Topoisomerase I Inhibitors

Topoisomerase I inhibitors (camptothecins) trap the topoisomerase I and DNA complex, so that collisions with replication forks cause lethal double-strand breaks in S phase. They are used in colorectal, small cell lung, ovarian, cervical and pancreatic cancers.

Classification. Irinotecan (including liposomal irinotecan) and topotecan.

Pharmacokinetics. Irinotecan is a prodrug converted by carboxylesterase to SN-38, which is inactivated by UGT1A1 glucuronidation; reduced UGT1A1 activity (the *28 variant) causes severe neutropenia and diarrhoea. Topotecan is renally cleared.

• Irinotecan 180 mg/m2 every 2 weeks (with fluorouracil and folinic acid), 125 mg/m2 weekly for 4 of 6 weeks, or 350 mg/m2 every 3 weeks (320 mg/m2 if the patient is frail or older).
• Liposomal irinotecan 70 mg/m2 every 2 weeks with fluorouracil and folinic acid after gemcitabine in pancreatic cancer.
• Topotecan 1.5 mg/m2 intravenously daily for 5 days every 21 days; oral 2.3 mg/m2 daily for 5 days; weekly 4 mg/m2 on days 1, 8 and 15 for ovarian and small cell lung cancer.

Differences. Irinotecan is limited by diarrhoea and neutropenia; topotecan is limited by myelosuppression, especially thrombocytopenia, and has little diarrhoea.

• Colorectal cancer: irinotecan with fluorouracil and folinic acid (FOLFIRI), or as part of triplet regimens.
• Small cell lung cancer and ovarian cancer (relapse): topotecan.
• Cervical cancer: topotecan with cisplatin.
• Early cholinergic diarrhoea (during or within 24 hours of irinotecan): atropine 0.25 to 1 mg subcutaneously or intravenously.
• Late diarrhoea (after 24 hours): loperamide 4 mg at the first loose stool, then 2 mg every 2 hours until 12 hours without diarrhoea (4 mg every 4 hours overnight, maximum 16 mg daily); oral fluids and electrolytes; for fever, severe diarrhoea or neutropenia admit for intravenous fluids and broad-spectrum antibiotics, as this is a medical emergency.
• UGT1A1 testing: reduce the starting dose of irinotecan by 25 to 30 percent in patients homozygous for *28 where testing is available.

Selection. Avoid in patients with bowel obstruction, Gilbert syndrome (caution), or chronic inflammatory bowel disease.

Contraindications. Chronic inflammatory bowel disease, bowel obstruction, bilirubin over 3 times the upper limit of normal (irinotecan), severe marrow suppression, and pregnancy.

Adverse effects. Neutropenia, severe diarrhoea, nausea and vomiting, alopecia, cholinergic syndrome (irinotecan), interstitial lung disease, thrombocytopenia (topotecan), and fatigue.

Interactions. Strong CYP3A4 inducers (rifampicin, phenytoin, carbamazepine, St John's wort) lower SN-38 levels and efficacy; strong CYP3A4 inhibitors (ketoconazole, ritonavir- or cobicistat-boosted regimens) raise toxicity; atazanavir inhibits UGT1A1 and increases SN-38 exposure (avoid or choose another antiretroviral); laxatives should be withheld during treatment.

Special groups.

• Pregnancy: avoid; teratogenic.
• Breastfeeding: avoid.
• Children: used in specialist regimens at weight- or surface-area-based doses.
• Older adults: start at the lower dose.
• Kidney impairment: reduce topotecan to 0.75 mg/m2 at creatinine clearance 20 to 39 mL/min; avoid under 20 mL/min; irinotecan needs caution.
• Liver impairment: reduce irinotecan when bilirubin is 1.5 to 3 times the upper limit of normal.

Monitoring. Full blood count before each cycle and at nadir, bilirubin, bowel habit and fluid status, and hydration.

Referral and escalation. Diarrhoea with fever, neutropenia, dehydration, or 4 or more stools over baseline daily needs urgent admission.