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BACKGROUND: genotype-guided dosing reduces severe toxicity in UGT1A1 poor metaboliser (PM) patients treated with irinotecan. However, the impact of a dose reduction on survival remains unknown. This study evaluated whether upfront 30% dose reductions of irinotecan in UGT1A1 PMs affect survival by comparing progression-free survival (PFS) and overall survival (OS) between 30% dose-reduced PMs and fully-dosed UGT1A1 intermediate and normal metaboliser (IM/NM) patients. METHODS: We conducted a retrospective, multicentre cohort study in patients with pancreatic cancer or colorectal cancer treated with genotype-guided irinotecan dosing at six Dutch hospitals between August 2017 and April 2024. Patients were included in the primary analysis if irinotecan was dosed according to genotype (i.e. an initial 100% ± 10% dose intensity for IM/NMs and an initial 70% ± 10% dose intensity for PMs) in at least cycle 1. Survival analyses for PFS and OS were performed using Kaplan-Meier estimates and univariable and multivariable Cox regressions, stratified by tumour type. Safety was also assessed. FINDINGS: The primary analysis included 779 patients, 76 (9.8%) of whom were PMs. The median follow-up was 27.8 months (95% CI 15.2-31.6). No significant differences in PFS and OS rates were found between 30% dose-reduced PMs and fully-dosed IM/NMs (stratified log-rank test: PFS: = 0.54; OS: = 0.42). In stratified Cox regression analyses, the adjusted hazard ratio of PMs IM/NMs was 1.02 (95% CI 0.78-1.32; = 0.90) for PFS and 1.10 (95% CI 0.82-1.48; = 0.51) for OS, indicating no significant differences exist in PFS or OS between 30% dose-reduced PMs and fully-dosed IM/NMs. Severe toxicity rates were comparable between 30% dose-reduced PMs and fully-dosed IM/NMs ( = 0.59). INTERPRETATION: An upfront 30% dose reduction of irinotecan in UGT1A1 PMs does not lead to statistically significant differences in survival outcomes compared to fully-dosed IM/NMs. Therefore, genotype-guided dosing of irinotecan can be confidently performed to improve patient safety. FUNDING: No funding.