Norbert Sipos: Principles of cancer therapy

Principles of cancer therapy:
chemotherapy, irradiation
Norbert Sipos M.D.

Chemotherapy (antineoplastic agents): narrower
therapeutic index than drugs of other types.
Issues to be considered before using antineoplastic drugs
1. Natural History of the particular malignancy
a. Diagnosis of a malignancy made by biopsy (when doubt
exists concerning the diagnosis, it is preferable to delay
initial therapy and not use response to chemotherapy as a
diagnostic trial)
b. rate of disease progression
c. extent of disease spread
2. Patient’s circumstances and tolerance
a. Age, general health, underlying diseases
b. extent of previous treatment
c. adequate facilities to evaluate , monitor, and treat
potential drug toxicities
d. the patient’s emotional, social, and financial situation

3. Likelihood of achieving a beneficial response
a. cancers in which chemotherapy is curative in
patients (e.g., ovarian germ-cell tumors,
choriocarcinoma)
b. cancers in which chemotherapy has demonstrated
improvement in survival (e.g., epithelial ovarian
cancer)
c. cancers that respond to treatment but in which
improved survival has not been clearly demonstrated
(e.g., cervical cancer)
d. cancers with marginal or no response to
chemotherapy (e.g., melanoma)
- it is important that there be an evaluable tumor so
that response can be assessed.
- chemotherapy should not be used unless facilities are
available for careful monitoring and treatment of the
resulting toxicities.

The window between antitumor effect
and normal tissue toxicity may be small,
because most chemotherapeutic agents
work by disrupting DNA or RNA
synthesis, affecting crucial cellular
enzymes, or altering protein synthesis.
Nowadays
Targeted therapeutic agents:inhibit or
alter specific tumorous cell functions
—> less side effects, more antitumor
effects.

Patterns of Normal Cell Growth
Static population: after initial proliferative
activity in the embryonic and neonatal period,
rarely undergo cell division (examples:
striated muscle and neurons)
Expanding population: has the capacity to
proliferate under special stimuli (tissue injury)
(examples:liver or kidney cells)
Renewing population:of cells is constantly in a
proliferative state. High degree of cell
turnover. (examples:bone marrow, epidermis,
gastrointestinal mucosa). Their cell cycle is
the mostly similar to cancer cell cycle. The
typical chemotherapeutic side effects reach
these cells.

Cancer cell growth
- disruption in the normal cellular brake
mechanisms
- continued proliferation and eventual death of
the host
- it is not the speed of cell proliferation but the
failure of the regulated balance between cell
loss and cell proliferation that differentiates
tumorous tissues from normal tissues.

Gompertzian Growth
When tumors are extremely small, growth
follows an exponential pattern, but later
seems to slow.
Gompertzian growth means that as a
tumor mass increases, the time required
to double the tumor’s volume also
increases.

Doubling of tumor cells
1. 1 mm mass will have undergone 20
tumor doublings.
2. 5 mm mass (a size that might be first
visualized on a radiograph) will have
undergone 27 doublings.
3. 1 cm mass will have undergone 30
doublings. (clinically diagnosed tumor) -
metastasis may well have occured long
before.

Cell cycle
1. M phase (mitotic phase) of the cell cycle is
the phase of cell division.
2. G1 phase (postmitotic phase) is a period of
variable duration when cellular activities and
protein and RNA synthesis continue.
3. S phase (DNA synthetic phase) is the period
in which new DNA replication occurs.
4. G2 phase (postsynthetic phase)
The cell remains in this phase for a relatively
short time and then enters the mitotic phase
again.
5. G0 phase (the resting phase) or the M phase
again

Cell cycle specific drugs
hydroxyurea, methotrexate, cytosine
arabinoside, 5-Fluorouracil
Cell cycle nonspecific drugs (kill cells in all
phase)
paclitaxel, cyclophosphamide, carboplatin,
cisplatin, topotecan

Site of Action in cell cycle
G1: Actinomycin D
early S: hydroxyurea, cytosine
arabinoside, 5-fluorouracil,
methotrexate
late S: doxorubicin
G2: Bleomycin, radiation, etoposide
M: Vincristine

Principles of Combination Chemotherapy
Major limitations of single-agent
chemotherapy
1. Toxicity limits the dose and duration of
drug administration
2. Spontaneous development of drug
resistance

Combination Chemotherapy mechanisms
Drug resistance: the probability of the
emergence of drug-resistant cells in any
given population is reduced if two or more
agents with different mechanisms of action
can be used.
Drug interaction (optimally synergism):
Combinations that result in improved therapy
because of increased antitumor activity or
decreased toxicity are said to be synergistic.

