PRINCIPLES OF RADIATION THERAPY

AND CHEMOTHERAPY IN
GYNECOLOGIC CANCER

VICTORINO C. GARCIA, JR., MD

Fellow, Philippine Obstetrical and Gynecological Society
Fellow, Philippine Society for Cervical Pathology and Colposcopy
Diplomate, Society of Gynecologic Oncologists of the Philippines
Radiation Therapy Principles
Radiation Therapy Principles
• The dose response curve of tumor cells after
radiation treatment follows a sigmoid curve, no
normal tissue damage, only a small proportion of a
tumor would be controlled by radiation-induced
damage. If one were to treat a total dose that could
eradicate almost all the entire tumor, irreparable
damage to normal tissue would often occur.
• The therapeutic goal of radiation therapy is to
balance attempts at maximum local control while
minimizing adverse symptoms of treatment and
normal tissue damage
Radiation Therapy Principles
• Fractional cell kill: Each radiation dose kills a
constant fraction of the tumor cell population.
Tumor cell kill follows a linear quadratic
relationship with a potential for cell-mediated repair
of radiation-induced damage between dose fractions
• Radiation dose rate: Large radiation doses per
fraction produce the greatest number of tumor cell
kills; these also produces the greater damage burden
on normal tissues leading to early and late adverse
complications
Radiation Therapy Principles
• Radiation resistance: Select malignant tumors
show reduced radiosensitivity, resulting in slow
tumor regression or renewed tumor
repopulation during and after radiation
treatment. This is associated with (1) enhanced
cell-mediated repair of radiation-induced
damage, (2) active concentration of chemical
radioprotectors, or (3) cellular hypoxia or
nutritional deficiency
Radiation Therapy Principles
• Cell-cycle dependency of cell kill:
▫ Actively proliferating cells are most often killed by
radiation therapy
▫ Ionizing radiation imparts its greatest cell-kill
effect during the mitotic phase (M phase) and to a
lesser extent the late G1 phase and the early DNA
synthesis phase (G1/S)
▫ Radiation has little effect during the late synthetic
phase (S phase)
Cell cycle
Basic Radiation Physics
• Matter is made up of subatomic particles that
are bound together by energy to form atoms
• Atom consists of a central core of one ore more
positively charged PROTONS and a zero or more
uncharged NEUTRONS surrounded by a cloud
of negatively charged orbital ELECTRONS
Basic Radiation Physics
• 4 fundamental forces that hold these subatomic
particles
▫ Strong nuclear force: acts over a short range,
keeping an atom’s protons from repelling one
another because of similar electrostatic charge
▫ Coulomb/ electromagnetic force: binds orbital
electrons to the nucleus such that the closer an
electron is to the nucleus, the higher the binding
energy an electron has.
▫ Weak force
▫ Gravitational force
Basic Radiation Physics
• When an atom is neutral it has no charge.
• When charge is acquired, an atom is said to be ionized
• Removal of an orbital electron renders an atom
positively charged
• Addition of an electron results in a negative charge
• Atoms can also undergo excitation, a process whereby an
incident particle’s energy is not sufficient to eject an
atom’s orbital electron but rather raises one or more
electrons to a higher orbital energy state
• Though these types of interactions that radiation therapy
elicits biologic consequences within tissues
Basic Radiation Physics
• Radiation itself can be defined as the emission and
propagation of energy through space or a physical
medium.
• Radiation can be particulate, meaning that units of
matter with discrete mass and momentum propagate
energy (for example, alpha particles, protons, neutrons,
electrons) or can be electromagnetic (photons), meaning
energy travels in oscillating electric and magnetic fields
that have no mass and no charge and that have velocity
of the speed of light.
• Both particulate radiation and electromagnetic radiation
can ionize atoms, events occurring randomly throughout
the medium
Basic Radiation Physics
• In the treatment of gynecologic malignancies,
the most common source of radiation is
electromagnetic (photon) radiation.
• Photons are generally referred to as either x-rays
(extranuclear or from the atom) or gamma rays
(from the nucleus) based on origin
• Important properties of photons include its
wavelength (λ). Frequency (v), speed c=(λ v), and
energy E=(hv), where h is Planck’s constant
Basic Radiation Physics
• A photon’s energy E is proportional to its
frequency. The higher energies are transmitted
at higher frequencies. Frequency of a photon is
inversely proportional to the wavelength,
electromagnetic radiation with shorter
wavelength has higher frequency and thus
higher energy.
