Netherlands Cancer Institute, Amsterdam, Netherlands.
Lancet Oncol. 2013 May;14(6):543-51. doi: 10.1016/S1470-2045(13)70125-6. Epub 2013 Apr 12.
Standard chemotherapy does not lead to long-term survival in patients with malignant pleural mesothelioma. Malignant pleural mesothelioma is strongly dependent on vasculature with high vessel counts and high concentrations of serum vascular growth factors. Thalidomide has shown antiangiogenic activity, and we hypothesised that its use in the maintenance setting could improve outcomes.
In this open-label, multicentre, randomised phase 3 study, eligible patients had proven malignant pleural or peritoneal mesothelioma and had received a minimum of four cycles of first-line treatment containing at least pemetrexed, with or without cisplatin or carboplatin, and had not progressed on this treatment. Patients were randomly assigned (in a 1:1 ratio, stratified by previous first-line chemotherapy, histological subtype, and recruiting hospital) to receive thalidomide 200 mg per day (including a 2 week run in of 100 mg per day) plus active supportive care or active supportive care alone until disease progression. Patients were required to be registered and to start treatment with thalidomide within 10 weeks after the end of the first-line chemotherapy. Thalidomide was given for a maximum of 1 year or until unacceptable toxicity. The primary endpoint was time to progression. The primary analyses were by intention to treat. The study is registered, ISRCTN13632914.
Between May 11, 2004, and Dec 23, 2009, we randomly assigned 222 patients, 111 in each group (one patient on active supportive care later withdrew consent and was excluded from analyses). At the time of this final analysis, median follow-up was 33.1 months (IQR 22.3-66.8), and physician-reported disease progression had occurred in 104 patients in the thalidomide group and 107 in the active supportive care group; 92 patients in the thalidomide group and 93 in the active supportive care group had died. Median time to progression in the thalidomide group was 3·6 months (95% CI 3.2-4.1) compared with 3.5 months (2.3-4.8) in the active supportive care group (hazard ratio 0.95, 95% CI 0.73-1.20, p=0.72). 43 (39%) grade 3 or 4 adverse events were reported in the thalidomide group and 31 (28%) in the active supportive care group; neurosensory events were reported by two (2%) patients on thalidomide and none on active supportive care, cardiac events by two (2%) patients on thalidomide and three (3%) on active supportive care, and thromboembolic events by three (3%) patients on thalidomide and none on active supportive care.
No benefit was noted in time to progression with the addition of thalidomide maintenance to first-line chemotherapy. Different treatment strategies are needed to improve outcomes in patients with malignant mesothelioma.
Dutch Cancer Society (KWF), Eli Lilly, NSW Dust Disease Compensation Board, University of Sydney, and Cancer Australia.
标准化疗不能使恶性胸膜间皮瘤患者长期存活。恶性胸膜间皮瘤强烈依赖血管，血管计数高，血清血管生长因子浓度高。沙利度胺具有抗血管生成活性，我们假设在维持治疗中使用它可以改善结果。
在这项开放标签、多中心、随机 3 期研究中，合格的患者有明确的恶性胸膜或腹膜间皮瘤，并接受了至少 4 个周期的包含至少培美曲塞的一线治疗，无论是否联合顺铂或卡铂，并且在该治疗中没有进展。患者被随机分配（1:1 比例，按先前的一线化疗、组织学亚型和招募医院分层）接受沙利度胺 200mg/天（包括 2 周的 100mg/天起始期）加积极支持性治疗或单独积极支持性治疗，直到疾病进展。患者必须登记并在一线化疗结束后 10 周内开始沙利度胺治疗。沙利度胺的最大使用时间为 1 年或直至出现不可接受的毒性。主要终点是无进展时间。主要分析采用意向治疗。该研究已注册，ISRCTN13632914。
2004 年 5 月 11 日至 2009 年 12 月 23 日，我们随机分配了 222 名患者，每组 111 名（一名接受积极支持性治疗的患者后来撤回了同意并被排除在分析之外）。在本次最终分析时，中位随访时间为 33.1 个月（IQR 22.3-66.8），医生报告的疾病进展发生在沙利度胺组的 104 名患者和积极支持性治疗组的 107 名患者中；沙利度胺组有 92 名患者和积极支持性治疗组有 93 名患者死亡。沙利度胺组的中位无进展时间为 3.6 个月（95%CI 3.2-4.1），而积极支持性治疗组为 3.5 个月（2.3-4.8）（风险比 0.95，95%CI 0.73-1.20，p=0.72）。沙利度胺组报告了 43 例（39%）3 级或 4 级不良事件，而积极支持性治疗组报告了 31 例（28%）；沙利度胺组有 2 例（2%）患者报告了神经感觉事件，而积极支持性治疗组没有患者报告；沙利度胺组有 2 例（2%）患者报告了心脏事件，而积极支持性治疗组有 3 例（3%）；沙利度胺组有 3 例（3%）患者报告了血栓栓塞事件，而积极支持性治疗组没有。
在将沙利度胺添加到一线化疗的维持治疗中时，无进展时间没有改善。需要不同的治疗策略来改善恶性间皮瘤患者的预后。
荷兰癌症协会（KWF）、礼来公司、新南威尔士州尘埃病赔偿委员会、悉尼大学和澳大利亚癌症协会。
