GYNECOLOGY

PRINCIPLES OF RADIATION AND

CHEMOTHERAPY IN
7S-2 | CEU-SOM A & B GYNECOLOGIC CANCER:
ELEYNETH I. VALENCIA, MD Basic Principles, Uses, and Complications

OUTLINE  Cell cycle dependency of cell kill: actively proliferating tumor

cells are most often killed by radiation therapy
I. RADIATION THERAPY  Ionizing radiation imparts greatest cell kill effect during MITOTIC
II. CHEMOTHEAPY phase (M phase) and to a lesser extent late Gap1 phase and early
III. REFERENCES DNA synthesis phase (G1/S)

BASIC RADIATION PHYSICS

I. RADIATION THERAPY
 Safe clinical application of radiation for the local treatment of
abnormally proliferating benign or malignant tumors
 Dose-response of tumor cells: follows a sigmoid curve (effective
tumor kill or arrest of division = dose of radiation)
 To control malignancy on the greater tolerance of normal tissues to
radiation
 Diminished capacity of cancer cells to recover from radiation-
induced damage
MAIN THERAPEUTIC GOAL
 to balance attempts of maximum local tumor control while
minimizing adverse symptoms of treatment and normal tissue
damage
DEFINITION OF TERMS
Radiation
 Emission and propagation of energy through space or physical
medium
 Can be particulate (unit of matter with discrete mass and
momentum propagating energy (e.g. alpha particles, protons,
neutrons and electrons)
 Can be electromagnetic (photons)
 Energy levels in oscillating electric and magnetic fields
 Particulate and electromagnetic radiation can ionize atoms; occur
randomly throughout a medium
 Gynecologic malignancies: most common source of radiation –
electromagnetic (photon) radiation
 Photons to treat gynecologic malignancies can be generated:
o Externally at a distance from the woman’s tumor –
teletherapy
o Internally close to the woman’s tumor brachytherapy

 Fractional Cell Kill: constant fraction of tumor cell population killed THERAPEUTIC RADIATION PRODUCTION
by each radiation dose
Two Techniques used in Radiation Therapy Treatment:
 Radiation Dose Rate: large radiation dose per fraction: greatest 1. TELETHERAPY (external)
number of tumor cell kills but produces greatest damage burden on 2. BRACHYTHERAPY (external)
normal tissues (early or late adverse complications)
TELETHERAPY
 Radiation Resistance: selected malignant tumor cells may show  form of external beam radiation treatment producing ionizing
reduced radiosensitivity with slow tumor regression or renewed radiation through radioactive decay of unstable radionuclides
tumor repopulation (during/after tx) associated with: (cobalt) or acceleration of electrons
1. Enhanced cell-mediated repair of radiation-induced damage  360 degree gantry rotation around a patient
2. Active concentration of chemical radioprotectors
3. Cellular hypoxia or nutritional deficiency RADIATION BIOLOGY

 Nuclear DNA – the essential target of therapeutic radiation

 Radiation-induced DNA Damage:
o 1/3: from direct interaction of photons ionizing atoms
within DNA
o 2/3: consequence of indirect damage done by freely
diffusing hydroxyl radicals (cOH)
 Bystander Effect – lethal damage to cellular proteins, organelles
or cell-membrane in an irradiated cell -> neighboring cell death

 Not all radiation damage are lethal to the cells

 Some undergo sub-lethal DNA damage repair (both normal and
malignant cells)
 Increase time interval between radiation = increase cell survival
 Repair process: usually complete within 1-2 hours

