
patient population, and the FDA has approved new therapy with pancreatic cancer),23,24 but agreed that the high rate of
options for the target patient population. response provided justification for testing all patients who

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 Sohal et al

are considered to be candidates for treatment. The Expert discussions. Providers should ask patients about their
Panel recognized the challenges of implementing this personal goals and preferences. What do they hope for?
testing recommendation, including accessibility and cost— What is important to them in their personal lives? What do
many third-party payors in the United States and in- they value more: an extension of life or maintenance of the
ternational markets (eg, France) may not reimburse ade- best possible quality of life? An understanding of a patient’s
quately for such testing. There are various complexities specific goals should shape conversations about the goals
associated with testing for NTRK fusions and options for of care and treatment recommendations.
testing, including DNA- or RNA-level sequencing, or im-
Providers should also describe the potential impact (both
munohistochemistry.23 Each of these options has advan-
medical and emotional aspects) of genetic testing on both
tages under different circumstances and for different tumor
the patient with pancreatic cancer and their family. For the
types. These considerations and others are further
patient, germline testing can indicate potentially beneficial
addressed in Patient and Clinician Communication. A
treatment options while also identifying a potential risk of
complete discussion of a molecular biomarker testing al-
pancreatic cancer and other cancers for their family. For ad-
gorithm for metastatic pancreatic adenocarcinoma is out-
ditional recommendations and strategies to optimize patient-
side the scope of this guideline. Recommendations for
clinician communication regarding germline testing see
germline genetic testing are contained in the ASCO PCO,
ASCO’s PCO, Evaluating Susceptibility to Pancreatic Cancer.10
Evaluating Susceptibility to Pancreatic Cancer.10
Clinicians should clearly explain all potential treatment
Ongoing Research options, the specific somatic and germline testing needed
Patients can acquire resistance to first-generation TRK to determine the appropriateness of those treatment op-
inhibitors. To overcome this, trials of newer agents, such as tions, the potential outcomes of each, and possible adverse
LOXO-195 and TPX-00005, are currently underway.21 events so that patients understand the benefits and
Research is also underway to determine the extent of drawbacks of each option and can make an informed
cancer risk associated with PALB2 (partner and localizer of decision. Treatment discussions should include relevant
BRCA2), which occurs in 3% to 4% of cases of familial clinical trials at every stage of treatment. Patients should
pancreatic cancer.25 have the opportunity to participate in trials for their own
treatment and be given the opportunity to contribute to
PATIENT AND CLINICIAN COMMUNICATION research.
Patients with pancreatic cancer face difficult treatment Clinicians should also consider and proactively discuss
decisions while presented with complex medical in- quality-of-life issues. In patients with pancreatic cancer,
formation, especially somatic and germline testing in- dietary concerns, pain, and fatigue are major concerns.
formation, and a life-threatening diagnosis. Communication Dietary issues tend to be overlooked and yet are real
within the context of realistic hope and action between problems, with a significant impact on daily life. Referral to
patients and clinicians can improve patients’ ability to make a registered dietitian and/or gastroenterologist with early
sound, informed decisions within their own personal value intervention can be of great benefit. Clinicians should also
set. Patients should fully understand the goals of care consider the use of, and discuss the possible need for,
before making decisions about somatic and germline pancreatic enzyme replacement therapy.
testing, treatment, and care. Referral to palliative care services can facilitate addressing
Clear communication with patients with pancreatic cancer of the many non–treatment-related issues patients face, and
and their caregivers about the diagnosis, treatment options, this referral should be offered to all patients with pancreatic
and goals of care is key for patient understanding. The cancer, regardless of the stage of disease or expected
importance of both somatic and germline testing and the prognosis. Patients should understand that referral to
implications of testing on treatment options is a conversa- a consultation for palliative care services is not synonymous
tion that should be had soon after the patient’s diagnosis is with a referral to hospice care. This discussion is important
confirmed. The clinician must also balance describing the because palliative care provides important support and can
importance of testing while providing realistic hope around be part of an active cancer treatment paradigm.
the identification of actionable findings. Some actionable Patients must feel comfortable in the choices they make,
mutations are found in a small subset of patients but can and the knowledge that they have explored their options
have meaningful benefit for those patients. The clinician is can bring comfort. As such, clinicians should support
also responsible for offering ancillary support services, which a patient’s desire to get a second opinion. Clinicians should
include a referral to palliative care consultation and services. address the costs of care and offer referrals to specialists
For patients to make informed decisions, providers should within the health care system who can discuss in more
describe the potential impact of the diagnosis of pancreatic detail what a patient should expect as well as resources
cancer on the patient and his or her family. It is important to and information about managing the costs related to
provide realistic hope within honest, yet supportive, cancer care.

