Evaluating standard risk prediction tools for predicting cardiotoxicity in patients receiving fluoropyrimidine chemotherapy

Fluoropyrimidines (5-fluorouracil and capecitabine) underpin treatment for most gastrointestinal malignancies. Fluoropyrimidine-associated cardiotoxicity (FAC) is the second most common chemotherapy-related cardiotoxicity and often leads to treatment interruption and use of less effective oncologic alternatives. Despite this, no HFA/ICOS baseline risk stratification tool exists for fluoropyrimidines. We evaluated whether established cardiovascular risk tools, pharmacogenetics, and cardiac biomarkers predict FAC.

To determine the predictive value of baseline cardiovascular risk scores, biomarkers, and DPD genotype for incident FAC.

This prospective, two-centre observational cohort study enrolled consecutive gastrointestinal cancer patients prior to fluoropyrimidine-based chemotherapy. Baseline assessment included medical history, ECG, conventional cardiovascular risk scores (QRISK3 and SCORE2), blood biomarkers (NT-proBNP, troponin), and DPD genotype. Follow-up occurred after cycle one and at treatment completion. FAC was defined using prespecified clinical criteria, with events adjudicated by an endpoint committee. Time-to-event analyses used Cox proportional hazards models; Kaplan–Meier analysis evaluated 12-month overall survival.

Among 425 participants (median age 64 [IQR 55–71] years; 59.5% male, 59% White), cardiovascular risk factors were common (42.4% hypertension, 21.9% diabetes; medium/high QRISK3 and SCORE2 risk in 64.5% and 62.4%). Over a median follow-up of 424 (208–720) days, 37 patients (8.7%) developed FAC; 83% occurred during cycle one. The predominant phenotypes were myocardial ischaemia (4.2%), myocardial infarction (1.9%) and sudden cardiac death (0.5%).

Higher QRISK3 was weakly associated with FAC on univariable analysis (HR 1.02 per unit, 95% CI 1.00–1.04; p=0.036), as was prior myocardial infarction (HR 3.83, 95% CI 1.36–10.83; p=0.01), but overall discrimination was poor (C-index 0.54). SCORE2, NT-proBNP, and DPD status were not associated with FAC. Baseline troponin elevation (19.4%) did not predict FAC but was associated with reduced overall survival. Two-thirds (66.7%) of patients with FAC were rechallenged; 82.8% of those completed treatment without recurrence. Twelve-month survival was lower in patients with FAC compared with the non-cardiotoxicity group, with early excess mortality reflected by a significant log-rank test (χ²=4.5, p=0.033).

Although severe cardiotoxicity is rare, FAC is frequent, occurs early, and is associated with worse survival. Conventional cardiovascular risk scores and baseline biomarkers have limited predictive utility, highlighting the need for fluoropyrimidine-specific risk models. Carefully selected patients can be safely rechallenged with cardioprotective strategies.

Forest plot: Hazard ratios for FAC