5-fluorouracil and levofolinic acid with or without recombinant interferon-2b in patients with advanced colorectal carcinoma - A randomized multicenter study with stratification for tumor burden and liver involvement by the Southern Italy Oncology Group

BACKGROUND. The objectives of the current study were: 1) to verify whether the addition of modulating low doses of interferon-2b (IFN) to 5-fluorourac il (5-FU) and levofolinic acid (1-FA) could improve clinical results in pat ients with advanced colorectal carcinoma; and 2) to evaluate the role of tu mor burden and liver involvement as prognostic factors. METHODS. A total of 204 untreated patients were randomized to receive 1-FA at 100 mg/m2 and 5-FU at 375 mg/m2 for 5 consecutive days with or without I FN every 3 weeks. IFN was given subcutaneously at 3 MU/day for 7 days start ing 2 days before chemotherapy administration. Patients were slratified acc ording to the presence or absence of hepatic disease (H+ or H-) and to tota l tumor burden defined as "low" or "high" using an area of 10 cm(2) as the cutoff value. Thus, four patient categories were obtained: Group 1: H+ grea ter than or equal to 10 cm(2); Group 2: H+ < 10 cm(2); Group 3. H- greater than or equal to 10 cm(2); and Group 4: H- 10 cm(2); RESULTS. No differences were observed in the objective response rate (23% f or the combination of 1-FA and 5-FU vs. 24% for the 1-FA, 5-FU, and IFN reg imen), median duration of response (11 months vs. 10 months), time to progr ession (5 months in both arms), and median survival (11 months vs. 12 month s). A statistically significant improvement in response rate was observed i n patients with limited liver involvement versus those with massive involve ment independent of the chemotherapy arm (44% vs. 22%; P = 0.02). Overall s urvival also was improved in patients with limited liver disease (P = 0.000 1) and in those without liver involvement (P = 0.004). Multivariate analysi s confirmed these data and identified response and female gender as positiv e prognostic factors. Toxic side effects (mainly diarrhea, mucositis, and f ever) were statistically more frequent in the IFN arm. CONCLUSIONS. The addition of low modulating doses of IFN to the regimen of 5-FU and I-FA failed to increase the response rate and survival of patients with advanced colorectal adenocarcinoma and significantly worsened toxicit y. High tumor bur den and the presence of liver involvement were confirmed prospectively as poor prognostic factors and should be taken in account in designing future Phase II or comparative trials. Cancer 1999;85:535-45. (C) 1999 American Cancer Society.