Safety and Efficacy of FOLFIRI-3 (Split-Dose Irinotecan) for Unresectable Colorectal Cancer: A Stratified Analysis Based on UGT1A1 Gene Polymorphisms

Purpose: UGT1A1 gene polymorphisms are established risk factors for irinotecan (CPT-11)-induced toxicity. The FOLFIRI-3 regimen, incorporating split-dose CPT-11 administration on Days 1 and 3, was developed to improve safety and efficacy. This study evaluated the clinical outcomes of FOLFIRI-3 stratified by UGT1A1 genotype. Methods: We retrospectively analyzed 147 patients with unresectable metastatic colorectal cancer (mCRC) treated with first-line FOLFIRI-3 between 2005 and 2020 who underwent UGT1A1 genotyping for *6 and *28 variants. During this period, FOLFIRI-3 was adopted as the standard first-line regimen for all eligible patients at our institution to standardize toxicity management. Patients were classified into three groups: Wild-type (negative for both variants; n = 82), Single-heterozygous (SH; n = 56), and Homo/Compound heterozygous (HCH; n = 8) group. Results: The HCH group maintained a relative dose intensity (RDI) of 57.7% with manageable toxicity. While time to treatment discontinuation (TTD) did not differ significantly among groups, overall survival (OS) was significantly longer in the SH group compared to the Wild-type group (Median Survival Time: 30.4 vs. 21.7 months, p = 0.0058). Conclusions: For high-risk HCH patients, our findings regarding the tolerability of FOLFIRI-3 are strictly preliminary due to the small sample size and require further validation in larger, multi-institutional cohorts. Despite this limitation, this regimen serves as a valuable alternative for high-risk patients and provides superior survival benefits for single heterozygotes, likely due to optimized pharmacokinetics.