Comparison of unique leucovorin and 5-fluorouracil "escalating" and "maximum" dosage strategies

In this study (GI 6384), regimens are compared which, in phase II investigations, produced 2-fold increases in the historical rates of objective and minor responses. These regimens were associated with overall survival exceeding 1 year. In arm 1, 5-fluorouracil (FUra) alone, 500 mg/m2 on days 1 through 5 was escalated in 25-mg/m2 increments in monthly courses to produce mild to moderate toxicity. This allows an examination of dose-response relationships and comparisons of therapeutic index. In arm 2, leucovorin (LV), was escalated from 25 to 250 to 500 mg/m2 beginning 1 hour before a bolus FUra (30 mg/kg) every 3 weeks. Arm 3 (not previously tested) employed LV (25 mg/m2) 1 hour before FUra (600 mg/m2) given weekly for 6 weeks. It tested the efficacy of low-dose LV. Arm 4 tested high-dose LV (500 mg/m2) as a 2-hour infusion beginning 1 hour before a bolus FUra (600 mg/m2) weekly for 6 weeks. In a preliminary analysis of this study, findings are statistically consistent with the anticipated high frequencies of objective response. It also finds evidence of biological activity across the wide range of LV dosages and that LV produces an apparent favorable change in FUra side effects from hematological to gastrointestinal toxicities. One or more regimens may favorably change the anticipated prognosis of patients with measurable cancer of the colon and rectum.