Authors: (including presenting author): :
Chan Y, Wong NSM, Lee AS
Affiliation: :
Clinical Oncology, Tuen Mun Hospital
Keyword 3: :
Genetic polymorphism
Introduction: :
Irinotecan is a widely utilized chemotherapeutic agent and is critical in treating common malignancies such as colorectal cancer. UDP-glucuronosyltransferase (UGT) 1A1 polymorphisms impact Irinotecan toxicity, often necessitating hospitalization and posing lethal risks. Among poor metabolizers (PM, 10% patients), 24% develop febrile neutropenia, and 70% have ≥grade3 severe diarrhea. Intermediate metabolizers (IM, 40% patients) have higher prevalence and face heightened risks over normal metabolizers (NM). Real-world data and Asian-specific guidelines on genotype-guided Irinotecan dosing remain limited.
Objectives: :
This study evaluates the impact of preemptive UGT1A1 genotype-guided dose reduction, hypothesizing that it may mitigate treatment toxicity, prevent fatalities and alleviate healthcare burden.
Methodology: :
This retrospective review included patients given Irinotecan regimens (180-200 mg/m²) between May 2024 and July 2025, who underwent preemptive UGT1A1 testing. Initial dose reductions of at least 20% for IM and 30% for PM were implemented based on genotype, age, performance status etc. with subsequent dose escalation in tolerated individuals. Primary outcomes were grade≥3 toxicities; secondary outcomes included relative dose intensity (RDI), objective response rate (ORR), disease control rate (DCR), and time to treatment failure (TTF).
Result & Outcome: :
Of 492 patients treated with Irinotecan, 96 underwent preemptive UGT1A1 testing, and 61 eligible patients were included: 26 NM, 32 IM, and 3 PM. IM and PM contitute >50% of eligible patients. PM data were reported descriptively due to small sample size. Baseline characteristics (age, performance status, cancer types etc.) were comparable between groups. Average RDI over three cycles was 77.3% in NM vs. 59% in IM (p< 0.001) and 43% in PM. Grade≥3 toxicities were comparable: neutropenia (NM 23.1% vs. IM 15.6%,p=0.517), diarrhea (NM 3.8% vs. IM 3.1%,p=1.000), and febrile neutropenia (0% in both groups). Rates of further dose reduction (23.1% vs. 15.6%,p=0.517) and treatment interruption (30.8% vs. 28.1%,p=0.826) were similar. Despite lower dose intensity, early efficacy outcomes at 12 weeks showed no significant differences: ORR (NM 26.3% vs. IM 25.0%,p=1.000), DCR (NM 68.4% vs. IM 67.9%,p=0.968). Median TTF was 227 days for NM and 301 days for IM (log-rank p=0.36). In this first Hong Kong cohort, preemptive UGT1A1 testing with genotype-guided dose reduction in IM was associated with acceptable toxicity and maintained early efficacy despite lower dose intensity. These findings may suggest wider implementation, though larger prospective studies are needed for confirmation.
