Feasibility of 5-Fluorouracil resumption in a patient experiencing drug-induced acute Prinzmetal angina

To the Editor:Cardiotoxicity is a well-known adverse event associated with the administration of 5-Fluorouracil (5-FU) and occurs more often with continuous infusion than with bolus injection. Its incidence varies from 1% to as much as 18% [1–3]. Previous history of cardiac disease is a predisposing factor, but even in patients without a history of ischemic heart disease cardiotoxicity may develop occasionally. The suggested mechanism is a coronary vasospasm [4]. Since fatal events have been reported, the current standard is definitive 5-FU interruption.

Adjuvant chemotherapy with 5-FU containing regimens significantly improves survival in colorectal patients. In high-risk patients, early interruption of the drug should be carefully evaluated by weighing costs against benefits.

We report the case of a patient who developed typical Prinzmetal angina during a course of adjuvant chemotherapy with the FOLFOX regimen but then continued treatment as an inpatient in the cardiology department.

A 46-year-old man with an unremarkable medical history and no coronary risk factors was referred to our oncology department in May 2004 with a Stage IIIC rectal adenocarcinoma (TNM classification pT3N2M0) that had been completely resected 1 month earlier. Because five out of eight lymph nodes were metastatic, we proposed postsurgical chemoradiation using the new schedule FOLFOX4 [5]. On preliminary physical examination, the patient showed no signs of cardiac dysfunction, and ECG was normal.

During the first cycle of 5-FU infusion, the patient experienced recurrent episodes at home of long-lasting chest pain that spontaneously disappeared. ECG in absence of symptoms was normal. Twenty-four hours after starting the second cycle, the patient presented again with recurrent episodes of typical angina and diffuse persistent elevated ST segments. 5-FU infusion was stopped, and the patient was admitted to the coronary care unit. Nitrates, heparin and acetylsalicylic acid were administered. Coronary angiography showed a normal coronary artery tree. Echocardiography was normal. Serum markers of myocardial damage were normal.

Due to a high risk of tumor relapse and in the absence of coronary disease, treatment was resumed following extensive discussions with the patient on the risks and benefits of therapy. Subsequent chemotherapy cycles were delivered with the patient under continuous ECG monitoring in the cardiology department. Since the patient refused nitrates because of intense headaches, no prophylactic measures were adopted. Sublingual nitro-glycerine administered on demand was efficacious in controlling chest pain and ECG abnormalities that occurred during the second day of each subsequent cycle. No arrhythmia was recorded. No chest pain was observed in the chemotherapy-free intervals. At the last follow-up visit in June 2005, the patient was free of disease and asymptomatic. ECG and echocardiography were normal.

Acute heart ischemia is a well-recognized adverse event of 5-FU continuous infusion. After having experienced a cardiac side effect, patients are at increased risk of relapse if re-exposed to 5-FU. To date, no preventive measures against this side effect have been described. The current option is to definitely stop delivery of the drug in the event of cardiotoxicity.

Evidence from this case suggests that coronary vasospasm induced by 5-FU need not be an absolute contraindication to resuming administration of the agent in patients with normal coronary angiography and no major arrhythmias. Treatment should be administered on an inpatient basis in a cardiology department.