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.
Capecitabine (Xeloda; Genentech, South San Francisco, California), an oral 5-fluorouracil prodrug, is a member of a class of chemotherapeutic agents known as fluoropyrimidines and has played a prominent role in the treatment of solid tumors, including colorectal and breast cancer. Although most major phase II and III clinical trials studying capecitabine have reported no adverse cardiac side effects, 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. 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. 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 ).
| Patient | Age (years) | Gender | Colorectal Adenocarcinoma | Cancer Stage | Capecitabine Dose (mg/day) | Chest Pain Relieved by Discontinuing Capecitabine | Oxaliplatin Treatment | Diltiazem Treatment |
|---|---|---|---|---|---|---|---|---|
| 1 | 62 | M | + | T2N1b | 4,000 | + | + | + |
| 2 | 50 | M | + | T3N2b | 4,000 | + | + | + |
| 3 | 56 | F | + | T3N1 | 2,500 | + | 0 | + |
| 4 | 58 | F | O ⁎ | — | 3,300 | + | 0 † | + |
| 5 | 67 | M | + | T4 | 3,500 | + | 0 ‡ | 0 § |
† Received mitomycin C simultaneously.
‡ Switched from 5-fluorouracil to capecitabine after infusional pump failure.
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.
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.
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