The fluoropyrimidines, namely 5-fluorouracil (5-FU) and its oral prodrug, capecitabine, are the third most commonly used chemotherapeutic class for the treatment of solid tumors of glandular and squamous origin, such as head and neck, esophageal, stomach, and bladder. Use of fluoropyrimidines is standard of care for treatment of advanced colorectal cancers and may have synergetic effects with external beam radiation to enhance the radiosensitivity of tumors.¹ However, among conventional cytotoxic chemotherapies, 5-FU is likely one of the most common chemotherapeutic agents to cause cardiotoxicity, second only to anthracyclines. Reported clinical manifestations have largely been consistent with angina attributed to coronary vasospasm, although myocardial infarction, heart failure, arrhythmias, pericarditis, coronary dissection, QT prolongation, and sudden cardiac death have also been reported in the setting of fluoropyrimidine use.²

The mechanisms underlying the antitumor effect of fluoropyrimidines have been well-characterized, although the pathophysiology of fluoropyrimidine cardiotoxicity is not fully understood. 5-FU is a pyrimidine analog that inhibits thymidylate synthase, an enzyme involved in DNA replication. These agents therefore function as S-phase antimetabolites and promote genomic instability by inducing double-strand DNA and single-strand DNA breaks, as well as by interfering with DNA synthesis, repair, and elongation.³ Capecitabine is metabolized to 5-FU in a series of reactions involving the enzymes cytidine deaminase and thymidine phosphorylase, which are overexpressed in tumor cells, thus targeting cancerous over normally dividing tissue.⁴

Coronary vasospasm remains the most well-established manifestation of fluoropyrimidine cardiotoxicity, as supported by in vitro models of concentration-dependent vasoconstriction by 5-FU on vascular smooth muscle cells.⁵ However, some patients with reduced ejection fraction by echocardiography have been reported to demonstrate left ventricular wall motion abnormalities in areas that do not correspond to a classic coronary vessel distribution, suggesting that the mechanisms of cardiotoxicity may be multifactorial.⁶ Direct toxicity to the myocardium has been proposed to be mediated by cardiotoxic metabolites such as fluoroacetate and fluorocitrate.⁷ Direct toxicity to the coronary endothelial intima may contribute to thrombosis.⁸ In vivo studies in rabbits have demonstrated apoptosis of epicardial cardiomyocytes and endothelial cells of the distal coronary arteries as a consequence of 5-FU treatment, leading to inflammation as seen in myocarditis.⁹ An in vitro study demonstrated increased reactive oxygen species in cardiomyocytes and endothelial cells in the setting of 5-FU exposure.¹⁰ Takotsubo cardiomyopathy has been described in case reports and is thought to be secondary to an exaggerated sympathetic response.¹¹ Other suggested mechanisms include transformation of erythrocyte membranes to echinocytic shapes, leading to increased blood viscosity, reduced oxygen carrying capacity, and subsequent ischemia,¹² as well as vasospasm mediated by an allergic reaction arising from 5-FU exposure (Kounis syndrome).¹³

Although fluoropyrimidine-associated cardiotoxicity was first observed as early as the 1960s, there have been few clinical trials focused specifically on defining the incidence of cardiotoxicity, which is thought to range from 1% to 19%.¹⁴ In general, reported incidence data have been based largely on retrospective studies that lack consistent definitions of cardiotoxicity and have variable reporting of cardiac events. In a prospective surveillance study of patients treated with 5-FU, 19 of 102 patients developed angina within 24 hours of 5-FU initiation.¹⁴ These patients did not have previously diagnosed coronary disease, and subsequent coronary angiography showed minimal disease. Associated electrocardiographic changes, such as ST depression or ST elevation, resolved with the resolution of chest pain over a 2- to 12-hour period after drug cessation. Two patients demonstrated a reduction in left ventricular ejection fraction on echocardiogram compared with a recent baseline. A 2016 study by de Forni et al. consisted of 367 patients who were given high-dose 5-FU.⁶ There was a 7.6% incidence of 5-FU-associated cardiac events (28 individuals), and 32% of these subjects had a known history of cardiac disease. Events manifested as angina (n = 18), hypotension (n = 6), hypertension (n = 5), malaise (n = 4), dyspnea (n = 2), arrhythmia (n = 1), and sudden death (n = 1). Of the 28 patients with cardiac events, 75% had persistent symptoms after 5-FU discontinuation.

More recently, an analysis of 16 clinical trials incorporating 5-FU and capecitabine treatment in the Eastern Cooperative Group Cancer Research Group-American College of Radiology Imaging Network found that most trials excluded patients with known preceding cardiovascular disease.¹⁵ The remaining studies did not account for pre-existing cardiovascular disease. Overall, less than half of the trials reported adverse cardiac events potentially related to 5-FU administration, highlighting the need for more robust studies to assess the incidence and mechanisms associated with fluoropyrimidine cardiotoxicity.

