Dose-dependent association between UGT1A1∗28 polymorphism and irinotecan-induced diarrhoea: A meta-analysis

Life-threatening diarrhoea is observed in up to 25% of cancer patients receiving irinotecan. The associations between the UGT1A1∗28 polymorphism and irinotecan-induced diarrhoea remains controversial because of conflicting data in the literature. Meta-analyses were performed on published data in terms of relationships between UGT1A1∗28 and severe diarrhoea. We searched databases for relevant studies that were published in English or Chinese. Two reviewers extracted data and assessed methodological quality. UGT1A1∗28 related odds ratios (ORs) were pooled by use of a fixed-effects model. The studies included were stratified into subgroups representing different races and irinotecan doses, and meta-regression analyses were performed to investigate the effect of study characteristics on the association between UGT1A1∗28 and diarrhoea. Twenty trials including a total of 1760 cancer patients were included. The risk of severe diarrhoea at medium and high irinotecan doses was higher among patients with a UGT1A1∗28/∗28 genotype than among those with a UGT1A1∗1/∗1 genotype (OR = 3.69, 95% confidence interval [CI] = 2.00–6.83; P < 0.001). Considering the patients with a UGT1A1∗1/∗28 genotype, the risk of toxicity was also higher than among those with a wild-type genotype at medium and high doses (OR = 1.92, 95% CI = 1.31–2.82; P = 0.001). No association was observed between UGT1A1∗28 and severe diarrhoea at low doses (<125 mg/m2). In conclusion, patients carrying UGT1A1∗28 allele(s) are at an increased risk of irinotecan-induced severe diarrhoea. This increased risk is only apparent in those who are administrated with medium or high irinotecan doses.