A PHASE-II TRIAL OF WEEKLY INFUSIONAL 5-FLUOROURACIL IN COMBINATION WITH LOW-DOSE LEUCOVORIN IN PATIENTS WITH ADVANCED COLORECTAL-CANCER

Exogenous leucovorin is a source of reduced folate which enhances the inhibition of thymidylate synthase that results from 5-fluorouracil (5 -FU) administration. Extracellular reduced folate concentrations of 1 mu M have been reported to yield maximal enzyme inhibition in several cell lines treated with 5-FU in vitvo. Clinical studies indicate that low doses of leucovorin have equivalent efficacy to higher doses in su ccessfully modulating 5-FU in the treatment of colorectal cancer. Base d on pharmacokinetics at higher doses, steady-state total plasma reduc ed folate concentrations of 1 mu M would be expected from the administ ration of leucovorin 50 mg/m(2) by 24 h infusion. This dose was admire d with 5-FU 2300 mg/m(2) and administered by 24 h infusion weekly to 3 8 patients with advanced colorectal cancer, of whom 32 are evaluable f or response. Disease sites included liver (33 patients), lung (12 pati ents), and bone (4 patients). Toxicity was mild to moderate, except fo r grade 3 diarrhea in 5 patients, and chest pain in 2 patients. Among the 32 evaluable patients, there were 14 partial remissions for a tota l response rate of 44% (95% confidence interval 27-61%). The median du ration of response was seven (range 1 to 20+) months, and median durat ion of survival 16 months. These results support the use of low doses of leucovorin to modulate weekly infusional 5-FU in colorectal cancer, and provide a basis for the integration of this regimen with other mo dulators of 5-FU.