• Energy used is measured in electron volts; 1 eV =
1.6 x 10 -19 J, and it takes approximately 34 eV to
generate one ion pair in water
Basic Radiation Physics
• The photons used to treat gynecologic cancer can be
generated either externally at a distance from the
patient’s tumor (teletherapy) or internally close to the
patient’s tumor (brachytherapy).
• Teletherapy x-ray radiotherapy units can deliver a range
of photon energies from 50keV to more than 30MeV
• Nuclear decay of radioactive isotopes generates the
gamma ray photons used in brachytherapy, and such
decay or disintegration was measured in curies. One Ci is
defined as 3.7 x 1010 disintegrations per second, which is
equivalent to the rate of disintegration of 1 g of radium.
Modern standard of unit is Becquerel (Bq), which is one
disintegration per second or 2.7 x 10-11 Ci
Inverse square law

•The transmitted energy

diverges at a distance it travels
from the source increases.
•This divergence causes a
decrease in energy, and the
relationship is described by the
inverse square law
•The inverse square law states
that the energy dose of
radiation per unit area
decreases proportionately to
the square of the distance from
the site to the source (1/r2)
•For example, the dose of
radiation 3cm from a point
source is only one ninth of the
value of the dose at 1cm
Therapeutic Radiation Production
• Teletherapy in the form of external beam radiation
treatment produces ionizing radiation through
radioactive decay of unstable radionucleotides such
as cobalt (60Co) or more commonly, through
acceleration of electrons
• Collimators consisting of interleaved bars or
custom-made blocks can shape the treatment beam
to conform the dose to the target volume
• 60Co source has a half-life of 5.263 years and thus
the source must be replaced every 5 to 7 years
Therapeutic Radiation Production
• In the typical linear accelerator unit, electrons are
“boiled” off a filament and accelerated under vacuum
along an accelerating wave guide using alternating
microwave fields
• These accelerated electrons can be used to treat the
patients themselves or can hit a high Z material
transmission target to produce photons of various
energies by interaction known as bremsstrahlung or
“Braking radiation”
• Currently, most treatment machines generate photon
energies of 4 to 20 MeV and similar to 60Co teletherapy
units have 360-degree gantry rotation around the patient
• Typical linear accelerator dose rates are 3 Gy/min at
100cm from the source
Therapeutic Radiation Production
• Differences between 60Co and linear accelerator:
▫ a 60Co unit is always “on” when the source is not shielded
use radioactive decay always occurs, where as a linear
accelerator is “on” only when energized because there is no
radionucleotide source
▫ The photon spectra are different in that 60Co has a discrete
average monoenergenetic energy, whereas linear
accelerators produce photons of variable energies and an
average energy of one third the maximum generated energy
▫ 60Co produces treatment beams using only gamma ray
photons, whereas linear accelerator produces treatment
beams of either electrons or x-ray photons depending on its
treatment mode
5 Possible electromagnetic (photon)
interactions with matter
1. Coherent scattering (<10keV) occurs when an incident
photon scatters off an atom’s outer orbital without
losing energy. This produces no radiobiologic effect
2. Photoelectric effect (10-60 keV) occurs when an
incident photon interacts with an inner orbital electron
and the photon’s energy is completely absorbed by that
electron. If enough energy is transferred to the orbital
electron to exceed the binding energy of the inner
orbital electron, it is ejected, leaving a vacancy that an
outer orbital electron fills. When the outer orbital
electron fills the vacancy, a characteristic x-ray is
produced with energy equal the difference in binding
energy between the two electron orbitals
3. Compton effect
(60 keV to 10 MeV)

•Cells are composed of

biomolecules dissolved in an
aqueous solution
•Incident photons (p)
randomly ionize cellular water
to produce an ion radical
(water+) and a free fast
electron that can damage
biomolecules such as DNA
•The water ion radical interacts
with another molecule of water
to form a hydroxyl radical
(OH).
•Most often formed hydroxyl
radicals diffuse throughout the
cell, breaking chemical bonds
in target tissues such as
proteins and DNA
4. Pair production (>10 MeV) occurs when an incident photon
has an energy greater than 1.022 MeV. This threshold is
required because the photon disappears to form an
electron-positron pair. Once formed, free electrons slow by
nuclear attraction and are quickly stopped in tissues.
