5-FLUOROURACIL MONOTHERAPY VERSUS FOLINIC ACID AND 5-FLUOROURACIL IN ADVANCED COLORECTAL-CANCER - RESULTS OF A RANDOMIZED TRIAL

Background: In most studies comparing 5-fluorouracil (5-FU) monotherapy versus the combination of folinic acid and 5-FU in the treatment of advanced colorectal cancer, a low dose of 5-FU was given in monotherapy, possibly leading to impaired results in these groups. In a further study we therefore compared the combination treatment with an intensive 5-FU monotherapy regimen with a loading course followed by weekly injections. Patients and Methods: Patients were randomized to receive either 5-FU 370 mg/m2 i.v. days 1-5, followed by weekly administrations of 5-FU 600 mg/m2 or the same doses of 5-FU preceded by folinic acid 200 mg/m2. Because of toxicity, the weekly 5-FU dose in the combination treatment group was reduced to 500 mg/m2 in the second part of the study. Results: Overall, 144 patients were treated. 42 patients received combination therapy and 41 monotherapy before treatment dose modification (part 1). After dose reduction, 31 patients had combination therapy and 30 monotherapy (part 2). Treatment resulted in a complete or partial remission in 11 patients (26%) on combination therapy with the higher and 14 (45%) with the lower weekly dose of 5-FU as compared to 24 and 27%, respectively, treated with monotherapy. In the first part, neither time to progression nor overall survival was statistically different between the treatment groups. After treatment modification, time to progression was significantly longer with combination therapy compared to monotherapy. In both parts, there was no significant difference in survival time between the groups as a whole. However, patients with extensive metastatic disease had a survival benefit when treated with the modified combination therapy as compared to monotherapy. The main toxicity was diarrhea during weekly therapy. This was especially true for patients receiving combination treatment before the reduction of the 5-FU dosage. By reducing 5-FU dosage during weekly therapy, severe diarrhea could be clearly reduced. Conclusions: In patients with advanced colorectal cancer, combination treatment with folinic acid and the reduced form of 5-FU 500 mg/m2 weekly is well tolerated and significantly prolongs relapse-free and, in subgroups, even overall survival as compared to an intensive 5-FU monotherapy regimen.