Authors (including presenting author) :
Wong SMN(1), Yip PL(1), Wo BW(1), Wong LY(1), Tsang KF(1), Chow MY(1), Li CM(1), Ho PS(1), Law WK(1), Wong MC(1), Lee AS(1), Wong CS(1)
Affiliation :
(1)Department of Clinical Oncology, Tuen Mun Hospital, Hong Kong
Introduction :
Fluoropyrimidine and Irinotecan are commonly utilized in various (especially gastrointestinal) cancers. Severe toxicities are however present (up to 30%), especially among deficiencies of key metabolic enzymes dihydropyrimidine dehydrogenase (DPD) and uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1) resulting from DPYD and UGT1A1 gene polymorphism respectively. Despite well-recognized toxicity correlation and management guidance in the West, Asian/local data is scarce. We conducted this cross-sectional study to capture local prevalence, investigate genotypic-phenotypic correlation with hopes of shedding light on timely reduction of potentially preventable severe toxicities.
Objectives :
(1) To review prevalence of (a) fluoropyrimidine and/or irinotecan-related severe toxicities and (b) physician-led testing for DPYD and UGT1A1 polymorphism
(2) To investigate genotypic-phenotypic correlation of DPYD and UGT1A1 polymorphism
(3) To review individualized dose adjustments on patient outcomes
Methodology :
Patients with all tumor types utilizing fluoropyrimidine-based (capecitabine / fluorouracil) and/or irinotecan-based anticancer therapy experiencing severe toxicities (e.g. gastrointestinal, marrow, mucosal/skin, biochemical), as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0) grade >/=3 were identified. Retrospective, physician-led DPYD and/or UGT1A1 genotyping results were correlated with clinical outcomes.
Result & Outcome :
Between November 2020 and October 2022, 10,062 fluoropyrimidine and/or irinotecan-based treatment administration were identified in total. Of the 133patients amounting to 206 (2.0%) severe toxicity episodes, 30patients amounting to 48 admission episodes in total were identified by physicians as developing clinically severe toxicities with retrospective testing requested, and majority (87%) were identified within the first 2 chemotherapy cycles. Of the 25 and 20patients tested for DPYD and UGT1A1 polymorphism, 20% and 60% were identified as either intermediate or poor metabolizers correlating with severe clinical toxicities respectively. One capecitabine-related death was found 36days following the first adjuvant cycle due to neutropenic sepsis despite intensive-care support, correlating with an intermediate-metabolizer status. Treatment discontinuation occurred in 12patients (40%), and of the remaining 18 (60%) resuming culprit agent restarting at 50% dose, 4 (22%) were gradually able to escalate dose to >75% of original. No severe toxicity was found following a step-wise, individualized dose escalation.
Conclusion:
Fluoropyrimidine and/or irinotecan-related severe toxicities, although less common than in the west, can be potentially life-threatening. Valuable local/Asian data is required to enhance genotypic-phenotypic correlation for effective prediction and development of local guidelines. Early recognition of high-risk patients, vigilance in toxicities and individualized dose-adjustments are key to enhancing patient outcomes.
