Capecitabine-Induced Chest Pain Relieved by Diltiazem Andrew P. Ambrosy, MDc, Pamela L. Kunz, MDa, George A. Fisher, MD, PhDa, and Ronald M. Witteles, MDb,* Five patients with primary colorectal adenocarcinoma or anal squamous cell carcinoma were started on a 2-weeks-on, 1-week-off capecitabine dosing regimen in addition to other chemotherapeutic agents and/or radiation. Within the first few doses, patients experienced chest pain and/or dyspnea at rest or with exertion. Acute electrocardiographic findings suggestive of ischemia were found in some cases at initial presentation, and 1 patient had troponin elevation consistent with an acute ST-segment elevation myocardial infarction. Subsequent ischemia evaluations were not suggestive of clinically significant coronary artery disease. All patients experienced immediate and sustained relief from chest pain after discontinuation of capecitabine and were able to successfully tolerate retreatment using a novel management strategy based on secondary prophylaxis with diltiazem. In conclusion, guidelines for the evaluation of and therapy for capecitabine-induced chest pain are proposed. © 2012 Elsevier Inc. All rights reserved. (Am J Cardiol 2012;110: 1623–1626) Capecitabine (Xeloda; Genentech, South San Francisco, California), an oral 5-fluorouracil prodrug, is a member of a class of chemotherapeutic agents known as fluoropyrimidines1 and has played a prominent role in the treatment of solid tumors, including colorectal2– 4 and breast cancer.5 Although most major phase II and III clinical trials studying capecitabine have reported no adverse cardiac side effects,6 –9 an increasing number of case reports and small case series have emerged describing a spectrum of cardiac toxicities associated with capecitabine treatment, ranging from typical angina at rest or with exertion (in the presence or absence of electrocardiographic changes) to myocardial infarction and death.10 –22 Notably, although suspected capecitabine-induced coronary vasospasm has been acutely managed with calcium channel blockers and/or nitrates, all previously published cases have resulted in early treatment termination, which may have deleterious long-term prognostic implications.10 –22 We report for the first time our center’s experience successfully retreating 5 patients with colorectal and anal cancer previously diagnosed with suspected capecitabine-induced coronary vasospasm using a management strategy based on secondary prophylaxis with diltiazem. Methods Five patients with primary colorectal adenocarcinoma or anal squamous cell carcinoma and without histories of clinically significant coronary artery disease received capecitabine using a 2-weeks-on, 1-week-off schedule in addition to other chemotherapy and/or radiation (Table 1).
a Divisions of Medical Oncology and bCardiovascular Medicine, cDepartment of Medicine, Stanford University School of Medicine, Stanford, California. Manuscript received May 21, 2012; revised manuscript received and accepted July 12, 2012. *Corresponding author: Tel: 650-498-4343; fax: 650-725-1599. E-mail address: email@example.com (R.M. Witteles).
0002-9149/12/$ – see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2012.07.026
Results Within the first several doses of capecitabine administered, all 5 patients experienced chest pain and/or dyspnea at rest or with exertion. Patient 1 experienced typical angina during his initial capecitabine cycles, and the chest pain resolved between cycles; results of stress echocardiography were normal. Patient 2 underwent electrocardiography without evidence of acute ischemia during an episode of chest pain and subsequently had negative results on stress echocardiography. Patient 3 experienced chest pain during chemotherapy cycles, which persisted despite dose reduction of capecitabine; stress echocardiographic results were normal. Patient 4 developed chest pain followed by syncope, and initial electrocardiographic results revealed 1-mm ST-segment elevation in the inferior leads and a troponin I level that peaked at 0.84 ng/ml; stress echocardiographic results were normal. Patient 5 presented to the emergency department with electrocardiographic results showing dynamic hyperacute ST-segment elevations and emergently underwent cardiac catheterization, which revealed only mild coronary artery disease. Despite variable clinical presentations, all 5 patients experienced immediate and sustained chest pain relief after discontinuing capecitabine and were able to successfully tolerate retreatment after initiating diltiazem. Although able to complete multiple subsequent cycles of capecitabine therapy, patient 2 experienced ongoing albeit less frequent and milder episodes of chest pain with heavy exertion; none of the other 4 patients experienced any further chest pain after diltiazem initiation, and all were able to continue receiving their planned capecitabine. Discussion To the best of our knowledge, this is the first report to describe successful retreatment with capecitabine in patients www.ajconline.org
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Table 1 Clinical findings in 5 patients experiencing capecitabine-induced chest pain relieved by diltiazem Patient
Capecitabine Dose (mg/day)
Chest Pain Relieved by Discontinuing Capecitabine
1 2 3 4 5
62 50 56 58 67
M M F F M
⫹ ⫹ ⫹ O* ⫹
T2N1b T3N2b T3N1 — T4
4,000 4,000 2,500 3,300 3,500
⫹ ⫹ ⫹ ⫹ ⫹
⫹ ⫹ 0 0† 0‡
⫹ ⫹ ⫹ ⫹ 0§
* Squamous cell carcinoma. † Received mitomycin C simultaneously. ‡ Switched from 5-fluorouracil to capecitabine after infusional pump failure. § Treated concurrently with isosorbide mononitrate.
