Antitumour Antibiotics

Antitumour antibiotics are natural products from Streptomyces species that damage DNA by intercalation, strand breakage or cross-linking. They are cell cycle nonspecific or phase-specific depending on the drug, and several are vesicants.

Classification. Anthracyclines and anthracenediones (doxorubicin, daunorubicin, epirubicin, idarubicin, mitoxantrone), bleomycin, dactinomycin, and mitomycin.

Pharmacokinetics. Bleomycin is cleared by the kidney (about 60 percent) and inactivated by bleomycin hydrolase, which is low in lung and skin. Dactinomycin and mitomycin are metabolised by the liver.

• Bleomycin 10 to 20 units/m2 weekly; in germ cell tumour 30 units weekly intravenously; lifetime cumulative maximum 400 units.
• Dactinomycin 15 microgram/kg daily for 5 days every 3 to 4 weeks (maximum 500 microgram daily); pulse dosing 1.5 mg/m2 every 3 weeks in rhabdomyosarcoma and Wilms tumour.
• Mitomycin 10 to 20 mg/m2 intravenously every 6 to 8 weeks; intravesical 40 mg weekly for 6 weeks in bladder cancer; cumulative dose of 50 mg/m2 or more raises the risk of haemolytic uraemic syndrome.
• Mitoxantrone 12 mg/m2 every 3 weeks; cumulative maximum 140 mg/m2.

Differences. Bleomycin causes lung fibrosis and skin toxicity with little marrow suppression. Dactinomycin is a potent vesicant and causes veno-occlusive disease. Mitomycin causes cumulative marrow suppression and haemolytic uraemic syndrome.

• Germ cell tumour and Hodgkin lymphoma: bleomycin in combination.
• Wilms tumour, rhabdomyosarcoma, Ewing sarcoma, gestational trophoblastic disease: dactinomycin.
• Anal, gastric, breast and bladder cancer: mitomycin.
• Kaposi sarcoma: bleomycin with vincristine is a low-cost combination used where liposomal doxorubicin and paclitaxel are unavailable; check with local oncology for the schedule.
• Bleomycin safety: avoid high inspired oxygen during and after treatment (keep FiO2 under 30 percent in anaesthesia where possible); stop for dry cough, dyspnoea or a fall in diffusing capacity of 20 to 25 percent.
• Extravasation: dactinomycin and mitomycin are vesicants; stop infusion, aspirate, and follow the unit extravasation procedure.

Selection. Plan lifetime doses; avoid bleomycin in patients over 40 years with reduced kidney function, previous chest radiotherapy or smoking if alternatives exist.

Contraindications. Pulmonary fibrosis (bleomycin), severe marrow failure, pregnancy in the first trimester, and creatinine clearance under 30 mL/min (bleomycin, reduce dose).

Adverse effects. Pulmonary fibrosis and acute pneumonitis, skin hyperpigmentation, flagellate rash and nail changes (bleomycin), fever and anaphylactoid reactions, myelosuppression, mucositis, alopecia, veno-occlusive disease (dactinomycin), haemolytic uraemic syndrome, and tissue necrosis on extravasation.

Interactions. Cisplatin reduces bleomycin clearance; G-CSF may increase bleomycin lung toxicity; oxygen therapy; radiotherapy recall with dactinomycin.

Special groups.

• Pregnancy: avoid.
• Breastfeeding: avoid.
• Children: dactinomycin dosed by weight and surface area; avoid in infants under 6 months.
• Older adults: lower bleomycin doses; higher risk of fibrosis.
• Kidney impairment: reduce bleomycin by 25 percent at creatinine clearance 40 to 60 mL/min and by 50 percent at 25 to 40 mL/min; avoid under 25 mL/min.
• Liver impairment: reduce dactinomycin and mitomycin.

Monitoring. Chest examination and lung function (diffusing capacity) before and during bleomycin; chest radiograph at each cycle if symptoms; full blood count; creatinine; blood pressure and haemolysis markers for mitomycin.

Referral and escalation. New cough, dyspnoea or hypoxia on bleomycin, haemolysis with renal failure on mitomycin, and extravasation need urgent specialist care.