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Copyright © 2020 American Society of Clinical Oncology. All rights reserved.
 Metastatic Pancreatic Cancer

The provision of realistic hope to patients with pancreatic suitability of the recommendations to implementation in the
cancer, although the prognosis may be short, is important. community setting, but also to identify any other barrier to
Patients deserve to know that their medical team is working implementation a reader should be aware of. Barriers to
to help them reach their goals. Even if a cure is not possible, implementation include the need to increase awareness of
hope for an extension of life or a good quality of life is the guideline recommendations among front-line practi-
powerful. tioners and survivors of cancer and caregivers, and also to
The provision of resources to help patients communicate provide adequate services in the face of limited resources.
better with their health care team is also advisable. Patients The guideline Bottom Line Box was designed to facilitate
should be offered decision-making tools and be urged to implementation of recommendations. This guideline will be
write down questions between and in advance of ap- distributed widely through the ASCO PGIN. ASCO guide-
pointments. Patients can be referred to resources that will lines are posted on the ASCO website and most often
extend the support and information clinicians are able to published in the Journal of Clinical Oncology.
provide. For pancreatic cancer, two such resources are the ASCO believes that cancer clinical trials are vital to inform
ASCO patient-facing Web site (www.cancer.net) and the medical decisions and improve cancer care, and that all
Pancreatic Cancer Action Network (www.pancan.org). patients should have the opportunity to participate.

EXTERNAL REVIEW AND OPEN COMMENT ADDITIONAL RESOURCES

The draft recommendations were released to the public for More information, including a supplement with additional
open comment from January 15, 2020, through January evidence tables, slide sets, and clinical tools and resources, is
29, 2020. Response categories of “Agree as written,” available at http://www.asco.org/gastrointestinal-cancer-
“Agree with suggested modifications,” and “Disagree. See guidelines. Patient information is available at www.cancer.net.
comments,” were captured for every proposed recom-
mendation with 6 written comments received. A total of
100% of the 6 respondents either agreed or agreed with RELATED ASCO GUIDELINES
slight modifications to the recommendations and none of
• Integration of Palliative Care Into Standard On-
the respondents disagreed. One comment asked “What
cology Practice (http://ascopubs.org/doi/10.1200/
initial assessment is necessary?” in the context of genetic
JCO.2016.70.1474)26
testing, while emphasizing that the results of testing would
• Locally Advanced, Unresectable Pancreatic
not alter the choice of first-line therapy. The Expert Panel
Cancer (http://ascopubs.org/doi/10.1200/JCO.2016.
clarifies that the intention of conducting testing before
67.5561)27
treatment is to have this information available in a timely
• Potentially Curable Pancreatic Adenocarcinoma
manner in the event that it is relevant for the selection of
(https://ascopubs.org/doi/10.1200/JCO.19.00946)28
second-line therapy.
• Evaluating Susceptibility to Pancreatic Cancer
Provisional Clinical Opinion (https://ascopubs.org/
GUIDELINE IMPLEMENTATION
doi/10.1200/JCO.18.01489)10
ASCO guidelines are developed for implementation across • Venous Thromboembolism Prophylaxis and
health settings. Each ASCO guideline includes a member Treatment in Patients With Cancer (https://
from ASCO’s Practice Guideline Implementation Network ascopubs.org/doi/10.1200/JCO.19.01461) 29
(PGIN) on the panel. The additional role of this PGIN
representative on the guideline panel is to assess the

