Fluorouracil modulation in colorectal cancer: Lack of improvement with N-phosphonoacetyl-l-aspartic acid or oral leucovorin or interferon, but enhanced therapeutic index with weekly 24-hour infusion schedule - An Eastern Cooperative Oncology Group/Cancer and Leukemia Group B study

Purpose: To investigate mechanism-directed regimens in maximizing the effic acy of fluorouracil (5-FU) in advanced colorected cancer. Patients and Methods: Based on promising phase II data, a randomized compar ison of various methods for the biochemical modulation of 5-FU was undertak en in patients with advanced colorectal cancer. The control group received single-agent 5-FU as a 24-hour infusion weekly. Patients (N = 1,120)with no prior chemotherapy for metastatic disease were randomized to one of the fo llowing arms: arm A, 5-FU 2,600 mg/m(2) by 24-hour infusion, weekly arm B, N-phosphonoacetyl-l-aspartic acid 250 mg/m(2) day 1, 5-FU 2,500 mg/m(2) by 24-hour infusion day 2, weekly; arm C, 5-FU 600 mg/m2 with oral leucovorin (LV) 125 mg/m(2) hourly for the preceding 4 hours, weekly; arm D, 5-FU 600 mg/m(2) with intravenous (IV) LV 609 mg/m(2), weekly; arm E, 5-fU 750 mg/m( 2)/d IV by continuous infusion for 5 days, then 750 mg/m2 weekly, and recom binant interferon alfa-2a 9 million units subcutaneously three times weekly . Median follow-up was 4.8 years. Results: Of the 1,098 assessable patients, 57% had measurable disease. The toxicity of all the regimens was tolerable. Grade 4 or worse toxicity occur red in 11%, 11%, 30%, 24%, and 22% on each arm, respectively; diarrhea was the most common adverse effect. These toxicity patterns favored significant ly (P < .001) the 24-hour infusion arms. Median survival (months) by arm wa s A, 14.8; B, 11.9; C, 13.5; D, 13.6; and E, 15.2. These survival durations did not differ significantly. Conclusion: We conclude that a weekly infusion regimen of 5-FU is significa ntly less toxic than and as effective as 5-FU bolus regimens modulated by e ither LV or interferon in patients with metastatic colorectal cancer, J Cli n Oncol 19:2413-2421. (C) 2001 by American Society of Clinical Oncology.