Sequential methotrexate and 5-fluorouracil (FU) vs. FU alone in metastatic colorectal cancer. Results of a randomized multicenter trial. The Association of Medical Oncology (AIO) of the German Cancer Society.

Methotrexate (MTX) modulates 5-fluorouracil (FU) in several in vitro and in vivo experimental systems. Results of phase II studies have suggested improved response rates for the sequential application of MTX and FU in colorectal cancer. In a prospective randomized multicenter study we compared sequential MTX (300 mg/m2) and FU (900 mg/m2) using a seven-hour time interval and leucovorin rescue with FU (450 mg/m2/d for five days) in patients with previously untreated metastatic colorectal cancer. Of 172 patients randomized 159 were eligible for survival analysis and 153 for toxicity and response evaluation. Complete or partial response has been seen in 25.3% of patients receiving sequential MTX and FU and in 17.6% of those receiving FU alone (p = 0.11). There have been two long-term survivors, apparently cured by MTX/FU. Overall toxicity was more pronounced with FU alone, but sequential MTX/FU caused four toxic deaths. Median survival and survival rates at one and two years were not significantly different. It is concluded that this schedule of sequential MTX and FU is no more effective than a dose-intensive treatment with FU alone in metastatic colorectal cancer.