[Acute cardiac toxicity of 5-fluorouracil: pharmacokinetic correlation]

Abstract

High-dose 5-fluorouracil (5-FU) continuous infusion over a 4-day period seems to dramatically increase the frequency of cardiac complications, which were however extremely rare in the past when it was injected in bolus form (1.6%). In order to evaluate their real incidence we looked for a relation between cardiac toxicity and clinical or 5 FU pharmacokinetic parameters. One hundred and thirty-three patients were followed up from January 1989 to March 1990, treated for head and neck, breast and colorectal cancers by high-dose 5-FU infusion (1,000 mg/sqm/d x 4 d) and cis-platinum (20 mg/sqm/d x 4 d). During each treatment course, daily electrocardiogram and 5 FU plasma assays were performed by high performance liquid chromatography, at 8 am and 8 pm. Twenty-eight patients presented 36 ischemic cardiac manifestations which were sometimes severe. Of these, 29 were asymptomatic. Cardiac toxicity frequency was not increased in the group treated for head and neck cancers. Pharmacokinetic analysis showed wide variations in 5-FU plasma levels in the 133 patients under study (from 20 to 1,200 ng/ml). Cardiac manifestations always appeared during the hours following very high 5-FU plasma levels (greater than 450 ng/ml). Cardiotoxicity seems to be linked to 5-FU plasma levels. Cis-platinum probably increases toxicity in this regimen. These findings indicate the advisability of a close follow-up by daily ECG when 5-FU is administered at high doses in continuous infusion and associated with cis-platinum. We are continuing to study 5 FU cardiac toxicity, especially in other regimens containing 5 FU and aim to evaluate the contribution of cardiac isotopic exams.