WEEKLY HIGH-DOSE LEUCOVORIN VERSUS LOW-DOSE LEUCOVORIN COMBINED WITH FLUOROURACIL IN ADVANCED COLORECTAL-CANCER - RESULTS OF A RANDOMIZED MULTICENTER TRIAL

Purpose: To determine the most effective dose of leucovorin (folinic a cid [FA]) within a weekly bolus fluorouracil (FU) schedule, we conduct ed a randomized multicenter trial to compare therapeutic effects and t oxicity of high-dose FA versus low-dose FA combined with FU at equal d oses in both treatment groups. Patients and Methods: Patients with mea surable inoperable or metastatic colorectal cancer were randomized to receive weekly FU 500 mg/m(2) by intravenous (IV) bolus combined with high-dose FA 500 mg/m(2) (group A) or low-dose FA 20 mg/m(2) (group B) by 2-hour infusion. Results: Of 291 assessable patients (group A, n = 148; groups, n = 143), we observed, in group A, complete response (CR )/partial response (PR) in 32 (21.6%), no change (NC) in 64 (43.2%), a nd progressive disease (PD) in 52 (35.1%); and in group B, CR/PR in 25 (17.5%), NC in 63 (44.1%), and PD in 55 (38.5%). The median response duration was 24.8 weeks in group A and 23.1 weeks in group B. Median p rogression-free intervals were 29.3 weeks (group A) and 30 weeks (grou p B). The median survival time was 55.1 weeks in group A and 54.1 week s in group B. Overall toxicity wets moderate, Mild nausea and vomiting , and stomatitis were common side effects in both groups. The incidenc e of World Health Organization (WHO) grade III/IV diarrhea was signifi cantly higher in group A (40 v 23 patients). Severe side effects were observed only in a minority of patients in both arms. WHO grade IV dia rrhea was observed in seven patients: four in group A and three in gro up B. The rate of toxicity-related adjustments of dose and schedule wa s comparable in both groups. Conclusion: High-dose FA/FU is not superi or to low-dose FA/FU within a weekly treatment schedule. Response rate s and survival were comparable in both treatment arms, Treatment-relat ed toxicity was higher in group A (high-dose FA). Therefore, low-dose FA combined with weekly FU may be considered the preferred treatment f or metastatic colorectal cancer. (C) 1996 by American Society of Clini cal Oncology.