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 (I.V.) (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 l-leucovorin with I.V. leucovorin (Immunex Corp, Seattle, WA) at 100 mg/m2 and I.V. 5-FU at 370 mg/m2; (B) intensive-course 5-FU plus oral (d,l)-leucovorin with oral leucovarin 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 I.V. (d,l)-leucovorin with I.V. 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.