Fluoropyrimidine-induced cardiotoxicity: outcomes and safety of chemotherapy reintroduction in a retrospective cohort study

AIMS: Fluoropyrimidines, including 5-fluorouracil (5-FU) and capecitabine, remain foundational in the treatment of various cancers, despite their well-documented risk of cardiotoxicity. This study aimed to characterize cardiovascular events associated with fluoropyrimidine use, evaluate their management, and assess the prognostic impact of fluoropyrimidine reintroduction. METHODS: We conducted a retrospective cohort study of patients admitted for cardiovascular events between January 2014 and October 2024 at Croix-Rousse and Lyon Sud University Hospitals (Hospices Civils de Lyon, France), who had received fluoropyrimidine-based chemotherapy within the preceding year. RESULTS: Among 141 patients, the most frequent cardiovascular events were coronary artery disease (30.5%), atrial fibrillation (28.4%), and heart failure (19.9%). Post-event, three primary therapeutic strategies were implemented in the follow-up cohort (n = 114): fluoropyrimidine reintroduction (n = 54, 38.3%), switch to alternative chemotherapy (n = 25, 17.7%), and transition to palliative care (n = 36, 25.5%). Recurrent cardiotoxicity after reintroduction occurred in eight patients (14.8%), with only one recurrent coronary event. At 2-year follow-up, overall survival tended to be higher in the reintroduction group compared to the group of patients switching to an alternative chemotherapy (HR = 1.77 [0.92-3.42]; p = 0.088) and to palliative care (HR = 8.31 [4.67-14.79]; p < 0.001). No significant increase in unplanned hospitalizations was observed in the reintroduction group compared to the alternative chemotherapy group (HR = 1.48 [0.83-2.66]; p = 0.185). CONCLUSION: Our findings suggest that fluoropyrimidine reintroduction-guided by multidisciplinary evaluation, cardiovascular management, and close monitoring-appears to have a favorable benefit/risk balance for selected patients.