Fluoropyrimidine Cardiotoxicity: Time for a Contemporaneous Appraisal

Introduction: Fluoropyrimidines (FPDs) are a fundamental component of many chemotherapy regimens. Cardiotoxic adverse events (AEs) such as angina, ischemia, arrhythmias, and cardiomyopathy associated with 5-fluorouracil (5-FU) and capecitabine (CAPE) have been sparingly described in studies, primarily through case reports. Data from the 1990s revealed an estimated incidence of 0.5% to 19%, with cardiovascular fatalities occurring in ≤28%. The current use of FPDs includes multiple dosing regimens, oral or intravenous delivery, and administration with additional cardiotoxic therapies. As such, it is imperative to better define the cardiotoxicity risk in the modern treatment era. We comprehensively evaluated the incidence, prevalence, and ascertainment of cardiovascular risk factors and disease within ECOG-ACRIN (Eastern Cooperative Group Cancer Research Group – American College of Radiology Imaging Network) Cancer Research Group clinical trials incorporating 5-FU and CAPE. Materials and Methods: Case report forms and clinical study reports from the ECOG-ACRIN Cancer Research Group database of phase II and III clinical trials incorporating 5-FU and CAPE were evaluated. A total of 16 trials from 2002 to 2017 were identified that had used bolus 5-FU (n = 1), continuous infusion 5-FU (n = 10) or CAPE (n = 5). Results: A history of cardiovascular disease was variably defined and was an exclusion criterion in 13 of the 16 studies (81%). The baseline risk factors and history of cardiac disease were specifically collected in only 3 studies (19%). All studies collected cardiovascular AEs using the Common Terminology Criteria for Adverse Events version available at the time of the study. Fewer than half (7 of 16; 44%) of the study case report forms had also specifically requested information on cardiac ischemia/infarction. In the 12 completed studies with clinical study reports, the following AEs were reported: dyspnea, ≤16%; arrhythmias, ≤6%; and angina, ischemia, and elevated troponin, ≤5%. Some trials only recorded cardiac AEs that were possibly associated with the novel drug being studied and not those attributed to the standard of care in the 5-FU/CAPE arm, further decreasing the numerical incidence. Conclusion: Inconsistent clinical trial reporting of cardiac AEs precluded accurate and precise delineation of the epidemiology of FPD-related cardiovascular AEs. Prospective knowledge of the definition and natural history will lead to the development of risk factor stratification and prechemotherapy interventions to reduce or prevent cardiotoxicity. We propose that the prospective collection of baseline cardiac data and prespecified cardiac endpoints are necessary to fully understand the incidence and cardiac risk of FDPs.