PRINCIPLES OF

CANCER THERAPY
By
Dr Farah Al asadi
M.B.CH.B F.I.C.O.G
 objectives
1) List various modalities involved in the management of
gynecologic malignancies.
2) Describe various types of chemotherapeutic agents and
radiotherapy.
3) Discuss acute and chronic complications of
radiotherapy.
4) Discuss the role of hormonal therapy in the management of
gynecologic malignancies and targeted therapies.
5) Discuss pain management and end-of-life issues
 Cellular biology
◦ Modern gynecologic cancer management requires
a multidisciplinary approach and include
◦ Surgery.
◦ Chemotherapy.
◦ radiation therapy.
◦ hormonal therapy.
◦ targeted therapy.
◦ The characteristic feature of malignant tumor
growth is its uncontrolled cellular proliferation,
which requires replication of deoxyribonucleic acid
(DNA).
◦ There are two distinct phases in the life cycle
of all cells:
◦ Mitosis (M phase), during which cellular division
occurs.
◦ Interphase, the interval between successive
mitoses.
◦ Interphase is subdivided into three separate phases
◦ Immediately following mitosis is the G1phase,
which is of variable duration and is characterized
by a diploid content of DNA. DNA synthesis is
absent, but ribonucleic acid (RNA) and protein
synthesis occur.
◦ shorter S phase, the entire DNA content is
duplicated.
◦ G2 phase, which is characterized by a tetraploid
DNA content and by continuing RNA and protein
synthesis in preparation for cell division.
◦ When mitosis occurs, a duplicate set of
chromosomal DNA is inherited by each daughter cell,
thus restoring the diploid DNA content. Following
mitosis, some cells leave the cycle temporarily or
permanently and enter the G0 or resting phase.
◦ The growth fraction of the tumor is the proportion of actively
dividing cells. The higher the growth fraction, the
fewer the number of cells in the G0 phase and
the faster the tumor-doubling time.
•Chemotherapeutic agents and radiation kill cells by first-
order kinetics, which means that a constant proportion of
cells is killed for a given dosage.
•Both therapeutic modalities are most effective
against actively dividing cells because cells in
the resting (G0) phase are better able to repair
sublethal damage.
•Rapidly dividing normal cells also affected such as
those in the gastrointestinal mucosa, bone
marrow, and hair follicles.
 Chemotherapy
CLASSIFICATION OF CHEMOTHERAPEUTIC AGENTS
Chemotherapeutic agents act primarily by disrupting nuclear DNA
inhibiting cellular division.
Two categories according to their mode of action relative to the
cell cycle:
1. Cell cycle–nonspecific agents → alkylating agents, cisplatin, and
paclitaxel, exert their damage at any phase of the cell cycle. They
may damage resting as well as cycling cells, but the latter are
much more sensitive.
2. Cell cycle–specific agents→ exert their lethal effects exclusively or
primarily during one phase of the cell cycle. Example
methotrexate, which act primarily during the S phase.
 PRINCIPLES OF CHEMOTHERAPY
◦ Chemotherapeutic agents are selected on the basis of
previous experience with particular agents for a given
tumor, particularly after randomized controlled clinical
trials.
◦ The drugs are usually given systemically.
◦ the tumor can be treated regardless of its anatomic
location.
◦ To increase the local concentration, drugs may
occasionally be administered topically, by intraarterial
infusion, or by intrathecal or intracavitary instillation(e.g.,
intraperitoneal therapy for ovarian cancer).
◦ Chemotherapy is generally not administered if the
neutrophil count is less than 1500/mm3 or if the platelet
count is less than 100,000/mm3. Nadir blood counts
are obtained 7 to 14 days after treatment.
◦ Doses may need to be reduced
◦ → if there is significant myelosuppression
◦ → if the patient develops febrile neutropenia.
◦ → toxicity to other organs, such as the
gastrointestinal tract, liver, or kidneys.
◦ Resistance to chemotherapeutic agents may be temporary
or permanent.
◦ Temporary resistance is mainly related to the
poor vascularity of bulky tumors→ poor tissue
concentrations of the drugs and an increasing
proportion of cells in the relatively resistant G0
phase of the cell cycle.
◦ Permanent resistance mainly results from
1- spontaneous mutation to phenotypic resistance
2- bulky tumors.
3- acquired by frequent exposure to
chemotherapeutic agents.
CHEMOTHERAPEUTIC AGENTS
 Alkylating Agents
◦The cytotoxicity of alkylating agents results
from their ability to cause alkylation to
DNA, resulting in cross linkage between DNA
strands and prevention of DNA replication.
There is cross resistance among the various
alkylating agents.
