Cardiac Toxicity Associated with Capecitabine Therapy

Capecitabine (N-pentyloxycarbonyl-5?-deoxy-5-fluorocytidine) is a novel fluoropyrimidine carbamate that is orally administered and absorbed through the intestinal mucosa as an intact molecule (1). A series of three enzymatic steps are required to convert this prodrug to 5-fluorouracil (5-FU). The parent compound reaches the liver through the portal circulation, where it is metabolized to 5?-deoxy5-fluorocytidine by a 60 kDa carboyxlesterase. The latter compound is converted to 5?-deoxy-5 /fluorouridine by cytidine deaminase, which is widely distributed throughout the body and in plasma. Finally, 5-FU is released within the cell through the action of thymidine phosphorylase, and the plasma levels of 5-FU are relatively low. Since many tumor tissues contain higher levels of this enzyme compared to normal tissues, formation of 5-FU may occur preferentially within tumor tissue. The recommended schedule for capecitabine is 1 250 mg/m twice daily (morning and evening, equivalent to 2 500 mg/m total daily dose) dosing for 2 weeks followed by a one-week rest period every 3 weeks. Capecitabine was first given approval by the Food and Drug Administration for the treatment of patients with breast cancer whose disease has progressed on prior therapy (2). Two large PhaseIII trials comparing capecitabine with IV bolus 5-FU/leucovorin in patients with metastatic colorectal cancer have shown the oral drug has similar efficacy, with a reduction in mucositis and neutropenia (3, 4). Clinical safety data from patients included in these trials with either breast or colorectal cancer indicates that the most common toxicities include hand-foot syndrome, diarrhea, nausea and vomiting. Although cardiac symptoms have been reported with 5FU given alone or with other agents, cardiac toxicity in patients receiving capecitabine has only rarely been reported. We describe a patient who developed recurrent episodes of chest pain after 3 /5 doses of capecitabine while participating in a clinical trial of oxaliplatin in combination with capecitabine. Case report. The patient, a 54-year-old Caucasian male, was diagnosed with rectal cancer one year before entry in this clinical trial. He had initially undergone a diverting colostomy, with low anterior resection of the primary tumor. The patient received adjuvant chemoradiation with infusional fluorouracil, followed by 4 cycles of 5-FU, leucovorin and irinotecan given weekly for 4 out of 6 weeks. A CT scan taken after completion of this regimen revealed new metastatic disease involving the liver and diaphragm. The patient’s main symptom was mild fatigue. He had a 70-pack/ year history of smoking but had given up the habit the year before, and had alcohol only on occasion. There was no family history of cardiac disease, and he did not have any known cardiac risk factors. His medications at the time of enrolment in the study were terazosin hydrochloride, citalopram hydrobromide, enteric-coated aspirin, oxazepam, ranitidine, and celecoxib. The patient was enrolled in an Institutional Review Boardapproved Phase I study evaluating escalating doses of capecitabine given twice daily on days 1 /5 and 8 /12 in combination with oxaliplatin 130 mg/m infused IV over 2 h every 3 weeks. For the first cycle, the patient received oxaliplatin 130 mg/m on day 1; capecitabine 1 350 mg/m was given twice daily morning and evening starting the next day (total daily dose 2 700 mg/m). On day 4, the patient was referred to the Oncology Clinic complaining of mild substernal pressure while walking, but without shortness of breath. This occurred about 12 h after the dose of capecitabine the previous evening. The symptoms improved when he lay down, and lasted for about 30 min. An electrocardiogram (ECG) done in the clinic showed no acute ischemic changes. An echocardiogram showed an ejection fraction of 50 /70%, with normal left ventricular size and function. Cardiac enzymes and troponin levels were unremarkable, and no ECG changes were noted by telemetry throughout the next 24 h. The patient underwent a stress test the next day (about 26 h after the episode of chest pain); the examination was terminated during stage 2 (maximum workload 7 METS) because of fatigue. During the recovery period, the patient complained of chest pain, but no clear-cut signs of ischemia were seen on the ECG. Cardiac catheterization, performed on day 6, showed left dominant coronary circulation with non-obstructive coronary artery disease. The cardiologist suspected that the chest pain was not cardiac in origin, and a trial with prilosec was recommended for detection of possible esophageal reflux. No additional capecitabine therapy was given during that cycle, and no further episodes of chest pain occurred. When the patient returned for the start of cycle 2, a repeat stress test was terminated during stage 3 (10 METS) because of fatigue; the patient had no chest pain and the ECG was normal. He received oxaliplatin and capecitabine the next day. On day 3, about 3 h after the fifth dose of capecitabine, the patient experienced another episode of chest pain while walking to the clinic. The ECG was normal. A repeat stress test performed 4 h after the symptoms had resolved was stopped after reaching 7 METS owing to chest pain and fatigue. Nifedepine was prescribed for a possible capecitabine-associated coronary spasm. CASE REPORT