{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T08:22:23Z","timestamp":1791793343600,"version":"4.3.4"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,9,14]],"date-time":"2022-09-14T00:00:00Z","timestamp":1663113600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cardiovasc. Med."],"abstract":"<jats:p>The cardiotoxicity of fluoropyrimidines (FP) [5-Fluorouracil and Capecitabine] is often reported as acute cardiac ischemia with rest typical angina, signs of ischemia at electrocardiogram (ECG), and ventricular kinetics abnormalities. However, silent ischemia, effort-related toxicity, and ventricular arrhythmias (VA) have been also described. The aim of this study is to report a consecutive series of 115 patients with FP cardiotoxicity observed in a single center both within clinical prospective studies and during the clinical routine. The clinical presentation widely varied as regards symptoms, ECG abnormalities, and clinical outcomes. We report also the strategies used to prevent cardiotoxicity in a subgroup of 35 patients who continued o rechallenged FP therapy after cardiotoxicity. In nearly half of the patients, the cardiotoxicity was triggered by physical effort. Typical angina was rare: the symptoms were absent in 51% of cases and were atypical in half of the other cases. ST-segment elevation and VA were the most frequent ECG abnormality; however, ST segment depression or negative T waves were the only abnormalities in 1\/3 of the cases. Troponins essays were often within the normal limits, even in presence of extensive signs of ischemia. The most effective strategy to prevent cardiotoxicity at rechallenge was reducing FP dosage and avoiding physical effort. Anti-ischemic therapies were not always effective. Raltitrexed was a safe alternative to FP. Fluoropyrimidine cardiotoxicity shows a wide variety of clinical presentations in real life, from silent ischemia to atypical symptoms, acute coronary syndrome, left ventricular dysfunction (LVD), VA, or complete atrio-ventricular block. Physical effort is the trigger of cardiotoxicity in nearly half of the cases. The recognition of cardiotoxicity cannot rely on symptoms only but requires an active screening with ECG and stress test in selected cases.<\/jats:p>","DOI":"10.3389\/fcvm.2022.960240","type":"journal-article","created":{"date-parts":[[2022,9,14]],"date-time":"2022-09-14T05:22:28Z","timestamp":1663132948000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["The puzzling clinical presentation of fluoropyrimidines cardiotoxicity"],"prefix":"10.3389","volume":"9","author":[{"given":"Linda","family":"Cucciniello","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ettore","family":"Bidoli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elda","family":"Viel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Laura","family":"Canale","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenzo","family":"Gerratana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Lestuzzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,9,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1542","DOI":"10.1016\/j.ejca.2005.03.027","article-title":"The frequency and pattern of cardiotoxicity observed with capecitabine used in conjunction with oxaliplatin in patients treated for advanced colorectal cancer (CRC).","volume":"41","author":"Ng","year":"2005","journal-title":"Eur J Cancer."},{"key":"B2","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1111\/j.1445-5994.2009.02144.x","article-title":"Cardiotoxicity with 5-fluorouracil and capecitabine: more than just vasospastic angina.","volume":"40","author":"Stewart","year":"2010","journal-title":"Intern Med J."},{"key":"B3","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1007\/s00432-007-0250-9","article-title":"Cardiotoxicity of fluoropyrimidines in different schedules of administration: a prospective study.","volume":"134","author":"Kosmas","year":"2008","journal-title":"J Cancer Res Clin Oncol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"ytab079","DOI":"10.1093\/ehjcr\/ytab079","article-title":"Capecitabine-mediated heart failure in colorectal cancer: a case series.","volume":"5","author":"McAndrew","year":"2021","journal-title":"Eur Heart J Case Rep."