Prospective randomized comparison of fluorouracil versus fluorouracil and high-dose continuous infusion leucovorin calcium for the treatment of advanced measurable colorectal cancer in patients previously unexposed to chemotherapy.

Abstract

Seventy-nine patients with advanced, measurable, metastatic colorectal cancer previously unexposed to chemotherapy were randomly assigned to treatment with either fluorouracil (FUra) administered intravenously at a dose of 370 mg/m2/d for 5 days or the combination of FUra in the same dose and schedule with high-dose continuous infusion leucovorin calcium (500 mg/m2/d) beginning 24 hours before the first dose of FUra and continuing for 12 hours after the completion of FUra therapy. Patients whose disease progressed on treatment with FUra alone were, if eligible, crossed over to receive leucovorin and FUra. Three patients on the FUra plus leucovorin arm of the study were excluded from the analysis because they did not meet eligibility requirements. The treatment arms were well balanced for prognostic criteria including performance status, age, prior radiotherapy, distribution of metastatic sites, and on-study carcinoembryonic antigen (CEA), lactic dehydrogenase, and serum albumin. FUra plus leucovorin was superior to FUra alone for response (P = .0019) and for time to progression or death (log-rank, P = .045). Response rates were 16 of 36 (44%) versus five of 40 (13%), and median time to progression or death was 164 versus 120 days in the two arms of the trial, respectively. Overall survival, however, while longer in the FUra and leucovorin arm was not significantly so. An analysis of the toxicities experienced by the patients in the two treatment groups showed that, except for significantly more stomatitis in the leucovorin arm of the study, the side effects experienced by patients treated with either regimen were comparable. These results suggest that the efficacy of FUra in patients with advanced, measurable, metastatic colorectal cancer can be enhanced significantly by administration of a continuous high-dose infusion of leucovorin calcium.

Surgical treatment of colorectal metastases to the liver

“…The most consistently active agent for this disease has been 5-fluorouracil (5-FU), and most regimens have been based on this agent (Table 2). [17][18][19][20][21][22][23][24][25] Few studies, and certainly none of the most recent studies, have specifically examined the role of systemic chemotherapy for resectable liver disease. However, it is clear that for most chemotherapeutic regimens, less than one third of patients with liver metastases have shown any response.…”

Thymidylate synthase and methylenetetrahydrofolate reductase gene polymorphisms: relationships with 5-fluorouracil sensitivity

“…Experimental studies have clearly established that the stabilisation of the ternary complex, and thus optimal TS inhibition, requires elevated cellular concentrations of CH 2 FH 4 (Danenberg and Danenberg, 1978;Houghton et al, 1981;Rustum et al, 1987;Keyomarsi and Moran, 1988;Chéradame et al, 1997a). Accordingly, clinical studies have demonstrated higher antitumour efficacy when FU is associated with folinic acid (FA), a precursor of CH 2 FH 4 Poon et al, 1989;Doroshow et al, 1990;Piedbois et al, 1992;Jäger et al, 1996). We previously closely studied the role of FA supplementation and CH 2 FH 4 intratumoral concentration on FU efficacy in a panel of 14 human cell lines (Chéradame et al, 1997a).…”

Oral fluoropyrimidine S-1 combined with leucovorin is a promising therapy for colorectal cancer: Evidence from a xenograft model of folate-depleted mice

“…TS forms a covalent ternary complex with an active metabolite of 5-FU, 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP), in the presence of the folate co-factor, 5,10-methylenetetrahydrofolate (CH 2 FH 4 ) (8). LV increases the intracellular level of CH 2 FH 4 in vitro (9,10) and in vivo (11,12), and potentiates the cytotoxicity of fluoropyrimidines (13,14) and their anticancer activity (15)(16)(17)(18). It should be noted, however, that the effect of LV on the efficacy of 5-FU is masked in conventional mouse xenograft models, since the folate pool is higher in mice fed a normal diet than it is in humans (19,20).…”