Evaluation the response to drug treatment (CT,US)
Complete remission (CR): is the complete
disappearance of all objective evidence of
tumor as well as the resolution of all signs
and symptoms referable to the tumor.
Partial Remission (PR): is an at least 50%
reduction in the size of all measurable
lesions.
Follow-up by tumor-markers
For example:CA 125 for epithelial ovarian
cancer

Drug Toxicity and Supportive treatment
Supportive treatment: we can treat or prevent the different
kind of side effects.
Hematologic Toxitity: (nitrosoureas)
granulocytopenia: patients with an absolute granulocyte
count of less than 500/mm3 for 5 days or longer are at
high risk of rapidly fatal sepsis.
Therapy: G-CSF and GM-CSF (hematopoietic growth factors),
broad spectrum antibiotics
thrombocytopenia: patients with sustained
thrombocytopenia who have platelet counts of less than
20.000/mm3 are at risk of spontaneous hemorrhage.
Therapy: platelet transfusions
anaemia: the number of blood cells is less than 11 g/dl.
Therapy: blood cell transfusions, erithropoietin, darbopoietin.

Gastrointestinal toxicity (vincristin)
nausea and vomiting
therapy: serotonin-antagonists
(granisetron, ondansetron)
mucositis and diarrhea
therapy: antibiotics, antimycotics, fluid
replacement (infusions)

Dermatologic reactions (doxorubicin)
- skin necrosis
- alopecia: is the most common side effect of
many anticancer drugs.
Usage of wigs can solve the social problem.
-liposomal doxorubicin can produce a painful
dermatologic syndrome characterized by
desquamation of the skin.

Pulmonary complications (bleomycin)
- interstitial pneumonitis
- pulmonary fibrosis
Cardiac toxicity (doxorubicin)
- a cumulative dose of 500 mg/m2 body
surface area is widely used as the
maximum tolerable dose of doxorubicin.

Urinary toxicity
cisplatin: kidney damage
cyclophosphamide, ifosphamide: chronic
hemorrhagic cystitis
therapy: uromitexan (preventing cystitis),
vigorous hydration (infusions) can
reduce the risk.

Neurotoxicity
- vinca alkaloids
- cisplatin
- paclitaxel
therapy: B vitamin supplements.

Classification of antineoplastic drugs
Alkylating agents
- bind to the N-7 position of guanine
and other key DNA sites.
- cyclophosphamide, ifosphamide,
cisplatin, carboplatin, dacarbazine

Antitumor antibiotics
- The interaction between these drugs
and DNA often involves intercalation
- anthracyclines (doxorubicin,
daunorubicin), bleomycin, mitomycin C

Antimetabolites
- The drugs interact with vital intracellular
enzymes
- methotrexate: inhibits dihydrofolate
reductase
- 5 fluorouracil, gemcitabine are
pyrimidine antagonists
- hydroxyurea is a ribonucleotide
reductase inhibitor

Plant alkaloids
- vinca alkaloids: bind to intracellular
microtubular proteins
- paclitaxel: bind to microtubules and
results in their stabilization
- etoposide: DNA interactions
Topoisomerase-1 Inhibitors
- Topotecan bind to the enzyme-DNA
complex leading to permanent strand
breaks and cell death

Targeted therapy
- breast cancer: Her-2-receptor
antagonist trastuzumab
- inhibit or alter specific tumorous cell
functions
- result less side effects, more antitumor
effects than the classic chemotherapy
- recently there have been no effectiv
targeted therapy drug used in
gynecology

Useful drug combinations in
gynecology
Gestational trophoblast tumors and
choriocarcinoma:
- methotrexate alone (low-risk tumors)
- EMACO (etoposide, actinomycin D,
methotrexate, vincristin,
cyclophosphamide)

Epithelial ovarian cancers
- Paclitaxel/Carboplatin: first-line
chemotherapy
- second- and third-line chemotherapies:
 the same as the first-line (reinduction
therapy)
 Liposomal doxorubicin
 Topotecan
 Docetaxel/Cisplatin
 Gemcitabine/Carboplatin