Positron emission tomography scanners build images based
on coincident detection of photons formed by this process

5. Photodisintegration (>10 MeV): occurs when an energetic

photon penetrates the nucleus of an atom and dislodges a
neutron. Emitted neutrons cannot ionize tissue themselves
because they have no charge, but rather collide with
surrounding atomic nuclei to produce recoil, positively
charged protons that elicit radiobiologic effects through
subsequent ionizations
• One-third of radiation induced DNA damage is from
direct interaction of incident photons ionizing atoms
within DNA itself
• Two-thirds is a consequence of the indirect damage
by freely diffusing hydroxyl radicals (.OH)
• As the time interval between radiation doses
lengthens, cell survival increases due to the prompt
repair of radiation-induced damage. The repair
process is usually complete within 1 to 2 hours,
although may be longer in some slowly renewing
tissues
Radiation biology
• Intracellular molecular oxygen importantly modifies
radiation-induced DNA damage as it “fixes” damage by
free hydroxyl radicals. Molecular oxygen, when present,
reacts with the altered chemical bonds of ionized
molecules to produce organic peroxides, the
nonreparable form of the target molecule. Molecules
“fixed” in this manner are permanently altered and may
function abnormally.
• Practical implications in radiation therapy in gynecologic
cancers: rapidly proliferating malignancies, may have
poor blood supply, which decreases tumor cell
oxygenation, particularly at the center. Tumor tissue
hypoxia leads to radiation resistance
Radiation biology
• The radiation dose necessary to kill the same
proportion of hypoxic cells as compared to aerated
approaches 3:1. This ratio is commonly referred to
as the oxygen enhancement ratio. For oxygen to
have its maximal effect, dissolved oxygen
concentration in tumor must be approximately
3mmHg (venous blood is 30-40mmHg)
• In cervical cancer, serum hemoglobin greater than
10md/dL have improved tumor oxygenation
Radiation biology
• LET-rate of energy lost per unit length of medium,
imparts an effect on the accumulation of radiation
induced DNA changes.
• Low LET radiations produce one or more sublethal
events and thus necessitate multiple “hits” to kill the
cell
• Heavy particulate radiation resulting from alpha
particles or photons is densely ionizing as energy is
deposited more diffusely along its path, typical of
high LET radiation. High LET radiation- producing
high probability of lethal event in the cell. Cell death
is independent of tumor oxygenation
Cell Survival curves
•Cell death following radiation
therapy is modeled by a linear
quadratic relationship
•The initial slope of the cell
survival curve is shallow and
curvilinear, whereas the terminal
slope is more linear
•In the low dose region of the
survival curve typical of daily-dose
fractions used in radiation therapy,
the fraction of cells surviving is
high due to the repair of single-
event sublethal damage
•In the high dose region of the
survival curve, the fraction of cell
surviving in the form of DNA
double-stranded breaks or
accumulation of too many
sublethal events that can be
repaired before the next cell
division
Phases of the cell
•After mitosis (M), there is an
interval of variable duration during
which there is RNA and protein
synthesis and a diploid DNA
content (G1)
•The cell may also enter a
prolonged or resting phase (G0)
and then reenter the cycle during
DNA synthesis, the S phase, in
which DNA is duplicated.
•During the G2 phase, there again
is protein and RNA synthesis.
