introduction to chemotherapy in a gyn/onc context

Chemotherapy in a Gyn Oncology Context

Stuart S. Winkler, MD

Wake Forest Baptist Health

Objectives

Review principles of tumor cell growth and inhibition with chemotherapy

Discuss the mechanism of action and toxicities of chemotherapy agents used to treat gynecologic cancers

Discuss common chemotherapy regimens used in the treatment of gynecologic cancers and the evidence behind the regimens

Review tidbits that might pop up on CREOGs

Learn trivia for dinner parties (with other OB/GYNs)

Principles

Principles of chemotherapy: the target

Kill the neoplastic cells without killing the native cells

Cells in normal tissues are either:

Static

Expanding

Renewing

Neoplastic cells exhibit a loss of cell control mechanisms

Cell division is not more rapid

Overgrowth is due to loss of cell-cycle regulation and failure of apoptosis

The Cell Cycle

Tumor cell growth

Gompertzian growth: as tumor mass increases, the time required for tumor mass to double also increases

Laird, A.K. Laird, Dynamics of tumour growth,Br. J. Cancer 18 (1964), pp. 490–502.

Tumor cell growth

Palpable tumors are already “large” and correspond to the flat portion of this curve

Tumors reach 1 cm after about 30 doublings (10^9)

Doubling times for clinically detectable gynecologic cancers differ widely, from 1 month for some embryonal cancers to 6 months for adenocarcinomas

Chemotherapy used in the adjuvant setting works on a lower volume of tumor cells on the left side of the curve.

Principles of chemotherapy: pharmacokinetics

Most chemotherapy agents operate in a context of first-order kinetics

The effect of chemotherapy is seen when the active drug is in contact with the neoplastic cell

This is affected by

Prodrug conversion (e.g. Ifosfamide)

Solubility (binding)

Dose (AUC)

Tissue accessibility (delivery)

Active transport vs simple diffusion

Elimination mechanisms

Principles of chemotherapy: the bullet

Most CT drugs have a very narrow therapeutic window (effective but with tolerable toxicities)

Dosing is critical

Weight-based: mg/kg

Area under curve: the total drug exposure over time, expressed in mg/(mL x min), also called the definite integral

Calvert formula: target AUC x (GFR + 25)

Body surface area: m2 = 𝑤𝑒𝑖𝑔ℎ𝑡 × ℎ𝑒𝑖𝑔ℎ𝑡/60

Log kill hypothesis and chemotherapy schedules

A constant proportion of cells are killed with each cycle of chemo, not a constant number

Effective treatment requires cyclic administration and often multiple agents to:

Maximize killing of tumor cells

Vary toxicity profile

Deter development of tumor resistance

http://www.oncotherapynetwork.com/

Chemotherapy Agents

• Antimetabolites

• Alkylating agents

• Antitumor antibiotics

• Plant-derived agents

• Hormonal agents

• Monoclonal antibodies, targeted therapy

Chemotherapy Agents

• Antimetabolites

• Methotrexate

• Gemcitabine

• Fluorouracil

• Pemetrexed

Methotrexate

Mechanism: dihydrofolate reductase inhibition leading the thymidine depletion, inhibits synthesis of purines

Usage: GTD

Regimens: PO, IV, IM, IT; single agent for low risk GTD; given as part of EMA-CO for high risk GTD

Toxicity: myelosuppression, nephrotoxicity, elevated liver enzymes, mucositis

Fun fact: Sidney Farber

Gemcitabine (Gemzar)

Mechanism: nucleoside analog; phosphorylated intracellularly to active metabolite which inhibits

ribonucleotide reductase inhibit DNA synthesis; also incorporates into DNA resulting in strand breaks

Usage: EOC, sarcoma; radiosensitization

Regimens: 800-1000 mg/m2 weekly (3 of 4, or 2 of 3)

Toxicity: myelosuppression (thrombocytopenia), nephrotoxicity (rarely hemolytic uremic syndrome); flu-like syndrome

Chemotherapy Agents

• Antimetabolites




• Hormonal agents


Chemotherapy Agents


• Cyclophosphamide

• Ifosfamide

• Cisplatin

• Carboplatin

• Oxaloplatin

• Chlorambucil

• Hexamethylmelamine

• Melphalan

Cyclophosphamide

Mechanism: pro-drug converted to active 4-OH

cyclophosphamide enters cell and intercalates DNA

Usage: EOC, GTD, endometrial

Regimens: IV; Mesna given during high-dose regimens

Toxicity: pancytopenia (leukopenia), N/V, alopecia, hemorrhagic cystitis, SIADH

Fun fact: mustard gas

Ifosfamide (IFEX)