Germ-cell ovarian cancers
BEP (Bleomycin, etoposide, cisplatin)
Uterine sarcomas
CYVADIC (Cyclophosphamide, vincristin,
doxorubicin, dacarbasine)
VIP [etoposide, iphosphamide (with
uromitexan), cisplatin]

Radiation therapy
The biologic effect of a given dose of radiation is influenced
by:
- dose
- fraction size
- interfraction interval
- the time over which the dose is given
- oxygenation of tumor cells
- hyperthermia (between 42C and 43C)
- concomittant chemotherapy (cisplatin, 5-
fluorouracil): so called classical
radiochemotherapy
(chemotherapy takes the tumor-cells more
radiosensitive)

Effects of radiation on normal tissues
acute reactions: diarrhea
late reactions: occur months to years
after radiation therapy
- fibrosis
- loss of different kinds of tissue or
organ function

Combinations of surgery and radiation
preoperative radiation: used to sterilize possible microscopic
disease at the margins of a planned operative state
intraoperative radiation: rarely used (by isotops 125I, 198Au)
postoperative radiation: has been demonstrated to improve
local regional control and even survival in several settings:
1. Vulvar cancer—postoperative pelvic and groin irradiation
reduces groin recurrence and improves the survival rate of
patients with multiple positive inguinal nodes.
2. Endometrial cancer—postoperative pelvic irradiation reduces
the incidence of pelvic recurrences in patients with high-risk
stage I. disease.
3. Cervical cancer—postoperative radiochemotherapy reduces
pelvic recurrences in patients with lymph node or
parametral involvement.

Physical principles of radiation
- External-beam therapy is delivered by linear
accelerators that produce photon beams (x-
rays and -rays) by bombarding a target such
as tungsten with accelerated electrons.
- Electrons and other particles
• electrons
• protons
• neutrons
- the unit currently used to measure radiation
dose is the Gray (Gy).

Radiation Techniques
Teletherapy: X-ray therapy delivered at a distance
from the body (external-beam therapy)
Brachytherapy: radiation sources are placed within
or adjacent to a target volume
(intracavitary or interstitial therapy)
Radioactive solutions: solutions containing isotopes
(e.g. radioactive colloidal gold)
are introduced into a cavity
(e.g. peritoneum)

Vulvar Cancer Epidemiology
 The American Cancer Society estimates 4000 new cases of
invasive vulvar cancer in the US with 800 deaths (2003)
 Vulvar cancers compose 4% of malignancies of the female
genital tract
 Squamous cell carcinoma and its variants are the most
prevalent histologies, comprising 90% of invasive lesions
 Vulvar melanoma, basal cell cancer and rare sarcomas
constitute most of the remaining tumors
 Adenocarcinoma and adenoidcystic carcinoma of the vestibular
glands (Bartholin’s gland) are less common than the squamous
cancers arising from these structures
 Age-adjusted incidence increases steeply after age 70

Etiology of Vulvar Cancer
 An association is found with human papilloma virus
(HPV) in approximately one third of cases, primarily
in younger patients
 Vulvar cancer in older patients frequently arises in
association with lichen sclerosis or squamous
hyperplasia, although these conditions are not
clearly premalignant
 Chronic immunosuppression has been implicated in
some cases

Vulvar cancer-Differential Diagnosis
 Paget’s disease of the vulva and vulvar
intraepithelial neoplasia (VIN) are in the
differential diagnosis of a vulvar lesion
 Giant condyloma may mimic vulvar neoplasia,
and vulvar neoplasia may coexist with
condyloma accuminata

Vulvar cancer-Evaluation
 Complete history and physical examination
including and careful palpation of groin lymph
nodes
 Diagnosis must be confirmed by vulvar biopsy

Vulvar cancer-Staging (FIGO 2009)
IA Tumor confined to the vulva or perineum, < 2 cm in
size with stromal invasion < 1mm, negative nodes
IB Tumor confined to the vulva or perineum, > 2 cm in
size or with stromal invasion > 1mm, negative
nodes
II Tumor of any size with adjacent spread (1/3 lower
urethra, 1/3 lower vagina, anus), negative nodes

IIIA Tumor of any size with positive inguino-femoral
lymph nodes
- 1 lymph node metastasis greater than or equal
to 5mm
- 1-2 lymp node metastasis(es) of less than 5mm
IIIB - 2 or more lymph nodes metastases greater than
or equal to 5mm
- 3 or more lymph nodes metastases less than
5mm
IIIC Positive node(s) with extracapsular spread

