A phase I clinical trial of a protracted continuous infusion of 5-fluorouracil with oral folinic acid in patients with unresectable adenocarcinoma of the colon or rectum
Studies of the mechanism of action of 5-fluorouracil (5-FU) suggest that maximal inhibition of the target enzyme thymidylate synthase can be achieved with a protracted infusion of 5-FU and oral leucovorin. We report the results of a phase I study in which seven patients with advanced colorectal cancer were treated with a 30-day continuous infusion of 5-FU and a fixed 50 mg dose of oral folinic acid every 6 hours. The 5-FU dose started at 100 mg/m2/day with planned escalations of 50 mg/m2/day. The qualitative toxic effects observed included diarrhea, mucositis, and hand/foot syndrome. These toxic effects were manageable at 100 mg/m2/day, but became dose-limiting at 150 mg/m2/day with two of four patients unable to complete the planned 30-day infusion. No objective responses were observed, but minor activity was documented in two patients. We recommend a starting dose of 125 mg/m2/day for subsequent phase II trials of this regimen in patients with colorectal cancer.