CHEMOTHERAPY

Presentant:
dr. Dwi Cahya Puspitasari

BAGIAN/ KSM OBSTETRI DAN GINEKOLOGI

FAKULTAS KEDOKTERAN UNIVERSITAS SRIWIJAYA
RSUP Dr. MOHAMMAD HOESIN PALEMBANG
2022
 CHEMOTHERAPY

Has got the following objectives: Effective Chemotherapy:

Complete
01
Remission
Kill selectively the malignant
Partial
02 cells
Remission (30%)

Prevent Without producing serious

recurrence 03
irreversible harm to normal
cells.
04 Allevitae symptomps
 ↑ quality of life

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 CELL KINETICS

Cell cycle time Normal cells Cancer cells

Time needed a • Have inherent capacity to Uncontrolled & excessive
ploriferating cell  multiply proliferation
cell cycle  new • Controlled by external &
daughter cell internal forces Speed cell division =
normal cell
Vary widely (12-217 Classified as:
hours) • Proliferating cells: constant
cell division
• Quiescent cells: proliferate
under special conditions
• Static cells: rarely proliferate

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 CELL KINETICS

Doubling Time Growth Fraction Gompertzian Growth

Time taken by tumor Number cells in the tumor mass A tumor volume increases in
mass to double it size that are actively involved cell size  doubling time 
division phase. progressively longer

CELL CYCLE

M Phase  M Dividing tumor cells

phase = = most sensitive to
generation time cytotoxic agents Figure 1. The Cell
Cycle

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 DRUG ACTIVITY IN THE CELL CYCLE

Cell Cycle Non Spesific Cyclophosphamide

Cisplatin
Principle
Carboplatin
Each dose of cytotoxic drug killed constant
Cell Cycle Specific Actinomycin D fraction of neoplastic cell  log kill
On G1 hypothesis
On S Phase Methotrexate
5 FU
Doxorubicin Effect of drugs depends on:
• Tumor mass and growth rate
On G2 Bleomycin
Etoposide • Sensitivity of resting phase cells
• Immunocompetence of host cells
On M Phase Vinblastine • Type and dose schedule of agents.
Vincristine
Taxanes
G2 Nitrosoureas Combination agent chemotherapy > single
(BCNU, CCNU) agent therapy

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 SINGLE AGENT VS COMBINATION AGENTS

Principle Combination Agents

• Active as single agents
Combination attack • The specifity of drugs should differ
Combination (cell cycle
different phase cell cycle
specific + nonspecific)  • Different mechanisms should be
 ↓ tumor mass combine rather than drugs with
↑ tumor cell kill
effectively
similar action

Mechanism Drug Resistance

Dose & duration therapy
cannot be increased
Single agent therapt  ↑ • ↑ repair of DNA
drug resistance • ↓ cellular drug uptake
when single agent is used
• ↑ level target enzyme
• ↑ drug degradation
• Spontaneous tumor cell mutations

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 CLASSIFICATION CYTOTOXIC DRUGS

Based on Structural Similarity & Mechanism of Action:

Alkylating Agents Antimetabolites

• Cross-linking DNA strands  prevent cell • Inhibit essential metabolic processes
division (synthesis purine, pyrimidine, nucleic
• Produce single and double standed DNA Break acids)
Ex: cyclophosphamide, ifosfamide, melphalan, Ex: Methotrexate, 5-fluorouracil, 6-
tiotepa mercaptopurine, gemcitabine (new agent
Platinum: cisplatin, carboplatin, oxaliplatin used in ovarian, breast, cervical carcinoma)

Antibiotics Plant derivates and taxanes

• Nonspesicific agents  prevent DNA Specific agents  spindle poison  arrest
replication mitosis at metaphase. Tazanes: disturb the
• Ex: actinomycin D, bleomycin, doxorubicin, normal assembly. Camptothecin analogs:
mitocyn C inhibit topoisomerase-1
Ex: vincristine & vinblastine, etoposide
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 CLASSIFICATION CYTOTOXIC DRUGS

Based on Structural Similarity & Mechanism of Action:

Hormones Miscellaneous
Drugs induce regression of hormone responsive • Hexamethylamine: antimetabolite
tumor & ↑ anabolic processes. • Hydroxyurea: ↑ radiosensitivity malignant
Ex: progesterone preparations tissue
(hydroxyprogesterone caproate), antiestrogen
(tamoxifen)

Biological
• Improving host immune defense
Ex: Interferon, Mullerian inhibiting factor

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 TOXICITY
Depend on the drug type, method administration, dosage and general
condition of the patient.
Tissue or Toxic Effects and Drugs
organ affected
Gastrointestinal Nausea, vomiting, oral ulceration, stomatitis,
necrotizing enterocolitis, diarrhea (cisplatin,
methotrexate, paclitaxel, docetaxel, etoposide)
Hair Roots Alopecia (paclitaxel, cyclophosphamide)
Hematological Anemia, granulocytopenia, thrombocytopenia. The
(bone-marrow) danger level being: Hb percent < 8 gm percent,
leukocyte count < 3,000/mm3 and platelet count <
20,000/mm3 (paclitaxel, etoposide, carboplatin)
Skin Dermatitis, pigmentation (bleomycin),
extravasation, skin necrosis (actinomycin D,
doxorubicin)
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Management
Antiemetics used for emetogenic chemotherapy
Dexamethasone 20 mg IV
Ondansetron 8 mg IV every 4 hours 2–3 doses
Metoclopramide 80–120 mg IV every 3–4 hours
Generally reversible
Blood transfusion, platelet transfusion, drug dose
may be modified. Granulocyte colony-stimulating
factor (G-CSF) and granulocyte macrophage colony-
stimulating factor (GM-CSF) have been used (250
µg/m2, subcutaneously) for myelostimulation
For extravasation and skin necrosis—removal of
intravenous line, local infiltration of corticosteroids,
ice pack therapy
10
 TOXICITY

Tissue or Toxic Effects and Drugs Management

organ affected

Cardiac Cardiomyopathy, arrhythmias, endocardial fibrosis Discontinuation of drug, drug and dose modification,
(doxorubicin, cyclophosphamide), toxic myocarditis consult cardiologist
(Paclitaxel)
Liver epatitis, elevated transaminases, and bilirubin Discontinuation of drug, drug and dose modification
(methotrexate)
Lungs Fibrosis (bleomycin, alkylating agents doxorubicin) Pulmonary function tests, to stop therapy, steroids
may be helpful
Nervous System Neurotoxicity, ototoxicity, peripheral neuropathy Vitamin B complex, pyridoxine therapy, drug and
(cisplatin, ifosfamide) dose modification

Urinary System Renal failure, azotemia (cisplatin), hemorrhagic Prehydration and mannitol induced diuresis before
cystitis (cyclophosphamide, ifosfamide), red urine therapy, avoid simultaneous use of nephrotoxic drugs
(doxorubicin) (aminoglycosides). Mesna is used for hemorrhagic
cystitis due to cyclophosphamide or ifosfamide

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 TOXICITY

Tissue or Toxic Effects and Drugs Management

organ affected

Immune System Suppression of cellular and humoral immunity, loss Usually reversible
of host defense mechanism

Metabolix Hyperkalemia, hyperuricemia, hypocalcemia —due Estimation of serum electrolytes and appropriate
to rapid tumor lysis. Hyponatremia— due to correction
inappropriate ADH secretion
Surgical Wound Delayed healing

Gonads Infertility, amenorrhea, premature ovarian failure Patient counselling

Embryo Teratogenic effect, congenital malformations Patient counselling, to assess risk and benefits

Second Due to mutagenic effect-leukemia (melphalan)

malignancies

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 ROUTE OF ADMINISTRATION

Oral Parenteral Intraperitoneal

MEANS TO ASSES THE RESPON RESPONSE EVALUATION CRITERIA

SOLID TUMORS

• Clinical & physical examination • CR (complete response): disappearance all

• Assessing imaging studies (CT/MRI) lesions
• Serial measurement specific tumor • PR (partial response): diameter tumor ↓ 30%
markers • PD (progressive disease): diameter tumor ↑
• Detection hypermetabolic state by PET 20%
• SD (stable disease): small change, not meet
the above criteria