•During the M phase, the cell
divides into two cells, each of
which receives diploid DNA
Brachytherapy
• Involves the placement of radioactive sources within an
existing body cavity, eg., the vagina
• Radioactive sources are “afterloaded” some time later to
reduce radiation exposure to medical personnel
• The most widely used intracavitary applicator is the
Fletcher-Suit applicator, which is useful for treatment of
a cervical tumor or a tumor located near the cervix
• Radioisotopes with a short half-life such as 198Au may be
placed within the patient and left permanently. Those
with long half-life 137Cs are placed temporarily and are
removed after prescribed dose of radiation
Brachytherapy
Half-Lives of Commonly Used Radioisotopes
for Gynecologic Malignancies
Radionuclide Half-life
Gold (198Au) 2.7 days
Phosphorus (32P) 14.3 days
Iridium (192Ir) 73.8 days
Cobalt (60Co) 5.26 years
Cesium (137Cs) 30 years
Radium (226Ra) 1620 years
Teletherapy
• In the form of external beam radiotherapy
means that the source of radiation is at a
distance from the patient, sometimes located at
a distance 5 to 10 times greater than the depth of
the tumor being irradiated. This distance is
referred to as SSD (source to surface distance)
• Collimators limit scatter radiation and block
portions of the treatment beam from delivering
intolerant radiation dose to critical tissues
Teletherapy
•Isodose curves and depth dose
distributions for 6 and 22 MeV
photons shown
•For the 6 MeV, the maximum
dose near the surface with a
more rapid falloff in the deeper
tissues
•For the 22MeV, the maximum
dose is deep to surface, sparing
the effects of radiation on the
underlying skin
Tissue Tolerance and Radiation
Complications
• Early or acute effects: which involves tissues
undergoing rapid cell division to replace lost normal
functioning cells. Eg., skin, intestinal mucosa,
mucosa of the vagina and bladder, and the
hematopoietic system
• Late effects occur after a delay of months or years
after radiation therapy. Late effects often a product
of parenchymal connective tissue cell loss and
vascular damage. Late effects may be seen in slowly
renewing tissues such as lung, kidney, heart, liver
and CNS
• Late adverse effects include necrosis, fibrosis, fistula
formation, ulceration
Tissue Tolerance and Radiation
Complications
• Erythema progressing to dry or moist skin: treat with non-
metal containing creams and emollients
• Late skin fibrosis: use pentoxifylline and vitamin E
• Radiation cystitis manifested as dysuria, frequency treat with
analgesics such as pyridium
• Hematuria: use sclerosing solutions or fulguration through a
cystoscope
• Damage to bowel (sigmoiditis/enteritis)manifesting as
increased bowel motility or diarrhea: low roughage diet and
antispasmodic; worst cases bowel resection/colostomy
• Hematologic: growth factors: erythropoietin, granulocyte
colony stimulating factor
• Fistulas: diverting surgery or resection of fistula
Normal Tissue Tolerance to Radiation
Tissue Tolerance (Gy)
Kidney 20-23 Gy
Liver 25-35 Gy
Small Bowel 45-50 Gy
Rectum 60-70 Gy
Bladder 60-70 Gy
Vaginal mucosa 70-75 Gy
Cervix >120 Gy
Chemotherapy Principles and
Guidelines
• Fractional cell kill: Each dose of chemotherapy
kills a constant fraction of the tumor cell
population. Tumor cell kill correlates usually in
a linear relationship with the pharmacokinetic
parameter of the area under the drug
concentration curve (AUC)
• Dose intensity: High chemotherapy doses
interspersed with short test periods produce
greatest tumor cell kill in rapidly proliferating
malignancies
Chemotherapy Principles and
Guidelines
• Drug resistance: Single-agent chemotherapy
administration selectively isolates drug-resistant
tumor cells, leading to an outgrowth of hardy,
resistant malignant cells. Chemotherapy drug
resistance has been associated with (1) cell-
mediated modification of drug agents, (2) active
drug transport out of the cell and, (3) alteration
of drug activation or targeting
• Cell cycle dependency of cell kill
Approaches to treatment
• Dose of anticancer chemotherapy agent is
usually calculated as a function of body surface
area (square meters)
• Bone marrow toxicity- measure ANC-absolute
neutrophil count, platelet counts, use growth
factor, dosage reduction
• Hepatic metabolism and/or renal excretion, eg
doxorubicin and vincristine-metabolized in the
liver
Approaches to treatment
• Methotrexate and cisplatin- effects increased
with those with renal damage; both bound to
albumin and this binding is decreased if patient
taking sulfonamides or salicylates
• Chemotherapy can cause loss of ovarian function
and fertility
4 ways in which chemotherapy is
generally used
1. As an induction treatment for advanced
disease (neoadjuvant therapy) in which
additional treatment following chemotherapy
is planned
2. As an adjunct to radiation therapy
3. As primary treatment for cancer
4. By instillation into specific regions of the body
(e.g., intraperitoneal chemotherapy
RECIST (Response Evaluation Criteria in Solid
Tumors) Criteria to Assess Clinical response to
Therapy
• CR (Complete response) –disappearance of all
target lesions