 Antimetabolites
◦ Antimetabolites are compounds that closely resemble
normal intermediaries, for which they may substitute in
biochemical reactions, and thereby produce a metabolic
block; for example, methotrexate competitively inhibits
the enzyme dihydrofolate reductase, thus preventing the
conversion of dihydrofolate to tetrahydrofolate. The latter
is required for the methylation reaction necessary for
the synthesis of purine and pyrimidine subunits of
nucleic acid.
 Antibiotics
◦ Antibiotics are naturally occurring antitumor agents
elaborated by certain species of Streptomyces.
◦ They have no single, clearly defined mechanism of
action, but many agents in this group intercalate
between strands of the DNA double helix, thereby
inhibiting both DNA and RNA synthesis and
causing oxygen dependent strand breaks.
 Plant Alkaloids
◦ The most common plant alkaloids are the vinca
alkaloids.
◦ derived from the periwinkle plant. These include
vincristine and vinblastine
◦ spindle toxins that interfere with cellular
microtubules and cause metaphase arrest.
paclitaxel (Taxol), an extract from the bark of
the Pacific yew tree.
◦ Paclitaxel binds preferentially to microtubules, and
results in their polymerization and stabilization.
 Other Drugs
◦Other Drugs Cisplatin, one of the more
important drugs in gynecologic oncology,
causes inhibition of DNA synthesis by
forming interstrand and intrastrand linkages.
◦Carboplatin is an analogue of cisplatin with
a similar mechanism of action and efficacy,
but with less gastrointestinal and renal
toxicity.
 Radiation Therapy
◦Radiation may be defined as the
propagation of energy through space or
matter.
◦TYPES OF RADIATION
There are two main types of radiation:
electromagnetic and particulate.
 Electromagnetic Radiation
Include the following:
• Visible light.
• Infrared light.
• Ultraviolet light.
• X-rays (photons).
• Gamma rays (photons).
◦ X-rays and gamma rays are identical electromagnetic
radiations, differing only in their mode of production.
◦ X-rays are produced by bombardment of an
anode by a high-speed electron beam;
◦ gamma rays result from the decay of
radioactive isotopes, such as cobalt 60 (60Co).
◦ X-rays and gamma rays (photons) are
differentiated from electromagnetic radiation of
longer wavelength by their greater energy, which
allows them to penetrate tissues andcause
ionization.
 Particulate Radiation
◦ consists of moving particles of matter. Their
energy consists of the kinetic energy of the
moving particles.
◦ Energy =0.5 mass ×velocity²
◦ The particles vary greatly in size and include the
following:
• Neutrons (no charge)
• Protons (positive charge)
• Electrons (negative charge)
◦ The most commonly used particles are electrons.
◦ They may be derived from a linear
accelerator, the beam of electrons being
directed into the patient without first striking a
metal target and producing x-rays.
◦ Alternatively, high-energy electrons (called beta
particles) may be derived from the radio decay of
an unstable isotope, such as phosphorus 32
(32P). Particulate radiation penetrates tissues less
than photons but also produces ionization.
UNIT OF RADIATION
MEASUREMENT
◦ The Gray (Gy) is equivalent to an
absorbed energy of 1 joule per kilogram
of absorbing material.
◦ INVERSE SQUARE LAW
◦ The intensity of electromagnetic radiation is
inversely proportional to the square of the
distance from the source. Thus, the dose
of radiation 2 cm from a point source
will be 25% of the dose at 1 cm
 BIOLOGIC CONSIDERATIONS
Ionization of Molecules

◦ Radiation damage is caused by the ionization of molecules in

the cell, with the production of free radicals.
◦ 80% of a mammalian cell is water, most of the
cellular radiation damage is mediated by ionization
of water and the production of the free radicals H
(hydrogen) and OH (hydroxide).
◦ Free radicals may cause irreversible damage to DNA,
making it impossible for the cell to continue
replication.
 Oxygen Effect
◦ Hypoxic cells are less radiosensitive than are fully
oxygenated cells.
◦ The enhancement of the lethal effects of
radiation by oxygen is presumed to occur.
◦ Oxygen will combine with the free radicals
split from cell targets by the radiation. This
prevents the recombination of the free radicals
with the targets, which would restore the integrity
of the targets.
◦clinical implications. First, anemic patients
should undergo transfusion before radiation
therapy. Second, bulky tumors are usually
poorly vascularized and, therefore, are often
hypoxic.
 Pharmacologic Modification of the Effects
of Radiation
◦A variety of chemical compounds are capable
of enhancing the lethal effects of radiation.
◦ A series of randomized clinical trials has
demonstrated a significant survival advantage,
particularly in terms of local disease control, when
cisplatin-containing chemotherapy is given
concurrently with radiation for locoregionally
advanced cervical cancer.
