Irinotecan-induced toxicity pharmacogenetics: an umbrella review of systematic reviews and meta-analyses.

Irinotecan chemotherapy toxicities can be severe, and may result in treatment delay, morbidity and in some rare cases death. This systematic review of systematic reviews synthesises all meta-analyses on biomarkers for irinotecan toxicity across all genetic models for Asians, Caucasians, low dose, medium/high dose and regimens with and without fluorouracil. False-positive findings are a problem in pharmacogenetics, increasing the importance of systematic reviews. Four systematic reviews that investigated the effect of the polymorphisms UGT1A16 and/or28 on neutropenia or diarrhoea toxicity were included. Both UGT1A1*6 and 28 were reliably demonstrated to be risk factors for irinotecan-induced neutropenia, with tests for both polymorphisms potentially being particularly useful in Asian cancer patients. UGT1A16 and 28 were also related to diarrhoea toxicity; however, at low doses of irinotecan there was evidence that UGT1A128 was not. In synthesising the best available evidence, this umbrella systematic review provides a novel reference for clinicians applying personalised medicine and identifies important research gaps.