Cardiotoxicity of fluoropyrimidines in different schedules of administration: a prospective study

Abstract

Background: Cardiotoxicity associated with 5-Fluorouracil (5FU) administration has been infrequently reported in literature, albeit various series of acute coronary syndromes have recorded a low but definite incidence of the above toxicity. In the present study, patients undergoing 5FU-based and oral capecitabine (Xeloda-based chemotherapy were tested for the potential development of cardiac-related symptoms during their administration.

Patients and methods: Six hundred and forty-four patients entered the study. Those experiencing any cardiac-related symptoms during 5FU infusion or oral capecitabine were subjected to ECG and serum cardiac enzymes determination. If cardiotoxicity was confirmed, 5FU infusion or oral capecitabine were interrupted, sublingual nitrates administered and cardiac monitoring initiated, while patients with >two-fold enzyme elevation were followed in a coronary care unit for at least 72 h. Cases with acute myocardial infarction were excluded from further 5FU or oral capecitabine treatment.

Results: Overall 26 patients (4.03%) developed symptoms and/or ECG abnormalities due to 5FU and capecitabine. Patients with continuous 5FU infusion presented a higher incidence of cardiotoxicity [14/209; 6.7%, 95% confidence interval (CI) = 3.3-10.1%] than the remaining (7/317; 2.3%, 95% CI = 0.8-3.3%) (P < 0.012). Specifically, an increased incidence of cardiac-related events was encountered in patients with continuous 24-h 5FU + LV infusion for 5 days (12.5%, 95% CI = 2.3-22.7%) rather than in patients with the same schedule without LV (5.3%, 95% CI = 1.95-8.67%) (P < 0.027), as well as in patients with short 5FU + LV administration (2.4%, 95% CI = 0.9-3.9%) (P < 0.019). Overall, 3/54 patients (5.5%, 95% CI = -0.6-11.1%) on oral capecitabine developed cardiac-related events. Seven out of the 20 patients suffered an acute myocardial infarction, 6 developed ischemia only, while 4 more patients had ECG consistent with coronary vasospasm and 3 with conduction disturbances, of which one subsequently died. Patients administered oral capecitabine had a similar incidence of cardiac-related events; 1/22 (4.5%) patients with advanced breast cancer and 2/32 (6.2%) with colorectal cancer.

Conclusions: The present study supports the toxic effect of 5-FU on the myocardium, which is largely schedule-dependent, whereas a low but finite risk of such toxicity has been observed with oral capecitabine. A high level of alertness is required when using fluoropyrimidines (i.v. 5FU or oral capecitabine), while their toxic effect on the coronary endothelium and myocardium merits further investigation.

Fig. 1

Percentage of patients with ECG abnormalities during 5-FU administration according to the therapeutic schedules. There is a difference between 5FU + LV in short infusion and MMC + LV + 5-FU (P < 0.0003) and MMC + 5-FU for 5-day continuous infusion (P < 0.0003), and Capecitabine (P < 0.02), noticed that short infusion of 5FU every week or for 5 consequent days were almost the same. No statistically significant differences were noticed between CDDP + 5-FU for 5-day continuous infusion and MMC + LV + 5-FU for 5-day continuous infusion (P < 0.095), and LV + 5-FU for 5 days (P < 0.098), also Capecitabine and LV + 5-FU for 5 days (P < 0.29). MMC Mitomycin C, LV Leucovorin, CDDP Cisplatin, si short infusion, ci continuous infusion

Fig. 2

Percentage of patients with symptomatic ECG abnormalities during 5-FU administration according to the different therapeutic schedules, and Capecitabine therapy. There is a statistically significant difference between schedules with continuous 24-h infusion (ci ) of 5FU and short time infusion (si ) (P < 0.012), but not with capecitabine therapy (P < 0.77), but there is significant difference between patients receiving short infusion of 5-FU with LV (every week, or every day for 5 days), and capecitabine therapy (P < 0.019). si short infusion, ci continuous infusion