THE IMPACT OF ADDING LOW-DOSE LEUCOVORIN TO MONTHLY 5-FLUOROURACIL INADVANCED COLORECTAL-CARCINOMA - RESULTS OF A PHASE-III TRIAL

Purpose: A wide variety of fluorouracil (FU)-plus-leucovorin (LV) dose schedules are in clinical use for the treatment of advanced colorecta l cancer. Only the monthly low-dose LV-plus-FU regimen, as used by the North Central Cancer Treatment Group, has demonstrated a lasting surv ival benefit as opposed to FU alone (J Clin Oncol 1989; 7. 1407-1417). The Swiss Cancer Group adopted this regimen for a confirmatory phase III trial but used the same dose-intensity of fluorouracil in both tre atment arms. Patients and methods. Patients with inoperable or metasta tic colorectal cancer were randomized to receive monthly FU 400 mg/m(2 )/day plus LV 20 mg/m(2)/day as intravenous push daily for five days, or FU alone. Results: Three hundred nine of the 310 patients randomize d were eligible and included in the analysis. The objective response r ate for patients with measurable disease was 9% with FU alone and 22% with FU-plus-LV (P = 0.0001). The median progression-free survival was 3.9 versus 6.2 months (P = 0.003) and the overall survival 10 versus 12.4 months (P = 0.02). The major prognostic factors for survival were performance status, weight loss, and disease symptoms. WHO > 2 toxici ty, consisting of stomatitis (P = 0.001), diarrhea (P = 0.001), and na usea (P = 0.001), was more pronounced for FU-plus-LV, without fatal ev ents. Conclusions: This is the largest published randomized trial to c ompare FU-plus-LV to FU alone in advanced colorectal cancer. It confir ms the survival benefit obtained from biomodulating monthly FU with lo w-dose LV.The toxic effects of FU-plus-LV were acceptable to most pati ents, and they responded well to FU dose reductions. In the absence of an ideal dose-intense FU monotherapy regimen, monthly FU with low-dos e LV provides a simple and economical means by which to achieve adequa te FU efficacy in the treatment of advanced colorectal cancer.