Department of Pulmonology and Thoracic Oncology, University of Caen, Centre Hospitalier Universitaire Côte de Nacre, Caen, France; Department of Thoracic Oncology, Centre d'investigation clinique Institut national de la santé et de la recherche médicale 1425, Hospital Bichat-Claude Bernard, Assistance Publique-Hôpitaux de Paris, Paris-Diderot University (Paris 7), Paris, France.
Department of Pulmonology, Larrey Hospital, Toulouse, France.
Lancet. 2016 Apr 2;387(10026):1405-1414. doi: 10.1016/S0140-6736(15)01238-6. Epub 2015 Dec 21.
Malignant pleural mesothelioma is an aggressive cancer with poor prognosis, linked to occupational asbestos exposure. Vascular endothelial growth factor is a key mitogen for malignant pleural mesothelioma cells, therefore targeting of vascular endothelial growth factor might prove effective. We aimed to assess the effect on survival of bevacizumab when added to the present standard of care, cisplatin plus pemetrexed, as first-line treatment of advanced malignant pleural mesothelioma.
In this randomised, controlled, open-label, phase 3 trial, we recruited patients aged 18-75 years with unresectable malignant pleural mesothelioma who had not received previous chemotherapy, had an Eastern Cooperative Oncology Group performance status of 0-2, had no substantial cardiovascular comorbidity, were not amenable to curative surgery, had at least one evaluable (pleural effusion) or measurable (pleural tumour solid thickening) lesion with CT, and a life expectancy of >12 weeks from 73 hospitals in France. Exclusion criteria were presence of central nervous system metastases, use of antiaggregant treatments (aspirin ≥325 mg per day, clopidogrel, ticlopidine, or dipyridamole), anti-vitamin K drugs at a curative dose, treatment with low-molecular-weight heparin at a curative dose, and treatment with non-steroidal anti-inflammatory drugs. We randomly allocated patients (1:1; minimisation method used [random factor of 0·8]; patients stratified by histology [epithelioid vs sarcomatoid or mixed histology subtypes], performance status score [0-1 vs 2], study centre, or smoking status [never smokers vs smokers]) to receive intravenously 500 mg/m(2) pemetrexed plus 75 mg/m(2) cisplatin with (PCB) or without (PC) 15 mg/kg bevacizumab in 21 day cycles for up to six cycles, until progression or toxic effects. The primary outcome was overall survival (OS) in the intention-to treat population. Treatment was open label. This IFCT-GFPC-0701 trial is registered with ClinicalTrials.gov, number NCT00651456.
From Feb 13, 2008, to Jan 5, 2014, we randomly assigned 448 patients to treatment (223 [50%] to PCB and 225 [50%] to PC). OS was significantly longer with PCB (median 18·8 months [95% CI 15·9-22·6]) than with PC (16·1 months [14·0-17·9]; hazard ratio 0·77 [0·62-0·95]; p=0·0167). Overall, 158 (71%) of 222 patients given PCB and 139 (62%) of 224 patients given PC had grade 3-4 adverse events. We noted more grade 3 or higher hypertension (51 [23%] of 222 vs 0) and thrombotic events (13 [6%] of 222 vs 2 [1%] of 224) with PCB than with PC.
Addition of bevacizumab to pemetrexed plus cisplatin significantly improved OS in malignant pleural mesothelioma at the cost of expected manageable toxic effects, therefore it should be considered as a suitable treatment for the disease.
Intergroupe Francophone de Cancérologie Thoracique (IFCT).
恶性胸膜间皮瘤是一种预后不良的侵袭性癌症，与职业性石棉暴露有关。血管内皮生长因子是恶性胸膜间皮瘤细胞的关键有丝分裂原，因此靶向血管内皮生长因子可能有效。我们旨在评估贝伐单抗联合顺铂加培美曲塞作为晚期恶性胸膜间皮瘤一线治疗的标准治疗方案，对生存的影响。
在这项随机、对照、开放标签、3 期临床试验中，我们招募了年龄在 18-75 岁之间、未接受过化疗、东部合作肿瘤学组表现状态为 0-2、无严重心血管合并症、不能进行根治性手术、至少有一个可评估（胸腔积液）或可测量（胸腔肿瘤实性增厚）病变的不可切除恶性胸膜间皮瘤患者。这些病变在 CT 上可见，且从 73 家法国医院的角度来看，预期生存期>12 周。排除标准为存在中枢神经系统转移、使用抗聚集治疗（每天>325mg 阿司匹林、氯吡格雷、噻氯匹定或双嘧达莫）、维生素 K 拮抗药物的治疗剂量、低分子量肝素的治疗剂量、以及非甾体抗炎药物的治疗。我们将患者随机分配（1:1；最小化方法使用[0.8 的随机因子]；根据组织学[上皮样与肉瘤样或混合组织学亚型]、表现状态评分[0-1 与 2]、研究中心或吸烟状态[从不吸烟者与吸烟者]分层）接受静脉注射 500mg/m2培美曲塞加 75mg/m2顺铂加（PCB）或不加（PC）15mg/kg 贝伐单抗，每 21 天为一个周期，最多 6 个周期，直至疾病进展或出现毒性作用。主要终点是意向治疗人群的总生存期（OS）。治疗是开放标签的。这项 IFCT-GFPC-0701 试验在 ClinicalTrials.gov 注册，编号为 NCT00651456。
从 2008 年 2 月 13 日至 2014 年 1 月 5 日，我们随机分配了 448 名患者接受治疗（PCB 组 223 名[50%]，PC 组 225 名[50%]）。PCB 组的 OS 明显长于 PC 组（中位 18.8 个月[95%CI 15.9-22.6]）（16.1 个月[14.0-17.9]；风险比 0.77[0.62-0.95]；p=0.0167）。总体而言，222 名接受 PCB 治疗的患者中有 158 名（71%）和 224 名接受 PC 治疗的患者中有 139 名（62%）发生 3-4 级不良事件。我们注意到，PCB 组发生 3 级或以上高血压（51[23%]例与 0 例）和血栓事件（13[6%]例与 2[1%]例）的患者多于 PC 组。
贝伐单抗联合培美曲塞加顺铂显著提高了恶性胸膜间皮瘤的 OS，但代价是可预期的、可管理的毒性作用，因此它应该被认为是一种适合该疾病的治疗方法。
法国胸科肿瘤协作组（IFCT）。
