Interferon-alpha does not improve the antineoplastic efficacy of high-dose infusional 5-fluorouracil plus folinic acid in advanced colorectal cancer: First results of a randomized multicenter study by the Association of Medical Oncology of the German Cancer Society(AIO)

BACKGROUND: High-dose 5-FU given weekly as a 24-h infusion in combination with folinic acid (FA) has been associated with low toxicity and a high response rate. Interferon-alpha (IFN) either alone or in combination with FA has also improved treatment results by modulating 5-FU activity. We therefore initiated a randomized multicenter trial comparing the ability of FA or IFN to modulate infusional 5-FU. The statistical design using a sequential analysis allows us to report on the comparison of 5-FU/FA vs. 5-FU/FA/IFN while randomization of patients into 5-FU/FA vs. 5 FU/IFN continues. METHODS: Chemotherapy-naive patients with advanced progressive colorectal cancer and measurable metastatic lesions were randomized to receive 5-FU 2600 mg/m2 i.v. as a 24-h infusion, combined with either FA 500 mg/m2 as a 2-h infusion (A), or IFN 3 x 10(6) U s.c. 3 x/week (B), or the combination of FA plus IFN as in arms A and B (C). Treatment arms were repeated weekly for 6 weeks followed by a 2-week rest period. These 8-week cycles were administered until tumor progression. Because of the occurrence of 2 toxic deaths among the first 17 patients treated in arm C, 5-FU was reduced to 2000 mg/m2 for all patients in arm C. Sequential analysis according to Whitehead for objective response was planned with alpha = 0.05/3 and a power of 80% (beta = 0.2) to detect a difference of > or = 25% (delta = 0.25) or equivalence of response rates. For pairwise comparison of treatment arms a minimum of 30 patients per arm and a maximum of 90 patients per arm were expected in case of equivalence or difference. RESULTS: An interim analysis was performed after the first 93 of 149 randomized patients were evaluable for response and toxicity (A 31 pts, B 33 pts, C 29 pts). Despite the 5-FU dose reduction in arm C, 28% of patients experienced grade 3/4 toxicity (CTC) including diarrhea, mucositis and handfoot syndrome compared to 16% in arm A and 12% in arm B (not significant). No treatment related toxic death occurred in arms A or B, but 3 patients (10%) in arm C died of diarrhea and septicemia. Among patients treated with 5-FU/FA objective tumor response occurred in 12/31 patients (39%) (21%-56%, 95% confidence interval) (3 CR, 9 PR), no change in 13/31 (42%) and PD in 6/31 (19%) patients. Eleven of 29 patients (38%) (20%-56%, 95% confidence interval) receiving 5-FU/FA/IFN achieved complete (3 patients) or partial (8 patients) remissions, 10/29 patients (34%) had stable disease and 8/29 patients (28%) tumor progression. According to the sequential analysis the rates of objective responses observed in patients treated with 5-FU/FA or 5-FU/FA/IFN were equivalent. CONCLUSION: This interim analysis allows the conclusion that infusional 5-FU plus FA/IFN is no more active than infusional 5-FU plus FA alone. However, 5-FU/FA/IFN despite 5-FU dose reduction was associated with unacceptably high toxicity, including 10% deaths. Therefore, further investigation of this regimen is not justified. The study is continued with the comparison of 5-FU/FA vs. 5-FU/IFN.