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

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 ra nging from 20 to 30% and a median survival of about 12 months. Phase II stu dies suggest a distinctly higher remission rate and possibly longer surviva l 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 super ior to 5-FU/FA day 1-5 in terms of remission rate and survival time. Patien ts and Methods: Between January 1993 and December 1996 149 patients entered the study. 76 patients were randomized to receive treatment A (monthly sta ndard: 5-FU 425 mg/m(2) iv bolus days 1-5, FA 20 mg/m(2) iv bolus days 1-5, repeated every 28 days) and 73 patients were randomized to receive treatme nt B (weekly high dose: weekly 5-FU 2,600 mg/m(2) as 24-hour infusion and F A 500 mg/m(2) 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 slopped, whereas in cases of partia l remission (PR) or stable disease (SD) with improvement of the patient's c linical condition treatment was continued for a total of 6 courses of treat ment A and a total of 3 courses of treatment B. Results: 67 treatment A and 64 treatment B patients 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 c ompared with treatment B(p <0.01). Treatment B resulted in statistically si gnificant longer survival times compared with treatment A (p = 0.047): Medi an survival time with treatment B 463 daps (95% confidence interval 355-540 days) vs. 370 days (95% confidence interval 276-412 days) with treatment A . The differences in both effects, however, were also found statistically s ignificant in an analysis including other prognostic factors. Toxicity was moderate and roughly comparable between both treatment arms with the except ion of a higher occurrence of hand-foot syndrome under treatment B. Conclus ion: This is the first phase III study demonstrating a small. but statistic ally significant superiority of weekly FA/high-dose 5-FU over a conventiona l 5 day 5-FU/FA regimen in terms of survival time.