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PURPOSE: Even though fluorouracil (5FU) remains the standard treatment of advanced colorectal cancer, almost 90% of patients treated with 5FU alone do not achieve an objective response to chemotherapy. Biochemical modulation of 5FU by methotrexate (MTX) is an attempt to increase the sensitivity of tumor cells to 5FU. However, despite the inclusion of several hundreds of patients in randomized clinical trials, no definitive evidence is available on the clinical benefit of 5FU/MTX over 5FU alone. A meta-analysis was performed to assess this benefit objectively and quantitatively for tumor response rate and overall survival. DESIGN: The meta-analysis was based on individual data of 1,178 patients included in eight randomized clinical trials comparing 5FU alone with 5FU/MTX. Patient data were provided by all principal investigators. The analyses were performed by an independent secretariat, and then discussed with all collaborators. RESULTS: Tumor response rate was 10% for patients allocated to 5FU alone (complete response CR rate, 2%; partial response PR rate, 8%) compared with 19% for patients allocated to 5FU/MTX (CR rate, 3%; PR rate, 16%). This difference was highly significant, with an overall response odds ratio (OR) of 0.51 (95% confidence interval CI, 0.37 to 0.70) (P < .0001). Median overall survival times were 9.1 months and 10.7 months in the 5FU-alone and 5FU/MTX groups, respectively. This difference was also statistically significant, with an overall survival OR of 0.87 (95% CI, 0.77 to 0.98) (P = .024). Logistic regression model and Cox regression model showed that performance status and randomized treatment were the only two significant predictors of tumor response and survival. CONCLUSION: It is concluded that the modulation of 5FU by MTX doubles the response rate to 5FU, and yields a small improvement in survival.
A 1994 study studied this question.