A Randomized Phase III Study Comparing Weekly Folinic Acid(FA) and High-Dose 5-Fluorouracil (5-FU) with Monthly 5-FU/FA (days 1-5) in Untreated Patients with Metastatic Colorectal Carcinoma

Abstract

Background: The combination of 5-fluorouracil (5-FU) and folinic acid (FA) given over 5 days every 4 weeks is one of the most frequently used regimens in metastatic colorectal carcinoma (CRC). It results in remission rates ranging from 20 to 30% and a median survival of about 12 months. Phase II studies suggest a distinctly higher remission rate and possibly longer survival times for a combination of weekly FA and high-dose 5-FU 24-hour infusion. The aim of our study was to test whether weekly FA/high-dose 5-FU is superior to 5-FU/FA day 1–5 in terms of remission rate and survival time. Patients and Methods: Between January 1993 and December 1996 149 patients entered the study. 76 patients were randomized to receive treatment A (monthly standard: 5-FU 425 mg/m₂ iv bolus days 1–5, FA 20 mg/m₂ iv bolus days 1–5, repeated every 28 days) and 73 patients were randomized to receive treatment B (weekly high dose: weekly 5-FU 2,600 mg/m₂ as 24-hour infusion and FA 500 mg/m₂ as 1-hour infusion prior to 5-FU; one course consisting of 4 infusions and repeated after a therapy-free interval of 2 weeks). In cases of progressive disease (PD) therapy was stopped, whereas in cases of partial remission (PR) or stable disease (SD) with improvement of the patient’s clinical condition treatment was continued for a total of 6 courses of treatment A and a total of 3 courses of treatment B. Results: 67 treatment A and 64 treatment B pa-tients were evaluable for response. Treatment A led to 17.9% PR, 34.3% SD and 47.7% PD, and treatment B to 23.4% PR, 57.8% SD and 18.8% PD. PD occurred with statistically higher frequency under treatment A compared with treatment B (p <0.01). Treatment B resulted in statistically significant longer survival times compared with treatment A (p =0.047): Median survival time with treatment B 463 days (95% confidence interval 355–540 days) vs. 370 days (95percnt; confidence interval 276–412 days) with treatment A. The differences in both effects, however, were also found statistically significant in an analysis including other prognostic factors. Toxicity was moderate and roughly comparable between both treatment arms with the exception of a higher occurrence of hand-foot syndrome under treatment B. Conclusion: This is the first phase III study demonstrating a small, but statistically significant superiority of weekly FA/high-dose 5-FU over a conventional 5 day 5-FU/FA regimen in terms of survival time.