Two different durations of adjuvant therapy with intermediate-dose interferon alfa-2b in patients with high-risk melanoma (Nordic IFN trial): a randomised phase 3 trial

Background Adjuvant high-dose interferon alfa-2b improves relapse-free survival (RFS) in patients with high-risk melanoma, although benefits in overall survival are uncertain. Because of the toxic effects of high-dose regimens, intermediate doses are being explored. We investigated whether adjuvant therapy with intermediate-dose interferon alfa-2b for 1 or 2 years would improve outcomes in patients with stage IIB-IIC or III resected cutaneous melanoma. Methods This randomised, open-label, phase 3, parallel-group trial was undertaken between 1996 and 2004. 855 patients were randomly assigned at 35 centres in the Nordic countries by block randomisation to three groups: observation only (group A); 4 weeks of induction (interferon alfa-2b 10 million units flat dose subcutaneously 5 days per week) followed by 12 months of maintenance therapy (interferon alfa-2b 10 million units flat dose subcutaneously 3 days per week; group B); or 1 month of induction and 24 months of maintenance (group C). Neither investigators nor patients were masked to treatment assignment. Patients were stratified for country and tumour stage; patients with stage III disease were further stratified for presence of metastatic lymph nodes at primary diagnosis versus at relapse, palpable versus non-palpable lymph-node metastases, and number of metastatic lymph nodes. The primary endpoint was overall survival in the two interferon alfa-2b groups combined. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01259934. Findings 284 patients were assigned to group A, 285 to group B, and 286 to group C; all patients were analysed. The median follow-up time was 72.4 months (IQR 46.9-98.0). We recorded no significant improvement in overall survival in patients given interferon alfa-2b compared with observation: median overall survival was 56.1 months (IQR 22.3 to >120.0) in group A, 72.1 months (25.8 to >120) in group B, and 64.3 months (24.7 to >120) in group C (p=0.600). Hazard ratios (HR) for overall survival were 0.91 (95% CI 0.74-1.10; p=0.642) for groups B and C combined versus observation; 0.91 (0.72-1.14; p=0.652) for group B versus observation; and 0.91 (0.72-1.15; p=0.858) for group C versus observation. Median RFS was 23.2 months (IQR 5.6 to <120) in group A, 37.8 months (10.8 to >120) in group B, and 28.6 months (8.6 to >120) in group C (p=0.034). Hits for RFS were 0.80 (0.67-0.96; p=0.030) for groups B and C combined versus observation, 0.77 (0.63-0.96; p=0.034) for group B versus observation, and 0.83 (0.68-1.03; p=0.178) for group C versus observation. The most common grade 3 and 4 adverse events were fatigue (five in group A [1.8%], 28 in group B [9.8%], and 32 in group C [11.2%]), myalgia (three [1.1%], 15 [5.3%],14 [4.9%], respectively), and thrombocytopenia (15 [5.3%], 23 [8.1%], eight [2.8%], respectively). Interpretation Adjuvant therapy with intermediate-dose interferon alfa-2b did not significantly improve overall survival. Interferon alfa-2b with 1-year maintenance therapy significantly improved RFS, but we recorded no significant effect for 2-year maintenance therapy. Further research is in progress to define the subgroup of patients who benefit from adjuvant interferon alfa-2b.