Neoadjuvant cisplatin and fluorouracil versus epirubicin, cisplatin, and capecitabine followed by resection in patients with oesophageal adenocarcinoma (UK MRC OE05): an open-label, randomised phase 3 trial.
Neoadjuvant cisplatin and fluorouracil versus epirubicin, cisplatin, and capecitabine followed by resection in patients with oesophageal adenocarcinoma (UK MRC OE05): an open-label, randomised phase 3 trial.
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DOI：
10.1016/s1470-2045(17)30447-3
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发表时间：
2017-09
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通讯作者：
Langley RE
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作者：
Alderson D;Cunningham D;Nankivell M;Blazeby JM;Griffin SM;Crellin A;Grabsch HI;Langer R;Pritchard S;Okines A;Krysztopik R;Coxon F;Thompson J;Falk S;Robb C;Stenning S;Langley RE
与单纯手术相比，术前新辅助化疗可提高食管癌患者的生存率。OE 05试验评估了与目前的标准方案相比，增加新辅助化疗的持续时间和强度是否进一步改善了生存率。OE 05是一项开放标签、III期、随机化临床试验。从72家英国医院招募了cT 1 N1、cT 2N 1、cT 3 N 0/N1或cT 4 N 0/N1期可手术切除的食管腺癌患者。入选标准包括WHO体力状态0或1，足够的呼吸、心脏和肝功能，白色血细胞计数至少3 × 109个细胞/L，血小板计数至少100 × 109个血小板/L，肾小球滤过率至少60 mL/min。使用带有随机元素的计算机最小化程序并按中心和肿瘤分期分层，将参与者随机分配（1：1），接受两个周期的顺铂和氟尿嘧啶治疗（CF;顺铂[第1天静脉注射80 mg/m2]和氟尿嘧啶[第1-4天静脉注射1 g/m2/天]的两个3周周期或表阿霉素，顺铂，和卡培他滨（ECX; 4个3周周期，第1天静脉注射表阿霉素[50 mg/m2]和顺铂[60 mg/m2]，在整个4个周期中每日1次卡培他滨[1250 mg/m2]），根据中心和临床疾病分期分层。患者和研究工作人员均未对治疗分配设盲。化疗完成后4-6周内进行两阶段食管切除术和两区域（腹部和胸部）淋巴结切除术。主要结局指标是总生存率，主要和安全性分析在意向治疗人群中进行。本试验已在ISRCTN登记中心（编号01852072）和ClinicalTrials.gov（NCT 00041262）注册，并已完成。在2005年1月13日至2011年10月31日期间，招募了897例患者，其中451例分配至CF组，446例分配至ECX组。截至2016年11月14日，CF组451例患者中有327例（73%）死亡，ECX组446例患者中有302例（68%）死亡。CF组的中位生存期为23.4个月（95% CI 20.6 - 26.3），ECX组为26.1个月（22.5 - 29.7）（风险比0.90（95% CI 0.77 - 1.05，p= 0.19）。未观察到非预期的化疗毒性，中性粒细胞减少症是最常报告的事件（3级或4级中性粒细胞减少症：CF组446例患者中的74例[17%] vs ECX组441例患者中的101例[23%]）。两组术后并发症的患者比例（CF组有数据可用的398人中有224人[56%]，ECX组有数据可用的374人中有233人[62%]; p= 0.089）相似。ECX组1例患者死于疑似治疗相关的血小板减少性脓毒症。与2个周期的CF相比，4个周期的新辅助ECX并没有增加生存率，不能被认为是标准治疗。我们的研究涉及大量中心和详细的方案，对仅限于食管和胃食管交界处腺癌（Siewert 1型和2型）患者人群的健康相关生活质量进行全面的前瞻性评估。正在研究替代化疗方案和新辅助放化疗，以改善食管癌患者的预后。英国癌症研究和伦敦大学学院医学研究理事会临床试验单位。
Neoadjuvant chemotherapy before surgery improves survival compared with surgery alone for patients with oesophageal cancer. The OE05 trial assessed whether increasing the duration and intensity of neoadjuvant chemotherapy further improved survival compared with the current standard regimen. OE05 was an open-label, phase 3, randomised clinical trial. Patients with surgically resectable oesophageal adenocarcinoma classified as stage cT1N1, cT2N1, cT3N0/N1, or cT4N0/N1 were recruited from 72 UK hospitals. Eligibility criteria included WHO performance status 0 or 1, adequate respiratory, cardiac, and liver function, white blood cell count at least 3 × 109 cells per L, platelet count at least 100 × 109 platelets per L, and a glomerular filtration rate at least 60 mL/min. Participants were randomly allocated (1:1) using a computerised minimisation program with a random element and stratified by centre and tumour stage, to receive two cycles of cisplatin and fluorouracil (CF; two 3-weekly cycles of cisplatin [80 mg/m2 intravenously on day 1] and fluorouracil [1 g/m2 per day intravenously on days 1–4]) or four cycles of epirubicin, cisplatin, and capecitabine (ECX; four 3-weekly cycles of epirubicin [50 mg/m2] and cisplatin [60 mg/m2] intravenously on day 1, and capecitabine [1250 mg/m2] daily throughout the four cycles) before surgery, stratified according to centre and clinical disease stage. Neither patients nor study staff were masked to treatment allocation. Two-phase oesophagectomy with two-field (abdomen and thorax) lymphadenectomy was done within 4–6 weeks of completion of chemotherapy. The primary outcome measure was overall survival, and primary and safety analyses were done in the intention-to-treat population. This trial is registered with the ISRCTN registry (number 01852072) and ClinicalTrials.gov (NCT00041262), and is completed. Between Jan 13, 2005, and Oct 31, 2011, 897 patients were recruited and 451 were assigned to the CF group and 446 to the ECX group. By Nov 14, 2016, 327 (73%) of 451 patients in the CF group and 302 (68%) of 446 in the ECX group had died. Median survival was 23·4 months (95% CI 20·6–26·3) with CF and 26·1 months (22·5–29·7) with ECX (hazard ratio 0·90 (95% CI 0·77–1·05, p=0·19). No unexpected chemotherapy toxicity was seen, and neutropenia was the most commonly reported event (grade 3 or 4 neutropenia: 74 [17%] of 446 patients in the CF group vs 101 [23%] of 441 people in the ECX group). The proportions of patients with postoperative complications (224 [56%] of 398 people for whom data were available in the CF group and 233 [62%] of 374 in the ECX group; p=0·089) were similar between the two groups. One patient in the ECX group died of suspected treatment-related neutropenic sepsis. Four cycles of neoadjuvant ECX compared with two cycles of CF did not increase survival, and cannot be considered standard of care. Our study involved a large number of centres and detailed protocol with comprehensive prospective assessment of health-related quality of life in a patient population confined to people with adenocarcinomas of the oesophagus and gastro-oesophageal junction (Siewert types 1 and 2). Alternative chemotherapy regimens and neoadjuvant chemoradiation are being investigated to improve outcomes for patients with oesophageal carcinoma. Cancer Research UK and Medical Research Council Clinical Trials Unit at University College London.