SCHEDULE-SELECTIVE BIOCHEMICAL MODULATION OF 5-FLUOROURACIL - A PHASE-II STUDY IN ADVANCED COLORECTAL-CANCER

Based on experimental findings suggesting that 5-fluorouracil (FUra) m ay have different mechanisms of action depending on the schedule of ad ministration, we generated the hypothesis that biochemical modulation of this fluoropyrimidine should be schedule specific, We thus tested t he activity of a hybrid regimen consisting of two biweekly cycles of F Ura bolus (600 mg/m(2)) modulated by pretreatment (24-h interval) with methotrexate (200 mg/m(2)), alternating with a 3-week continuous infu sion of FUra (200 mg/m(2)/day) modulated by low-dose (6S)leucovorin (2 0 mg/m(2) bolus weekly). Thirty-three consecutive patients with advanc ed measurable colorectal cancer and no prior therapy for metastatic di sease entered the study from February 1992 to August 1993, They were t reated with two biweekly cycles of FUra bolus (600 mg/m(2)) preceded b y (24-h interval) methotrexate (200 mg/m(2)), alternating with a 3-wee k continuous infusion of FUra (200 mg/m(2)/day) modulated by low-dose (6S)leucovorin (20 mg/m(2) bolus weekly), The median Eastern Cooperati ve Oncology Group performance status was 1; the liver was the only met astatic site in 17 patients, Treatment outcome was evaluated by comput ed tomographic scan in all patients, except for two. Three complete an d 13 partial responses were obtained among these 33 patients (response rate, 48%; 95% confidence limits, 31-66%), Performance status (Easter n Cooperative Oncology Group) influenced clinical response, The combin ed complete response and partial response rate was 69%, 33%, and 25% i n patients with an Eastern Cooperative Oncology Group performance stat us of 0, 1, and 2, respectively (chi(2), 4.6, P = 0.032, two-tailed Ma ntel test for trend), After a median follow-up time of 26 months, 10 p atients are still alive, The median progression-free survival and over all survival were 9.5 and 20.2 months, respectively, No toxic deaths o r grade 4 toxicity occurred, The incidence of grade 3 toxicity per pat ient in any cycle was: mucositis 6%, diarrhea 3%, vomiting 3% for the bolus part and 21%, 3%, and 6%, respectively, for the continuous infus ion part of the regimen, Hand-foot syndrome occurred in 27% of the pat ients treated with the continuous infusion regimen.