• PR (Partial response)- 30% decrease in the sum
of the greatest diameters of target lesions
• PD (Progressive Disease)- 20% increase in the
sum of the greatest diameters of the target
lesions
• SD (Stable Disease)- small changes that do not
meet the above criteria
Evaluation of New Agents
• Phase I Trial: tests new drugs at various doses to
evaluate toxicity and to determine tolerance to the
drug. At the various doses tested, some therapeutic
effects may be observed, although this is not the
primary aim of the trial
• Phase II Trial: Tests the therapeutic effectiveness
and extent of toxicity of the drug at doses expected
to be effective against a specific tumor type
• Phase III Trial: Compares new treatment therapies
against treatment currently in use. For instance,
this trial design assess whether a new drug therapy
is superior, equivalent, or inferior to the
chemotherapy currently in use
Assessment of Performance Status
Score Karnofsky Performance Status
100 Normal, no complaints; no evidence of disease
90 Able to carry on normal activity; minor signs or symptoms of disease
80 Normal activity with effort; some signs or symptoms of disease
70 Cares for self but unable to carry on normal activity or do active work
60 Requires occasional assistance but is able to care for most personal needs
50 Requires considerable assistance and frequent medical care
40 Disabled; requires special care and assistance
30 Severely disabled; hospitalization indicated, although death not imminent
20 Very sick; hospitalization necessary’ active support treatment necessary
10 Moribund; fatal process progressing rapidly
0 Dead
Assessment of Performance Status
Grade Gynecologic Oncology Group Performance Status Scale
0 Fully active, able to carry on all predisease performance without
restriction
1 Restricted in physically strenuous activity but ambulatory and able to
carry out work of a light or sedentary nature, e.g., light housework,
office work
2 Ambulatory and capable of all self-care but unable to carry out any
work activities; Up and approximately ≥50% 0f waking hours
3 Capable of only limited self-care, confined to bed or chair >50% of
waking hours
4 Completely disabled; cannot carry on any self-care; totally confined to
bed or chair
5 Dead
Chemotherapy cell-cycle activity
•Alkylating agents facilitate
transfer of alkyl groups to DNA,
disrupting the G1/S transition
•Agents derived from bacteria
deregulate normal DNA and RNA
processing, slowing progression
through the G1/S and G2/M
transitions
•Antimetabolites result in faulty
base insertion into replicated DNA
or specifically inhibit rate-limiting
enzymes such as a ribonuclease
reductase that are needed to
produce deoxyribonucleotides for
DNA replication during the S phase
•Taxanes and vinca alkaloid agents
alter the mitotic spindle during
mitosis, preventing cell division
•Platinum agents show activity
throughout the cell cycle and cycle
form DNA structural adducts
limiting progression at various cell
cycle checkpoints
Platinum Agents
• Cisplatin and Carboplatin
• Primary treatment for ovarian, tubal, peritoneal,
endometrial, cervical, and vulvar cancers as well as
GTD
• Cisplatin binds to DNA causing intrastrand,
interstand and protein adducts and thereby
interferes with DNA processing and replication
synthesis
• Cisplatin is nephrotoxic, copious administration and
mannitol infusion prevent renal tubular necrosis
Platinum Agents
• Cisplatin induces myelosuppresion, high frequency
ototoxicity, severe peripheral neuropathy,
hypomagnesemia, hypokalemia, seizures, nausea
and vomiting
• Carboplatin is an analogue of cisplatin. Its
mechanism of action and antitumor activity is
similar to cisplatin. It is relatively nontoxic to the
kidney but more prone to leukopenia,
thrombocytopenia and anemia . Dose is usually
based on AUC, Typical dose 5-7 computed as dose in
(mg) = AUC x (creatinine clearance + 25)
Taxanes
• Paclitaxel (Taxol) and its synthetic analogue
docetaxel (taxotere) are derived from the bark of the
Western yew tree (Taxus baccata)
• Both promote microtubule assembly and inhibit
depolymerization of tubulin during mitosis. By
arresting cell division through a functional block of
the M phase
• Side effects: hypersensitivity reactions, hypotension,
neutropenia (major toxic effect), sensory peripheral
neuropathy
• Used in the treatment of ovarian, cervical,
endometrial cancers and uterine sarcomas
Antitumor Antibiotics
• Actinomycin D (Dactinomycin)
• Doxorubicin (Adriamycin)
• Bleomycin (Blenoxane)
Actinomycin D
• Derived from the bacteria Streptomyces parvulus
and used primarily for the treatment of GTD
• Drug lodges between adjacent purine-pyrimidine
(guanine-cytosine) base pairs blocking DNA-
dependent ribosomal RNA synthesis by RNA
polymerase
• Maximally effective in the G1 phase, but data
suggest that the drug may act all throughout the cell
cycle
• Causes myelosuppression- leukopenia and
thrombocytopenia , emesis, stomatitis, non-bloody
diarrhea, reversible alopecia, skin erythema
Doxorubicin
• Doxorubicin (Adriamycin) and its newer liposomal
formulation (Doxil) are anthracyclines derived from
the bacteria Streptomyces peucetius var. caesius.