},{"key":"B5","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1007\/s11912-016-0521-1","article-title":"Fluoropyrimidine-induced cardiotoxicity: manifestations, mechanisms, and management.","volume":"18","author":"Layoun","year":"2016","journal-title":"Curr Oncol Rep."},{"key":"B6","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1016\/j.ccl.2019.07.004","article-title":"Fluoropyrimidine-associated cardiotoxicity.","volume":"37","author":"Kanduri","year":"2019","journal-title":"Cardiol Clin."},{"key":"B7","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1007\/s11886-021-01441-2","article-title":"5-FU cardiotoxicity: vasospasm, myocarditis, and sudden death.","volume":"23","author":"More","year":"2021","journal-title":"Curr Cardiol Rep."},{"key":"B8","doi-asserted-by":"publisher","first-page":"316","DOI":"10.1016\/s0002-9343(01)00808-7","article-title":"Coronary vasospasm as a cause of effort-related myocardial ischemia during low-dose chronic continuous infusion of 5-fluorouracil.","volume":"111","author":"Lestuzzi","year":"2001","journal-title":"Am J Med."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1059","DOI":"10.1093\/annonc\/mdu055","article-title":"Effort myocardial ischemia during chemotherapy with 5-Fluorouracil: an underestimated risk.","volume":"25","author":"Lestuzzi","year":"2014","journal-title":"Ann Oncol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1186\/s40880-018-0292-1","article-title":"Cardiotoxicity of 5-fluorouracil and capecitabine in Chinese patients: a prospective study.","volume":"38","author":"Peng","year":"2018","journal-title":"Cancer Commun."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1758835918780140","DOI":"10.1177\/1758835918780140","article-title":"5-fluorouracil and cardiotoxicity: a review.","volume":"10","author":"Sara","year":"2018","journal-title":"Ther Adv Med Oncol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1002\/cncr.30321","article-title":"Emergency use of uridine triacetate for the prevention and treatment of life-threatening 5-fluorouracil and capecitabine toxicity.","volume":"123","author":"Ma","year":"2017","journal-title":"Cancer."},{"key":"B13","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1016\/j.jaccao.2020.04.005","article-title":"Uridine triacetate for severe fluoropyrimidine cardiotoxicity in a patient with thymidylate synthase gene variants.","volume":"2","author":"Raber","year":"2020","journal-title":"JACC CardioOncol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"e158","DOI":"10.1093\/oncolo\/oyab035","article-title":"Cardiotoxicity from capecitabine chemotherapy: prospective study of incidence at rest and during physical exercise.","volume":"27","author":"Lestuzzi","year":"2022","journal-title":"Oncologist."},{"key":"B15","doi-asserted-by":"publisher","first-page":"637","DOI":"10.2459\/01.JCM.0000237914.12915.dd","article-title":"Severe ventricular dysrhythmias and silent ischemia during infusion of the antimetabolite 5-fluorouracil and cis-platin.","volume":"7","author":"Hrovatin","year":"2006","journal-title":"J Cardiovasc Med."},{"key":"B16","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1007\/s00280-005-0178-1","article-title":"Risk factors and prevention of cardiotoxicity induced by 5-fluorouracil or capecitabine.","volume":"58","author":"Jensen","year":"2006","journal-title":"Cancer Chemother Pharmacol."},{"key":"B17","first-page":"3028","article-title":"In vitro evidence that myocardial ischemia resulting from 5-fluorouracil chemotherapy is due to protein kinase C-mediated vasoconstriction of vascular smooth muscle.","volume":"53","author":"Mosseri","year":"1993","journal-title":"Cancer Res."},{"key":"B18","doi-asserted-by":"publisher","first-page":"416","DOI":"10.1007\/s12032-009-9226-8","article-title":"5-Fluorouracil induces arterial vasoconstrictions but does not increase angiotensin II levels.","volume":"27","author":"Salepci","year":"2010","journal-title":"Med Oncol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"661","DOI":"10.1093\/annonc\/mdh150","article-title":"5-Fluorouracil induces arterial vasocontractions.","volume":"15","author":"Sudhoff","year":"2004","journal-title":"Ann Oncol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1186\/2050-6511-15-47","article-title":"A systematic review of the pathophysiology of 5-fluorouracil-induced cardiotoxicity.","volume":"15","author":"Polk","year":"2014","journal-title":"BMC Pharmacol Toxicol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"e0115686","DOI":"10.1371\/journal.pone.0115686","article-title":"Effects of 5-fluorouracil on morphology, cell cycle, proliferation, apoptosis, autophagy and ROS production in endothelial cells and cardiomyocytes.","volume":"10","author":"Focaccetti","year":"2015","journal-title":"PLoS One."