Chemotherapy in Chemotherapy in GynecologyGynecology

Brief HistoryBrief History

Exposure of military seamen to mustardExposure of military seamen to mustard

gas in WW 2 resulted in marrow andgas in WW 2 resulted in marrow and

lymphoid hypoplasialymphoid hypoplasia

1943 – Yale Cancer Center 1st used1943 – Yale Cancer Center 1st used

Nitrogen Mustard to cure hematological Nitrogen Mustard to cure hematological neoplasmsneoplasms

Brief HistoryBrief History

1946 – Sidney Farber observed folic acid1946 – Sidney Farber observed folic acid

had proliferative effect on leukemic cellhad proliferative effect on leukemic cell

growthgrowth

development of folic acid analogs to development of folic acid analogs to

inhibit folate metabolisminhibit folate metabolism

Goals of chemotherapyGoals of chemotherapy

cure of cancercure of cancer

control of cancercontrol of cancer

palliation of symptoms of cancerpalliation of symptoms of cancer

Synth DNA precursors,proteins, etc.

Premitotic synth ofstructures, mol’s

Cell Cycle Phases

Cell cycle non specific drugsCell cycle non specific drugs

Can kill either dividing cells at any pointCan kill either dividing cells at any point

in the cell cycle. Examples:in the cell cycle. Examples:

Alkylating agentsAlkylating agents

Platinum compoundsPlatinum compounds

Cell-signaling inhibitorsCell-signaling inhibitors

Can kill non-dividing cells. Examples:Can kill non-dividing cells. Examples:

SteroidsSteroids

Antitumor antibioticAntitumor antibiotic

Basic Concepts ofBasic Concepts ofChemotherapyChemotherapy

FRACTIONAL CELL KILL HYPOTHESIS -FRACTIONAL CELL KILL HYPOTHESIS - each time the chemotherapy dose is repeated, each time the chemotherapy dose is repeated,

thethe same proportion of cells not the same absolutesame proportion of cells not the same absolute number, is killed.number, is killed.

3 LOG KILL, 1 LOG REGROWTH PRINCIPLE -3 LOG KILL, 1 LOG REGROWTH PRINCIPLE - in a tumor w/ 10in a tumor w/ 101010 cells, a cycle of chemotx will cells, a cycle of chemotx will result in 10result in 1033 (3 log kill) cells dying & 10 (3 log kill) cells dying & 1077 cells cells remaining. Hence remaining. Hence repeated cyclesrepeated cycles are are

required torequired to eradicate remaining and re-growing cells.eradicate remaining and re-growing cells.

Combination chemotherapy - indicationsCombination chemotherapy - indications

Prevention of resistant clonesPrevention of resistant clones

Cytotoxicity to resting & dividing cellsCytotoxicity to resting & dividing cells

Biochemical enhancement or effectBiochemical enhancement or effect

Sanctuary accessSanctuary access

RescueRescue

Prevention of drug resistancePrevention of drug resistance

Reduce tumor bulk with surgery/ Reduce tumor bulk with surgery/ radiotherapyradiotherapy

Use combinations including drugs thatUse combinations including drugs that

affect resting populationaffect resting population

Schedule drugs to prevent phase escape Schedule drugs to prevent phase escape or to synchronize cell populations and or to synchronize cell populations and increase cell killincrease cell kill

Contraindications for CTContraindications for CT

• • InfectionInfection• • NeutropeniaNeutropenia• • ThrombocytopeniaThrombocytopenia• • Severe debilitationSevere debilitation• • Pregnancy (1st trimester)Pregnancy (1st trimester)• • Major surgery <2 wks priorMajor surgery <2 wks prior• • Poor patient follow-upPoor patient follow-up• • Psychological problemPsychological problem• • Terminal illnessTerminal illness

Classification Classification

Alkylating agentsAlkylating agents

• • Antibiotic agentsAntibiotic agents

• • Antimetabolic agentsAntimetabolic agents

• • Biologic agentsBiologic agents

• • Hormonal agentsHormonal agents

• • Plant-derived agentsPlant-derived agents

• • Novel therapiesNovel therapies

Rang 50.4

AntimetabolitesAntimetabolites

Mimic structures of normal metabolic Mimic structures of normal metabolic mol’smol’s Inhibit enz’s competitively ORInhibit enz’s competitively OR Inc’d into macromol’s Inc’d into macromol’s inappropriate inappropriate

structuresstructures

Kill cells in S phaseKill cells in S phaseThree main groupsThree main groups Folate antagonistsFolate antagonists Pyr analogsPyr analogs Pur analogsPur analogs

