Topoisomerase II Inhibitors

Topoisomerase II inhibitors stabilise the complex of topoisomerase II and cleaved DNA, producing double-strand breaks that block replication in late S and G2 phases. They are active in germ cell tumours, small cell lung cancer, lymphoma and leukaemia.

Classification. Epipodophyllotoxins (etoposide, etoposide phosphate, teniposide) and, by mechanism, anthracyclines and mitoxantrone. Dexrazoxane is a catalytic topoisomerase II inhibitor used as a cardioprotectant.

Pharmacokinetics. Etoposide is about 50 percent bioavailable orally, so oral doses are about double intravenous doses; it is cleared by the kidney and liver and is highly protein bound.

• Etoposide 100 mg/m2 intravenously on days 1 to 3 (with cisplatin and bleomycin in germ cell tumour) or days 1 to 5 (small cell lung cancer, lymphoma), every 3 weeks.
• Oral etoposide 50 mg/m2 daily (or 100 to 200 mg daily) for 14 to 21 days every 28 days in palliative regimens.
• Mitoxantrone 12 mg/m2 every 3 weeks; cumulative maximum 140 mg/m2.
• Teniposide 165 mg/m2 twice weekly (paediatric leukaemia, specialist use).

Differences. Etoposide has marrow and mucosal toxicity but little cardiotoxicity; mitoxantrone and anthracyclines carry cumulative cardiotoxicity.

• Testicular germ cell tumour: etoposide with cisplatin (with or without bleomycin).
• Small cell lung cancer: etoposide with cisplatin or carboplatin.
• Lymphoma and leukaemia: etoposide in salvage and induction regimens.
• Gestational trophoblastic neoplasia: etoposide in multi-drug regimens.
• Kaposi sarcoma: oral etoposide is a low-cost option in some settings.
• Administration: infuse over 30 to 60 minutes (not rapidly) to avoid hypotension and bronchospasm; dilute to a concentration of 0.4 mg/mL or less to avoid precipitation.

Selection. Prefer intravenous administration for curative germ cell and small cell lung regimens; oral dosing in palliative care.

Contraindications. Severe marrow failure, pregnancy in the first trimester, and hypersensitivity (polysorbate vehicle).

Adverse effects. Myelosuppression (nadir 7 to 14 days), nausea, mucositis, alopecia, hypersensitivity and hypotension on infusion, secondary acute myeloid leukaemia with 11q23 rearrangement (cumulative dose and schedule related), and peripheral neuropathy.

Interactions. Ciclosporin and cisplatin raise etoposide exposure; phenytoin and other CYP3A4 inducers lower it; warfarin effect may rise; azoles and macrolides increase toxicity.

Special groups.

• Pregnancy: avoid.
• Breastfeeding: avoid.
• Children: used in specialist regimens at surface-area dosing.
• Older adults: monitor marrow closely.
• Kidney impairment: reduce etoposide by 25 percent at creatinine clearance 15 to 50 mL/min; avoid under 15 mL/min.
• Liver impairment: bilirubin 1.5 to 3.0 mg/dL, reduce by 50 percent; over 3.0 mg/dL, avoid.

Monitoring. Full blood count before each cycle, creatinine, bilirubin, blood pressure during infusion, and cumulative mitoxantrone dose with cardiac imaging.

Referral and escalation. Febrile neutropenia, severe infusion reaction, and suspicion of secondary leukaemia (new cytopenias months later) need urgent review.