Cunningham David, Stenning Sally P, Smyth Elizabeth C, Okines Alicia F, Allum William H, Rowley Sam, Stevenson Laura, Grabsch Heike I, Alderson Derek, Crosby Thomas, Griffin S Michael, Mansoor Wasat, Coxon Fareeda Y, Falk Stephen J, Darby Suzanne, Sumpter Kate A, Blazeby Jane M, Langley Ruth E
Department of Oncology, Royal Marsden NHS Foundation Trust, London, UK.
Medical Research Council Clinical Trials Unit, University College London, London, UK.
Lancet Oncol. 2017 Mar;18(3):357-370. doi: 10.1016/S1470-2045(17)30043-8. Epub 2017 Feb 3.
Peri-operative chemotherapy and surgery is a standard of care for patients with resectable oesophagogastric adenocarcinoma. Bevacizumab, a monoclonal antibody against VEGF, improves the proportion of patients responding to treatment in advanced gastric cancer. We aimed to assess the safety and efficacy of adding bevacizumab to peri-operative chemotherapy in patients with resectable gastric, oesophagogastric junction, or lower oesophageal adenocarcinoma.
In this multicentre, randomised, open-label phase 2-3 trial, we recruited patients aged 18 years and older with histologically proven, resectable oesophagogastric adenocarcinoma from 87 UK hospitals and cancer centres. We randomly assigned patients 1:1 to receive peri-operative epirubicin, cisplatin, and capecitabine chemotherapy or chemotherapy plus bevacizumab, in addition to surgery. Patients in the control group (chemotherapy alone) received three pre-operative and three post-operative cycles of epirubicin, cisplatin, and capecitabine chemotherapy: 50 mg/m epirubicin and 60 mg/m cisplatin on day 1 and 1250 mg/m oral capecitabine on days 1-21. Patients in the investigational group received the same treatment as the control group plus 7·5 mg/kg intravenous bevacizumab on day 1 of every cycle of chemotherapy and for six further doses once every 21 days following chemotherapy, as maintenance treatment. Randomisation was done by means of a telephone call to the Medical Research Council Clinical Trials Unit, where staff used a computer programme that implemented a minimisation algorithm with a random element to establish the allocation for the patient at the point of randomisation. Patients were stratified by chemotherapy centre, site of tumour, and tumour stage. The primary outcome for the phase 3 stage of the trial was overall survival (defined as the time from randomisation until death from any cause), analysed in the intention-to-treat population. Here, we report the primary analysis results of the trial; all patients have completed treatment and the required number of primary outcome events has been reached. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN 46020948, and with ClinicalTrials.gov, number NCT00450203.
Between Oct 31, 2007, and March 25, 2014, 1063 patients were enrolled and randomly assigned to receive chemotherapy alone (n=533) or chemotherapy plus bevacizumab (n=530). At the time of analysis, 508 deaths were recorded (248 in the chemotherapy alone group and 260 in the chemotherapy plus bevacizumab group). 3-year overall survival was 50·3% (95% CI 45·5-54·9) in the chemotherapy alone group and 48·1% (43·2-52·7) in the chemotherapy plus bevacizumab group (hazard ratio [HR] 1·08, 95% CI 0·91-1·29; p=0·36). Apart from neutropenia no other toxic effects were reported at grade 3 or worse severity in more than 10% of patients in either group. Wound healing complications were more prevalent in the bevacizumab group, occurring in 53 (12%) patients in this group compared with 33 (7%) patients in the chemotherapy alone group. In patients who underwent oesophagogastrectomy, post-operative anastomotic leak rates were higher in the chemotherapy plus bevacizumab group (23 [10%] of 233 in the chemotherapy alone group vs 52 [24%] of 220 in the chemotherapy plus bevacizumab group); therefore, recruitment of patients with lower oesophageal or junctional tumours planned for an oesophagogastric resection was stopped towards the end of the trial. Serious adverse events for all patients included anastomotic leaks (30 events in chemotherapy alone group vs 69 in the chemotherapy plus bevacizumab group), and infections with normal neutrophil count (42 events vs 53).