12
AFFILIATIONS Barbara Ann Karmanos Cancer Institute, Farmington Hills, MI
13
1
University of Cincinnati, Cincinnati, OH MD Anderson Cancer Center, Houston, TX
14
2
American Society of Clinical Oncology, Alexandria, VA New York Presbyterian/Weill Cornell Medical Center, New York, NY
15
3
University of California, San Francisco, San Francisco, CA University of Michigan, Ann Arbor, MI
16
4
Université de Lorraine and Institut de Cancérologie de Lorraine, Duke University, Durham, NC
17
Lorraine, France Johns Hopkins Medicine, Baltimore, MD
18
5
Morrison Cancer Center, Hastings, NE Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins,
6
Memorial Sloan Kettering Cancer Center, New York, NY Baltimore, MD
7
Huntsman Cancer Institute, University of Utah School of Medicine, Salt
Lake City, UT CORRESPONDING AUTHOR
8
Phoenix VA Medical Center, Phoenix, AZ Erin B. Kennedy, MHSc, American Society of Clinical Oncology, 2318
9
Stanford University, Palo Alto, CA Mill Rd, Suite 800, Alexandria, VA 22314; e-mail: [email protected].
10
Cleveland Clinic, Cleveland, OH
11
Pancreatic Cancer Action Network, Manhattan Beach, CA D.P.S.S. and D.L. were Expert Panel co-chairs.

Journal of Clinical Oncology 13

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Copyright © 2020 American Society of Clinical Oncology. All rights reserved.
 Sohal et al

EDITOR’S NOTE AUTHOR CONTRIBUTIONS

This American Society of Clinical Oncology (ASCO) Clinical Practice Manuscript writing: All authors
Guideline provides recommendations, with comprehensive review and Final approval of manuscript: All authors
analyses of the relevant literature for each recommendation. Additional Accountable for all aspects of the work: All authors
information, including a supplement with additional evidence tables,
slide sets, clinical tools and resources, and links to patient information at
ACKNOWLEDGMENT
www.cancer.net, is available at www.asco.org/gastrointestinal-
The Expert Panel thanks Dr. Elise C. Kohn, MD and Dr. Matthew B.
cancer-guidelines.
Yurgelun, MD, and the Clinical Practice Guidelines Committee for their
thoughtful reviews and insightful comments on this guideline.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF

INTEREST AND DATA AVAILABILITY STATEMENT
Disclosures provided by the authors and data availability statement (if
applicable) are available with this article at DOI https://doi.org/10.1200/
JCO.20.01364.

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1. Siegel RL, Miller KD, Jemal A: Cancer statistics, 2020. CA Cancer J Clin 70:7-30, 2020
2. World Cancer Research Fund: Pancreatic cancer statistics. https://www.wcrf.org/dietandcancer/cancer-trends/pancreatic-cancer-statistics
3. National Cancer Institute: Cancer stat facts: Pancreatic cancer. https://seer.cancer.gov/statfacts/html/pancreas.html
4. Sohal DP, Mangu PB, Khorana AA, et al: Metastatic pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 34:
2784-2796, 2016
5. Sohal DPS, Kennedy EB, Khorana A, et al: Metastatic pancreatic cancer: ASCO Clinical Practice Guideline update. J Clin Oncol 36:2545-2556, 2018
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 Metastatic Pancreatic Cancer

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Metastatic Pancreatic Cancer: ASCO Guideline Update
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted.
Relationships are self-held unless noted. I 5 Immediate Family Member, Inst 5 My Institution. Relationships may not relate to the subject matter of this manuscript.
For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.
Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).

