Fluoropyrimidine Therapy in Gastrointestinal Cancer

Corresponding Author

Fluoropyrimidines, including capecitabine and 5-fluorouracil (5-FU), remain the foundation of most chemotherapy regimens for gastrointestinal cancers.¹ These agents are commonly used either as monotherapy or in combination with other agents such as oxaliplatin and/or irinotecan. Treatment intent varies from curative in the preoperative and postoperative settings, aiming to reduce recurrence risk, to palliative in the metastatic setting, where the goal is to prolong life and improve quality of life. These agents are generally well-tolerated, with hematologic and gastrointestinal toxicities manageable through supportive care. However, fluoropyrimidine-associated cardiotoxicity is a well-documented, but often under-recognized, complication, ranging from asymptomatic electrocardiogram changes to severe toxicities such as arrhythmias, ischemia, myocarditis, and even sudden cardiac death.² Coronary vasospasm is one of the most concerning presentations, yet estimates of fluoropyrimidine-related cardiac events vary widely from 0% to 35%, due to differences in study populations and inconsistent definitions of cardiotoxicity.³

In this issue of JACC: CardioOncology, Abiodun et al⁴ conducted an observational study using data from England’s national disease registries, provided by the Virtual Cardio-Oncology Research Initiative (VICORI), to assess the risks of all-cause mortality and hospitalization for acute cardiovascular events associated with fluoropyrimidine treatment. The study included patients with stage II-IV gastroesophageal cancers or stage III-IV colorectal cancer who were treated with either curative or palliative intent. The investigators compared patients receiving a fluoropyrimidine-based chemotherapy regimen (5-FU or capecitabine) to those who did not receive fluoropyrimidine chemotherapy within the first 8 weeks of diagnosis. Using a target trial emulation approach, all patients were followed for 1 year from diagnosis.

The study included 103,110 patients, with colorectal cancer representing 66.3% of the cohort. After excluding patients who died within the first 8 weeks, 89,990 patients remained in the analysis: 25,401 (28.2%) in the fluoropyrimidine group and 64,589 (71.8%) in the no-fluoropyrimidine group. The 1-year all-cause mortality was lower in the fluoropyrimidine group (41.9%; 95% CI: 41.1% to 42.8%) than in the no-fluoropyrimidine group (49.6%; 95% CI: 49.1% to 50.3%), with an absolute risk reduction of 7.7% (95% CI: −8.7% to −6.7%). Conversely, the 1-year absolute risk of composite cardiovascular events was slightly higher in the fluoropyrimidine group (15.8%) compared with the no-fluoropyrimidine group (14.9%), with an absolute risk increase of 0.9%. Specifically, there was a modestly higher risk of cardiac arrhythmia (0.82% risk difference; 95% CI: 0.11% to 1.58%) and cardiac arrest (0.34% risk difference; 95% CI: 0.13% to 0.47%) associated with fluoropyrimidine treatment.

The strength of this study lies in its large sample size and real-world applicability, making the findings highly generalizable. The inclusion of no-fluoropyrimidine group enhances its value by quantifying both the risks of cardiac toxicity and the overall survival benefit. However, the study has limitations. The control cohort is not a truly fluoropyrimidine-free group, as some patients may have started treatment after the 8-week grace period. Additionally, the study does not explain why the majority of patients (71.8%) did not receive fluoropyrimidine therapy, despite its standard use in gastrointestinal cancers. Although some patients may have been ineligible due to comorbidities, cardiovascular risk, or performance status, this remains an important factor to explore in future research to ensure the findings are broadly applicable to routine clinical practice.

This study contributes important real-world evidence on the cardiovascular risks associated with fluoropyrimidine chemotherapy while reinforcing its survival benefit. Such data are crucial in guiding clinical discussions when considering initiating fluoropyrimidine therapy in a patient with pre-existing cardiovascular disease. It is reassuring that cardiovascular events were only slightly increased in the fluoropyrimidine group with no increase in risk of cardiac death. Additionally, data are mixed with respect to whether pre-existing cardiovascular disease increases the risk of cardiovascular events related to fluoropyrimidine therapy.³ A recent single center study of 4,019 patients treated with 5-FU found that patients who developed vasospasm were younger and less likely to have cardiovascular risk factors than those who did not.⁵ These findings taken together suggest that it may not be in the patient’s best interest to withhold fluoropyrimidine therapy based on pre-existing heart disease alone.

The decision of how to manage fluoropyrimidine therapy after a cardiac event such as coronary vasospasm remains challenging. This study did not evaluate the safety of continuing fluoropyrimidine therapy after an initial cardiac event. The decision to continue, modify, or discontinue treatment after a cardiac event depends on factors such as treatment intent and the severity of the event. In a curative-intent setting, risk-mitigation strategies may allow continuation, whereas in a palliative setting, quality-of-life considerations may justify discontinuation.