Figure 1. Stanford algorithm for the evaluation and management of suspected capecitabine-induced coronary vasospasm. CAD ⫽ coronary artery disease; CCB ⫽ calcium channel blocker; EKG ⫽ electrocardiography; ER ⫽ emergency room; PRN ⫽ as needed; SLN ⫽ sublingual nitroglycerin.
Coronary Artery Disease/Capecitabine Chest Pain Relieved by Diltiazem
with suspected capecitabine-induced coronary vasospasm using prophylactic diltiazem. There are several salient features of the clinical presentations that have been previously highlighted that merit further mention.10 –22 First, our cohort was relatively young, had no known histories of coronary artery disease, and had normal results on exercise stress imaging. Second, all 5 of our patients developed anginal-type chest pain within a few days of beginning treatment, suggesting this toxicity to be a cumulative-dose effect, not a peak-dose effect. Third, the clinical presentation of capecitabine-induced coronary vasospasm can be highly variable, ranging from typical angina at rest or with exertion to myocardial infarction. Additionally, shortness of breath and dyspnea on exertion should be considered possible anginal equivalents in patients who are actively being treated with capecitabine. Importantly, the absence of electrocardiographic changes characteristic of acute ischemia does not rule out capecitabine-induced coronary vasospasm, and suspicion for this diagnosis should remain high in the right clinical context. Although capecitabine-related cardiac toxicity has been well described, the mechanism of action has been a focus of considerable controversy. Although theoretically, capecitabine or any of its metabolic intermediates could be cardiotoxic, similar clinical presentations have been previously attributed to 5-fluorouracil,23 making this molecule (or its metabolites) the likely culprit. Coronary vasospasm during infusion of 5-fluorouracil has been documented in animal models as well as vascular studies conducted in humans.24 Our center’s experience controlling anginal symptoms to the extent that chemotherapy can be administered with minimal or no delay strongly supports coronary vasospasm as the putative mechanism of capecitabine-associated cardiac toxicity. The Stanford algorithm for managing suspected capecitabine-induced cardiac toxicity is illustrated in Figure 1. Before starting capecitabine, we recommend obtaining a baseline electrocardiogram in all patients who have not undergone recent previous electrocardiography, to allow comparison if possible cardiac symptoms develop. The suspicion for this toxicity should be highest within the first few days of initiating therapy, and patients should be urgently or emergently evaluated if the chest pain occurs at rest. Importantly, capecitabine-induced coronary vasospasm is a diagnosis of exclusion, and it is necessary to rule out acute coronary syndromes. If typical angina at rest or positive cardiac enzymes are present, patients should receive full-dose aspirin and be considered for aggressive management of acute coronary syndromes as clinically indicated. Once acute coronary syndromes have been ruled out, all patients should complete appropriate ischemia evaluation on the basis of cardiac history and risk factors. Although it is more practical to start with stress testing, patients with suspected capecitabine-induced coronary vasospasm may have electrocardiac and echocardiographic signs of ischemia, making it necessary to proceed to coronary angiography for a definitive assessment of coronary artery disease. Conversely, there may be no stress-induced electrocardiographic or echocardiographic signs of ischemia, particularly
