Elucidating the role of pharmacogenetics in irinotecan efficacy and adverse events in metastatic colorectal cancer patients

Irinotecan is a cytotoxic agent that is widely used in the treatment of several types of solid tumors. However, although it is generally well tolerated, approximately 20% to 35% of patients develop severe toxicity, particularly delayed-type diarrhea and neutropenia. As the incidence of such toxicities is often associated with the UGT1A1 *28/*28, *6/*28 and *6/*6 genotypes, individualized dosing could reduce these adverse events. Furthermore, prospective trials have shown that patients harboring the UGT1A1 *1/*1 and *1/*28 genotypes can tolerate higher doses of irinotecan, which may in turn impact on a better outcome. Upfront UGT1A1 genotyping could therefore be a usefulness strategy in order to individualize irinotecan dosing, but consensus on the recommended dose based on the UGT1A1 genotype is still lacking.This review summarizes the results of the main pharmacogenetic studies focused on irinotecan. We provide an overview of current evidence and recommendations for individualized dosing of irinotecan in metastatic colorectal cancer patients.Implementation of UGT1A1*28 and UGT1A1*6 genotyping in clinical practice is a first step toward personalizing irinotecan therapy. This approach is likely to improve patient care and reduce healthcare costs. Future large and prospective studies will help to clarify the clinical value of other genetic markers in irinotecan treatment personalization.