Irinotecan is a prodrug. It is hydrolysed to SN-38, and SN-38 is inactivated almost entirely by uridine diphosphate glucuronosyltransferase 1A1. Patients carrying two reduced-function UGT1A1 variants clear SN-38 poorly and carry a higher risk of severe neutropenia and diarrhoea. Allele frequencies differ substantially between populations, so the proportion of poor metabolisers is not the same everywhere.

The guideline's recommendation is specific enough to act on: anyone about to be prescribed irinotecan for an epithelial malignancy should have pharmacogenetic testing where it is available, and poor metabolisers should have the cycle 1 dose reduced by 30% for all indications, with subsequent doses titrated against tolerability and neutrophil counts. The 30% figure applies at the first cycle only; it is a starting position, not a permanent ceiling.

The authors decline to make a recommendation for rare malignancies such as sarcomas, on the grounds that the evidence does not exist. That restraint is worth noticing, because irinotecan's off-label use across gastrointestinal and rare tumours is exactly where a guideline is most tempted to extrapolate.

Test before cycle 1, not after the first episode of febrile neutropenia
Reduce by 30% at cycle 1 in poor metabolisers, then titrate on neutrophil count and tolerability
Do not carry the reduction forward automatically — patients who tolerate cycle 1 can be escalated
Intermediate metabolisers are not covered by the 30% recommendation; treat them on standard dosing with closer monitoring
Where testing is not available, say so in the record and monitor counts accordingly rather than reducing the dose empirically

Why it matters

It moves UGT1A1 from a test ordered after toxicity to one ordered before the first dose, which is the only point at which it can prevent anything.

Don't overread it

The recommendation is for epithelial malignancies. The guideline explicitly declines to extend it to sarcomas and other rare tumours for want of evidence.