in the subset of patients presenting with new-onset exertional angina. In patients without ongoing ischemia, in whom capecitabine is clinically indicated (i.e., no alternatives with comparable efficacy and safety), we recommend starting diltiazem, prescribing sublingual nitroglycerin as needed for acute events, and continuing capecitabine therapy with close follow-up. 1. Venturini M. Rational development of capecitabine. Eur J Cancer 2002;38(suppl):3–9. 2. Hoff PM, Ansari R, Batist G, Cox J, Kocha W, Kuperminc M, Maroun J, Walde D, Weaver C, Harrison E, Burger HU, Osterwalder B, Wong AO, Wong R. Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study. J Clin Oncol 2001;19:2282–2292. 3. 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. 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. 4. Van Cutsem E, Findlay M, Osterwalder B, Kocha W, Dalley D, Pazdur R, Cassidy J, Dirix L, Twelves C, Allman D, Seitz JF, Scholmerich J, Burger HU, Verweij J. Capecitabine, an oral fluoropyrimidine carbamate with substantial activity in advanced colorectal cancer: results of a randomized phase II study. J Clin Oncol 2000;18:1337–1345. 5. Oshaughnessy JA, Blum J, Moiseyenko V, Jones SE, Miles D, Bell D, Rosso R, Mauriac L, Osterwalder B, Burger HU, Laws S. Randomized, open-label, phase II trial of oral capecitabine (Xeloda) vs. a reference arm of intravenous CMF (cyclophosphamide, methotrexate and 5-fluorouracil) as first-line therapy for advanced/ metastatic breast cancer. Ann Oncol 2001;12:1247–1254. 6. Cassidy J, Twelves C, Van Cutsem E, Hoff P, Bajetta E, Boyer M, Bugat R, Burger U, Garin A, Graeven U, McKendric J, Maroun J, Marshall J, Osterwalder B, Perez-Manga G, Rosso R, Rougier P, Schilsky RL. First-line oral capecitabine therapy in metastatic colorectal cancer: a favorable safety profile compared with intravenous 5-fluorouracil/leucovorin. Ann Oncol 2002;13:566 –575. 7. Scheithauer W, McKendrick J, Begbie S, Borner M, Burns WI, Burris HA, Cassidy J, Jodrell D, Koralewski P, Levine EL, Marschner N, Maroun J, Garcia-Alfonso P, Tujakowski J, Van Hazel G, Wong A, Zaluski J, Twelves C. Oral capecitabine as an alternative to i.v. 5-fluorouracil-based adjuvant therapy for colon cancer: safety results of a randomized, phase III trial. Ann Oncol 2003;14: 1735–1743. 8. Sharma R, Rivory L, Beale P, Ong S, Horvath L, Clarke SJ. A phase II study of fixed-dose capecitabine and assessment of predictors of toxicity in patients with advanced/metastatic colorectal cancer. Br J Cancer 2006;94:964 –968. 9. Blum JL, Jones SE, Buzdar AU, LoRusso PM, Kuter I, Vogel C, Osterwalder B, Burger HU, Brown CS, Griffin T. Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 1999;17:485– 493. 10. Schnetzler B, Popova N, Collao Lamb C, Sappino AP. Coronary spasm induced by capecitabine. Ann Oncol 2001;12:723–724. 11. 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. 12. Rizvi AA, Schauer P, Owlia D, Kallal JE. Capecitabine-induced coronary vasospasm—a case report. Angiology 2004;55:93–97. 13. Kuppens IE, Boot H, Beijnen JH, Schellens JH, Labadie J. Capecitabine induces severe angina-like chest pain. Ann Intern Med 2004; 140:494 – 495. 14. Aksoy S, Karaca B, Dincer M, Yalcin S. Common etiology of capecitabine and fluorouracil-induced coronary vasospasm in a colon cancer patient. Ann Pharmacother 2005;39:573–574.
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