Mechanism: pro-drug converted to active drug in liver (saturable)

Usage: cervix, EOC, endometrial sarcoma

Regimens: IV; daily slow infusions for 3-5 days; Mesna given during high-dose

Toxicity: pancytopenia, N/V, alopecia, hemorrhagic cystitis, CNS toxicity

Cisplatin

Mechanism: covalent bonds formed between G-G in DNA and platinum atom distorting the DNA helix

Usage: EOC, GC, GTD, endometrial, cervix, vulva

Regimens: IV or IP, q3w; weekly for radiosensitization

Toxicity : neuropathy, myelosuppression (anemia), N/V, nephrotoxicity

Fun fact: none

Carboplatin

Mechanism: similar to cisplatin

Usage: EOC, GC, GTD, endometrial, cervix, vulva

Regimens: IV; q3w, dosed as AUC

Toxicity : thrombocytopenia, hypersensitivity

Fun fact: first cisplatin analog to be approved

Platinum resistance

Most important compound in GYN cancers

Platinum sensitive: > 6 months

Platinum resistant: < 6 months

Platinum refractory: progress on therapy

Mechanisms

CTR-1 transporter: regulates cisplatin influx

Increased intracellular glutathione inhibits adducts

Nucleoside excision repair

Chemotherapy Agents

• Antimetabolites




• Hormonal agents


Chemotherapy Agents


• Doxorubicin

• Liposomal doxorubicin

• Bleomycin

• Dactinomycin

• Mitomycin C

Doxorubicin (Adriamycin)

Mechanism: inhibits topoisomerase-II; adriamycinone ring intercalates with DNA leading to multiple DNA double-strand breaks; quinone group leads to free radical formation

Usage: endometrial, EOC, cervix, vulva

Regimens: IV; bolus infusion every 3 weeks or weekly

Toxicity: cardiotoxicity, myelosuppression (leukopenia, thrombocytopenia), alopecia, vesicant

Fun fact: “red devil”

Vesicant injury

Irritant vs. Vesicant

In the event of extravasation:

Stop drug

Withdraw drug from line

Elevate extremity

Doxorubicin: topical dimethysulfoxide, cold compress

Cisplatin: SC sodium thiosulfate, cold compress

Taxol: SC hyaluronidase, cold compress

Vincas, Etoposide: SC hyaluronidase, warm compress

Liposomal doxorubicin (Doxil)

Mechanism: same as doxorubicin, but…

Usage: EOC

Regimens: IV; 40-50 mg/m2 monthly

Toxicity: cardiotoxicity (less severe), myelosuppression (less severe), palmar-plantar erythrodysesthesia (more severe), acute infusion reaction

Bleomycin

Mechanism: uses copper or iron as cofactor in creating superoxide free radicals leading to DNA damage

Usage: germ cell

Regimens: IV; dosage is expressed in units/m2, given weekly or twice weekly, intracavitary for effusions

Toxicity: interstitial pneumonitis and pulmonary fibrosis, hyperpigmentation, fever, anaphylaxis

Actinomycin D

Mechanism: phenoxazone ring intercalates at guanine residues which plug the minor groove on DNA

Usage: GTD

Regimens: IV; EMA-CO

Toxicity: myelosuppression, alopecia, N/V

Chemotherapy Agents

• Antimetabolites




• Hormonal agents


Chemotherapy Agents


• Vinca alkaloids

• Etoposide

• Topotecan

• Paclitaxel

• Docetaxel

Vincristine (Oncovin) and Vinblastine (Velban)

Mechanism: binds to tubulin subunit leading to mitotic arrest by inhibition of the mitotic spindle

Usage: germ cell tumors, GTD, EOC

Regimens: IV; EMA-CO, Navelbine q1-2w

Toxicity: myelosuppresssion (Vb), alopecia (Vc), neuropathy (Vc), constipation/ileus (Vc), vesicant

Fun fact: derived from periwinkle

Etoposide (VP-16)