 Tumor and Tissue oxygenation have implication in radiation

therapy:
o rapidly proliferating tumors may have poor blood supply
(poor oxygenation) particularly at the center of large
tumors -> radiation resistance (increase cell survival
after irradiation)
 Oxygen Enhancement Ratio
o radiation dose needed to kill hypoxic cells compared to
aerated cells -> 3:1
o for O2 to have its maximal effect: dissolved O2 of tumor:
3 mmHg
o e.g.: cervical cancer patient, Hgb > 10mg/dl has
improved tumor oxygenation -> superior local control/
7S-2 PRINCIPLES OF RADIATION AND CHEMOTHERAPY ESTUYE | HO | JAVIER | RAMOS | ROCHA
PAGE 1 of 5
 clinical outcomes; or may give hypoxic cell sensitizers
like nitroimidazoles
 Rate of Energy Lost per Unit Path Length of Medium or Linear
Energy Transfer (LET) has effect on radiation-induced DNA
damage
 Cell death is independent of tumor oxygenation
 Low LET – infrequent energy loss along path length; produces sub-
lethal event: multiple hits needed to kill the cell
 High LET – probability of producing lethal event in a cell is higher
 + Radioprotector (e.g. Amifostine) to decrease radiation-induced
DNA damage and limit normal tissue radiation-related side effects
 Studies: chemoprotectant; reduce renal toxicity associated with
repeated Cisplatin Tx (ovarian CA)
 Cell death: cessation of cellular respiration and vital function
 Death in Radiation Biology: loss of cellular integrity or inability to
maintain uninterrupted cellular proliferation with high fidelity
 Radiation kills without the physical disappearance of malignant
cells (may be engulfed by macrophages) causing tumor to shrink
in size
 Malignant cells may remain part of the tumor but discontinued
cellular metabolism and proliferation
 Mitotic cell death: the cells die at the next or a subsequent cell
division; all progeny also dying
 + inflammation – resulting in local adverse side effects
 Alternative forms of loss of reproductive capacity caused by
radiation:
o Terminal differentiation
o Senescence
o Apoptosis – complex process of programmed cellular
involution and phagocytosis by neighboring cells
 DNA Double-stranded Breaks – most crucial radiobiologic effect
of radiation therapy
7S-2 PRINCIPLES OF RADIATION AND CHEMOTHERAPY
RADIOSENSITIVITIES IN CELL CYCLE
 M phase – radiosensitive; causes lethal DNA double strand breaks
 S phase – cells are radioresistant – enzymes responsible for
ensuring high-fidelity DNA replication are relatively overexpressed
and recognize altered DNA bases or inappropriate strand breaks
 G1/G2 phase – relatively radiosensitive compared to S phase
BRACHYTHERAPY
 Involves placement of radioactive sources within the existing body
cavity (e.g. vagina)
 In close proximity to the tumor
 Radioactive sources placed within hollow needles implanted
directly into the tissue for irradiation (interstitial implant) or within
hollow cylinder in tandem into the uterus through cervical os
 40-70 cGy/hr (low dose)
TELETHERAPY
 Form of external beam radiation
 Source of radiation is at a distance from the woman
 Sometimes located 5-10x more than the depth of tumor for
irradiation (distance: source-to-source distance or SSD)
 180-200 cGy/day given 5x/week
 Radiation dose delivered to tumor is affected by:
o Energy of the source
o Depth of the tumor beneath the surface
o Size of the field undergoing irradiation
TISSUE TOLERANCE AND RADIATION COMPLICATIONS
ADVERSE RADIATION EFFECTS – important for physicians to
understand critical issues and organ systems at risk or radiation damage
 Early or Acute Effects
o Manifest as a result of death in large population of cells
within days or weeks after initiation of radiation therapy
o Acutely affects tissues undergoing rapid cell division to
replace the lost normal functioning cells
o Skin, intestinal mucosa, mucosa of the vagina and
bladder, hematopoietic system
 Late Effects
o Occur after a delay of months or year after the radiation
o Often the product of parenchymal connective tissue cell
loss and vascular damage
o May be seen in slowly renewing cells
o Lung, kidney, heart, liver, CNS
 Gynecologic Cancers
o Includes tissue necrosis
o Fibrosis
o Fistula formation
o Ulceration
 Skin Effects
o Reddening of the skin -> dry or moist skin breakdown ->
desquamation (loss of actively proliferating basal layer of
the epidermis)
o Loss of hair
o Late skin fibrosis
 Radiation-induced Normal Tissue Damage:
o Bladder – radiation cystitis, hematuria, ureteral stricture,
bladder fibrosis, reduced bladder capacity
o Intestines/ rectum – sigmoiditis, enteritis, diarrhea,
bleeding, radiation proctitis, bowel stenosis, enteric
fistula, bowel perforation
o Lowering circulating lymphocytes, granulocytes,
platelets, and RBCs (EBRT)
ESTUYE | HO | JAVIER | RAMOS | ROCHA
PAGE 2 of 5
 o Fistulas between vagina and bladder (vesicovaginal or FOUR WAYS IN WHICH CHEMO IS USED FOR TREATMENT OF
between vagina and rectum (rectovaginal): usually GYNECOLOGIC CA
occurs between 6-24 months after treatment
1. Neoadjuvant chemotherapy: induction treatment for an advanced
II. CHEMOTHERAPY disease
2. Adjunct to Radiation Therapy
 For gynecologic surgeries: evolved since 1940’s 3. Primary treatment after tumor debulking/surgery
 Discovery of cisplatin and cyclophosphamide – combo for 4. Consolidation after a complete response to target undetectable
standard of care microscopic disease.
 1980’s: Paclitaxel + Cisplatin – standard of care for ovarian CA
 Over-all: primary chemotherapy should include a taxane and a HOW TO ASSESS CLINICAL RESPONSE TO TREATMENT
platinum agent.
 Physical examination
CHEMOTHERAPY PRINCIPLES AND GUIDELINES  Imaging (CT or MRI)
 Serial assessment of specific tumor markers (CA 125 or βHCG)
 Cancer is composed of heterogenous cells with:
o Different cell cycle durations CHEMOTHERAPEUTIC AGENTS
o Varying growth fractions
o Diverse expression of genes 1. Platinum compounds
o Potential mutations and proteins responsible for cell 2. Taxanes
proliferation and metastasis 3. Anti-tumor antibiotics
 Challenge: 4. Vinca Alkaloids
o Intrinsic and acquired drug resistance of gynecologic 5. Biologic and targeted therapy
cancers. 6. Anti-cancer hormones

