Phase II study of fluorouracil, leucovorin, and interferon alfa-2a in metastatic colorectal carcinoma

Purpose: To test the activity of a regimen of interferon alfa-2a (IFN α-2a) 5 × 10⁶U/m² subcutaneously (SC) days 1 through 7 combined with leucovorin 500 mg/m²/d intravenously (IV) over 30 minutes and fluorouracil (5-FU) 370 mg/m³/d through IV push 1 hour after leucovorin days 2 through 6 in a phase II study. Forty-six patients with a good performance status (PS) with measurable colorectal cancer and no prior therapy for metastatic disease were entered. Cycles were repeated at 3-week intervals if toxicity had resolved. The 5-FU dose was increased by 15% if toxicity was mild, and decreased by 15% for grade 3 to 4 nonhematologic or grade 4 hematologic toxicity. Three complete responses (CRs) and 21 partial responses (PRs) were seen among 44 assessable patients (54%; 95% confidence interval, 39% to 70%). A moderately strong association was noted between PS and response: PS 0 (n = 26), two CRs and 15 PRs (65%); PS 1 (n = 13), one CR and six PRs (54%); PS 2 (n = 5), zero CRs and zero PRs (0%; two-tailed P = .026). With a median follow-up duration of 18.8 months, the median time to treatment failure (TTF) and survival were 7.8 months and 16.3 months, respectively. Doses were escalated to 425 mg/m²/d 5-FU in 10 patients, but only four tolerated the higher dose. When expressed as the most severe degree of toxicity experienced by each patient across all cycles, grade 3 to 4 toxicity of the following types was observed; mucositis, 37%; diarrhea, 40%; rash, 7%; fatigue, 14%; granulocytopenia, 13%. Dose-limiting toxicity at 370 mg/m²/d 5-FU eventually occurred in 28 patients (61%). Twelve patients (26%) required an IFN α-2a dose reduction for constitutional toxicity. This regimen has promising activity in advanced colorectal cancer, particularly in patients with an Eastern Cooperative Oncology Group (ECOG) PS of 0 to 1.