Mechanism: inhibition of topoisomerase-2 activity

Usage: GTD, EOC, GC, uterine sarcoma

Regimens: IV, daily (germ cell) or PO (salvage EOC)

Toxicity: Pancytopenia (leukopenia), N/V, alopecia, hypotension, vesicant, secondary leukemia

Fun fact: derived from podophyllotoxin, produced by the mandrake or mayapple

Topotecan (Hycamtin)

Mechanism: binds to topoisomerase I causing single strand DNA breaks

Usage: EOC, cervical

Regimens: IV or PO; daily x5 days q3w or weekly; ?IP

Toxicity: myelosuppression (severe), alopecia

Fun fact: Wani and Wall

Paclitaxel (Taxol)

Mechanism: stabilizes microtubules

Usage: EOC, endometrial

Regimens: IV or IP; 175 mg/m2 every 3 weeks or 80 mg/m2 weekly (dose-dense)

Toxicity: neurotoxicity (peripheral neuropathy), pancytopenia, alopecia, hypersensitivity reaction, bradycardia

Fun fact: Pacific Yew

Taxol reaction

Characterized by hypotension, urticaria, bronchospasm, dyspnea, stridor

Similar to type 1 hypersensitivity

Severe enough to be dose-limiting and those with severe reactions should not be re-challenged

Heavy premedication with H1 blockers, H2 blockers, and corticosteroids

Treatment starts with:

Stop infusion

Give hydrocortisone 100 mg IV x1

Taxol reaction

Further treatment based on presenting symptoms:

Hives/flushing: Benadryl or Cimetidine

Wheezing: Albuterol nebulizer

Chest tightness: Hydrocortisone

Stridor: 100% oxygen via face mask

Bronchospasm: Epinephrine (0.3 mg SC q10m)

Hypotension: Fluid, hydrocortisone, Benadryl, epinephrine

Docetaxel (Taxotere)

Mechanism: similar to Taxol

Usage: EOC

Regimens: IV, q3w

Toxicity: less neurotoxicity, more neutropenia

Fun Fact: European yew

Chemotherapy Agents

• Antimetabolites




• Hormonal agents


Chemotherapy Agents

• Hormonal agents

• Megesterol acetate

• Tamoxifen

• Levonorgestrel IUD

Megesterol acetate (Megace)

Mechanism: unknown, but may be due to down-regulation of estrogen receptors in tumor

Usage: endometrial, ESS

Regimens: 80 mg PO BID

Toxicity: alopecia, Cushinoid faces, thromboembolism

Tamoxifen

Mechanism: reversibly binds ER receptor thereby decreasing estrogen-mediated protein synthesis

Usage: EOC, ovarian stromal tumor

Regimens: 20 mg PO BID

Toxicity: thrombocytopenia, hot flushes, thromboembolism, endometrial polyps and CA

Chemotherapy Agents

• Antimetabolites




• Hormonal agents


Chemotherapy Agents


• Bevacizumab

• Olaparib

Bevacizumab (Avastin)

Mechanism: inhibits binding of VEGF-A to its receptors thereby inhibiting angiogenesis

Usage: EOC, cervical

Regimens: IV, 15 mg/m2 q3w with standard treatment, maintenance

Toxicity: hypertension, mucocutaneous bleeding, bowel perforation

Olaparib (Lynparza)

Mechanism: poly ADP-ribose polymerase (PARP) inhibition leads to impairment of DNA repair mechanisms through synthetic lethality

Usage: recurrent EOC (BRCA+)

Regimens: PO monotherapy

Toxicity: thrombocytopenia, N/V

www.nature.com

Olaparib (Lynparza)

Mechanism: poly ADP-ribose polymerase (PARP) inhibition leads to impairment of DNA repair mechanisms through synthetic lethality

Usage: recurrent EOC (BRCA+)

Regimens: PO monotherapy

Toxicity: thrombocytopenia, N/V

Fun fact: most recent drug to be FDA approved for ovarian cancer

Objectives

Review principles of tumor cell growth and inhibition with chemotherapy

Discuss the mechanism of action and toxicities of chemotherapy agents used to treat gynecologic cancers

Discuss common chemotherapy regimens used in the treatment of gynecologic cancers and the evidence behind the regimens

Review tidbits that might pop up on CREOGs

Learn trivia for dinner parties (with other OB/GYNs)

Questions?

introduction to chemotherapy in a gyn/onc context

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