50.8 Rand

DactinomycinDactinomycinIntercalates in DNA minor groove between adjacent Intercalates in DNA minor groove between adjacent GC pairsGC pairs

Interferes w/ RNA polymerase movement Interferes w/ RNA polymerase movement decr’d decr’d transcr’ntranscr’n

Also may work through topoisomerase IIAlso may work through topoisomerase II BleomycinBleomycin

GlycopeptideGlycopeptide

Chelates Fe, which interacts w/ O2Chelates Fe, which interacts w/ O2

Gen’n superoxide and/or hydroxyl radicalsGen’n superoxide and/or hydroxyl radicals

Radicals degrade DNA Radicals degrade DNA fragmentation, release of fragmentation, release of free basesfree bases

Most effective in G2, also active against cells in G0Most effective in G2, also active against cells in G0

Little myelosuppression BUT pulmonary fibrosisLittle myelosuppression BUT pulmonary fibrosis

Plant AlkaloidsPlant Alkaloids

Work at mitosisWork at mitosis

Effect tubulin, therefore microtubule Effect tubulin, therefore microtubule activityactivity Prevention spindle form’n ORPrevention spindle form’n OR Stabilize (“freeze”) polymerized microtubulesStabilize (“freeze”) polymerized microtubules

Arrest of mitosisArrest of mitosis

Other effects due to tubulin defectsOther effects due to tubulin defects Phagocytosis/chemotaxisPhagocytosis/chemotaxis Axonal transport in neuronsAxonal transport in neurons

Investigations to be done before and Investigations to be done before and during CTduring CT

Complete haemogram including platelet Complete haemogram including platelet

count.count.

Liver function testsLiver function tests

Blood Urea & S. CreatinineBlood Urea & S. Creatinine

Chest X-RayChest X-Ray

Chemotherapy preparationChemotherapy preparation

Hydration – 1l RLHydration – 1l RL

Antiemetics – Inj Ondonsetron 8mg i.v 8Antiemetics – Inj Ondonsetron 8mg i.v 8thth hrlyhrly

Inj. Ranitidiine 150mg 12Inj. Ranitidiine 150mg 12thth hrly hrly

Inj Dexamethasone 5mg 12Inj Dexamethasone 5mg 12thth hrly hrly

After chemotherapyAfter chemotherapy

Hydration – 1l NS with 40mg Frusemide i.vHydration – 1l NS with 40mg Frusemide i.v

Gestational trophoblastic Gestational trophoblastic neoplasianeoplasia

Clinical stage in GTNClinical stage in GTNAnatomic stage of trophoblastic cell Anatomic stage of trophoblastic cell tumortumorstageI tumor is located in uterusstageI tumor is located in uterus

stageII tumor spread to adnex,vagina,broad stageII tumor spread to adnex,vagina,broad ligamentligament

stageIIIstageIII tumor spread to lung,there is no tumor in tumor spread to lung,there is no tumor in reproductive systemreproductive system

stageIV metastasis to other organs stageIV metastasis to other organs

Protocol In GTNProtocol In GTN

Stage 1 – Single agent chemotherapy or Stage 1 – Single agent chemotherapy or

hysterectomy with adjunctive chemotherapyhysterectomy with adjunctive chemotherapy

Stage 2 & 3- Stage 2 & 3- low risk- single agent CTlow risk- single agent CT

--High risk –Combination CTHigh risk –Combination CT

Stage 4 – Combination CT & resection of lung or Stage 4 – Combination CT & resection of lung or

brain metastasisbrain metastasis

Single agent CT in GTNSingle agent CT in GTN

Inj Inj MethotrexateMethotrexate 20-40mg/m 20-40mg/m2 2 i.m twice weekly + i.m twice weekly + Folinic Folinic

AcidAcid alternate days alternate days

weekly serum Beta-hCG monitoring.weekly serum Beta-hCG monitoring.

Continue MTX until Serum Beta hCG is negative and the Continue MTX until Serum Beta hCG is negative and the

give for 3 more weeks and stop.give for 3 more weeks and stop.