IVA - Tumor invades other regional structures (2/3
upper urethra, 2/3 upper vagina), bladder
mucosa, rectal mucosa, or fixed to pelvic bone
- Fixed or ulcerated inguino-femoral lymph nodes
IVB Any distant metastasis including pelvic lymph
nodes

Treatment of Squamous cell
carcinoma of the vulva I
 Treatment should be individualized on the
basis of disease volume and anatomic extent,
histology, age, comorbidities and patient
preference
 Stage I lesions may be treated with radical
local excision alone, or combined with
inguino-femoral lymphadenectomy if depth
invasion exceeds 1mm

Vulvar Cancer-Treatment II.
 Surgery for stage II vulvar cancer usually consists of
modified radical vulvectomy and inguinofemoral
lymphadenectomy
 Locally extensive vulvar cancer, or cansers invading
or encroaching on functionally important midline
structures can be managed with synchronous
preoperative chemotherapy and radiation
(chemoradiation) followed by conservative excision of
residual disease, or by radical chemoradiation alone

Vulvar Cancer-Treatment III
 Management of inguinofemoral nodes may consist of
surgical dissection alone, or surgery coordinated with
preoperative or postoperative radiation if nodes
harbor metastatic deposits
 Surgery of the primary and the groin nodes may be
conducted through separate incisions ( triple
incisions) to reduce both acute and late surgical
morbidity

Vulvar Cancer-Treatment IV
 Elective radiation or chemoradiation may be
an alternative to surgical treatment of
inguinofemoral nodes in selected patients
with clinically and radiographically negative
groin nodes
 Sentinel lymph node biopsy may be a useful
discriminator to guide the selection and
sequencing of modalities used to treat the
groin nodes

Cancer of the endometrium
Incidence
 Each year, there are an estimated 40 100 new cases of
endometrial cancer and 6800 related deaths in the US
Etiology and epidemiology
 The median age of onset for endometrial cancer is 65,8 years;
most cases occur after menopause
 Hormonally dependent subtypes arise in hypertrophic
endometrium
 Lifetime estrogen exposure contributes to the risk of disease
 Hormonally independent types occur at an older age and arise
in atrophic endometrium
 Other risk factors include family history, certain systemic
diseases and tamoxifen use

Pathology and biology
 Atypical hyperplasia confers a 25% risk of invasive
cancer
 Agressive subtypes include uterine serous and clear
all cancers
 Estrogen and progesterone receptor expression
infuence biologic behavior
 Uterine serous pathogenesis is p53-mediated

Clinical findings
 Abnormal uterine bleeding and discharge are
present in 90% of cases
 Biopsy or dilation and curettage is required
for diagnosis
 Surgical staging is used usually
 Clinical staging is used for patients with
inoperable disease

Surgical staging for carcinoma of
endometrium (FIGO 2009)
IA Tumor confined to the uterus , no or <1/2
myometrial invasion
IB Tumor confined to the uterus, >1/2 myometrial
invasion
II Cervical stromal invasion, but not beyond uterus
IIIA Tumor invades serosa or adnexa
IIIB Vaginal and/or parametrial involvement
IIIC1 Pelvic node involvement
IIIC2 Para-aortic involvement
IVA Tumor invasion of bladder and/or bowel mucosa
IVB Distant metastases including abdominal metastases and/or
inguinal lymph nodes

Primary therapy of endometrial cancer I
 Surgery, including hysterectomy, bilateral salpingo-
oophorectomy, lymph node sampling, and pelvic
washings is performed in all patients with operable
disease; lymph node sampling may be omitted in
patients with grade 2 tumours limited to the
endometrium or stage IA tumours
 Adjuvant radiation to the pelvis is indicated for
patients with high-risk factors, including high-grade
lesions, deep myometrial invasion, and spread to the
lymph nodes

Primary therapy of endometrial cancer II
 Systemic treatment with doxorubicin, cisplatin
and cyclophosphamide is used for metastatic
disease
 For serous type carcinoma
paclitaxel/carboplatin chemotherapy can be
used
 Radiation alone is used for patients with
inoperable disease and for palliation

Salvage therapy of endometrial cancer
 Pelvic recurrence after surgery alone is
treated with radiation therapy
 Salvage after surgery and radiation therapy is
seldom successful, although systemic therapy
may be used

Norbert Sipos: Principles of cancer therapy

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Norbert Sipos: Principles of cancer therapy