与GM2-KLH/QS-21疫苗相比，高剂量干扰素α-2b显著延长了IIB-III期黑色素瘤切除术后患者的无复发生存期和总生存期：组间试验E1694/S9512/C509801的结果

High-dose interferon alfa-2b significantly prolongs relapse-free and overall survival compared with the GM2-KLH/QS-21 vaccine in patients with resected stage IIB-III melanoma: results of intergroup trial E1694/S9512/C509801.

作者信息

Kirkwood J M, Ibrahim J G, Sosman J A, Sondak V K, Agarwala S S, Ernstoff M S, Rao U

机构信息

Division of Hematology-Oncology and Department of Pathology, Department of Medicine, University of Pittsburgh Cancer Institute Melanoma Center, University of Pittsburgh Medical Center, Pittsburgh, PA 15213-2582, USA.

出版信息

J Clin Oncol. 2001 May 1;19(9):2370-80. doi: 10.1200/JCO.2001.19.9.2370.

DOI:10.1200/JCO.2001.19.9.2370

PMID:11331315

Abstract

PURPOSE

Vaccine alternatives to high-dose interferon alfa-2b therapy (HDI), the current standard adjuvant therapy for high-risk melanoma, are of interest because of toxicity associated with HDI. The GM2 ganglioside is a well-defined melanoma antigen, and anti-GM2 antibodies have been associated with improved prognosis. We conducted a prospective, randomized, intergroup trial to evaluate the efficacy of HDI for 1 year versus vaccination with GM2 conjugated to keyhole limpet hemocyanin and administered with QS-21 (GMK) for 96 weeks (weekly x 4 then every 12 weeks x 8).

PATIENTS AND METHODS

Eligible patients had resected stage IIB/III melanoma. Patients were stratified by sex and number of positive nodes. Primary end points were relapse-free survival (RFS) and overall survival (OS).

RESULTS

Eight hundred eighty patients were randomized (440 per treatment group); 774 patients were eligible for efficacy analysis. The trial was closed after interim analysis indicated inferiority of GMK compared with HDI. For eligible patients, HDI provided a statistically significant RFS benefit (hazard ratio [HR] = 1.47, P = .0015) and OS benefit (HR = 1.52, P = .009) for GMK versus HDI. Similar benefit was observed in the intent-to-treat analysis (RFS HR = 1.49; OS HR = 1.38). HDI was associated with a treatment benefit in all subsets of patients with zero to > or = four positive nodes, but the greatest benefit was observed in the node-negative subset (RFS HR = 2.07; OS HR = 2.71 [eligible population]). Antibody responses to GM2 (ie, titers > or = 1:80) at days 29, 85, 365, and 720 were associated with a trend toward improved RFS and OS (P2 = .068 at day 29).

CONCLUSION

This trial demonstrated a significant treatment benefit of HDI versus GMK in terms of RFS and OS in melanoma patients at high risk of recurrence.

摘要

目的

高剂量干扰素α-2b疗法（HDI）是目前高危黑色素瘤的标准辅助治疗方法，但由于其毒性问题，人们对其替代疫苗产生了兴趣。GM2神经节苷脂是一种明确的黑色素瘤抗原，抗GM2抗体与预后改善相关。我们进行了一项前瞻性、随机、组间试验，以评估HDI治疗1年与接种结合了钥孔戚血蓝蛋白并与QS-21联合使用的GM2（GMK）96周（每周1次，共4次，然后每12周1次，共8次）的疗效。

患者和方法

符合条件的患者为已切除的IIB/III期黑色素瘤患者。患者按性别和阳性淋巴结数量分层。主要终点为无复发生存期（RFS）和总生存期（OS）。

结果

880例患者被随机分组（每个治疗组440例）；774例患者符合疗效分析条件。中期分析表明GMK比HDI疗效差，试验因此提前结束。对于符合条件的患者，与GMK相比，HDI在RFS（风险比[HR]=1.47，P=0.0015）和OS（HR=1.52，P=0.009）方面具有统计学显著优势。在意向性分析中也观察到了类似的优势（RFS HR=1.49；OS HR=1.38）。HDI在所有阳性淋巴结数为零至≥4个的患者亚组中均显示出治疗优势，但在淋巴结阴性亚组中优势最大（RFS HR=2.07；OS HR=2.71[符合条件人群]）。在第29、85、365和720天时对GM2的抗体反应（即滴度≥1:80）与RFS和OS改善趋势相关（第29天时P2=0.068）。