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.

摘要

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). HRs 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. FUNDING: Schering-Plough (now Merck); the Radiumhemmet Research Funds, Stockholm; the Stockholm County Council; and the Swedish Cancer Society.