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 th at maximal inhibition of the target enzyme thymidylate synthase can be achieved with a protracted infusion of 5-FU and oral leucovorin. We r eport the results of a phase I study in which seven patients with adva nced 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/m(2)/day with planned escalations of 50 m g/m(2)/day. The qualitative toxic effects observed included diarrhea, mucositis, and hand/foot syndrome. These toxic effects were manageable at 100 mg/m(2)/day, but became dose-limiting at 150 mg/m(2)/day with two of four patients unable to complete the planned 30-day infusion. N o objective responses were observed, but minor activity was documented in two patients. We recommend a starting dose of 125 mg/m(2)/day for subsequent phase II trials of this regimen in patients with colorectal cancer.