The results of this trial do not provide any evidence for the use of bevacizumab in combination with peri-operative epiribicin, cisplatin, and capecitabine chemotherapy for patients with resectable gastric, oesophagogastric junction, or lower oesophageal adenocarcinoma. Bevacizumab might also be associated with impaired wound healing.
Cancer Research UK, MRC Clinical Trials Unit at University College London, and F Hoffmann-La Roche Limited.
围手术期化疗和手术是可切除食管胃腺癌患者的标准治疗方案。贝伐单抗是一种抗血管内皮生长因子（VEGF）的单克隆抗体，可提高晚期胃癌患者的治疗反应率。我们旨在评估在可切除的胃癌、食管胃交界癌或食管下段腺癌患者的围手术期化疗中加入贝伐单抗的安全性和有效性。
在这项多中心、随机、开放标签的2-3期试验中，我们从英国87家医院和癌症中心招募了年龄在18岁及以上、经组织学证实为可切除食管胃腺癌的患者。我们将患者按1:1随机分配，除手术外，分别接受围手术期表柔比星、顺铂和卡培他滨化疗或化疗加贝伐单抗治疗。对照组（单纯化疗）患者接受三个术前和三个术后周期的表柔比星、顺铂和卡培他滨化疗：第1天给予表柔比星50mg/m²和顺铂60mg/m²，第1-21天给予口服卡培他滨1250mg/m²。研究组患者接受与对照组相同的治疗，外加在每个化疗周期的第1天给予7.5mg/kg静脉注射贝伐单抗，并在化疗后每21天再给予6次剂量作为维持治疗。通过致电医学研究理事会临床试验单位进行随机分组，该单位的工作人员使用一种计算机程序，该程序采用带有随机因素的最小化算法来确定随机分组时患者的分配。患者按化疗中心、肿瘤部位和肿瘤分期进行分层。试验3期的主要结局是总生存期（定义为从随机分组至因任何原因死亡的时间），在意向性治疗人群中进行分析。在此，我们报告试验的主要分析结果；所有患者均已完成治疗，且已达到主要结局事件的所需数量。本研究已注册为国际标准随机对照试验，编号ISRCTN 46020948，并在ClinicalTrials.gov注册，编号NCT00450203。
2007年10月31日至2014年3月25日期间，共纳入1063例患者并随机分配，分别接受单纯化疗（n=533）或化疗加贝伐单抗（n=530）治疗。在分析时，记录到508例死亡（单纯化疗组248例，化疗加贝伐单抗组260例）。单纯化疗组的3年总生存率为50.3%（95%CI 45.5-54.9），化疗加贝伐单抗组为48.1%（43.2-52.7）（风险比[HR]1.08，95%CI 0.91-1.29；p=0.36）。两组中超过10%的患者除中性粒细胞减少外，未报告其他3级或更严重程度的毒性反应。贝伐单抗组伤口愈合并发症更为常见，该组有53例（12%）患者发生，而单纯化疗组有33例（7%）患者发生。在接受食管胃切除术的患者中，化疗加贝伐单抗组的术后吻合口漏发生率更高（单纯化疗组233例中有23例[10%]，化疗加贝伐单抗组220例中有52例[24%]）；因此，在试验接近尾声时，停止了招募计划进行食管胃切除术的食管下段或交界性肿瘤患者。所有患者的严重不良事件包括吻合口漏（单纯化疗组30例事件，化疗加贝伐单抗组69例事件），以及中性粒细胞计数正常的感染（42例事件对53例）。
本试验结果未提供任何证据支持在可切除的胃癌、食管胃交界癌或食管下段腺癌患者的围手术期化疗中使用贝伐单抗联合表柔比星、顺铂和卡培他滨。贝伐单抗还可能与伤口愈合受损有关。
英国癌症研究中心、伦敦大学学院医学研究理事会临床试验单位和F. Hoffmann-La Roche有限公司。
