Continuous ambulatory ECG monitoring during fluorouracil therapy: a prospective study.

Abstract

Although there have been anecdotal reports of cardiac toxicity associated with fluorouracil (5-FU) therapy, this phenomenon has not been studied in a systematic fashion. We prospectively performed continuous ambulatory ECG monitoring on 25 patients undergoing 5-FU infusion for treatment of solid tumors in order to assess the incidence of ischemic ST changes. Patients were monitored for 23 +/- 4 hours before 5-FU infusion, and 98 +/- 9 hours during 5-FU infusion. Anginal episodes were rare: only one patient had angina (during 5-FU infusion). However, asymptomatic ST changes (greater than or equal to 1 mm ST deviation) were common: six of 25 patients (24%) had ST changes before 5-FU infusion v 17 (68%) during 5-FU infusion (P less than .002). The incidence of ischemic episodes per patient per hour was 0.05 +/- 0.02 prior to 5-FU infusion v 0.13 +/- 0.03 during 5-FU infusion (P less than .001); the duration of ECG changes was 0.6 +/- 0.3 minutes per patient per hour before 5-FU v 1.9 +/- 0.5 minutes per patient per hour during 5-FU (P less than .01). ECG changes were more common among patients with known coronary artery disease. There were two cases of sudden death, both of which occurred at the end of the chemotherapy course. We conclude that 5-FU infusion is associated with a significant increase in silent ST segment deviation suggestive of ischemia, particularly among patients with coronary artery disease. The mechanism and clinical significance of these ECG changes remain to be determined.

Raltitrexed (Tomudex): an alternative drug for patients with colorectal cancer and 5-fluorouracil associated cardiotoxicity

“…Several causative mechanisms for 5-FU cardiotoxicity have been postulated, including an autoimmune response to damaged cells (Stevenson et al, 1977), increased oxygen demand in patients receiving 5-FU (Rezkalla et al, 1989), coronary spasm (Burger and Mannino, 1987) due to protein kinase C-mediated vasoconstriction (Mosseri et al, 1993) and the 5-FU contaminant fluoroacetate (FAC) (Lemaire et al, 1992).…”

5-fluorouracil induced cardiotoxicity: Review of the literature

“…Recently, a review of 377 cases of 5-FU associated cardiotoxicity confirmed that the majority of cases of cardiotoxicity occur in the setting of continuous infusion [6]. And while overall cardiac toxicity with 5-FU administration may vary, rates are uniformly higher in patients with underlying heart disease, including coronary artery disease (CAD), structural heart disease, and cardiomyopathies [2,16].…”

“…A study by Rezkalla et al [16] demonstrated ischemic and arrhythmic ECG changes, to include ST-segment deviation and QT-prolongation, in nearly 68% of patients receiving infusions of 5-FU. Others have noted incidences of asymptomatic diagnostic ECG changes in up to 88% of patients during 5-FU infusion, with nearly 7% demonstrating elevated cardiac enzymes [12,35].…”

The anti-cancer drug 5-fluorouracil is metabolized by the isolated perfused rat liver and in rats into highly toxic fluoroacetate

“…Its chief side-effects are myelosuppression, diarrhoea, vomiting and mucositis. However, over the last decade, the number of reports of cardiotoxicity and neurotoxicity attributed to FU has rapidly increased, probably because of the use of higher doses in continuous perfusion (Moertel et al, 1964;Rezkalla et al, 1989;Moore et al, 1990;Gamelin et al, 1991; De Fomi et al, 1992;Robben et al, 1993;Anand, 1994). The precise biochemical mechanism underlying these two side-effects remains unclear, although several investigators have postulated, but never demonstrated experimentally, that FU might be transformed into fluoroacetate (FAC), a highly cardiotoxic and neurotoxic poison (Koenig and Patel, 1970;Okeda et al, 1990).…”