Anthracyclines

Anthracyclines intercalate into DNA, inhibit topoisomerase II, and generate free radicals. They are among the most active anticancer drugs, used in breast cancer, lymphoma, sarcoma, acute leukaemia and myeloma. Dose-dependent, cumulative cardiotoxicity limits lifetime exposure.

Classification. Doxorubicin, daunorubicin, epirubicin, idarubicin, liposomal doxorubicin, liposomal daunorubicin with cytarabine, and the related anthracenedione mitoxantrone.

Pharmacokinetics. Hepatic metabolism and biliary excretion; doxorubicin and epirubicin are substrates of P-glycoprotein and CYP3A4. Half life is long (20 to 48 hours for doxorubicin), with persistent tissue levels.

• Doxorubicin 60 to 75 mg/m2 every 3 weeks as a single agent, or 40 to 60 mg/m2 in combinations; lifetime cumulative maximum 450 to 550 mg/m2 (about 400 mg/m2 after chest radiotherapy or with other cardiac risk).
• Daunorubicin 45 to 90 mg/m2 daily for 3 days with cytarabine in acute myeloid leukaemia; cumulative maximum about 550 mg/m2 in adults.
• Epirubicin 90 to 100 mg/m2 every 3 weeks; cumulative maximum 900 mg/m2.
• Idarubicin 12 mg/m2 daily for 3 days in acute myeloid leukaemia; cumulative maximum about 150 mg/m2 orally or intravenously.
• Liposomal doxorubicin 20 mg/m2 every 2 to 3 weeks (Kaposi sarcoma) or 40 to 50 mg/m2 every 4 weeks (ovarian cancer, myeloma).
• Mitoxantrone 12 mg/m2 every 3 weeks; cumulative maximum 140 mg/m2.
• Dexrazoxane at 10 times the doxorubicin dose (10:1) protects the heart when the cumulative dose is high and treatment is to continue.

Differences. Epirubicin and idarubicin have somewhat less cardiotoxicity at equal effect; liposomal forms reduce cardiac toxicity but cause hand and foot syndrome and infusion reactions.

• Breast cancer, lymphoma, sarcoma: doxorubicin with cyclophosphamide, or in multi-drug lymphoma regimens.
• Acute myeloid leukaemia: daunorubicin or idarubicin with cytarabine.
• Kaposi sarcoma: liposomal doxorubicin is the preferred drug in advanced disease where available.
• Cardiac assessment before treatment: history, blood pressure, electrocardiogram, and echocardiographic or radionuclide left ventricular ejection fraction; avoid when ejection fraction is under 50 percent.
• Risk factors for cardiotoxicity: age over 65 or under 5 years, prior chest radiotherapy, hypertension, diabetes, existing heart disease, concurrent trastuzumab or taxanes.

Selection. Use the lowest effective cumulative dose; consider non-anthracycline regimens in patients with cardiac risk and when benefit is modest.

Contraindications. Heart failure, left ventricular ejection fraction under 50 percent, recent myocardial infarction, severe arrhythmia, severe hepatic impairment, and cumulative maximum already reached.

Adverse effects. Myelosuppression, nausea and vomiting, mucositis, alopecia, red urine (harmless, not haematuria), acute arrhythmia, chronic cardiomyopathy and heart failure (risk rises steeply over a cumulative 400 mg/m2 of doxorubicin), radiation recall, secondary acute myeloid leukaemia and myelodysplasia, and severe tissue necrosis on extravasation.

Interactions. Trastuzumab and cyclophosphamide add cardiotoxicity; paclitaxel raises doxorubicin levels (give the anthracycline first); P-glycoprotein and CYP3A4 inhibitors raise exposure; avoid live vaccines.

Special groups.

• Pregnancy: avoid in the first trimester; second and third trimester use is described for life-threatening breast cancer.
• Breastfeeding: avoid.
• Children: cardiac effects appear years later; dose by surface area and track cumulative dose.
• Older adults: reduce the dose or use liposomal or lower-dose regimens.
• Kidney impairment: no adjustment for doxorubicin.
• Liver impairment: bilirubin 1.2 to 3.0 mg/dL, reduce doxorubicin by 50 percent; 3.1 to 5.0 mg/dL, reduce by 75 percent; over 5.0 mg/dL, avoid.

Monitoring. Left ventricular ejection fraction before treatment, after a cumulative 250 to 300 mg/m2 of doxorubicin, and at the end of treatment; stop if ejection fraction falls under 50 percent or by 10 percentage points or more; full blood count; liver function; heart failure symptoms at each visit; and long-term cardiac surveillance in survivors.

Referral and escalation. New dyspnoea, oedema or arrhythmia, ejection fraction decline, or extravasation (stop infusion, aspirate, apply cold compress, and give dexrazoxane within 6 hours where available) need urgent specialist care.