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 PRETREATMENT EVALUATION
• Hematological • Cardiac function
• Complete hemogram & platelet count
• ECG, ventricular ejection fraction
>100.000

• Pulmonary function
• Serum
• When bleomycin is used
• Electrolytes

• Throat swab, urine

• Renal functions
• For culture & sensitivity
• Serum urea, uric acid, creatinine,
creatinine clearance

• Liver function
• Serum proteins, liver enzymes, bilirubin

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 CALCULATION OF DOSE

Dose of chemotheraupeutic Surface area  reflexts Surface area better than

agent = calculated as square cardiac output & blood body weight
meter of body surface area. flow

USES OF DRUGS

Minor complications like nausea, vomiting, alopecia,

glossitis should not preclude full treatment protocol

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 USES OF DRUGS
Drugs Dosage & route of therapy Type of Neoplasm Toxicity Precaution

Alkylating 750–1,000 mg/m2 of body Carcinoma Bone marrow Adequate fluid

agent surface/IV. Ovary depression (BD), intake
ˆCyclophosp Single dose every 3 weeks 50–110 Endometrium alopecia, cystitis
hamide mg/m2 by mouth (PO) Cervix
(Endoxan) Fallopian tube

Ifosfamide 7-10 gm/m2 IV over 3–5 days, to be Carcinoma and sarcoma of BD, alopecia, Uroprotectant
(Ifex) repeated every 3–4 weeks Ovary cystitis (mesna)
Cervix
Endometrium
Cisplatin 50–75 mg/m2 IV every 1–3 weeks Ovary Nephrotoxicity, Adequate
(cis-diamine —usually 4–6 such 300–400 mg/m2 Endometirum neurotoxicity, prehydration,
dichloroplati IV. Cervix myelosuppression, monitor renal
num) Repeat every 3–4 weeks for 6 thrombocytopenia function
Carboplatin courses

Oxaliplatin 59–130 mg/m2 IV over 2 hours, Ovary Myelosuppression, Contraindicated in

every 3 weeks peripheral hepatic and renal
neuropathy dysfunction
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 USES OF DRUGS
Drugs Dosage & route of therapy Type of Toxicity Precaution
Neoplasm

Melphalan 0.2 mg/kg/day orally × 5 days. Cervix, Ovary, BD -

(Alkeran) Repeat after 4–6 weeks Endometrium,
Fallopian tube
Chlorambucil 0.1–0.2 mg/kg of body weight Cervix, Ovary, BD Adequate fluid
(leukeran) orally/day for 4–6 weeks Endometrium, intake
Fallopian tube
Antimetabolit 10–30 mg/day PO × 5 days 240 Choriocarcinoma BD, megaloblastic anemia, Adequate renal
es mg/m2 IV with leucovorin rescue • Carcinoma stomatitis, vomiting, alopecia, function and urine
Methotrexate ˆ Ovary hepatic/ pulmonary fibrosis output to maintain
ˆ Cervix
5-Fluorouracil 10–15 mg/kg/day IV × 5 days. Carcinoma Bone Mineral Density (BMD), Dose reduction with
(5-Fu) Repeat after 3-4 weeks. 10–15 Ovary diarrhea, stomatitis, alopecia compromised renal,
mg/kg IV weekly, maximum up to Endometrium hepatic or bone
1 gram marrow function

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 USES OF DRUGS
Drugs Dosage & route of therapy Type of Neoplasm Toxicity Precaution

Gemcitabine 800–1000 mg/m2 IV weekly every 3 Carcinoma Myelosuppression -

weeks Breast, Ovary
Leiomyosarcoma of
uterus
Antibiotics 0.5 mg/m2/IV/weekly, repeat 3–4 Embryonal D, stomatitis, Dose adjustment in
Actinomycin weeks or 0.5 mg/m2/IV daily × 5 rhabdomyosarcoma, hyperpigmentation in liver disease and
D days 15 mcg/kg/day IV or 0.5 choriocarcinoma, ovarian areas of irradiation decrease bone
mg/day for 5 days germ cell tumors. marrow function
Mitomycin C 8 mg/m2/IV every 3 weeks Cancer cervix Neutropenia, Prevention of
thrombocytopenia, extravasation
oral ulceration
Doxorubicin 50 mg/m2/IV weekly. Repeat every Adenocarcinoma, BD, alopecia, cardiac Avoid insignificant
(adriamycin) 3–4 weeks Endometrium, Ovary, toxicity myopathy, heart disease, ECG
Vagina,Tube, Uterine stomatitis monitoring
sarcoma