 Fractional Cell Kill: constant fraction of tumor cell population
killed for each dose of chemotherapy.
 Dose Intensity: high chemo dose in short rest periods of
producing greatest tumor kill
 Drug Resistance: single chemo agent isolates drug resistant
tumor cells leading to overgrowth of hardy resistant malignant
cells.
 Cell Cycle Dependency of Cell Kill: Actively proliferating tumor
cells most often killed by chemo agents.
APPROACHES TO TREATMENT
 Dose of anticancer chemo agent: calculated as a function of
body surface area (BSA- square meters m 2)
 Chemo agents: varying toxicity
 Most agents are administered in IV from weekly to 3 or 4 week
intervals between each cycle.
 If mature WBC (Absolute Neutrophil Count) and platelets :
delay treatment or dose reduction.
 Major problem: Bone marrow toxicity (others: hepatotoxicity,
renal toxicity)
o Doxorubicin (Adriamycin) and Paclitaxel: metabolized
in the liver
o Methotrexate and Cisplatin: effects increases if + renal
damage.
 Chemo agents can be toxic to other organs
 Primary toxicities
o Nausea and vomiting: prevented by serotonin
antagonist + steroid
o Myelosuppression: may use myeloid growth factor G-
CSF
o Loss of ovarian function and fertility
GOAL OF TREATMENT
PLATINUM ANALOGUES
 Cisplatin and Carboplatin: most active and widely used chemo
agent
 Platinum (PLT) analogues form PLT-DNA adducts that
intercalate the DNA, interrupting DNA synthesis
 Forms toxic intermediates in the presence of radiation-induced
free radicals
 Increased cellular platinum uptake
 Inhibition of DNA repair
 Cell cycle arrest at G2-M transition
 Given in IV or IP, emetogenic
 Effects:
o Hypomagnesemia: Mg replacement
o Nephrotoxic: needs copious hydration and mannitol
infusion
o Induces myelosuppression
o High frequency ototoxicity
o Severe peripheral neuropathy
 Carboplatin
o Analogue of cisplatin
o For ovarian epithelial carcinoma
o Mechanism of action: same as Cisplatin but less
potent in producing DNA interstrand cross-links
compared to Cisplatin
o Excreted renally but not associated with same degree of
nephrotoxicity as Cisplatin (rigorous prehydration not
required)
o Effects:
 Neurotoxicity, nausea and vomiting (lesser
extent)
 Myelosuppresion
(thrombocytopenia: dose limiting toxicity)
 Less common: alopecia, hepatotoxicity,
ototoxicity
 Reported with more hypersensitivity reaction
(given histamine and steroids;
desensitization)

