Acute presentation of vasospastic angina induced by oral capecitabine: a case report
© Golias et al.; licensee BioMed Central Ltd. 2014
Received: 31 May 2013
Accepted: 11 November 2013
Published: 15 January 2014
Oral capecitabine is an oral prodrug of 5-fluorouracil that has been integrated into the management of multiple cancer types because of the convenience of administration and its efficacy compared with 5-fluorouracil. Capecitabine mimics the pharmacokinetics of intravenous 5-fluorouracil. While cardiac events associated with the use of 5-fluorouracil are a well-known side effect, capecitabine-induced cardiotoxicity has only been rarely reported.
We present a case of a 46-year-old woman of Greek ethnicity who presented to our institution with an operated gastric sarcoma who experienced capecitabine-induced vasospastic angina. Primarily a clinical diagnosis of a possible acute coronary syndrome was proposed and the patient was admitted to the hospital for further investigation which was proved between normal limits. After a witnessed episode of angina, her prior history of capecitabine intake and an undertaken further imaging investigation we associated anginal symptoms and signs with vasospastic angina induced by capecitabine 36 hours prior to hospital admission.
Cardiologists should be aware of the potential cardiac hazards of capecitabine, especially in patients with cardiovascular risk factors. Due to the increasing usage of capecitabine during the last years, patients should be warned for the possibility of chest pain, particularly during the first few days of capecitabine treatment. Specifically, patients developing acute coronary syndrome should not be retreated with capecitabine. On the other hand, due to its promising antitumoral efficacy, its use should not be discouraged.
KeywordsAcute coronary syndrome Capecitabine Cardiotoxicity Vasospastic angina
Oral capecitabine is an oral prodrug of 5-fluorouracil (5-FU) that has been integrated into the management of multiple cancer types. Capecitabine, a thymidine phosphorylase– activated fluoropyrimidine carbamate, is absorbed by the gastrointestinal tract and metabolized to 5-FU by a cascade of three enzymes. It is currently considered the only universally approved orally administered 5-FU prodrug. It belongs to a new generation of orally administered fluoropyrimidines. It has been developed because of the clinical need for efficient, tolerable and convenient agents that do not require continuous infusion. Capecitabine is not a cytotoxic drug itself; by a three-step enzymatic cascade, it is converted to 5-FU mainly within human cancer cells. Capecitabine is converted by carboxylesterase in the liver to 5′-deoxy-5-fluorocytidine and by cytidine deaminase in the liver and tumor tissue to 5′-deoxy-5-fluorouridine. Furthermore, it is converted by thymidine phosphorylase to 5-FU in tumor tissue. Thymidine phosphorylase is found in higher concentrations in tumor tissue than in normal tissue and is upregulated by radiation in tumor tissue, but not in normal tissue. Thus, oral capecitabine can result in higher intratumoral and lower systemic 5-FU concentration than bolus delivery of 5-FU. The drug compares favorably with 5-FU in patients with colorectal cancer and breast cancer, and it has a better toxicity profile with mainly gastrointestinal and dermatologic effects. Capecitabine shows antineoplastic activity and synergy with other cytotoxic agents, including cyclophosphamide and docetaxel, in animal models. Bioavailability after oral administration is close to 100%. Although patients may receive the drug orally in the convenience of their own homes, the key to successful management of capecitabine is the clinician’s awareness of its severe, but low in incidence, adverse effects and the patient’s education, emphasizing compliance with the treatment plan, adverse effect prevention and timely recognition of the drug’s toxicities. This improved therapeutic index, along with more favorable pharmacokinetics (similar to those of protracted infusion of 5-FU) and convenient oral administration without the need for central venous access and an ambulatory infusion pump, make capecitabine particularly appealing to use.
In particular, although cardiac events associated with the use of 5-FU are a well- known side effect, capecitabine-induced cardiotoxicity has only rarely been reported [1–4]. Walko et al. compiled a review of reports in the literature describing adverse effects observed in capecitabine-treated patients . Chest pain occurred in 6% of 758 breast and colorectal cancer patients treated with capecitabine at a dose of 2500mg/m2 per day in two divided doses for 14 days followed by 1 week of rest. The authors concluded that this complication is more frequent in patients who have a history of coronary artery disease and recommended close monitoring for cardiac abnormalities during therapy. Herein we present the case of a 46-year-old woman with an operated gastric sarcoma who presented to our institution with capecitabine-induced vasospastic angina.
Capecitabine is an oral prodrug that is converted through a three-stage enzymatic reaction to 5-FU primarily in liver and tumor cells. Through the years, it has gained popularity as well as support from the oncologic community because of its efficacy, ease of administration and milder toxicity profile. The cardiotoxic effects of intravenously administered 5-FU pyrimidine analogues have been well-described in the literature, with a reported incidence ranging from 1% to 68% [7, 8], whereas the cardiotoxic effects of capecitabine, the oral formulation of 5-FU, are less familiar to cardiologists. These manifestations include acute coronary syndrome (ACS), heart failure, hypertension, hypotension, cardiomyopathy and arrhythmias. Myocardial injury, thrombogenic effects, immunoallergic reaction and coronary vasospasm have all been implicated in the mechanism underlying 5-FU cardiotoxicity [9, 10]. Capecitabine toxicity is thought to have the same etiology as the toxicity of 5-FU, although capecitabine and its metabolites are minimally cytotoxic in vitro compared with 5-FU . Our present case report demonstrates that capecitabine can induce ACS. Although the true incidence of this complication still has not been defined, chest pain during capecitabine therapy has been reported in 6% of patients . Acute coronary thrombosis cannot completely be excluded by angiography. Coronary vasospasm is another mechanism that might possibly be involved. However, the efficacy of vasodilating drugs given prophylactically to patients with previous episodes of chest pain during 5-FU treatment has been reported, but with inconsistent results .