• Drug wedges between stacked nucleotide pairs in
the DNA helix and because of its bulk, inhibits the
enzymes needed for DNA-directed RNA and DNA
transcription as well as DNA replication
• Maximal activity in the G1 and S pases, second
mechanism includes inhibition of topoisomerase II
in the G2 phase. Topoisomerase assists in the coiling
and supercoiling of DNA prior to mitosis
Doxorubicin
• Must be careful not to cause extravasation
during administration because it can lead to soft
tissue and skin necrosis and ulceration
• Causes myelosuppression, complete but
reversible alopecia, binds with cardiac myocytes
leading to congestive heart failure
• Adriamycin encapsulated with liposomes
(Doxil), less cardiotoxic
Bleomycin
• Derived from bacteria Streptomyces verticillis
• When complexed with ferrous iron, is a potent
oxidase producing single-stranded DNA breaks
by hydroxyl radical formation
• Toxic to the lungs, pnemonitis and pulmonary
fibrosis
• Effective against ovarian germ cell tumors
Antimetabolites
• Interfere with cell metabolism by competing
with naturally occurring purinse and
pyrimidines
• 5-Fluorouracil(5-FU)
• Methotrexate
• Gemcitabine
5-FU
• Is a fluorinated pyrimidine analogue resembling the
DNA nucleoside thymine and different from the
RNA nucleoside uracil by a fluorinated carbon in the
fifth position in the nucleoside ring
• Conversion of 5-FU into a fluorodeoxyuridine
monophosphate blocks DNA synthesis by covalently
binding to thymidylate synthase. This inhibits the
formation of de novo thymidylate, a necessary
precursor of thymidine triphosphate that is essential
for DNA synthesis and cell division
• 5-FU perturbs normal progression through the G1/S
transition
5-FU
• One advantage is that 5-FU can be administered as a
bolus or continuous infusion or orally as a prodrug
that is metabolized to 5-FU (capecitabine-Xeloda)
• Stomatitis, diarrhea, alopecia, nail changes,
dermatitis, acute cerebellar syndrome, cardiac
toxicity, hyperpigmentation over the vein used for
infusion, and hand=foot syndrome
• Used in conjunction with cisplatin as a
radiosensitizer in the treatment of advanced cervical
and vulvar cancer
Methotrexate
• A folic acid analogue that binds tightly to
dihydrofolate reductase, which plays a critical role in
intra cellular folate metabolism. This prevents
metabolic transfer of one carbon unit within the cell
and thereby arrests DNA, RNA, and protein
synthesis
• Predominant sensitivity to the S phase of the cell
cycle
• Administered IM, IV or orally
• Severe myelosuppression, stomatitis, nausea,
emesis, hepatotoxicity
• Used in GTD
Gemcitabine
• A synthetic deoxycytidine nucleoside analogue,
targets ribonucleotide reductase (RR), the rate
limiting enzyme in the deoxyribonucleotide
metabolism during the S phase. RR enzyme used to
transform ribonucleotides into deoxyribonucleotides
needed for DNA replication
• Toxicities: myelosuppression, elevation of liver
enzymes, nausea, vomiting, flu-like symptoms, and
fatigue.
• Used in the treatment of recurrent ovarian
carcinoma and uterine sarcoma
Alkylating agents
• Facilitates the replacement of hydrogen for an
alkyl group, potentially disrupting normal
function of the altered molecule. They interact
directly with DNA by transferring positively
charged alkyl group to negatively charged
chemical groups intrinsic to the DNA molecule.