Davendra P.S. Sohal Philip A. Philip

Honoraria: Foundation Medicine Honoraria: Celgene, Bayer, Bristol Myers Squibb, Ipsen, Merck, AstraZeneca,
Consulting or Advisory Role: Perthera, Ability Pharma, PierianDx TriSalus, Blueprint, Syncore, Array BioPharma
Research Funding: Novartis (Inst), Celgene (Inst), OncoMed (Inst), Bayer (Inst), Consulting or Advisory Role: Celgene, Ipsen, Merck, TriSalus
Genentech (Inst), Bristol Myers Squibb (Inst), Agios (Inst), Incyte (Inst), Loxo Speakers’ Bureau: Celgene, Bayer, Ipsen
(Inst), Rafael Pharmaceuticals (Inst) Research Funding: Bayer (Inst), Incyte (Inst), Karyopharm Therapeutics (Inst),
Merck (Inst), Taiho Pharmaceutical (Inst), Momenta Pharmaceuticals (Inst),
Mehmet S. Copur
Novartis (Inst), Plexxikon (Inst), Immunomedics (Inst), Regeneron (Inst),
Honoraria: Amgen, Bristol Myers Squibb, DAVAOncology, AstraZeneca
Genentech (Inst), TYME (Inst), Caris Life Sciences (Inst), ASLAN
Christopher H. Crane Pharmaceuticals (Inst), QED (Inst), Halozyme (Inst), Boston Biomedical (Inst),
Consulting or Advisory Role: Trisalis Advanced Accelerator Applications (Inst), Eli Lilly (Inst)
Travel, Accommodations, Expenses: Rafael, Celgene, AbbVie
Ignacio Garrido-Laguna
Consulting or Advisory Role: Array BioPharma, Eisai Uncompensated Relationships: Rafael, Caris Life Sciences
Research Funding: Novartis (Inst), Ignyta (Inst), Halozyme (Inst), Bayer (Inst), Shubham Pant
Bristol Myers Squibb (Inst), Pfizer (Inst), Newlink Genetics (Inst), MedImmune Honoraria: 4D Pharma
(Inst), Eli Lilly (Inst), Incyte (Inst), GlaxoSmithKline (Inst), OncoMed (Inst), ARMO Consulting or Advisory Role: TYME, Xencor
BioSciences (Inst), Glennmark (Inst) Research Funding: Mirati Therapeutics (Inst), Eli Lilly (Inst), RedHill Biopharma
Tyler Johnson (Inst), Xencor (Inst), Five Prime Therapeutics (Inst), Novartis (Inst), Rgenix (Inst),
Sanofi (Inst), ArQule (Inst), Bristol Myers Squibb (Inst), Onco Response (Inst),
Employment: HemOncReview.com
GlaxoSmithKline (Inst), Ipsen
Other Relationship: Heme/Onc Questions
Manish A. Shah
Smitha Krishnamurthi
Consulting or Advisory Role: Astellas Pharma, Eli Lilly
Consulting or Advisory Role: Array BioPharma
Research Funding: Celgene (Inst), AbbVie (Inst), Bristol Myers Squibb Research Funding: Gilead Sciences (Inst), Merck (Inst), Boston Biomedical
(Inst), Oncolys BioPharma (Inst), Bristol Myers Squibb (Inst)
Cassadie Moravek
Consulting or Advisory Role: AstraZeneca Vaibhav Sahai
Consulting or Advisory Role: Celgene, Halozyme, Newlink Genetics, Ipsen,
Other Relationship: AbbVie (Inst), AngioDynamics (Inst), AstraZeneca (Inst), Amgen
Foundation (Inst), Baxter International Foundation (Inst), Boston Biomedical (Inst), Incyte, QED, Klus Pharma, AstraZeneca
Boston Scientific (Inst), Bristol Myers Squibb (Inst), Celgene (Inst), Clovis Oncology Research Funding: Celgene (Inst), Bristol Myers Squibb (Inst), Agios (Inst),
Incyte (Inst), Clovis Oncology (Inst), Debiopharm Group (Inst), FibroGen (Inst),
(Inst), Eli Lilly (Inst), Eli Lilly Foundation (Inst), Elstar Therapeutics (Inst), ERYTECH
Pharma (Inst), Genentech (Inst), GlaxoSmithKline Foundation (Inst), Halozyme (Inst), Halozyme (Inst), MedImmune (Inst), Rafael Pharmaceuticals (Inst), Ipsen (Inst)
Travel, Accommodations, Expenses: American Society of Clinical Oncology,
Immunovia (Inst), Interpace Diagnostics (Inst), Ipsen Biopharmaceuticals (Inst),
FibroGen
Janssen Research & Development (Inst), Johnson & Johnson (Inst), Merck Sharp &
Dohme (Inst), Myriad Genetics Laboratories (Inst), Novartis Matching Gifts (Inst), Hope E. Uronis
Novartis Pharmaceuticals (Inst), Novocure (Inst), Pfizer (Inst), Rafael Pharmaceuticals Employment: GeneCentric (I)
(Inst), Servier Pharmaceuticals (Inst), Shire (Inst), Takeda Pharmaceuticals (Inst), The Stock and Other Ownership Interests: GeneCentric (I)
Allergan Foundation (Inst), TriSalus Life Sciences (Inst), TYME (Inst) Consulting or Advisory Role: Bristol Myers Squibb
Eileen M. O’Reilly Research Funding: Genentech (Inst), Bristol Myers Squibb (Inst), Advaxis (Inst),
Consulting or Advisory Role: Merck, Agios (I), AstraZeneca (I), Bayer (I), Macrogenics (Inst), Merck (Inst), Lycera (Inst), Dekkun (Inst)
Travel, Accommodations, Expenses: Bristol Myers Squibb
BeiGene (I), Berry Genomics (I), Celgene (I), CytomX Therapeutics, Debiopharm
Group (I), Eisai (I), Exelixis (I), Ipsen (I), Flatiron Health (I), Incyte (I), Janssen, No other potential conflicts of interest were reported.
LAM Therapeutics (I), Eli Lilly (I), Loxo, Genentech (I), MINA (I), QED (I), RedHill
Biopharma (I), Sillajen (I), SOBI, Yiviva (I), Autem (I), Gilead Sciences (I), Ipsen
(I), Silenseed, Therabionics (I), twoXAR, Vector (I)
Research Funding: AstraZeneca (Inst), MedImmune (Inst), Acta Biologica
(Inst), Bristol Myers Squibb (Inst), Celgene (Inst), Genentech (Inst), Halozyme
(Inst), MabVax (Inst), Roche (Inst), Silenseed (Inst)

