Wakelee Heather A, Dahlberg Suzanne E, Keller Steven M, Tester William J, Gandara David R, Graziano Stephen L, Adjei Alex A, Leighl Natasha B, Aisner Seena C, Rothman Jan M, Patel Jyoti D, Sborov Mark D, McDermott Sean R, Perez-Soler Roman, Traynor Anne M, Butts Charles, Evans Tracey, Shafqat Atif, Chapman Andrew E, Kasbari Samer S, Horn Leora, Ramalingam Suresh S, Schiller Joan H
Department of Medicine (Oncology), Stanford Cancer Institute, Stanford University, Stanford, CA, USA.
Dana-Farber Cancer Institute and Harvard T H Chan School of Public Health, Boston, MA, USA.
Lancet Oncol. 2017 Dec;18(12):1610-1623. doi: 10.1016/S1470-2045(17)30691-5. Epub 2017 Nov 9.
Adjuvant chemotherapy for resected early-stage non-small-cell lung cancer (NSCLC) provides a modest survival benefit. Bevacizumab, a monoclonal antibody directed against VEGF, improves outcomes when added to platinum-based chemotherapy in advanced-stage non-squamous NSCLC. We aimed to evaluate the addition of bevacizumab to adjuvant chemotherapy in early-stage resected NSCLC.
We did an open-label, randomised, phase 3 trial of adult patients (aged ≥18 years) with an Eastern Cooperative Oncology Group performance status of 0 or 1 and who had completely resected stage IB (≥4 cm) to IIIA (defined by the American Joint Committee on Cancer 6th edition) NSCLC. We enrolled patients from across the US National Clinical Trials Network, including patients from the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network (ECOG-ACRIN) affiliates in Europe and from the Canadian Cancer Trials Group, within 6-12 weeks of surgery. The chemotherapy regimen for each patient was selected before randomisation and administered intravenously; it consisted of four 21-day cycles of cisplatin (75 mg/m on day 1 in all regimens) in combination with investigator's choice of vinorelbine (30 mg/m on days 1 and 8), docetaxel (75 mg/m on day 1), gemcitabine (1200 mg/m on days 1 and 8), or pemetrexed (500 mg/m on day 1). Patients in the bevacizumab group received bevacizumab 15 mg/kg intravenously every 21 days starting with cycle 1 of chemotherapy and continuing for 1 year. We randomly allocated patients (1:1) to group A (chemotherapy alone) or group B (chemotherapy plus bevacizumab), centrally, using permuted blocks sizes and stratified by chemotherapy regimen, stage of disease, histology, and sex. No one was masked to treatment assignment, except the Data Safety and Monitoring Committee. The primary endpoint was overall survival, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00324805.
Between June 1, 2007, and Sept 20, 2013, 1501 patients were enrolled and randomly assigned to the two treatment groups: 749 to group A (chemotherapy alone) and 752 to group B (chemotherapy plus bevacizumab). 383 (26%) of 1458 patients (with complete staging information) had stage IB, 636 (44%) had stage II, and 439 (30%) had stage IIIA disease (stage of disease data were missing for 43 patients). Squamous cell histology was reported for 422 (28%) of 1501 patients. All four cisplatin-based chemotherapy regimens were used: 377 (25%) patients received vinorelbine, 343 (23%) received docetaxel, 283 (19%) received gemcitabine, and 497 (33%) received pemetrexed. At a median follow-up of 50·3 months (IQR 32·9-68·0), the estimated median overall survival in group A has not been reached, and in group B was 85·8 months (95% CI 74·9 to not reached); hazard ratio (group B vs group A) 0·99 (95% CI 0·82-1·19; p=0·90). Grade 3-5 toxicities of note (all attributions) that were reported more frequently in group B (the bevacizumab group) than in group A (chemotherapy alone) were overall worst grade (ie, all grade 3-5 toxicities; 496 [67%] of 738 in group A vs 610 [83%] of 735 in group B), hypertension (60 [8%] vs 219 [30%]), and neutropenia (241 [33%] vs 275 [37%]). The number of deaths on treatment did not differ between the groups (15 deaths in group A vs 19 in group B). Of these deaths, three in group A and ten in group B were considered at least possibly related to treatment.
