Schedule-selective biochemical modulation of 5-fluorouracil in advanced colorectal cancer--a phase II study

5-fluorouracil remains the standard therapy for patients with advanced/metastatic colorectal cancer. Pre-clinical studies have demonstrated the biological modulation of 5-fluorouracil by methotrexate and leucovorin. This phase II study was initiated to determine the activity and toxicity of sequential methotrexate--leucovorin and 5-fluorouracil chemotherapy in patients with advanced colorectal cancer.

Ninety-seven patients with metastatic colorectal cancer were enrolled onto the study. Methotrexate--30 mg/m2 was administered every 6 hours for 6 doses followed by a 2 hour infusion of LV--500 mg/m2. Midway through the leucovorin infusion, patients received 5-fluorouracil--600 mg/m2. This constituted a cycle of therapy and was repeated every 2 weeks until progression.

The median age was 64 yrs (34-84) and the Eastern Cooperative Group Oncology performance score was 0 in 37%, 1 in 55% and 2 in 8% of patients. Partial and complete responses were seen in 31% of patients with a median duration of response of 6.4 months. The overall median survival was 13.0 months. The estimated 1-year survival was 53.7%. Grade III and IV toxic effects were modest and included mucositis, nausea and vomiting.

This phase II study supports previously reported data demonstrating the modest clinical benefit of 5-FU modulation utilizing methotrexate and leucovorin in patients with metastatic colorectal cancer. Ongoing studies evaluating 5-fluorouracil modulation with more novel agents (Irinotecan and/or oxaliplatin) are in progress and may prove encouraging.