Predictive importance of ulceration on the efficacy of adjuvant interferon-a (IFN): An individual patient data (IPD) meta-analysis of 15 randomized trials in more than 7,500 melanoma patients (pts).

Background: Many randomised trials have evaluated the role of adjuvant IFN in high-risk melanoma, some suggesting benefit and others not. To assess the evidence of IFN vs. no IFN, an IPD meta-analysis of these trials was performed. Methods: Standard IPD meta-analysis methods were used to assess event-free (EFS) and overall survival (OS), with odds ratios (OR) and confidence intervals (CI) calculated. Trials were divided by dose of IFN – high (10-20MU/m2), Peg-IFN (3-6µg/Kg), intermediate (5-10MU flat), low (3MU flat) and very low (1MU). Results: IPD was provided for 11 of 15 reported trials of IFN vs. no IFN (for the other 4 trials published data were used). Over 7500 pts were included in the analysis, with over 4700 and 3800 events for EFS and OS. There was benefit for IFN for both EFS (P<0.00001) and OS (P=0.003) (Table). This translated into increased 5-year OS from 46.1% to 49.1%. There was no evidence of differences according to dose, duration of IFN, gender, Breslow thickness or disease stage, but ulceration status impacted the IFN benefit regarding EFS (interaction test: P=0.04) and OS (P=0.002) (Table). For the ulcerated melanoma, IFN increased the OS from 38.1% to 46.0%, at 5 yrs, and from 28.0% to 38.5%, at 10 yrs. Conclusions: This meta-analysis provides evidence that adjuvant IFN significantly reduces the risk of relapse and improves overall survival. This analysis does not identify the optimal dose or duration of IFN. OS benefit was confined to pts with ulcerated tumours. The biological basis of this action is incompletely defined, and being studied in the ongoing study (EORTC 18081 and ECOG-ACRIN Intergroup Trial E1609).