Addition of bevacizumab to adjuvant chemotherapy did not improve overall survival for patients with surgically resected early-stage NSCLC. Bevacizumab does not have a role in this setting and should not be considered as an adjuvant therapy for patients with resected early-stage NSCLC.
National Cancer Institute of the National Institutes of Health.
辅助化疗对早期非小细胞肺癌（NSCLC）患者的生存获益有限。贝伐单抗是一种抗血管内皮生长因子（VEGF）的单克隆抗体，在晚期非鳞NSCLC患者中，联合铂类化疗可改善预后。我们旨在评估在早期可切除NSCLC患者中，辅助化疗联合贝伐单抗的疗效。
我们开展了一项开放标签、随机、3期临床试验，纳入年龄≥18岁、美国东部肿瘤协作组（ECOG）体能状态为0或1、完全切除的IB期（≥4 cm）至IIIA期（根据美国癌症联合委员会第6版定义）NSCLC成年患者。我们从美国国家临床试验网络中招募患者，包括来自欧洲的ECOG-美国放射学会影像网络（ECOG-ACRIN）附属机构的患者以及加拿大癌症试验组的患者，在术后6-12周内入组。每位患者的化疗方案在随机分组前选定并静脉给药；方案包括四个21天周期的顺铂（所有方案均为第1天75 mg/m²），联合研究者选择的长春瑞滨（第1天和第8天30 mg/m²）、多西他赛（第1天75 mg/m²）、吉西他滨（第1天和第8天1200 mg/m²）或培美曲塞（第1天500 mg/m²）。贝伐单抗组患者从化疗第1周期开始，每21天静脉注射贝伐单抗15 mg/kg，持续1年。我们采用中心随机化，使用置换块大小，按化疗方案、疾病分期、组织学类型和性别进行分层，将患者（1:1）随机分配至A组（单纯化疗）或B组（化疗联合贝伐单抗）。除数据安全与监测委员会外，无人对治疗分配情况不知情。主要终点为总生存期，采用意向性分析。本试验已在ClinicalTrials.gov注册，注册号为NCT00324805。
2007年6月1日至2013年9月20日期间，共纳入1501例患者并随机分配至两个治疗组：749例至A组（单纯化疗），752例至B组（化疗联合贝伐单抗）。1458例（有完整分期信息）患者中，383例（26%）为IB期，636例（44%）为II期，439例（30%）为IIIA期疾病（43例患者疾病分期数据缺失）。1501例患者中，422例（28%）报告为鳞状细胞组织学类型。所有四种基于顺铂的化疗方案均有使用：377例（25%）患者接受长春瑞滨，343例（23%）接受多西他赛，283例（19%）接受吉西他滨，497例（33%）接受培美曲塞。中位随访50.3个月（IQR 32.9 - 68.0），A组的估计中位总生存期未达到，B组为85.8个月（95%CI 74.9至未达到）；风险比（B组对比A组）0.99（95%CI 0.82 - 1.19；p = 0.90）。B组（贝伐单抗组）比A组（单纯化疗组）更常报告的3 - 5级值得关注的毒性反应（所有归因）为总体最严重级别（即所有3 - 5级毒性反应；A组738例中的496例[67%]对比B组735例中的610例[83%]）、高血压（60例[8%]对比219例[30%]）和中性粒细胞减少（241例[33%]对比275例[37%]）。两组治疗期间的死亡人数无差异（A组15例死亡对比B组19例死亡）。在这些死亡病例中，A组3例和B组10例被认为至少可能与治疗有关。
对于手术切除的早期NSCLC患者，辅助化疗联合贝伐单抗并未改善总生存期。在这种情况下，贝伐单抗没有作用不应被视为早期可切除NSCLC患者的辅助治疗方法。
美国国立卫生研究院国家癌症研究所。
