Intensified high-dose intravenous interferon alpha 2b (IFNa2b) for adjuvant treatment of stage III melanoma: A randomized phase III Italian Melanoma Intergroup (IMI) trial [ISRCTN75125874

Abstract

8506 Background: High dose IFNalfa2b, according to the ECOG 1684 schedule, is the only approved adjuvant treatment for stage III melanoma. The risk/benefit profile has limited its use, while efficacy of intravenous (iv) phase and optimal duration have not been defined. The IMI Mel.A. trial evaluated the efficacy and safety of a pulsed high dose iv IFNa2b regimen. Methods: Following lymphadenectomy, stage III (AJCC2002) patients (pts), were randomly assigned to either 4 courses of IFNa2b 20 MU/m2iv 5 d/wk for 4 wks every other month (IHDI arm) or the standard high dose regimen of a 4 week iv course followed by 10 MU/m2IFNa2b sc 3 times/wk for 11 months (HDI Arm). Overall survival (OS) was the primary end point. The sample size of 328 pts and 118 deaths was determined assuming a 55% 5-y OS for HDI and an increase of 15% in IHDI (β=20%, α=5%, 2-sided test). Results: From 1998 to 2010, 336 pts were randomized and 330 evaluated for OS: 172 in IHDI, 158 in HDI. Pts were well balanced according to age, sex, PS (WHO), tumor ulceration (41% vs 46%) and number of metastatic lymph-nodes (N1: 64% vs 60%, N2: 22% vs 28%, N3: 13% vs 10%). Relapse occurred in 87 (IHDI: 50.6%) vs 80 (HDI: 50,6%) pts with a median relapse free survival (RFS) time of 47.9 (IHDI) vs 35.6 (HDI) months, not statistically different and a 5-y RFS of 45.8% (95%CI: 37.4;53.7) in IHDI vs 44.3% (95%CI: 35.7;52.6) in HDI arm. 72 pts (40.8%) died in IHDI arm vs 64 (40.7%) in HDI arm. The median and 5-y OS were 88.7 months (95%CI: 61.2;–) and 60.1% (95%CI: 53;66.5) in IHDI vs 82.6 (95%CI: 45.8;-) and 52.7% (95%CI: 44.9;59.8) in HDI arm, and were not significantly different. Discontinuation due to toxicity or refusal was 20% in IHDI vs 28% in HDI with 66% of pts in IHDI completing the treatment vs 49% in HDI (p=0.0026). The distribution of all grades of toxicity was similar in both groups, except for leucopenia, higher in IHDI arm (23% vs 12%, p=0.0331). Conclusions: Our data show that a shorter but more intensive HDI regimen is more feasible and not more toxic than conventional HDI. No significant differences in efficacy were observed and a meta-analysis of our and DeCog Ma-ADJ-5 trial data could better establish the role of iv HDI.