Cell Cycle Nonspecific Anticancer Drugs

Cell cycle nonspecific drugs damage DNA or its template in cells in any phase, including resting cells, though cycling cells are more vulnerable. Kill rises in a near-linear way with dose, so higher doses give greater tumour kill, which makes them useful for short, high-dose, intermittent schedules and for conditioning before stem cell transplant.

Classification. Alkylating agents (cyclophosphamide, ifosfamide, melphalan, busulfan, dacarbazine, nitrosoureas), platinum compounds (cisplatin, carboplatin, oxaliplatin), anthracyclines (doxorubicin, epirubicin, daunorubicin), and antitumour antibiotics (dactinomycin, mitomycin).

Dose-response. The dose-limiting toxicity is usually marrow, and with higher doses also the gut, liver, kidney or heart.

• Cyclophosphamide 500 to 1,000 mg/m2 intravenously every 3 weeks; high-dose 50 mg/kg daily for 2 days in transplant conditioning.
• Melphalan 8 to 10 mg/m2 orally daily for 4 days; intravenous 140 to 200 mg/m2 before autologous transplant in myeloma.
• Cisplatin 50 to 100 mg/m2 every 3 weeks; weekly 40 mg/m2 with radiotherapy.
• Carboplatin target area under the curve 5 to 6 every 3 weeks.
• Doxorubicin 40 to 75 mg/m2 every 3 weeks; cumulative maximum about 450 to 550 mg/m2.
• Mitomycin 10 to 20 mg/m2 every 6 to 8 weeks.

Differences. Alkylating agents have delayed marrow nadirs and secondary leukaemia; platinum drugs add nephrotoxicity, ototoxicity and neuropathy; anthracyclines cause cardiomyopathy; mitomycin causes cumulative marrow toxicity and haemolytic uraemic syndrome.

• Short, intensive regimens: used for lymphoma, myeloma conditioning, sarcoma and germ cell tumours.
• Combination with phase-specific drugs: a nonspecific drug first reduces tumour bulk; a phase-specific drug then acts on recruited cells.
• Palliative oral therapy: chlorambucil, melphalan and low-dose cyclophosphamide are used in chronic lymphocytic leukaemia and myeloma.

Selection. Use for chemosensitive tumours with a high growth fraction and for conditioning; use caution in patients with previous radiotherapy to the same field or prior anthracycline exposure.

Contraindications. Pregnancy in the first trimester; severe heart failure (anthracyclines); creatinine clearance under 60 mL/min (cisplatin); active haemorrhagic cystitis (cyclophosphamide).

Adverse effects. Myelosuppression, nausea and vomiting, mucositis, alopecia, infertility, secondary acute myeloid leukaemia and myelodysplasia, haemorrhagic cystitis (oxazaphosphorines), cardiomyopathy (anthracyclines), nephrotoxicity and ototoxicity (cisplatin), pulmonary fibrosis (busulfan, mitomycin).

Interactions. Aminoglycosides, loop diuretics and amphotericin B add to cisplatin toxicity; allopurinol raises cyclophosphamide marrow toxicity; trastuzumab and radiotherapy raise anthracycline cardiotoxicity.

Special groups.

• Pregnancy: avoid; second and third trimester use only for life-threatening disease.
• Breastfeeding: avoid.
• Children: higher risk of late cardiac and fertility effects.
• Older adults: anthracycline cardiotoxicity risk rises with age and prior hypertension.
• Kidney impairment: avoid cisplatin; adjust carboplatin by area under the curve; reduce melphalan and cyclophosphamide.
• Liver impairment: reduce anthracyclines by bilirubin.

Monitoring. Full blood count at the nadir, creatinine and electrolytes, echocardiography before anthracyclines and at cumulative thresholds, audiology with cisplatin, and urinalysis for blood with cyclophosphamide and ifosfamide.

Referral and escalation. Cardiac failure, haematuria, rising creatinine, and hearing loss need review; febrile neutropenia is an emergency.