Oxaliplatin added to fluorouracil-based preoperative chemoradiotherapy and postoperative chemotherapy of locally advanced rectal cancer (the German CAO/ARO/AIO-04 study): final results of the multicentre, open-label, randomised, phase 3 trial
Oxaliplatin added to fluorouracil-based preoperative chemoradiotherapy and postoperative chemotherapy of locally advanced rectal cancer (the German CAO/ARO/AIO-04 study): final results of the multicentre, open-label, randomised, phase 3 trial
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DOI：
10.1016/s1470-2045(15)00159-x
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发表时间：
2015-08-01
期刊：
影响因子：
51.1
通讯作者：
Seipelt, G.
中科院分区：
文献类型：
--
作者：
Roedel, Claus;Graeven, Ullrich;Seipelt, G.
德国CAO/ARO/AIO-94试验确立了术前输注氟尿嘧啶放化疗+全肠系膜切除手术+术后氟尿嘧啶化疗作为局部晚期直肠癌的标准联合治疗方式。在这里，我们比较了先前建立的方案与在术前放化疗和术后化疗中添加奥沙利铂的研究方案。在这项多中心、开放标签、随机的3期研究中，我们将临床分期为cT3-4或任何淋巴结阳性疾病的直肠腺癌患者随机分为两组：对照组接受以氟尿嘧啶为基础的标准联合治疗，术前放疗剂量为50.4 Gy，分28个分量，加输注氟尿嘧啶（1000 mg/m(2)，第1-5天和第29-33天），随后进行手术，并在第1-5天和第29天给予4个周期的氟尿嘧啶（500 mg/m(2)）；术前放疗剂量为50.4 Gy，分28组，加输注氟尿嘧啶（250 mg/m(2)，第1-14天和22-35天）和奥沙利铂（50 mg/m(2)，第1、8、22和29天），随后进行手术和8个周期的奥沙利铂（100 mg/m(2)，第1和15天），亚叶酸素（400 mg/m(2)，第1和15天），输注氟尿嘧啶（2400 mg/m(2)，第1-2天和15-16天）。随机化使用计算机生成的块随机化代码进行分层，按中心、临床T类别（cT1-3 vs cT4）和临床N类别（cN0 vs cN1-2）分层，无屏蔽。主要终点是无病生存期，定义为随机化和原发肿瘤非根治性手术（R2切除术）之间的时间，R0/1切除术后局部区域复发，转移性疾病或进展，或任何原因导致的死亡，以先发生者为例。生存率和累积复发率分析遵循意向治疗原则；毒性分析包括所有接受治疗的患者。该试验的患者入组已完成，随访正在进行中。本研究已在ClinicalTrials.gov注册，注册号为NCT00349076。在最初纳入的1265例患者中，1236例可评估（研究组613例，对照组623例）。中位随访50个月（IQR 38-61），研究组3年无病生存率为75.9% (95% CI 72.4-79.5)，对照组为71.2% (95% CI 67.6-74.9)（风险比[HR] 0.79, 95% CI 0.64-0.98; p=0.03）。607例在放化疗期间实际接受氟尿嘧啶和奥沙利铂的患者中有144例（24%）发生术前3-4级毒性反应，625例实际接受氟尿嘧啶放化疗的患者中有128例（20%）发生术前3-4级毒性反应。在445例实际接受氟尿嘧啶辅助治疗、亚叶酸钙和奥沙利铂的患者中，158例（36%）有3-4级毒性作用，而在470例实际接受氟尿嘧啶辅助治疗的患者中，170例（36%）有3-4级毒性作用。在接受方案规定的术前和术后治疗的患者中，研究组445例患者中有112例（25%）发生晚期3-4级不良事件，对照组470例患者中有100例（21%）发生不良事件。与我们之前基于氟尿嘧啶的联合治疗方案（基于CAO/ARO/AIO-94）相比，在基于氟尿嘧啶的新辅助放化疗和辅助化疗中加入奥沙利铂（本试验使用的剂量和强度）可显著提高临床分期cT3-4或cN1-2直肠癌患者的无病生存期。CAO/ARO/AIO-04建立的方案可视为局部晚期直肠癌患者新的治疗选择。
Background Preoperative chemoradiotherapy with infusional fluorouracil, total mesorectal excision surgery, and postoperative chemotherapy with fluorouracil was established by the German CAO/ARO/AIO-94 trial as a standard combined modality treatment for locally advanced rectal cancer. Here we compare the previously established regimen with an investigational regimen in which oxaliplatin was added to both preoperative chemoradiotherapy and postoperative chemotherapy.Methods In this multicentre, open-label, randomised, phase 3 study we randomly assigned patients with rectal adenocarcinoma, clinically staged as cT3-4 or any node-positive disease, to two groups: a control group receiving standard fluorouracil-based combined modality treatment, consisting of preoperative radiotherapy of 50.4 Gy in 28 fractions plus infusional