Proposed risk factors for fluoropyrimidine cardiotoxicity include older age, concurrent administration of other cardiotoxic medications, and a preceding history of cardiac disease and cardiovascular risk factors. Continuous infusions have been associated with a higher incidence of cardiotoxicity as opposed to bolus dosing.¹⁶ Cardiotoxicity most commonly occurs during the first cycle of 5-FU administration, with a mean time to symptoms around 12 hours.¹⁷ Diagnosis is typically based on the presence of symptoms such as chest pain, electrocardiographic changes, elevated cardiac biomarkers, and changes in left ventricular function by echocardiography and/or the results of coronary angiography.

When acute cardiotoxicity is suspected, it is recommended that fluoropyrimidines be stopped immediately, followed by treatment with aspirin, calcium channel blockers, and long-acting nitrates. In general, reintroduction of the fluoropyrimidine after a known cardiotoxic event is not advised due to the risk of recurrence associated with complications including death, myocardial infarction, and the development of cardiogenic shock.¹⁸ However, fluoropyrimidine re-challenge may be necessary for some patients in whom alternative chemotherapy regimens of equivalent efficacy are lacking. In a single center case series, 11 patients with suspected fluoropyrimidine-associated coronary vasospasm were successfully re-challenged with the culprit drug to allow for planned chemotherapy completion.¹⁹ Based on this experience, recommendations for re-challenge included the following:

1. Switching to a bolus regimen rather than a continuous infusion
2. Pre-treatment with extended-release nifedipine and isosorbide mononitrate 3-4 hours prior to the 5-FU infusion
3. Treatment during the infusion with short-acting diltiazem and sublingual nitroglycerin as needed
4. Post-treatment with nifedipine and isosorbide mononitrate 12 hours after the first dose of pre-treatment nitrate/calcium channel blocker
5. Post-treatment with nifedipine 24 hours after the first dose

High-risk patients presenting with 5-FU-associated angina should undergo emergent coronary angiography with revascularization as needed, and lower-risk patients with anginal symptoms should undergo exercise stress testing or coronary computed tomography angiography after symptom resolution.

In addition to the use of commonly accepted cardiovascular medications, uridine triacetate was approved by the US Food and Drug Administration in 2015 as an antidote for fluoropyrimidine toxicity. Uridine triacetate is the oral prodrug of uridine, a natural pyrimidine nucleoside that competes with 5-fluorouridine-5′-triphosphate incorporation into RNA, therefore attenuating fluoropyrimidine toxicity in normal tissue. Uridine triacetate is efficiently absorbed from the gastrointestinal tract and can be used for early-onset, severe fluoropyrimidine toxicity including neutropenia, gastrointestinal toxicity, or cardiac toxicity unresponsive to cessation of the drug and/or initiation of antianginal therapy. A study in 17 5-FU overdose patients showed promising results with uridine triacetate.²⁰ Larger prospective studies are needed to develop a formal standardized and evidence-based algorithm for the implementation of cardioprotective strategies in this setting.

In summary, fluoropyrimidines are chemotherapeutic agents that confer great benefit to many patients with solid tumors, but their use is limited by cardiotoxicity in 1-19% of patients. The exact incidence and mechanisms of cardiotoxicity have yet to be elucidated. A diverse range of clinical presentations have been reported, including the development of angina mediated by coronary vasospasm, myocardial infarction, acute cardiomyopathy, and arrhythmias. Proposed mechanisms include coronary vasospasm, coronary endothelial damage, direct myocardial toxicity, myocarditis, and takotsubo cardiomyopathy. Therapeutic interventions primarily target coronary vasospasm as the primary mechanism. More comprehensive observational and prospective studies are needed to guide cardioprotective strategies in patients receiving fluoropyrimidines.

References

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Keywords: Cardiotoxicity, Cardiotoxins, Calcium Channel Blockers, Coronary Vasospasm, Diltiazem, Coronary Vessels, Thymidine Phosphorylase, Nifedipine, Thymidylate Synthase, Fluorouracil, Nitroglycerin, Nitrates, Prodrugs, Reactive Oxygen Species, Shock, Cardiogenic, Stroke Volume, Retrospective Studies, Antimetabolites, Anthracyclines, Coronary Angiography, Risk Factors, Ventricular Function, Left, Takotsubo Cardiomyopathy, Aspirin, Myocarditis, Cardiovascular Diseases, Myocytes, Cardiac, United States Food and Drug Administration, DNA Breaks, Single-Stranded, Vasoconstriction, Cytidine Deaminase, Erythrocyte Membrane, Blood Viscosity, Muscle, Smooth, Vascular, Angina Pectoris, Acetates, Citrates, Heart Failure, Arrhythmias, Cardiac, Echocardiography, Death, Sudden, Cardiac, Colorectal Neoplasms, Neutropenia, Hypertension, Thrombosis, Genomic Instability, Hypotension, Pericarditis, Inflammation, Dyspnea, Apoptosis, Fluoroacetates, Endothelial Cells, Radiation Tolerance, Algorithms, Isosorbide, Carcinoma, Squamous Cell

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