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1795","DOI":"10.1200\/JCO.1992.10.11.1795","article-title":"Cardiotoxicity of high-dose continuous infusion fluorouracil: a prospective clinical study.","volume":"10","author":"de Forni","year":"1992","journal-title":"J Clin Oncol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"795","DOI":"10.1111\/j.1742-1241.2007.01323.x","article-title":"5-fluorouracil increases the number and complexity of premature complexes in the heart: a prospective study using ambulatory ECG monitoring.","volume":"61","author":"Yilmaz","year":"2007","journal-title":"Int J Clin Pract."},{"key":"B24","first-page":"430","article-title":"A retrospective study of cardiotoxicities induced by 5-fluouracil (5-FU) and 5-FU based chemotherapy regimens in Pakistani adult cancer patients at Shaukat Khanum Memorial Cancer Hospital & Research Center.","volume":"62","author":"Khan","year":"2012","journal-title":"J Pak Med Assoc."},{"key":"B25","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1016\/j.jaccao.2020.12.005","article-title":"The incidence, risk factors, and outcomes with 5-fluorouracil-associated coronary vasospasm.","volume":"3","author":"Zafar","year":"2021","journal-title":"JACC CardioOncol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"475","DOI":"10.1080\/0284186X.2019.1711164","article-title":"Incidence and risk markers of 5-fluorouracil and capecitabine cardiotoxicity in patients with colorectal cancer.","volume":"59","author":"Dyhl-Polk","year":"2020","journal-title":"Acta Oncol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"e012798","DOI":"10.1136\/bmjopen-2016-012798","article-title":"Incidence and risk factors for capecitabine-induced symptomatic cardiotoxicity: a retrospective study of 452 consecutive patients with metastatic breast cancer.","volume":"6","author":"Polk","year":"2016","journal-title":"BMJ Open."},{"key":"B28","doi-asserted-by":"publisher","first-page":"e403","DOI":"10.1002\/onco.13536","article-title":"Myocardial ischemia induced by 5-fluorouracil: a prospective electrocardiographic and cardiac biomarker study.","volume":"26","author":"Dyhl-Polk","year":"2021","journal-title":"Oncologist."},{"key":"B29","doi-asserted-by":"publisher","first-page":"475","DOI":"10.2165\/00003495-199957040-00003","article-title":"Cardiotoxicity of the antiproliferative compound fluorouracil.","volume":"57","author":"Becker","year":"1999","journal-title":"Drugs."},{"key":"B30","doi-asserted-by":"publisher","first-page":"225","DOI":"10.3390\/jpm12020225","article-title":"Elevated risk of fluoropyrimidine-associated toxicity in European patients with DPYD genetic polymorphism: a systematic review and meta-analysis.","volume":"12","author":"Kim","year":"2022","journal-title":"J Pers Med."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.critrevonc.2018.02.002","article-title":"Fluoropyrimidine-induced cardiotoxicity.","volume":"124","author":"Depetris","year":"2018","journal-title":"Crit Rev Oncol Hematol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1517\/14740330902733961","article-title":"Fluoropyrimidine-associated cardiotoxicity: revisited.","volume":"8","author":"Wasif Saif","year":"2009","journal-title":"Expert Opin Drug Saf."},{"key":"B33","doi-asserted-by":"publisher","first-page":"700","DOI":"10.2459\/JCM.0b013e328332e873","article-title":"Capecitabine cardiac toxicity presenting as effort angina: a case report.","volume":"11","author":"Lestuzzi","year":"2010","journal-title":"J Cardiovasc Med."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1623","DOI":"10.1016\/j.amjcard.2012.07.026","article-title":"Capecitabine-induced chest pain relieved by diltiazem.","volume":"110","author":"Ambrosy","year":"2012","journal-title":"Am J Cardiol."},{"key":"B35","first-page":"531","article-title":"Bolus 5-fluorouracil as an alternative in patients with cardiotoxicity associated with infusion 5-fluorouracil and capecitabine: a case series.","volume":"27","author":"Saif","year":"2013","journal-title":"In Vivo."