◦ This is called chemoradiation.
 Time-Dose Fractionation of
Radiation
◦ Successful radiation therapy requires a delicate balance
between dosage to the tumor and that to the
surrounding normal tissues.
◦ A dose of radiation that is too high sterilizes the
tumor but results in an unacceptably high complication
rate because of the destruction of normal tissues.
◦ gastrointestinal mucosa and bone marrow, have a
remarkable capacity to recover from radiation damage
by the division of stem cells as well as by repair of
sublethal radiation damage.
◦ Tumors, in general, have less ability to repair
and repopulate. This difference can be exploited
by administering the radiation in multiple
fractions, thereby allowing some recovery,
particularly of normal cells, between fractions.
◦ If the interval between each fraction increases, the total dose
must increase to produce the same biologic effect.
◦ Cells that survive the acute effects of radiation usually repair
sublethal damage within 24 hours; therefore,
conventionally fractioned radiation is usually given in
daily increments.
 MODALITIES OF RADIATION
THERAPY
◦ Two radiation techniques: teletherapy and
brachytherapy.
◦ In teletherapy, a device quite removed from the
patient is used, as with external beam techniques. is
a linear accelerator used to deliver external beam
pelvic radiation.
◦ In brachytherapy, the radiation source is placed
either within or close to the target tissue, as with
intracavitary and interstitial techniques.
 Teletherapy
◦ EXTERNAL BEAM THERAPY.
As the energy of the electromagnetic radiation
increases, the penetration of the tissues increases,
resulting in a relative sparing of the skin and
an increased dosage to deeper tissues.
◦ Orthovoltage machines are no longer used except to treat
skin cancers.
◦ External radiation allows a uniform dose to be delivered to a
given field.
◦ External radiation is usually used to
shrink a large tumor mass before
brachytherapy. When used alone, it is
generally useful only when there is small
residual macroscopic or microscopic disease
following surgery. With highly radiosensitive
tumors (e.g., dysgerminoma),
 INTENSITY MODULATED RADIATION
THERAPY
◦ Three-dimensional treatment planning based on computed
tomographic (CT) imaging has allowed better definition of the
specific target volume and the surrounding normal tissues.
◦ Intensity modulated radiation therapy (IMRT) delivers
radiation from multiple beam angles with
nonuniform dose intensities, but the collective set
of beams produces a more homogenous dose to
the target volume.
◦ The end result is a high dose delivered to the target volume
and acceptably low dose to the surrounding normal tissues.
 Brachytherapy
◦ Intracavitary therapy is used particularly
in the treatment of cervical and vaginal
cancer. All applicators now in use should be
“afterloaded,” which means that they are
placed in the patient and their position
checked by radiography before the
radioactive substance is loaded into the
applicator.
◦ More recently, high dose rate brachytherapy has
been given, using radioactive sources such as iridium
(192Ir). Treatment is given as an outpatient,
which is much more acceptable for patients.
 INTERSTITIAL RADIATION.
◦ (in which the radioactive source is placed directly
in the tumor) may be delivered by removable or
permanent implants. Permanent implants are used for
inaccessible tumors. They use radioisotopes such as radon
222 (222Rn) or iodine 125 (125I) seeds and are usually
placed in an unresectable tumor nodule at the
time of laparotomy.
◦ Removable implants are placed in tumors that are accessible
(e.g., cervical or vaginal tumors).
 COMPLICATIONS ASSOCIATED WITH
RADIATION
◦ Acute Complications
◦ Acute cystitis, manifested by hematuria, urgency, and
frequency.
◦ Proctosigmoiditis, manifested by tenesmus, diarrhea, and
passage of blood and mucus in the stool.
◦ Enteritis, manifested by nausea, vomiting, diarrhea, and
colicky abdominal pain.
◦ Bone marrow suppression, is uncommon with pelvic
radiation, but common with whole-abdominal radiation,
particularly if the patient has had previous chemotherapy,
or extended field (pelvic and paraaortic) radiation,
particularly if the patient is given concurrent chemotherapy.
 Chronic Complications
◦ Occur 6 months or more after completion of
radiation.
◦ Radiation Enteropathy Previous surgery, with resultant
loops of small bowel adherent in the pelvis,
predisposes the patient to chronic radiation enteritis.
Small bowel injuries usually present with cramping
abdominal pain and vomiting, or with alternating
diarrhea and constipation.
◦ Large bowel injuries, which are best diagnosed by
sigmoidoscopy or colonoscopy, may include:
proctosigmoiditis,manifested by pelvic pain, tenesmus,
diarrhea, and rectal
bleeding;
◦ Ulceration, manifested by rectal bleeding and
tenesmus;
◦ Rectal or sigmoid stenosis, manifested by
progressive large bowel obstruction.
