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Journal of Clinical Oncology, Vol 26, No 22 (August 1), 2008: pp. 3802-3804 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2008.17.1637
Capecitabine-Induced Coronary VasospasmDepartment of Cardiology, Memorial Sloan-Kettering Cancer Center, New York, NY A 38-year-old woman with a history of hyperlipidemia and breast cancer was hospitalized after undergoing an exercise stress echocardiogram, which was markedly positive for ischemia. The patient reported a strong family history of premature coronary artery disease (CAD). She denied smoking and admitted to social use of alcohol. Five years before the current events, ductal carcinoma in situ was treated with lumpectomy, radiation therapy, and chemotherapy with cyclophosphamide, paclitaxel, and doxorubicin (a total dose of 240 mg/m2), which she tolerated without any apparent cardiac toxicity. Two months prior to the stress test, a recurrence of cancer in the lumpectomy bed was detected. She underwent bilateral mastectomy with reconstruction, and adjuvant oral capecitabine therapy was initiated at 3500 mg daily. A few days after beginning capecitabine, she noted dyspnea, lightheadedness, and palpitations with mild exertion, and was no longer able to tolerate her usual high-intensity workouts. She was referred for an echocardiographic stress test. Her resting electrocardiogram (ECG) was normal (Fig 1A). The resting ECG (Fig 1: Apical four-chamber view of the left ventricle; 1B, diastole; and 1C, systole) demonstrated normal cardiac function with left ventricular ejection fraction of 64%. The patient exercised on a treadmill using the Bruce Protocol for 5 minutes and 18 seconds attaining a peak workload of seven metabolic equivalent units (METs). The heart rate quickly rose from 62 to 171 (93% predicted heart rate). She developed dyspnea, palpitations, and slight nausea which reproduced her symptoms and which resolved within minutes after the exercise was stopped. The ECG at end exercise showed diffuse ST segment elevation, which persisted for over 20 minutes into recovery (Fig 2A). Post exercise ejection fraction was 36% with a global decrease in left ventricular wall motion (Fig 2: Apical four-chamber view of the left ventricle; 2B, diastole; and 2C, systole). Several minutes into the recovery period left ventricular wall motion returned to normal. She was admitted for observation because of the persistent ECG changes. Her vital signs, physical exam, and cardiac enzymes remained normal and the capecitabine therapy was stopped. Aspirin and beta-blocker were initiated and the patient was observed on telemetry for 24 hours with no further events. Computed tomography angiogram demonstrated normal coronary arteries. Her symptoms resolved completely and she regained her full exercise capacity. A stress echocardiogram was repeated 10 days after discontinuation of capecitabine therapy. The patient now was able to reach a high level of exercise (15.3 METs), with normal ECG and functional response. There was global hyperdynamic left ventricular wall motion with a postexercise ejection fraction of 81% and no evidence of ischemia.