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 USES OF DRUGS
Drugs Dosage & route of Type of Neoplasm Toxicity Precaution
therapy

Bleomycin 10–12 mg/m2/IV/IM • Squamous cell cancer of
weekly skin, vulva, cervix
• Choriocarcinoma, germ
cell and sex cord stromal
tumors of ovary
Skin: Hyperpigmentation, Avoid in renal or
ulceration, alopecia. Pulmonary: pulmonary disease
Pneumonitis, fibrosis, dyspnea

Plant 0.4–1.4 mg/m2 IV Uterine sarcoma • Ovarian Paresthesia, weakness, loss of Avoid extravasation,
derived weekly germ cell tumor reflexes, foot drop, BMD, dose adjustment
Vincristine reticulocytopenia, alopecia, with liver disease
(Oncovin) hoarseness, anemia
Vinblastine 5–6 mg/m2 IV every Choriocarcinoma BD, neutropenia, alopecia, Avoid extravasation,
(Velban) 1–2 weeks peripheral neuropathy dose adjustment
depression, weakness with liver disease
Etoposide 100 mg/m2 IV on GTN Leukopenia, thrombocytopenia, Dose reduction up
(Epipodophyl days — 1,3 and 5 Germ Cell tumors alopecia, headache, fever to 50% to prevent
lotoxin) repeat every 3–4 toxicity
weeks

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 USES OF DRUGS
Drugs Dosage & route of Type of Neoplasm Toxicity Precaution
therapy

Taxanes 10–12 mg/m2/IV/IM • 135–250 mg/m2 IV over Carcinoma • Ovary • Avoid in renal or
Paclitaxel weekly 3 hours every 3–4 weeks Endometrium • Cervix • Ovarian pulmonary disease
(taxol) 60–100 mg/m2 IV over 1 carcinoma
Docetaxe hour every 3–4 weeks
Campotheci .5 mg/m2 IV/day for 5 Ovary, servix BD To guard against
n analogs days; 4 mg/m2 IV on neutropenia
Topotecan D-1, D-8 every 3
weeks

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 USES OF ANTIEMETICS

The most side effect: nausea & vomiting

Due to stimulation of chemoreceptor trigger zone 

neutrotransmitters  serotonin, dopamine, histamine
activate vomiting center

Commonly used:
Ondansetron, Dexamethasone, Metoclopramide
Bevacizumab, matuzumab, trastuzumab

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 GROWTH FACTOR THERAPY

To minimize hematologic toxicity:

CYTOKIINES FUNCTION
- Myelosuppression
Granulocyte-macrophage • Stimulates
- Acute granulocytopenia colony stimulating factor hematopoiesis
- Thrombocytopenia (GM-CSF) • Activates granulocytes
and macrophages
Granulocyte-colony Activates granulocytes
stimulating factor (G-CSF)
Mostly from cytokines family Erythropoietin Stimulates erythroid growth
and development

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 OTHER CHEMOTHERAPEUTIC AGENTS: USE, TOXICITY AND
PRECAUTIONS

Hormones Progestogens Antiestrogen

• 17α-Hydroxyprogesterone caproate (1 g IM twice a
week for 1 year)
• Medroxyprogesterone acetate (Depo-Provera)
(400–800 mg orally/IM weekly for 1 year
• Megestrol acetate (Megace) (40–120 mg tablet
oral/day for 1 year)
– Type of neoplasm: Carcinoma • Endometrium
– Toxicity: • Hepatic dysfunction • Alopecia
– Precaution: Monitor liver function
• Tamoxifen (10–20 mg twice daily orally)
‒ Type of neoplasm: Carcinoma • Breast •
Endometrium
‒ Toxicity: Hot flashes, pruritus vulvae, vaginal
bleeding
• Leuprolide (Lupron) (1 mg daily SC)
‒ Type of neoplasm: Carcinoma • Endometrium
‒ Toxicity: Antiestrogen effects
‒ Precaution: Addback therapy

