Prospectively randomized north central cancer treatment group trial of intensive-course fluorouracil combined with the l-isomer of intravenous leucovorin, oral leucovorin, or intravenous leucovorin for the treatment of advanced colorectal cancer

Purpose: A three-arm randomized phase III trial in advanced colorectal cancer patients was designed to test whether substitution of an equivalent dose of (1) l-leucovorin or (2) oral leucovorin would more effectively potentiate fluorouracil (5-FU) than standard intravenous (IV) (d,l)- leucovorin. Patients and Methods: A total of 926 chemotherapy-naive patients participated. Patients received one of three treatments: (A) intensive- course 5-FU plus/-leucovorin with IV leucovorin (Immunex Corp, Seattle, WA) at 100 mg/m² and IV 5-FU at 370 mg/m²; (B) intensive-course 5-FU plus oral (d,I)-leucovorin with oral leucovorin at 125 mg/m² on hours 0, 1, 2, and 3 (total dose, 500 mg/m²) followed by 5-FU 370 mg/m² on hour 4; or (C) intensive-course 5-FU plus IV (d,I)-leucovorin with IV leucovorin 200 mg/m² and 5-FU 370 mg/m². Drugs were administered daily for 5 consecutive days. Courses were repeated at 4 and 8 weeks, and every 5 weeks thereafter. Dosage was reduced for neutropenia, thrombocytopenia, diarrhea, stomatitis, and dermatitis. Results: Of 926 eligible patients, 756 have died. The overall response rate for patients with measurable disease was 32% (165 of 514). There were no differences between regimens in response rates (arm A, 28% [47 of 140]; arm B, 34% [60 of 174]; and arm C, 34% [58 of 170]) or in survival. There have been nine possible chemotherapy-related fatalities. Grade III to IV toxic effects did not differ appreciably by arm and included stomatitis (12% to 14%), diarrhea (15% to 19%), nausea (7% to 9%), and vomiting (6% to 8%). Conclusion: There was no difference in response, survival, or toxicity between these three different leucovorin formulations combined with 5-FU.