 To provide high dose chemo agent at planned frequency defined

by clinical data
 To produce maximum chemotherapeutic effectiveness without
causing unacceptable toxicity and side effects

7S-2 PRINCIPLES OF RADIATION AND CHEMOTHERAPY ESTUYE | HO | JAVIER | RAMOS | ROCHA

PAGE 3 of 5
TAXANES
 Paclitaxel
o Naturally derived from the bark of the Pacific or Western
Yew (Taxus brevifolia)
 Docetaxel
o From the bark of the English Yew (Taxus baccata)
 Both promote microtubule assembly
 Inhibit depolymerization of tubulin during mitosis (M phase)
 Arresting cell division in M phase
 With activity in most solid tumors
 Associated with hypersensitivity reactions and hypotension
 Neutropenia: major toxic side effect
 Other serious problem: peripheral neuropathy
 Also reported: bradycardia and severe cardiac problems
 Rare complication: bowel perforation
 May be used also in other CA: other cervical, endometrial, uterine
sarcomas.
ANTITUMOR ANTIBIOTICS
 From products of bacterial or fungal cultures
o Actinomycin D (Dactinomycin)
o Doxorubicin
o Bleomycin
 Actinomycin D
o From bacteria Streptomyces parvulus
o Used primarily in the treatment of GTD
o MOA: lodges between adjacent purine-pyrimidine
(guanine-cytosine) base pairs
o Blocking DNA-dependent ribosomal RNA synthesis by
RNA polymerase
o Maximally effective in G1 phase of the cell cycle
o Data suggest: may act throughout the entire cell cycle
o Effects:
 Severe myelosuppression: leukopenia and
thrombocytopenia
 Toxicity to GI mucosa: vomiting, stomatitis
and non-bloody diarrhea
 Reversible alopecia
 Dermatitis
 Doxorubicin
o From bacteria Streptomyces peucetius vs caesius
o MOA: wedges between stacked nucleotide pairs in the
DNA helix – inhibits DNA directed RNA and DNA
transcription; DNA replication
o Maximal activity in G1 and S phases of the cell cycle
o 2nd MOA: inhibition Topoisomerase II: assists in the
coiling and supercoiling DNA prior to mitosis; facilitates
DNA double-strand breaks
o Metabolized in the liver
o Effects:
 Myelosuppression
 Reversible alopecia
 Significant cardiotoxicity (binds with cardiac
myocytes) – irreversible CHF
 Skin Toxicity: palmar plantar
erythrodysesthesia (PPE)
 Bleomycin
o From bacteria Streptomyces verticillus
o MOA: when complexed with ferrous iron – potent
oxidase.
o Producing single-strand DNA breaks by hydroxyl radical
formation
o Excreted via kidney
o Effects:
 No significant myelosuppression
 Highly toxic to lungs: pneumonitis, pulmonary
fibrosis (10%)
 Toxic to skin: erythema, peeling, pigmentation
 Particularly effective in ovarian germ cell
tumors
7S-2 PRINCIPLES OF RADIATION AND CHEMOTHERAPY
TOPOISOMERASE I AND II INHIBITORS
 DNA enzymes that control the topology of cellular functions
during transcription and replication
 Examples:
o Topotecan
o Etoposide
 Topotecan
o For treatment of cervical and epithelial ovarian CA
o Inhibits topoisomerase I: breaks and ultimately cell
death
o Semisynthetic analog of camptothecin from
Camptotheca acuminata tree native in China
o Relaxes DNA structural tension facilitating single-
strand breaks
o Greatest activity during G1/S phases of cell cycle
o Toxicities: Bone marrow suppression, nausea,
vomiting, alopecia, mucositis and diarrhea.
 Etoposide
o Epipodophyllotoxin
o Derived from the root of mayapple and mandrake
plant
o Stabilizes DNA strand breaks by topo II during
coiling and supercoiling of DNA during mitosis
o Toxicities: Myelosuppression, anorexia, nausea,
vomiting, stomatitis, severe hypotension (infused
less than 30 mins)
ALKYLATING AGENTS
 Chemical compounds that facilitate replacement of hydrogen
from an alkyl group – disrupting normal function of the altered
molecule.
 Interact directly with DNA by transferring positively charged alkyl
groups to negatively charged chemical groups
 Affects rapidly dividing cells: bone marrow
 e.g. Cyclophosphamide and Ifosphamide
 Both drugs interact with N7 position of guanine in DNA helix –
impair the functional binding of enzymes used to process or
replicate DNA.
 Disrupts G1/S phase transition of the cell cycle
 Effects: leukopenia, thrombocytopenia, alopecia, nausea,
vomiting, amenorrhea.
ANTIMETABOLITES
 Interfere with cell metabolism by competing with naturally
occurring purines and pyrimidines
 Interfere with vital biochemical reactions
 5-Fluorouracil (5-FU)
o Perturbs normal progression through G1/S transition
o Toxicities: myelosuppression, stomatitis, diarrhea,
alopecia, nail changes, dermatitis, acute cerebellar
syndrome, cardiac toxicity, hyperpigmentation
 Methotrexate
o Folic acid analogue that binds tightly to dihydrofolate
reductase– critical role in intracellular folate
metabolism
o Metabolic transfer of one carbon unit in the cell –
arresting DNA, RNA, and protein synthesis
o Hepatotoxic, severe myelosuppression, stomatitis,
nausea and vomiting
o Effective treatment of trophoblastic diseases.
ESTUYE | HO | JAVIER | RAMOS | ROCHA
PAGE 4 of 5
VINCA ALKALOIDS