◦ Rectovaginal fistula, manifested by passage of
stool through the vagina.
◦ Vaginal Vault Necrosis This is associated with
severe pain and tenderness of the vaginal vault
and a profusevaginal discharge.
◦ Urologic Injuries
◦ Hemorrhagic cystitis.
◦ Ureteric stenosis.
◦ Vesicovaginal fistula.
◦ Ureterovaginal fistula.
 Hormonal Therapy
◦ MECHANISM OF ACTION OF HORMONAL RECEPTORS
◦ Most steroid hormones influence their target tissues by the
following series of steps:
◦ passive diffusion of the hormone through the cell membrane,
◦ specific binding in the cytoplasm with the hormone receptor,
◦ translocation of the receptor-hormone complex to the nucleus,
◦ binding of the receptor-hormone complex to an “acceptor” site
on the chromatin,
◦ and transcription of DNA in a manner characteristic of the
specific hormone–target cell interaction, eventually resulting in
either anincrease or a decrease in specific protein synthesis.
◦ Tamoxifen binds with the ER and is translocated
to the nucleus, where it binds to chromatin. It
does not influence gene transcription, so
functionally, tamoxifen acts as an antiestrogen.
◦ Aromatase inhibitors work by blocking aromatase,
the enzyme that is responsible for the final
step of estrogen synthesis.
◦ Luteinizing hormone-releasing hormone agonists act by
pituitary desensitization and receptor
downregulation, suppressing gonadotrophin release.
 CLINICAL APPLICATIONS
◦ In breast cancer, patients whose tumors contain ER and PR have an
80% response rate to hormonal manipulation, whereas fewer
than 10% of receptor-poor tumors respond.
◦ An objective response to progestin therapy occurs in about one-third
of patients with recurrent or metastatic endometrial carcinoma.
Progestin therapy is more likely to be effective in
well differentiated endometrioid adenocarcinomas than in
more poorly differentiated tumors. Tamoxifen is effective in up
to 30% of women with recurrent ovarian cancer, and aromatase
inhibitors are also active agents.
◦ Bevacizumab (Avastin) is a recombinant humanized
monoclonal immunoglobulin G1 (IgG1) antibody that
targets VEGF-A. It is being used for patients with
ovarian cancer, either in conjunction with chemotherapy,
or alone as maintenance therapy.
◦ Side effects :hypertension, thromboembolism, and an
increased risk of bowel perforation.
◦ polyadenosine diphosphate-ribose polymerase (PARP) inhibitors.
These agents target DNA repair and are particularly
effective in patients with BRCA 1 or 2 germline
mutations.
 Pain Management
◦ 70% of patients with cancer will develop
significant pain at some point in their disease.
◦ Pain in gynecologic cancer may be the result of
◦ Soft tissue infiltration,
◦ Bone involvement,
◦ Neural involvement,
◦ Muscle spasm (e.g., psoas spasm),
◦ Infection within or near tumor masses, or bowel colic.
◦Peripherally acting drugs such as acetaminophen
(paracetamol) should rarely be omitted from
analgesic regimes, and rectal suppositories are useful
if oral intake is not appropriate.
◦Opioid use will be necessary for severe pain.
◦When pain is neurogenic in origin, an opioid and a
peripherally acting drug should usually be
supplemented by a tricyclic antidepressant, an
anticonvulsant, or a corticosteroid.
 End-of-Life Issues
◦ When it becomes clear that the patient is
dying, the goals are to control symptoms,
maintain dignity, and allow time and privacy for
communication with loved ones.
◦ Medications should usually be given
subcutaneously or rectally.
◦ unnecessary tubes or equipment should be
removed to facilitate contact with loved ones.
◦ nursing care should particularly focus on pressure
areas, mouth care, and “grooming. Sedation, for
example, with sublingual lorazepam 0.5 to 2.5 mg
every 4 to 6 hours, may be helpful if the
patient is agitated.

◦ pain and symptom management, avoiding

inappropriate prolongation of dying, achieving a
sense of control, relieving the burden on
caregivers, and strengthening relationships with
loved ones.
 summary
◦ Chemotherapy and radiation therapy both work primarily by
disrupting nuclear deoxyribonucleic acid and inhibiting cellular
division.
◦ Toxicity from radiation therapy can be minimized by ensuring
that the maximum dose of radiation is delivered to the cancer
and the minimum dose to the surrounding normal tissue.
◦ Hormonal therapy relies on the fact that some tumors contain
receptors for estrogen and progesterone.
◦ Nearly three-quarters of cancer patients experience significant pain
that should be properly managed without delay. When it becomes
clear that death is near, the goals should be to control
symptoms, maintain dignity, and allow for time with loved ones.