• Examples of this class: Cyclophosphamide and
Ifosfamide
• Side effect: severe myelosuppression
Alkylating agents
• Cyclophosphamide and its structural analogue
ifosfamide are bifunctional cyclic phosphamide
esters of nitrogen mustard
• Both interacts with the N7 position of guanine
within the DNA helix to form cross-link bridges
between the same strand of DNA (intrastrand),
opposite strands of DNA (interstrand), and
between DNA and cellular proteins
• Disrupts G1/S phase
• Inactivated by liver and excreted by the kidney
Alkylating agents
• Urinary metabolite ACROLEIN results in
hemorrhagic cystitis
• Prophylactic hydration and administration of 2-
mercaptoethane sulfonate (MESNA), a
compound that binds acrolein, prevents
urotoxicity
• Leukopenia, thrombocytopenia. Alopecia,
nausea and emesis and amenorrhea
Vinca (Plant) Alkaloids
• Vinblastine
• Vincristine
• VP-16 (Etoposide)
• Vinblastine and vincristine are derived from the
periwinkle plant (Vinca rosea), both block the
assembly of tubulin and causing toxic
destruction of the mitotic spindle, which arrests
cellular mitosis
• Vinorelbine is a synthetic vinca alkaloid derived
from vinblastine and is a radiosensitizing agent
Vinca (Plant) Alkaloids
• VP-16 (Etoposide) is a epipodophyllotoxin derived from the
root oft he May apple or mandrake plant, stabilizes DNA
strand breaks made by topoisomerase II during coiling and
supercoling of DNA during mitosis
• Affects late G1 and M phases
• Vincristine is neurotoxic- numbness, motor weakness and
constipation
• Vinblastine is myelotoxic, but tend to be dose limiting
• VP-16 is myelotoxic, induces anorexia, nausea, emesis,
stomatitis, severe hypotension
• Uncommon toxicities: cardiotoxicity, bronchospasm and
somnolence
• Drugs are used to treat ovarian germ cell tumors, cervical
cancer (vinoreline), and GTD
Topoisomerase inhibitors
• Topoisomerases are DNA enzymes that control the
topology of DNA double-helix cellular functions during
transcription and replication of genetic material
• Topotecan, a topoisomerase I inhibitor, is used in the
treatment of cervical cancer and epithelial ovarian tumor
• Topotecan is a semisynthetic analogue of camptothecin,
a chemical derived from the Camptotheca accuminata
tree native to China
• Greatest activity during G1/S
• Toxicities: bone marrow suppression, nausea, vomiting,
alopecia, mucositis and diarrhea
Growth Factor receptors Targeting and
Hormone Therapy
• EGF family transmembrane receptor kinases:
HER2, HER3, HER4 and EGFR
• HER2 and EGFR overexpression results in
relative radioresistance among cancer, and
therefore drugs that target these receptors may
promote radiosensitization
• The chimeric antibodies against EGFR
(Cetuximab, Erbitux) and HER2 (trastuzumab,
Herceptin) are being investigated in gynecologic
cancers
Growth Factor receptors Targeting and
Hormone Therapy
• VEGF(vascular endothelial growth factor)- receptor-
targeted therapies have emerged as clinically efficacious
antiangiogenic and tumor-vasculature-stabilizing agents
• Bevacizumab (Avastin)- inhibit new blood vessel
proliferation limit successful growth of malignant cells
• VEGF render small vessels hyperpermeable to
circulating macromolecules, promoting steady tumor cell
oxygenation (and thereby enhancing radiation
sensitivity) and limiting intermittent tumor hypoxia
from random opening and closing of small vessels
• Used in advanced ovarian cancer
Growth Factor receptors Targeting and
Hormone Therapy
• Hormone therapy has been effective in the
treatment of breast cancer
• Estrogen and progesterone receptors clearly
identified in endometrial cancer and ovarian
epithelial carcinoma
• Progestins such as megestrol (Megace), depo-
medroxyprogesterone (Depo-Provera), and 17-OH
progesterone caproate (Delalutin) as well as
antiestrogens as tamoxifen and raloxifene, have
been used in the treatment of endometrial
carcinomas and seem to have their best effects
against well-differentiated tumors
Good morning!