Finding ferritin footprints in 5-fluorouracil-induced cardiotoxicity

Abstract Introduction Fluoropyrimidines including 5-fluorouracil (5-FU) are used in the treatment of patients with gastrointestinal malignancies. 5-FU based therapies are associated with an increased risk of atherosclerotic coronary artery disease (CAD), coronary artery vasospasm, and heart failure. As a result, baseline transthoracic echocardiogram (TTE) and consideration of CAD screening are recommended prior to drug administration. Although the mechanism of 5-FU-induced cardiotoxicity remains unclear, in vivo studies have suggested that 5-FU triggers iron-dependent cell death by enhancing transferrin receptor expression. Moreover, rat models treated with 5-FU have higher iron concentrations in myocardial tissue compared to controls. Based on these molecular findings, we sought to examine whether ferritin could be a clinical biomarker of cardiotoxicity among patients receiving 5-FU-based chemotherapy. Methods We performed a retrospective chart review on patients aged 18 and older receiving 5-FU-based intravenous chemotherapy (including 5-FU, FOLFOXIRI, FOLFIRI, FOLFIRINOX) at a single academic center from June 1, 2022 to June 1, 2024. Patients were identified via Clinical Data Warehouse (CDW) query and data were collected by manual chart review; values limited to those obtained closest to and within 24 months following receipt of 5-FU-based chemotherapy. Values for iron, total iron binding capacity (TIBC), ferritin, and transferrin saturation (TSAT) excluded if within 6 weeks of iron infusion. Potential cardiotoxicity was defined by the presence of any of the following: obstructive coronary artery disease detected on coronary angiography, new wall motion abnormalities on echocardiography, LVEF (left ventricular ejection fraction) decrease ≥10% from pre-treatment TTE, coronary vasospasm, pericardial effusion, or incident heart failure. Statistical analyses were performed in R version 4.4.1. Results Of the 93 patients receiving intravenous 5-FU at Boston Medical Center from 6/1/22-6/1/24, those with ferritin ≥100 ng/mL were nearly 5 times as likely to exhibit a potential manifestation of cardiotoxicity (adjusted odds ratio [aOR] 4.7, confidence interval [CI] 1.0-23.5) after adjusting for age and gender. Similarly, patients with ferritin ≥100 ng/mL were approximately 3 times as likely to experience treatment failure (aOR 3.2, CI 1.1-9.7). Discussion Based on the apparent relationship between ferritin ≥100 ng/mL, cardiotoxicity, and treatment outcomes, we encourage oncologists to routinely obtain iron studies in addition to pre- and post-treatment TTE among patients receiving 5-FU. Should ferritin be elevated, we advise clinicians to maintain a high index of suspicion for obstructive CAD and heart failure. Larger multi-institutional studies on biomarkers predicting cancer therapy-related cardiovascular toxicity or treatment failure rates merit future consideration.