Capecitabine is a fluoropyrimidine antimetabolite that is converted to fluorouracil (FU) via a complex enzymatic pathway with its final steps preferentially occurring in tumor tissue.1 Cardiotoxicity has been reported in 1.2% to 18% of patients treated with FU.2 Coronary vasospasm has been demonstrated in animal models as well as human vascular studies during FU infusion.3 In addition, direct cytotoxic endothelial injury with subendothelium exposure and thrombus formation has been observed in animal models.4 Patients with fluoropyrimidine-induced vasospasm usually present with chest pain at rest and ischemic ECG changes, and less frequently myocardial infarction, ventricular arrhythmias and death.2 Capecitabine cardiotoxicity is thought to occur by the same mechanism as FU, as its pharmacokinetics closely resemble that of FU infusion, but its exact incidence is still unknown. Thymidine phosphorylase, one of the enzymes responsible for conversion of capecitabine to FU, is present in higher concentrations in tumor tissues than in normal tissues, which suggests a favorable toxicity profile. Notably, thymidine phosphorylase activity is expressed in atherosclerotic plaques as well.5 This may explain a higher prevalence of capecitabine cardiotoxicity in patients with CAD. There are, however, several reports in current literature describing capecitabine cardiotoxicity in patients with no history of cardiovascular disease. Typical presentations and pathophysiologic mechanisms of FU or capecitabine toxicity closely resemble variant angina which classically manifests as chest pain at rest with ST segment changes and is caused by focal major coronary artery spasm that typically occurs at the sites of or adjacent to atherosclerotic fatty streaks or a fibrous plaques.6 Typical variant angina has been described in people with normal exercise tolerance, but some patients also experience exertional chest pain due to exercise-induced vasospasm with or without fixed coronary stenosis.7 Focal endothelial dysfunction and reduced bioavailability of nitric oxide are implicated in the pathogenesis of this type of coronary vasospasm.8 Noninvasive imaging may show regional wall motion abnormalities and even segmental dyskinesis during the episodes of chest pain.9 Rare cases of FU exercise-induced coronary artery spasm have been reported and exercise-induced ST segment elevation has been documented with capecitabine.10 To our knowledge, this is the first reported case of capecitabine causing exercise-induced global myocardial ischemia and a significant decrease in ejection fraction in a patient with normal resting left ventricular function and normal coronaries. There was rapid resolution of both symptoms and exercise-related left ventricular dysfunction after cessation of capecitabine therapy. Exercise-provoked diffuse coronary microspasm due to capecitabine-induced endothelial dysfunction could potentially explain the findings of global left ventricular dysfunction in this patient. This unusual presentation of capecitabine cardiotoxicity without chest pain could easily have been dismissed as fatigue and deconditioning due to chemotherapy and the postoperative state. The main treatment of fluoropyrimidine-induced vasospasm is discontinuation of the drug, and the risk of cardiotoxicity increases with repeat administration. The consequences of not recognizing capecitabine cardiotoxicity could have been perilous. A fuller awareness of the spectrum of capecitabine toxicity may prevent adverse patient outcomes. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
REFERENCES 1. Jones RL, Ewer MS: Cardiac and cardiovascular toxicity of non-anthracycline anticancer drugs. Expert Rev Anticancer Ther 6:1249-1269, 2006[CrossRef][Medline] 2. Jensen SA, Sorensen JB: Risk factors and prevention of cardiotoxicity induced by 5-fluorouracil or capecitabine. Cancer chemothera pharmacol 58:487-493, 2006[CrossRef] 3. Südhoff T, Enderle MD, Pahlke M, et al: 5-Fluorouracil induces arterial vasoconstriction. Ann Oncol 15:661-664, 2004 4. Cwikiel M, Zhang B, Eskilsson J, et al: Influence of 5-fluorouracil on the endothelium in small arteries: An electron microscopic study in rabbits. Scanning Microsc 9:561-576, 1995[Medline] 5. Boyle JJ, Wilson B, Harrower S, et al: Expression of angiogenic factor thymidine phosphorylase and angiogenesis in human atherosclerosis. J Pathol 192:234-242, 2000[CrossRef][Medline] 6. Hong M-K, Park S-W, Lee CW, et al: Intravascular ultrasound findings of negative arterial remodeling at sites of focal coronary spasm in patients with vasospastic angina. Am Heart J 140:395-401, 2000[CrossRef][Medline] 7. Bugiardini R, Bairey Merz CN: Angina with "normal" coronary arteries. JAMA 293:477-484, 2005 8. Kugiyama K, Yasue H, Okumura K, et al: Nitric oxide activity is deficient in spasm arteries of patients with coronary spastic angina. Circulation 94:266-271, 1996 9. Distante A, Rovai D, Picano E, et al: Transient changes in left ventricular mechanics during attacks of Prinzmetal angina: A two-dimensional echocardiographic study. Am Heart J 108:440-446, 1984[CrossRef][Medline] 10. Wijesinghe N, Thompson P, McAlister H: Acute coronary syndrome induced by capecitabine therapy. Heart Lung Circ 15:337-339, 2006[CrossRef][Medline]
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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