Miscellaneous
• Hydroxyurea (80 mg/kg PO every 3 days or 20–30 mg/kg/day)
‒ Type of neoplasm: Carcinoma cervix (with radiotherapy)
‒ Toxicity: Reduction of bone mineral density (BMD), megaloblastic anemia, stomatitis, alopecia, diarrhea
‒ Precaution: Dose reduction in bone marrow and renal dysfunction

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 CHEMOTHERAPY IN GYNECOLOGIC MALIGNANCIES

Type of neoplasm Indication(remarks) Chemotherapy used

Squamous cell • Adjuvant chemotherapy in combination • Various combinations are tried

carcinoma of cervix with radiation • Bleomycin/vincristine/doxorubicin/vinblastine
• Neoadjuvant chemotherapy • Cisplatin, actinomycin D, ifosfamide
• Palliation in recurrences • Mitomycin, hydroxyurea—to increase
radiosensitivity
Squamous cell In advanced or recurrence as palliation Bleomycin
carcinoma of vulva and
vagina
Endometrial carcinoma As a routine or in late cases Progestational agents, ifosfamide, doxorubicin,
cisplatin, tamoxifen, leuprolide
Endometrial sarcoma As an alternative to radiotherapy Doxorubicin and cyclophosphamide, VAC,
progesterone, ifosfamide
Tubal carcinoma Late cases Doxorubicin/melphalan/cyclophosphamide

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 CHEMOTHERAPY IN GYNECOLOGIC MALIGNANCIES

Type of neoplasm Indication(remarks) Chemotherapy used

Ovarian tumors • Stage 1A: May be used as a routine
• Epithelial carcinoma following surgery to improve the result
• Advanced stage
• Palliative chemotherapy
• Gradually replacing radiotherapy
• Neoadjuvant therapy
Single or multiple drug therapy:
Cisplatin or carboplatin (less toxic), taxol, melphalan,
thiotepa, chlorambucil, hexamethyl melamine,
cyclophosphamide and adriamycin/(CAP or CP),
gemcitabine.
Usually multiple drug therapy :
• Taxol and carboplatin
• Adriamycin and cyclophosphamide
• Adriamycin, cyclophosphamide and cisplatin

Gonadal stromal tumor: Alternative to postoperative radiotherapy • Vincristine + Adriamycin + Cyclophosphamide

• Granulosa cell tumor —do— (VAC)
Secondary metastatic • Bleomycin + Etoposite + Cisplatin (BEP) Depends
upon the primary lesion
Germ cell tumor Radiotherapy preferred Combination agents: Vinblastin, bleomycin and
• Dysgerminoma cisplatin (VBP) can be used for successful
treatment and preservation of fertility

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 CHEMOTHERAPY IN GYNECOLOGIC MALIGNANCIES

Type of neoplasm Indication(remarks) Chemotherapy used

• Endodermal sinus cell • Highly malignant Combination of drugs is used:

tumor, embryonal • Chemotherapy preferred • POMB-ACE = Vincristine, methotrexate,
carcinoma bleomycin, cisplatin, etoposide, actinomycin D,
• Choriocarcinoma cyclophosphamide
• Malignant immature • VAC therapy/BEP therapy/VBP therapy
teratoma, • Methotrexate/actinomycin
polyembryoma • Vincristine/adriamycin/cyclophosphamide
• Cisplatin/adriamycin/cyclophosphamide

Hydatidiform mole As a prophylactic therapy in selected • Methotrexate 5 days at every 14 days till β subunit
cases becomes negative, thereafter 3 such
• Actinomycin D—5 days every 14 days till β
subunit becomes negative
• Three courses thereafter

GTN Mainstay in the manage ment of GTN—

nonmetastatic and metastatic groups.

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 FORMALITIES MAINTAINED IN SYSTEMIC
CHEMOTHERAPY

Infusion set should

Drug used in The drugs should be
be flushed with
combination should washed through
normal saline
not be mixed with normal saline to
between of each
together avoid vein sclerosis
drug

Antiemetics should
Extravasation
be given before start
should be avoided
of therapy

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THANKYOU