Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Lancet Oncol. 2011 Feb;12(2):144-52. doi: 10.1016/S1470-2045(10)70288-6. Epub 2011 Jan 20.
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.
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.
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).
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.
Schering-Plough (now Merck); the Radiumhemmet Research Funds, Stockholm; the Stockholm County Council; and the Swedish Cancer Society.
辅助高剂量干扰素 alfa-2b 可改善高危黑色素瘤患者的无复发生存（RFS），尽管总体生存获益尚不确定。由于大剂量方案的毒性作用，正在探索中等剂量方案。我们研究了辅助治疗中间剂量干扰素 alfa-2b 1 年或 2 年是否会改善 IIB-IIC 期或 III 期切除皮肤黑色素瘤患者的结局。
这是一项随机、开放标签、III 期、平行组试验，于 1996 年至 2004 年在北欧国家的 35 个中心进行。855 名患者通过区块随机分组，分为三组：仅观察（A 组）；4 周诱导（干扰素 alfa-2b 1000 万单位皮下注射，每周 5 天），随后进行 12 个月的维持治疗（干扰素 alfa-2b 1000 万单位皮下注射，每周 3 天）；或 1 个月诱导和 24 个月维持（C 组）。研究者和患者均未对治疗分组进行盲法。患者按国家和肿瘤分期分层；III 期疾病患者按原发诊断时是否存在转移性淋巴结、可触及或不可触及的淋巴结转移、以及转移性淋巴结的数量进一步分层。主要终点是两组干扰素 alfa-2b 联合的总生存。分析采用意向治疗。本研究在 ClinicalTrials.gov 注册，编号为 NCT01259934。
284 名患者被分配到 A 组，285 名患者被分配到 B 组，286 名患者被分配到 C 组；所有患者均进行了分析。中位随访时间为 72.4 个月（IQR 46.9-98.0）。与观察组相比，接受干扰素 alfa-2b 治疗的患者总生存无显著改善：A 组中位总生存时间为 56.1 个月（IQR 22.3->120.0），B 组为 72.1 个月（25.8->120.0），C 组为 64.3 个月（24.7->120.0）（p=0.600）。B 组和 C 组联合与观察组相比，总生存的危险比（HR）为 0.91（95%CI 0.74-1.10；p=0.642）；B 组与观察组相比为 0.91（0.72-1.14；p=0.652）；C 组与观察组相比为 0.91（0.72-1.15；p=0.858）。A 组中位 RFS 为 23.2 个月（IQR 5.6-<120），B 组为 37.8 个月（10.8->120），C 组为 28.6 个月（8.6->120）（p=0.034）。B 组和 C 组联合与观察组相比，RFS 的 HR 为 0.80（0.67-0.96；p=0.030）；B 组与观察组相比为 0.77（0.63-0.96；p=0.034）；C 组与观察组相比为 0.83（0.68-1.03；p=0.178）。最常见的 3 级和 4 级不良事件为疲乏（A 组 5 例[1.8%]，B 组 28 例[9.8%]，C 组 32 例[11.2%]）、肌痛（A 组 3 例[1.1%]，B 组 15 例[5.3%]，C 组 14 例[4.9%]）和血小板减少症（A 组 15 例[5.3%]，B 组 23 例[8.1%]，C 组 8 例[2.8%]）。
辅助治疗中间剂量干扰素 alfa-2b 并未显著改善总体生存。干扰素 alfa-2b 1 年维持治疗显著改善了 RFS，但我们记录到 2 年维持治疗没有显著效果。目前正在进行进一步的研究，以确定从辅助干扰素 alfa-2b 治疗中获益的患者亚组。
先灵葆雅（现为默克）；斯德哥尔摩 Radiumhemmet 研究基金；斯德哥尔摩郡委员会；和瑞典癌症协会。
