A controlled evaluation of recent approaches to biochemical modulation or enhancement of 5-fluorouracil therapy in colorectal carcinoma.

Abstract

Three hundred thirty-five previously untreated patients with advanced colorectal carcinoma were randomly assigned to treatment with 5-fluorouracil (5-FU) alone, 5-FU plus N-(phosphonacetyl)-L-aspartic acid (PALA), 5-FU plus high-dose thymidine, 5-FU plus levamisole, or 5-FU plus methyl CCNU, vincristine, and streptozotocin (MOF-Strept). Dosages were designed to produce definite toxicity in the majority of patients, although the nature of dose-limiting reactions varied considerably among regimens. 5-FU alone and 5-FU plus levamisole produced mucocutaneous reactions, diarrhea, and leukopenia; 5-FU plus PALA produced primarily mucocutaneous reactions and diarrhea; 5-FU plus thymidine produced leukopenia with occasional neurotoxicity and hypotension; and MOF-Strept produced substantial nausea and vomiting with both thrombocytopenia and leukopenia. Objective response rates among patients with measurable disease varied from 12% (5-FU plus PALA) to 34% (MOF-Strept), but none of the regimens were significantly superior to 5-FU alone. Both interval to progression and survival were comparable among the five regimens with no reasonable chance that any combination regimen could produce as much as a 50% improvement when compared with 5-FU alone. Whereas we observed definite modulation of 5-FU dose--toxicity relationships, particularly with the thymidine and PALA combinations, this did not result in a detectable improvement in therapeutic effect. None of the combination regimens, administered in the dosages and schedules we used, can be recommended as standard therapy of advanced colorectal carcinoma.

Phase II study of the thymidylate synthetase inhibitor CB3717 (N10-propargyl-5,8-dideazafolic acid) in colorectal cancer

“…The most effective single agent is 5-fluorouracil, with a 20% response rate; and randomised trials have not yet shown any benefit for combination chemotherapy (Buroker et al, 1985). The major metabolite of 5-fluorouracil is a potent inhibitor of thymidylate synthetase, though whether this is the principal mode of cytotoxicity remains to be established (Benz & Cadman, 1981).…”

5-FU therapeutic monitoring with dose adjustment leads to an improved therapeutic index in head and neck cancer

“…There was a statistical difference in complete response rates between group 1 (31%) and group 2 (47%), (0.02<P<0.05) and a statistically significant reduction was observed in the incidence of toxic cycles (>grade 2, group 1= 20% versus group 2 = 12.4%; 0.02 <P <0.05). Pharmacokinetic follow-up of these patients has proved to be an objective means to improve therapeutic index significantly.In addition to the digestive tract, where its efficacy remains limited (Buroker et al, 1985), chemotherapy by 5-FU is used for other disease sites. In squamous cell carcinoma of the head and neck very high response rates have been observed when the drug is combined with cisplatin (CDDP) (Thyss et al, 1986b;Amrein & Weitzman, 1985;Kish et al, 1982).…”

“…In addition to the digestive tract, where its efficacy remains limited (Buroker et al, 1985), chemotherapy by 5-FU is used for other disease sites. In squamous cell carcinoma of the head and neck very high response rates have been observed when the drug is combined with cisplatin (CDDP) (Thyss et al, 1986b;Amrein & Weitzman, 1985;Kish et al, 1982).…”

A prospective randomised trial to study the role of levamisole and interferon alfa in an adjuvant therapy with 5-FU for stage III colon cancer

“…In addition, the combination of LEV with 5-FU in advanced colon cancer was shown not to be superior to 5-FU single-agent therapy (Buroker et al, 1985). At the time the present study was initiated, combination of LEV and 5-FU was considered to be standard therapy to eliminate minimal residual disease.…”