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 N-OF-MEDICAL-ONCOLOGY-OF-THE-GERMAN-CANCER-SOCIETY (AIO)

Background: High-dose 5-FU given weekly as a 24-h infusion in combinat ion with folinic acid (FA) has been associated with low toxicity and a high response rate. Interferon-alpha (IFN) either alone or in combina tion with FA has also improved treatment results by modulating 5-FU ac tivity. We therefore initiated a randomized multicenter trial comparin g the ability of FA or IFN to modulate infusional 5-FU. The statistica l design using a sequential analysis allows us to report on the compar ison 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 wi th advanced progressive colorectal cancer and measurable metastatic le sions were randomized to receive 5-FU 2600 mg/m(2) i.v. as a 24-h infu sion, combined with either FA 500 mg/m(2) as a 2-h infusion (A), or IF N 3 x10(6) U s.c. 3 x/week (B), or the combination of FB plus IFN as i n arms A and B (C). Treatment arms were repeated weekly for 6 weeks fo llowed by a 2-week rest period. These 8-week cycles were administered until tumor progression. Because of the occurrence of 2 toxic deaths a mong the first 17 patients treated in arm C, 5-FU was reduced to 2000 mg/m(2) for all patients in arm C. Sequential analysis according to Wh itehead for objective response was planned with alpha = 0.05/3 and a p ower of 80% (beta = 0.2) to detect a difference of greater than or equ al to 25% (delta = 0.25) or equivalence of response rates. For pairwis e 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 firs t 93 of 149 randomized patients were evaluable for response and toxici ty (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 hand-foot syndrome compared to 16% in arm A an d 12% in arm B (not significant). No treatment related toxic death occ urred in arms A or B, but 3 patients (10%) in arm C died of diarrhea a nd septicemia. Among patients treated with 5-FU/FA objective tumor res ponse occurred in 12/31 patients (39%) (21%-56%, 95% confidence interv al) (3 CR, 9 PR), no change in 13/31 (42%) and PD in 6/31 (19%) patien ts. Eleven of 29 patients (38%) (20%-56%, 95% confidence interval) rec eiving 5-FU/FA/IFN achieved complete (3 patients) or partial (8 patien ts) remissions, 10/29 patients (34%) had stable disease and 8/29 patie nts (28%) tumor progression. According to the sequential analysis the rates of objective responses observed in patients treated with 5-FU/ F A or 5-FU/FA/IFN were equivalent. Conclusion: This interim analysis al lows 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, includ ing 10% deaths. Therefore, further investigation of this regimen is no t justified. The study is continued with the comparison of 5-FU/FA vs. 5-FU/IFN.