Ischemic cardiopathy induced by capecitabine in gastric cancer: The role of dihydropyrimidine dehydrogenase metabolites.

Objectives: Fluoropyrimidine-based therapies, 5-fluorouracil (5-FU) and its oral prodrugs, capecitabine and tegafur/oteracil/gimeracil (S-1), are pivotal drugs to treat gastric cancer. Fluoropyrimidines are associated with cardiotoxicity including ischemic cardiopathy. The mechanisms of ischemic cardiopathy are considered to be multifactorial, potentially involving metabolites of 5-FU generated by the dihydropyrimidine dehydrogenase (DPD). By using Vigibase®, the World Health Organization pharmacovigilance database, we aimed to investigate the implication of the 5-FU metabolites induced by DPD in the occurrence of ischemic cardiopathy in patients with gastric cancer using capecitabine.

Methods: In Vigibase®, we included serious reports of ischemic cardiopathy with capecitabine and S-1 from January 1st, 2013, to September 16th, 2023. Among patients with gastric cancer, we calculated the reporting odds ratio (ROR) of ischemic cardiopathy to compare capecitabine (a prodrug without DPD antagonist) with S-1 (a prodrug associated with a DPD antagonist). The ROR was also calculated regardless of the drug indication. An ancillary analysis based on the French pharmacovigilance database was also performed. We evaluated the ROR of serious cardiac disorders induced by 5-FU intravenous infusion according to the DPD status (no deficiency versus complete or partial deficiency).

Results: In gastric cancer, 1843 reports (including 23 ischemic cardiopathy) for capecitabine and 2225 reports (including 17 ischemic cardiopathy) for S-1 were included. Median time-to-onset was 7 (3-26) days for capecitabine and 22 (13.25-30) days for S-1. Capecitabine was associated with an increased ROR of ischemic cardiopathy compared with S-1 in gastric cancer (ROR=1.6; [95% CI=1.5-1.8]) and regardless of the indication (7.3; [95% CI=6.6-8.0]). In the ancillary analysis, among 5-FU users, the lack of DPD deficiency increased the ROR for cardiac disorders (2.1; [95% CI=1.9-2.3]) compared to the DPD deficiency.

Conclusion: This work supports the role of toxic 5-FU metabolites generated by dihydropyrimidine dehydrogenase in the occurrence of ischemic cardiopathy among patients with gastric cancer using capecitabine.