},{"key":"B36","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/j.clcc.2012.09.003","article-title":"Alternative treatment options in colorectal cancer patients with 5-fluorouracil- or capecitabine-induced cardiotoxicity.","volume":"12","author":"Deboever","year":"2013","journal-title":"Clin Colorectal Cancer."},{"key":"B37","doi-asserted-by":"publisher","first-page":"2303","DOI":"10.1016\/j.ejca.2013.03.004","article-title":"Use of raltitrexed as an alternative to 5-fluorouracil and capecitabine in cancer patients with cardiac history.","volume":"49","author":"Kelly","year":"2013","journal-title":"Eur J Cancer."},{"key":"B38","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1093\/annonc\/mdt479","article-title":"Final results of Australasian Gastrointestinal Trials Group ARCTIC study: an audit of raltitrexed for patients with cardiac toxicity induced by fluoropyrimidines.","volume":"25","author":"Ransom","year":"2014","journal-title":"Ann Oncol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1016\/j.clcc.2018.09.010","article-title":"Efficacy and cardiotoxic safety profile of raltitrexed in fluoropyrimidines-pretreated or high-risk cardiac patients with GI malignancies: large single-center experience.","volume":"18","author":"Khan","year":"2019","journal-title":"Clin Colorectal Cancer."},{"key":"B40","doi-asserted-by":"publisher","first-page":"453","DOI":"10.5603\/cj.2012.0084","article-title":"5-fluorouracil induced cardiotoxicity: review of the literature.","volume":"19","author":"Sorrentino","year":"2012","journal-title":"Cardiol J."},{"key":"B41","doi-asserted-by":"publisher","first-page":"6881","DOI":"10.1200\/JCO.20005.14.589","article-title":"Randomized phase III study of cisplatin with or without raltitrexed in patients with malignant pleural mesothelioma: an intergroup study of the European organisation for research and treatment of cancer lung cancer group and the National cancer institute of Canada.","volume":"23","author":"van Meerbeeck","year":"2005","journal-title":"J Clin Oncol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"1555","DOI":"10.1016\/s0140-6736(02)08514-8","article-title":"Comparison of survival, palliation, and quality of life with three chemotherapy regimens in metastatic colorectal cancer: a multicentre randomised trial.","volume":"359","author":"Maughan","year":"2002","journal-title":"Lancet."},{"key":"B43","doi-asserted-by":"publisher","first-page":"816","DOI":"10.1038\/sj.bjc.6601224","article-title":"Plasma concentrations of 5-fluorouracil and F-beta-alanine following oral administration of S-1, a dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine, as compared with protracted venous infusion of 5-fluorouracil.","volume":"89","author":"Yamada","year":"2003","journal-title":"Br J Cancer."},{"key":"B44","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1007\/s10147-005-0516-7","article-title":"5-Fluorouracil cardiotoxicity induced by alpha-fluoro-beta-alanine.","volume":"10","author":"Muneoka","year":"2005","journal-title":"Int J Clin Oncol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1007\/s11864-020-0719-1","article-title":"Cardiotoxicities of 5-fluorouracil and other fluoropyrimidines.","volume":"21","author":"Shiga","year":"2020","journal-title":"Curr Treat Options Oncol."},{"key":"B46","doi-asserted-by":"publisher","first-page":"100427","DOI":"10.1016\/j.esmoop.2022.100427","article-title":"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.","volume":"7","author":"Osterlund","year":"2022","journal-title":"ESMO Open."}],"container-title":["Frontiers in Cardiovascular Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2022.960240\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,9,14]],"date-time":"2022-09-14T05:22:33Z","timestamp":1663132953000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2022.960240\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,14]]},"references-count":46,"alternative-id":["10.3389\/fcvm.2022.960240"],"URL":"https:\/\/doi.org\/10.3389\/fcvm.2022.960240","relation":{},"ISSN":["2297-055X"],"issn-type":[{"value":"2297-055X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,14]]},"article-number":"960240"}}