 Bind to β-tubulin subunits of the mitotic spindles blocking

polymerization of the microtubules in the mitosis.
 Examples:
o Vincristine
o Vinrelbine

 Vincristine
o From periwinkle plant (Vinca rosea)
o Acts in cell dependent manner, blocking assembly of
tubulin and causing toxic destruction of mitotic spindle
arresting mitosis
o Severely neurotoxic

 Vinorelbine
o Semisynthetic vinca alkaloid from Vinblastine
o Affects late G2 and M phases

BIOLOGIC AND TARGETED AGENTS

 Monoclonal antibodies (Bevacizumab)

 Small tyrosine inhibitors (Sorafenib, Sunitinib, Pazopinib,
Cediranib)
 Added with first line and recurrent treatment regimens to improve
progression-free survival especially for ovarian cancers
 e.g. Bevacizumab, Targeted agents.

ANTICANCER HORMONE THERAPY

 Hormone therapy especially in breast cancer

 Estrogen and progesterone receptors clearly identified in
endometrial carcinomas
 Progestins e.g. Megestrol, DMPA, Delalutin
 Anti-estrogens e.g. Tamoxifen, Raloxifene
 Used in the treatment of endometrial carcinomas especially to well
differentiated tumors.

III. REFERENCES

 Comprehensive Gynecology (Lentz et al)

 PPT of Dra. Valencia
 Notes and Recordings of OBGYN2 Trans Team

7S-2 PRINCIPLES OF RADIATION AND CHEMOTHERAPY ESTUYE | HO | JAVIER | RAMOS | ROCHA

PAGE 5 of 5