BOLUS INFUSIONAL 5-FLUOROURACIL AND FOLINIC ACID - A REPORT ON 2 PROSPECTIVE, CONSECUTIVE PHASE-II STUDIES WITH 5-FLUOROURACIL DOSE-ESCALATION/

We have used a relatively new trial methodology. the group sequential design, to prospectively evaluate two dose levels of bolus/infusional 5-fluorouracil (5-FU) and folinic acid in 192 consecutive-patients wit h advanced colorectal carcinoma. On day 1, all patients received 200 m g m(-2) of folinic acid infusion over 2 h. Cohort A (n = 102 patients) received 500 mg m(-2) 5-FU by i.v. 15-min infusion followed by an inf usion of 500 mg m(-2) 5-FU over 22 h. Treatment was repeated on day 2 and further cycles given 2-weekly. After sequential analysis excluded a response rate of over 40%, cohort B (n = 90 patients) received an in creased dose of 600 mg m(-2) 5-FU bolus and infusion. Patients had rec eived no prior 5-FU therapy and the two cohorts had similar demographi c features. In 179 evaluable patients, the overall response rate was 1 8% (95% CI 12-24%) with CR of 6% and PR of 12%, with no difference bet ween the two cohorts. Overall median survival was 34 weeks (95% CI 30- 39) with no significant difference between cohorts (median survival 32 and 37 weeks in cohort A and B respectively; P = 0.27). On multivaria te analysis, poor performance status, elevated initial WBC and alkalin e phosphatase and low serum albumin were associated with reduced survi val (P < 0.05), and initial raised WBC showed an association with redu ced likelihood of response (P = 0.002). Overall toxicity was low with CTC grade 3 mucositis, diarrhoea, nausea or vomiting in less than or e qual to 6% of patients and no treatment-related deaths. Significant (g rade 3 or above) leucopenia was more common in cohort B than in cohort A (9% and 1% respectively); there were more dose reductions, and the median administered dose intensity was lower in cohort B than in cohor t A (89% and 97% respectively; P = 0.006). In this group of relatively unselected patients, we have confirmed a relatively low objective res ponse rate and median survival of 7.8 months with this regimen. There was no significant difference in outcome between the two dose levels b ut the higher dose of 5-FU was associated with more dose reductions an d greater toxicity.