MODULATION OF HIGH-DOSE INFUSIONAL FLUOROURACIL BY LOW-DOSE METHOTREXATE IN PATIENTS WITH ADVANCED OR METASTATIC COLORECTAL-CANCER - FINAL RESULTS OF A RANDOMIZED EUROPEAN-ORGANIZATION-FOR-RESEARCH-AND-TREATMENT OF-CANCER STUDY

Purpose: Methotrexate (MTX) has been described to modulate the activit y of fluorouracil (5-FU) in patients with metastatic colorectal cancer . The European Organization for Research and Treatment of Cancer (EORT C) Gastrointestinal Tract Cancer Cooperative Group (GITCCG) conducted a phase III trial to investigate the efficacy and tolarability of the addition of low-dose MTX (40 mg/m(2)) to high-dose infusional 5-FU (60 mg/kg over 48 hours) given weekly for 4 weeks and thereafter every 2 (for 4 weeks) and 3 weeks. Patients and Methods: Three hundred ten pat ients were randomized between 1987 and 1992. Eligible patients had mea surable advanced or metastatic colorectal cancer and had not been pret reated with antifolates or fluorodinated pyrimidines. All 297 eligible patients were evaluated for survival; toxicity was assessed in 292 pa tients who received at least one course of treatment. Patients with bi dimensionally measurable disease (n = 230) were also evaluated for res ponse according to standard criteria. Results: The addition of low-dos e MTX to high-dose infusional 5-FU led to a doubling of the response r ate from 10% to 21% (P = .025). The median survival time also increase d from 9.3 to 12.5 months, but this difference was not statistically s ignificant (P = .12), High-dose infusional 5-FU with or without low-do ss MTX was well tolerated, with grade 3 to 4 toxicity in greater than 10% of patients only occurring for stomatitis with the combination tre atment. Performance status was the sole prognostic factor for survival in a multivariate analysis. Conclusion: Low-dose MTX effectively modu lated high-dose infusional 5-FU in a large, randomized trial in which less than 5% of patients received leucovorin. (C) 1996 by American Soc iety of Clinical Oncology.