Pyrimidine Analogues

Pyrimidine analogues are converted intracellularly into nucleotides that inhibit thymidylate synthase or are incorporated into DNA and RNA. They are active against gastrointestinal, breast, pancreatic, lung and head and neck cancers and against acute myeloid leukaemia.

Classification. Fluoropyrimidines (fluorouracil, capecitabine, trifluridine with tipiracil), cytidine analogues (cytarabine, gemcitabine) and hypomethylating agents (azacitidine, decitabine).

Pharmacokinetics. Over 80 percent of fluorouracil is catabolised by dihydropyrimidine dehydrogenase in the liver; capecitabine is an oral prodrug converted to fluorouracil in tumour tissue.

• Fluorouracil 400 mg/m2 intravenous bolus, then 2,400 mg/m2 over 46 hours every 2 weeks (with folinic acid 400 mg/m2); other schedules use 1,000 mg/m2 daily for 4 to 5 days by infusion.
• Capecitabine 1,250 mg/m2 orally twice daily for 14 days every 21 days (monotherapy); 1,000 mg/m2 twice daily with a platinum drug; swallow with water within 30 minutes of a meal.
• Cytarabine 100 to 200 mg/m2 daily by continuous infusion for 7 days with an anthracycline (induction); 1 to 3 g/m2 every 12 hours for consolidation; 40 to 50 mg intrathecally.
• Gemcitabine 1,000 mg/m2 over 30 minutes on days 1, 8 and 15 every 28 days (pancreas), or on days 1 and 8 every 21 days with cisplatin.
• Azacitidine 75 mg/m2 subcutaneously daily for 7 days every 28 days.
• Trifluridine with tipiracil 35 mg/m2 (trifluridine component) twice daily on days 1 to 5 and 8 to 12 every 28 days.

Differences. Fluorouracil and capecitabine cause mucositis, diarrhoea and hand and foot syndrome; cytarabine causes marrow aplasia, cerebellar toxicity and conjunctivitis; gemcitabine is better tolerated, with fever, rash and rarely haemolytic uraemic syndrome.

• Colorectal, gastric, breast cancer: fluorouracil or capecitabine.
• Acute myeloid leukaemia: cytarabine with daunorubicin (seven days of cytarabine and three of anthracycline).
• Pancreatic, biliary, bladder, lung, ovarian cancer: gemcitabine.
• Older adults with myelodysplasia or acute myeloid leukaemia who cannot have intensive therapy: azacitidine.
• Before fluoropyrimidines: DPYD testing where available. Complete deficiency is fatal; treat early severe toxicity (within 96 hours of a dose) with uridine triacetate, 10 g orally every 6 hours for 20 doses, where available.
• Cytarabine safety: give corticosteroid eye drops during high doses; stop at any sign of cerebellar toxicity (nystagmus, ataxia, dysarthria).

Selection. Use infusional fluorouracil for cure-intent colorectal regimens; use capecitabine when infusion is not feasible.

Contraindications. Pregnancy; severe DPD deficiency; severe kidney impairment (capecitabine under 30 mL/min); brivudine within 4 weeks of a fluoropyrimidine.

Adverse effects. Myelosuppression, diarrhoea, mucositis, hand and foot syndrome, coronary vasospasm and chest pain, hyperammonaemic encephalopathy (fluorouracil), cerebellar toxicity, conjunctivitis and fever (cytarabine), pneumonitis and haemolytic uraemic syndrome (gemcitabine).

Interactions. Capecitabine increases warfarin effect markedly; phenytoin levels rise with fluorouracil; folinic acid increases fluorouracil toxicity.

Special groups.

• Pregnancy: avoid.
• Breastfeeding: avoid.
• Children: cytarabine is used in leukaemia regimens at weight- and surface-area-based doses.
• Older adults: reduce capecitabine and cytarabine doses.
• Kidney impairment: reduce or avoid capecitabine and high-dose cytarabine; gemcitabine needs no change at mild impairment.
• Liver impairment: caution with all; reduce gemcitabine at elevated bilirubin.

Monitoring. Full blood count, creatinine, liver function, bowel habit, skin, neurological examination (cytarabine), INR with warfarin, and cardiac symptoms.

Referral and escalation. Severe diarrhoea with fever, chest pain, cerebellar signs, confusion, or early severe toxicity after the first cycle needs emergency care.