Carboplatin plus etoposide versus topotecan as second-line treatment for patients with sensitive relapsed small-cell lung cancer: an open-label, multicentre, randomised, phase 3 trial
Carboplatin plus etoposide versus topotecan as second-line treatment for patients with sensitive relapsed small-cell lung cancer: an open-label, multicentre, randomised, phase 3 trial
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DOI：
10.1016/s1470-2045(20)30461-7
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发表时间：
2020-09-01
期刊：
影响因子：
51.1
通讯作者：
Chouaid, Christos
中科院分区：
文献类型：
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作者：
Baize, Nathalie;Monnet, Isabelle;Chouaid, Christos
背景拓扑替康是目前欧洲唯一批准用于小细胞肺癌二线治疗的药物。本研究调查了卡铂加足叶乙甙的双联治疗是否上级于拓扑替康作为敏感复发性小细胞肺癌患者的二线治疗。方法在法国38家医院进行的开放标签、随机、3期试验中，我们招募了经组织学或细胞学证实的晚期IV期或局部复发性小细胞肺癌患者，对一线铂类加依托泊苷治疗有反应，但在一线治疗完成后至少90天出现疾病复发或进展的患者。符合条件的患者年龄为18岁或以上，东部肿瘤协作组体能状态评分为0-2。入组患者随机（1：1）接受卡铂+依托泊苷联合治疗（6个周期，第1天静脉注射卡铂[曲线下面积5 mg/mL/min]+静脉注射依托泊苷[100 mg/m2，第1天至第3天]）或口服拓扑替康（2.3 mg/m2，第1天至第5天，共6个周期）。使用最小化方法和偏倚硬币平衡法对ECOG体能状态、一线化疗应答和治疗中心进行随机化。主要终点是无进展生存期，在意向治疗人群中进行集中审查和分析。该试验注册于ClinicalTrials.gov，NCT 02738346。结果在2013年7月18日至2018年7月2日期间，我们招募并随机分配了164例患者（每个研究组82例）。每组各有1例患者撤回知情同意，因此162例患者（每组81例）被纳入意向治疗人群。中位随访时间为22.7个月（IQR 20.0-37.3），联合化疗组的中位无进展生存期显著长于拓扑替康组（4.7个月，90% CI 3.9-5.5 vs 2.7个月，2.3-3.2;分层风险比0.57，90% CI 0.41-0.73; p=0.0041）。最常见的3-4级不良事件是中性粒细胞减少症（拓扑替康组81例患者中18例[22%] vs联合化疗组81例患者中11例[14%]），血小板减少症（29例[36%] vs 25例[31%]）、贫血（17例[21%] vs 20例[25%]）、发热性中性粒细胞减少（9例[11%] vs 5例[6%]）和虚弱（8例[10%] vs 7例[9%]）。两个治疗相关的死亡发生在拓扑替康组（均为发热性中性粒细胞减少症与脓毒症），并没有治疗相关的死亡发生在combinationgroup.Interpretation我们的研究结果表明，卡铂加依托泊苷再激发可以被认为是一个合理的二线化疗方案敏感的复发性小细胞肺癌患者。版权所有（C）2020爱思唯尔有限公司保留所有权利。
Background Topotecan is currently the only drug approved in Europe in a second-line setting for the treatment of small-cell lung cancer. This study investigated whether the doublet of carboplatin plus etoposide was superior to topotecan as a second-line treatment in patients with sensitive relapsed small-cell lung cancer.Methods In this open-label, randomised, phase 3 trial done in 38 hospitals in France, we enrolled patients with histologically or cytologically confirmed advanced stage IV or locally relapsed small-cell lung cancer, who responded to first-line platinum plus etoposide treatment, but who had disease relapse or progression at least 90 days after completion of first-line treatment. Eligible patients were aged 18 years or older and had an Eastern Cooperative Oncology Group performance status 0-2. Enrolled patients were randomly assigned (1:1) to receive combination carboplatin plus etoposide (six cycles of intravenous carboplatin [area under the curve 5 mg/mL per min] on day 1 plus intravenous etoposide [100 mg/m(2) from day 1 to day 3]) or oral topotecan (2.3 mg/m(2) from day 1 to day 5, for six cycles). Randomisation was done using the minimisation method with biased-coin balancing for ECOG performance status, response to the first-line chemotherapy, and treatment centre. The primary endpoint was progression-free survival, which was centrally reviewed and analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02738346.Findings Between July 18, 2013, and July 2, 2018, we enrolled and randomly assigned 164 patients (82 in each study group). One patient from each group withdrew consent, therefore 162 patients (81 in each group) were included in the intention-to-treat population. With a median follow-up of 22.7 months (IQR 20.0-37.3), median progression-free survival was significantly longer in the combination chemotherapy group than in the topotecan group (4.7 months, 90% CI 3.9-5.5 vs 2.7 months, 2.3-3.2; stratified hazard ratio 0.57, 90% CI 0.41-0.73; p=0.0041). The most frequent grade 3-4 adverse events were neutropenia (18 [22%] of 81 patients in the topotecan group vs 11 [14%] of 81 patients in the combination chemotherapy group), thrombocytopenia (29 [36%] vs 25 [31%]), anaemia (17 [21%] vs 20 [25%]), febrile neutropenia (nine [11%] vs five [6%]), and asthenia (eight [10%] vs seven [9%]). Two treatment-related deaths occurred in the topotecan group (both were febrile neutropenia with sepsis) and no treatment-related deaths occurred in the combination group.Interpretation Our results suggest that carboplatin plus etoposide rechallenge can be considered as a reasonable second-line chemotherapy option for patients with sensitive relapsed small-cell lung cancer. Copyright (C) 2020 Elsevier Ltd. All rights reserved.