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 efficacy of fluorouracil (5-FU) in advanced colorected cancer. Patients and Methods: Based on promising phase II data, a randomized comparison of various methods for the biochemical modulation of 5-FU was undertaken 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 following arms: arm A, 5-FU 2,600 mg/m² by 24-hour infusion, weekly; arm B, N-phosphonoacetylI-aspartic acid 250 mg/m² day I, 5-FU 2,600 mg/m² by 24-hour infusion day 2, weekly; arm C, 5-FU 600 mg/m² with oral leucovorin (LV) 125 mg/m² hourly for the preceding 4 hours, weekly; arm D, 5-FU 600 mg/m² with intravenous (IV) LV 600 mg/m², weekly; arm E, 5-FU 750 mg/m²/d IV by continuous infusion for 5 days, then 750 mg/m² weekly, and recombinant 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 ali the regimens was tolerable. Grade 4 or worse toxicity occurred in 11%, 11%, 30%, 24%, and 22% on each arm, respectively; diarrhea was the most common adverse effect. These toxicity patterns favored significantly (P < .001) the 24-hour infusion arms. Median survival (months) by arm was 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 significantly less toxic than and as effective as 5-FU bolus regimens modulated by either LV or interferon in patients with metastatic colorectal cancer.