Journal of Clinical Oncology

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Copyright © 2020 American Society of Clinical Oncology. All rights reserved.
 Sohal et al

APPENDIX

TABLE A1. Metastatic Pancreatic Cancer Guideline Update Expert Panel Membership
Name Affiliation/Institution Role/Area of Expertise
Davendra P.S. Sohal, MD, MPH, University of Cincinnati, Cincinnati, OH Medical oncology
co-chair
Daniel Laheru, MD, co-chair Sidney Kimmel Comprehensive Cancer Center at Johns Medical oncology
Hopkins, Baltimore, MD
Pelin Cinar, MD, MS University of California, San Francisco, San Francisco, CA Medical oncology
Thierry Conroy, MD Université de Lorraine and Institut de Cancérologie de Medical oncology
Lorraine, Lorraine, France
Mehmet S. Copur, MD Morrison Cancer Center, Hastings, NE PGIN representative
Christopher H. Crane, MD Memorial Sloan Kettering Cancer Center, New York, NY Radiation oncology
Ignacio Garrido-Laguna, MD, PhD Huntsman Cancer Institute, University of Utah School of Medical oncology
Medicine, Salt Lake City, UT
Tyler Johnson, MD Stanford University, Palo Alto, CA Medical oncology
Smitha Krishnamurthi, MD Cleveland Clinic, Cleveland, OH Medical oncology
Michelle W. Lau, MD Phoenix VA Medical Center, Phoenix, AZ PGIN representative
Cassadie Moravek Pancreatic Cancer Action Network, Manhattan Beach, CA Patient representative
Eileen M. O’Reilly, MD Memorial Sloan Kettering Cancer Center, New York, NY Medical oncology
Philip A. Philip, MD, PhD Barbara Ann Karmanos Cancer Institute Farmington Hills, MI Medical oncology
Shubham Pant, MD MD Anderson Cancer Center, Houston, TX Medical oncology
Vaibhav Sahai, MBBS, MS University of Michigan, Ann Arbor, MI Medical oncology
Manish A. Shah, MD New York Presbyterian/Weill Cornell Medical Center, New Medical oncology
York, NY
Hope E. Uronis, MD, MHS Duke University, Durham, NC Medical oncology
Neeha Zaidi, MD Johns Hopkins Medicine, Baltimore, MD Medical oncology
Erin B. Kennedy, MHSc American Society of Clinical Oncology, Alexandria, VA ASCO Practice Guideline Staff (Health
Research Methods)

Abbreviation: PGIN, Practice Guidelines Implementation Network.

© 2020 by American Society of Clinical Oncology

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