BACKGROUND: Any benefit of adjuvant interferon alfa-2b for melanoma could depend on dose and duration of treatment. Our aim was to determine whether pegylated interferon alfa-2b can facilitate prolonged exposure while maintaining tolerability. METHODS: 1256 patients with resected stage III melanoma were randomly assigned to observation (n=629) or pegylated interferon alfa-2b (n=627) 6 mug/kg per week for 8 weeks (induction) then 3 mug/kg per week (maintenance) for an intended duration of 5

more »

... . Randomisation was stratified for microscopic (N1) versus macroscopic (N2) nodal involvement, number of positive nodes, ulceration and tumour thickness, sex, and centre. Randomisation was done with a minimisation technique. The primary endpoint was recurrence-free survival. Analyses were done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00006249. FINDINGS: All randomised patients were included in the primary efficacy analysis. 608 patients in the interferon group and 613 patients in the observation group were included in safety analyses. The median length of treatment with pegylated interferon alfa-2b was 12 (IQR 3.8-33.4) months. At 3.8 (3.2-4.2) years median follow-up, 328 recurrence events had occurred in the interferon group compared with 368 in the observation group (hazard ratio 0.82, 95% CI 0.71-0.96; p=0.01); the 4-year rate of recurrence-free survival was 45.6% (SE 2.2) in the interferon group and 38.9% (2.2) in the observation group. There was no difference in overall survival between the groups. Grade 3 adverse events occurred in 246 (40%) patients in the interferon group and 60 (10%) in the observation group; grade 4 adverse events occurred in 32 (5%) patients in the interferon group and 14 (2%) in the observation group. In the interferon group, the most common grade 3 or 4 adverse events were fatigue (97 patients, 16%), hepatotoxicity (66, 11%), and depression (39, 6%). Treatment with pegylated interferon alfa-2b was discontinued because of toxicity in 191 (31%) patients. INTERPRETATION: Adjuvant pegylated interferon alfa-2b for stage III melanoma has a significant, sustained effect on recurrence-free survival. Summary Background Any benefit of adjuvant interferon α-2b (IFNα-2b) for melanoma may depend on dose and duration of treatment. Pegylated interferon α-2b (PEG-IFNα-2b) may facilitate prolonged exposure while maintaining tolerability. Methods 1256 patients with resected Stage III melanoma were randomised to receive observation or PEG-IFNα-2b induction 6 µg/kg/wk for 8 weeks then maintenance 3 µg/kg/wk for an intended duration of 5 years. Randomization was stratified for microscopic (N1) vs macroscopic (N2) nodal involvement, number of positive nodes, ulceration and tumour thickness. Recurrence-free survival (RFS) (primary endpoint), distant-metastasis-free survival (DMFS), and overall survival (OS) were analyzed for the intent-to-treat population. Results At 3.8 years median follow-up, RFS was reduced by 18% (hazard rate [HR] 0.82; P=0.01) in the PEG-IFNα-2b arm compared with observation; the 4-year RFS rate was 45.6% vs 38.9%. DMFS was improved, but non-significantly (P=0.11). OS was unchanged. In stage III-N1, both RFS (HR 0.72, 57.7% vs 45.4%, P=0.01) and DMFS (HR 0.73, 60.5% vs 52.6%, P=0.01) were prolonged in the PEG-IFNα-2b arm, whereas in stage III-N2 there was no benefit. Grade 3 and 4 adverse events occurred in 38% and 9% in the PEG-IFNα-2b arm and 9% and 7% in the observation arm. PEG-IFNα-2b was discontinued in 31% because of fatigue (15%), depression (6%), hepatotoxicity (10%). Interpretation Adjuvant PEG-IFNα-2b for stage III melanoma had a significant sustained impact on RFS. For N1 disease the impact was also significant for DMFS. Patients with lower disease burden clearly benefited more, consistent with our previous trial EORTC 18952 of IFNα-2b. Trial registration information: Clinicaltrials.gov NCT number (NCT00006249). ·