UGT1A1*28 genotype predicts gastrointestinal toxicity in patients treated with intermediate-dose irinotecan

Aims: Variants in UGT1A1 have previously been associated with toxicity from irinotecan chemotherapy. We conducted a pragmatic prospective cohort study to establish the relevance of UGT1A1 variants in the prediction of severe diarrhea and neutropenia in patients with colorectal cancer receiving irinotecan in a routine clinical setting. Materials & methods: Genotyping of UGT1A1(star)28 and c.-31566>A was undertaken in an unselected, prospective cohort of 96 individuals treated with irinotecan at a single major UK oncology centre. Data on cytotoxic drugs received, and toxicity for all irinotecan treatment cycles were collected from case notes. Over 95% (92/96) of patients received an intermediate dose of irinotecan (180 mg/m(2), twice weekly). Irinotecan was given in combination with other cytotoxic drugs in 93/96 subjects and Grade 3 or 4 toxicity occurred in 23% of subjects. Results: No association was found between UGT1A1*28 or c.-3156G>A and neutropenia. However, individuals carrying two copies of UGT1A1(star)28 (p = 0.04; OR: 14; 95% CI: 1.1-185) or c.-31566>A (p = 0.03) had a significantly increased risk of diarrhea over all cycles. Conclusion: Our findings indicate that UGT1A1 genotyping is not a good predictor of hematological toxicity in patients treated with intermediate irinotecan doses. However, it may be useful in the identification of patients at risk of severe diarrhea.