fluorouracil (1000 mg/m(2) on days 1-5 and 29-33), followed by surgery and four cycles of bolus fluorouracil (500 mg/m(2) on days 1-5 and 29); or to an investigational group receiving preoperative radiotherapy of 50.4 Gy in 28 fractions plus infusional fluorouracil (250 mg/m(2) on days 1-14 and 22-35) and oxaliplatin (50 mg/m(2) on days 1, 8, 22, and 29), followed by surgery and eight cycles of oxaliplatin (100 mg/m(2) on days 1 and 15), leucovorin (400 mg/m(2) on days 1 and 15), and infusional fluorouracil (2400 mg/m(2) on days 1-2 and 15-16). Randomisation was done with computer-generated block-randomisation codes stratified by centre, clinical T category (cT1-3 vs cT4), and clinical N category (cN0 vs cN1-2) without masking. The primary endpoint was disease-free survival, defined as the time between randomisation and non-radical surgery of the primary tumour (R2 resection), locoregional recurrence after R0/1 resection, metastatic disease or progression, or death from any cause, whichever occurred first. Survival and cumulative incidence of recurrence analyses followed the intention-to-treat principle; toxicity analyses included all patients treated. Enrolment of patients in this trial is completed and follow-up is ongoing. This study is registered with ClinicalTrials.gov, number NCT00349076.Findings Of the 1265 patients initially enrolled, 1236 were assessable (613 in the investigational group and 623 in the control group). With a median follow-up of 50 months (IQR 38-61), disease-free survival at 3 years was 75.9% (95% CI 72.4-79.5) in the investigational group and 71.2% (95% CI 67.6-74.9) in the control group (hazard ratio [HR] 0.79, 95% CI 0.64-0.98; p=0.03). Preoperative grade 3-4 toxic effects occurred in 144 (24%) of 607 patients who actually received fluorouracil and oxaliplatin during chemoradiotherapy and in 128 (20%) of 625 patients who actually received fluorouracil chemoradiotherapy. Of 445 patients who actually received adjuvant fluorouracil and leucovorin and oxaliplatin, 158 (36%) had grade 3-4 toxic effects, as did 170 (36%) of 470 patients who actually received adjuvant fluorouracil. Late grade 3-4 adverse events in patients who received protocol-specified preoperative and postoperative treatment occurred in 112 (25%) of 445 patients in the investigational group, and in 100 (21%) of 470 patients in the control group.Interpretation Adding oxaliplatin to fluorouracil-based neoadjuvant chemoradiotherapy and adjuvant chemotherapy (at the doses and intensities used in this trial) significantly improved disease-free survival of patients with clinically staged cT3-4 or cN1-2 rectal cancer compared with our former fluorouracil-based combined modality regimen (based on CAO/ARO/AIO-94). The regimen established by CAO/ARO/AIO-04 can be deemed a new treatment option for patients with locally advanced rectal cancer.