When fluoropyrimidine cardiotoxicity occurs, initial management typically involves stopping the agent and treating the acute event.² If rechallenge is considered, prophylactic strategies such as calcium channel blockers and nitrates for prevention of vasospasm are often employed, and a switch from infusional 5-FU to bolus 5-FU may be considered in select cases, as bolus dosing has been associated with a lower incidence of cardiotoxicity compared with continuous infusion.⁶ Capecitabine rechallenge is another option but requires careful monitoring given the risk of recurrence, which has been estimated at approximately 20% despite prophylactic measures.⁷

An alternative strategy is S-1, an oral fluoropyrimidine consisting of tegafur and metabolic inhibitors that slow 5-FU metabolism.⁸ S-1 has been widely used in Asian countries and has demonstrated comparable efficacy to 5-FU and capecitabine, with lower incidence of cardiac toxicity, leading to European Medicines Agency approval for patients unable to tolerate 5-FU due to cardiotoxicity.⁹ The CardioSwitch (Continuation of fluoropyrimidine treatment with S-1 after cardiotoxicity on capecitabine- or 5-fluorouracil-based therapy in patients with solid tumours: a multicentre retrospective observational cohort study) study, the largest retrospective analysis on the topic to date, found that switching to S-1 resulted in lower cardiotoxicity recurrence while maintaining oncologic efficacy.¹⁰ Although not widely adopted outside of Europe and Asia, S-1 represents a promising alternative for patients who experience fluoropyrimidine-related cardiovascular toxicity and require continued chemotherapy.

Another factor that may influence fluoropyrimidine toxicity is dihydropyrimidine dehydrogenase (DPD) deficiency, which impairs metabolism of fluoropyrimidines and increases the risk of severe, potentially life-threatening toxicities.¹¹ Recently, the U.S. Food and Drug Administration issued an update advising health care providers to inform patients about the risks of DPD deficiency and discuss the option of genetic testing before initiating fluoropyrimidine.¹² However, routine testing is not yet widely implemented as standard practice, in part possibly given that partial deficiency does not have a clearly established safe dose.

Additionally, clonal hematopoiesis (CH), a condition linked to aging and cardiovascular risk, may contribute to chemotherapy-related toxicities.¹³ CH has been implicated in vascular inflammation and endothelial dysfunction, which could theoretically contribute to fluoropyrimidine-induced coronary vasospasm or other cardiac events.¹⁴ Future studies should explore whether biomarkers at both the pharmacological level (DPD activity) and genetic level (CH mutations) could improve risk stratification and guide cardioprotective strategies.

The investigators should be commended for providing real-world data on fluoropyrimidine-associated cardiotoxicity and mortality.⁴ Their findings offer critical insights for clinical decision-making. Future studies should focus on refining risk stratification to better identify patients at heightened risk of cardiotoxicity and developing effective cardioprotective strategies to optimize treatment safety. Multidisciplinary collaboration between oncologists and cardio-oncologists remains essential in ensuring that patients receive optimal cancer therapy while minimizing cardiovascular risk.

Funding Support and Author Disclosures

Dr Sonbol has received consulting fees from Novartis (to self) and Boehringer Ingelheim (to his institution); has received institutional research support from Taiho and Eli Lilly. Dr Bekaii-Saab has received institutional research funding from Agios, Arys, Arcus, Atreca, Boston Biomedical, Bayer, Eisai, Celgene, Lilly, Ipsen, Clovis, Seattle Genetics, Genentech, Novartis, Mirati, Merus, Abgenomics, Incyte, Pfizer, and BMS; has received consulting fees (to his institution) from Servier, Ipsen, Arcus, Pfizer, Seattle Genetics, Bayer, Genentech, Incyte, Eisai, Merus, Merck KGaA, and Merck, and (to self) from Stemline, AbbVie, Blueprint Medicines, Boehringer Ingelheim, Janssen, Daiichi Sankyo, Natera, TreosBio, Celularity, Caladrius Biosciences, Exact Science, Sobi, Beigene, Kanaph, AstraZeneca, Deciphera, Zai Labs, Exelixis, Elevar, Illumina, Foundation Medicine, Sanofi, Glaxo SmithKline, and Xilio; has served on independent data monitoring committees or data safety monitoring boards for The Valley Hospital, Fibrogen, Suzhou Kintor, AstraZeneca, Exelixis, Merck/Eisai, PanCan, and 1Globe; has served on scientific advisory boards for Imugene, Immuneering, Xilis, Replimune, Artiva, and Sun Biopharma; has received royalties from UpToDate; and holds patents licensed to Imugene and Recursion. Dr Larsen has reported that she has no relationships relevant to the contents of this paper to disclose.