Capecitabine should be considered a drug with cardiotoxic potential , even in the absence of prior cardiac history. It can induce coronary spasm at the macro- or microvascular level . Cardiologists should be aware of its potential cardiac hazards, which might be manifested by coronary angiospasm, especially in patients with cardiovascular risk factors. Because of the increasing use of capecitabine during the past several years, patients should be warned and informed about the possibility of chest pain and other possible emergent anginal symptoms, particularly during the first few days of capecitabine treatment. Most importantly, patients who develop ACS should not be retreated with capecitabine. However, because of capecitabine’s promising antitumoral efficacy, its use should not be discouraged.
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
- Tsibiribi P, Descotes J, Lombard-Bohas C, Barel C, Bui-Xuan B, Belkhiria M, Tabib A, Timour Q: Cardiotoxicity of 5-fluorouracil in 1350 patients with no prior history of heart disease. Bull Cancer. 2006, 93: E27-E30.PubMedGoogle Scholar
- Aksoy S, Karaca B, Dinçer M, Yalçin S: Common etiology of capecitabine and fluorouracil-induced coronary vasospasm in a colon cancer patient. Ann Pharmacother. 2005, 39: 573-574.View ArticlePubMedGoogle Scholar
- Rizvi AA, Schauer P, Owlia D, Kallal JE: Capecitabine-induced coronary vasospasm: a case report. Angiology. 2004, 55: 93-97. 10.1177/000331970405500114.View ArticlePubMedGoogle Scholar
- Schnetzler B, Popova N, Collao Lamb C, Sappino AP: Coronary spasm induced by capecitabine. Ann Oncol. 2001, 12: 723-724.View ArticlePubMedGoogle Scholar
- Walko CM, Lindley C: Capecitabine: a review. Clin Ther. 2005, 27: 23-44. 10.1016/j.clinthera.2005.01.005.View ArticlePubMedGoogle Scholar
- Ginghina C, Bejan I, Ceck CD: Modern risk stratification in coronary heart disease. J Med Life. 2011, 4: 377-386.PubMedPubMed CentralGoogle Scholar
- Saif MW, Shah MM, Shah AR: Fluoropyrimidine-associated cardiotoxicity: revisited. Expert Opin Drug Saf. 2009, 8: 191-202. 10.1517/14740330902733961.View ArticlePubMedGoogle Scholar
- Kosmas C, Kallistratos MS, Kopterides P, Syrios J, Skopelitis H, Mylonakis N, Karabelis A, Tsavaris N: Cardiotoxicity of fluoropyrimidines in different schedules of administration: a prospective study. J Cancer Res Clin Oncol. 2008, 134: 75-82.View ArticlePubMedGoogle Scholar
- Jensen SA, Sørensen JB: Risk factors and prevention of cardiotoxicity induced by 5-fluorouracil or capecitabine. Cancer Chemother Pharmacol. 2006, 58: 487-493. 10.1007/s00280-005-0178-1.View ArticlePubMedGoogle Scholar
- Duncker DJ, Bache RJ: Regulation of coronary blood flow during exercise. Physiol Rev. 2008, 88: 1009-1086. 10.1152/physrev.00045.2006.View ArticlePubMedGoogle Scholar
- Shoemaker LK, Arora U, Rocha Lima CM: 5-fluorouracil -induced coronary vasospasm. Cancer Control. 2004, 11: 46-49.PubMedGoogle Scholar
- Südhoff T, Enderle MD, Pahlke M, Petz C, Teschendorf C, Graeven U, Schmiegel W: 5-fluorouracil induces arterial vasocontractions. Ann Oncol. 2004, 15: 661-664. 10.1093/annonc/mdh150.View ArticlePubMedGoogle Scholar
- Frickhofen N, Beck FJ, Jung B, Fuhr HG, Andrasch H, Sigmund M: Capecitabine can induce acute coronary syndrome similar to 5-fluorouracil. Ann Oncol. 2002, 13: 797-801. 10.1093/annonc/mdf035.View ArticlePubMedGoogle Scholar
- Van Cutsem E, Twelves C, Cassidy J, Allman D, Bajetta E, Boyer M, Bugat R, Findlay M, Frings S, Jahn M, McKendrick J, Osterwalder B, Perez-Manga G, Rosso R, Rougier P, Schmiegel WH, Seitz JF, Thompson P, Vieitez JM, Weitzel C, Harper P, Xeloda Colorectal Cancer Study Group: Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol. 2001, 19: 4097-4106.PubMedGoogle Scholar
- Kuppens IE, Boot H, Beijnen JH, Schellens JH, Labadie J: Capecitabine induces severe angina-like chest pain. Ann Intern Med. 2004, 140: 494-495. 10.7326/0003-4819-140-6-200403160-00034.View ArticlePubMedGoogle Scholar
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