If no response to MTX – Switch over to If no response to MTX – Switch over to Actinomycin DActinomycin D

Adverse effects of MTXAdverse effects of MTX

VomitingVomiting

DiarrheaDiarrhea

Bone marrow suppression- Megaloblastic Bone marrow suppression- Megaloblastic

anemia, Pancytopeniaanemia, Pancytopenia

Desquamation & Bleeding from GITDesquamation & Bleeding from GIT

Combination Chemotherapy in Combination Chemotherapy in GTNGTN

EMA- COEMA- CO

EtoposideEtoposide

MethotrexateMethotrexate

Actinomycin-DActinomycin-D

CyclophosphamideCyclophosphamide

VincristineVincristine

Epithelial ovarian cancerEpithelial ovarian cancer

Treatment of epithelial ovarian cancers:Treatment of epithelial ovarian cancers:

Stage 1low grade – Staging laparotomyStage 1low grade – Staging laparotomy

Stage 1 high grade – Staging laparotomy with Stage 1 high grade – Staging laparotomy with

Chemotherapy.Chemotherapy.

Stage 2, 3 & 4 – Cytoreductive surgery with Stage 2, 3 & 4 – Cytoreductive surgery with

ChemotherapyChemotherapy

CT in epithelial ovarian cancersCT in epithelial ovarian cancers

Combination CT with Combination CT with Carboplatin & PaclitaxelCarboplatin & Paclitaxel every 21 days for 6 cyclesevery 21 days for 6 cycles

Adverse effectsAdverse effects

Carboplatin – Carboplatin – Bone marrow suppressionBone marrow suppression

Paclitaxel – Paclitaxel – Peripheral neuropathyPeripheral neuropathy

- Bone marrow suppression- Bone marrow suppression

Neoadjuvant CTNeoadjuvant CT

3 cycles of CT 3 cycles of CT prior to cytoreductive surgeryprior to cytoreductive surgery in: in:

Advanced ovarian cancers where surgery is Advanced ovarian cancers where surgery is

difficult initiallydifficult initially

Massive ascitisMassive ascitis

Large pleural effusions Large pleural effusions

Immunotherapy in ovarian cancerImmunotherapy in ovarian cancer

As second line therapyAs second line therapy

Cytokines – Interferon-alfa, Interleukin-2Cytokines – Interferon-alfa, Interleukin-2

Monoclonal antibodies directed towardsCA-125.Monoclonal antibodies directed towardsCA-125.

Antibodies against mutated p53 tumor Antibodies against mutated p53 tumor

suppressor genesuppressor gene

Hormone therapyHormone therapy

ProgesteronesProgesterones in recurrent well in recurrent well

differentiated endometroid carcinomasdifferentiated endometroid carcinomas

Tamoxifen & Leuprolide Tamoxifen & Leuprolide in estrogen in estrogen

receptor positive tumorsreceptor positive tumors

CT in Germ cell tumorsCT in Germ cell tumors

4 cycles of 4 cycles of BEPBEP regimen regimen

BleomycinBleomycin

EtoposideEtoposide

CisplatinCisplatin

Adverse effectsAdverse effects

Bleomycin – Bleomycin – Pulmonary fibrosisPulmonary fibrosis

Etoposide – Etoposide – AlopeciaAlopecia,Gonadal toxicity ,Gonadal toxicity

leading to infertilityleading to infertility

Cisplatin – Severe vomiting, Cisplatin – Severe vomiting, Renal toxicityRenal toxicity, ,

ototoxicityototoxicity

Endometrial Carcinoma- CTEndometrial Carcinoma- CT

ProgesteronesProgesterones are recommended as initial are recommended as initial

treatment for treatment for Recurrent endometrial CancerRecurrent endometrial Cancer

Medroxyprogesterone acetate 100mg 3 times a Medroxyprogesterone acetate 100mg 3 times a

day for at least 3 months.day for at least 3 months.

If progesterones are contraindicated If progesterones are contraindicated

TamoxifeneTamoxifene can be used. can be used.

Endometrial CaEndometrial Ca

If no response to progesteronesIf no response to progesterones

CAP regimen givenCAP regimen given

CyclophosphamideCyclophosphamide

DoxorubicinDoxorubicin

CisplatinCisplatin

Uterine sarcomasUterine sarcomas

Treatment is Exploratory laparotomy Treatment is Exploratory laparotomy followed by Chemotherapyfollowed by Chemotherapy

Doxorubicin + IfosfamideDoxorubicin + Ifosfamide

Doxorubicin – Doxorubicin – Cardiac toxicityCardiac toxicity

Ifosfamide – Hemorrhagic cystitis ( hence Ifosfamide – Hemorrhagic cystitis ( hence given with given with mesna )mesna )

Advanced Ca CervixAdvanced Ca Cervix

Concurrent ChemoradiationConcurrent Chemoradiation with with

CisplatinCisplatin is the treatment of choice for is the treatment of choice for

advanced stageadvanced stage Ca Cx Ca Cx

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