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) monotherap y 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 monotherap y, possibly leading to impaired results in these groups. In a further study we therefore compared the combination treatment with an intensiv e 5-FU monotherapy regimen with a loading course followed by weekly in jections. Patients and Methods: Patients were randomized to receive ei ther 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 2 00 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 st udy. Results: Overall, 144 patients were treated. 42 patients received combination therapy and 41 monotherapy before treatment dose modifica tion (part 1). After dose reduction, 31 patients had combination thera py and 30 monotherapy (part 2). Treatment resulted in a complete or pa rtial remission in 11 patients (26%) on combination therapy with the h igher and 14 (45%) with the lower weekly dose of 5-FU as compared to 2 4 and 27%, respectively, treated with monotherapy. In the first part, neither time to progression nor overall survival was statistically dif ferent between the treatment groups. After treatment modification, tim e to progression was significantly longer with combination therapy com pared to monotherapy. In both parts, there was no significant differen ce in survival time between the groups as a whole. However, patients w ith extensive metastatic disease had a survival benefit when treated w ith the modified combination therapy as compared to monotherapy. The m ain toxicity was diarrhea during weekly therapy. This was especially t rue for patients receiving combination treatment before the reduction of the 5-FU dosage. By reducing 5-FU dosage during weekly therapy, sev ere diarrhea could be clearly reduced. Conclusions: In patients with a dvanced colorectal cancer, combination treatment with folinic acid and the reduced form of 5-FU 500 mg/m2 weekly is well tolerated and signi ficantly prolongs relapse-free and, in subgroups, even overall surviva l as compared to an intensive 5-FU monotherapy regimen.