Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC 40983): long-term results of a randomised, controlled, phase 3 trial
Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC 40983): long-term results of a randomised, controlled, phase 3 trial
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DOI：
10.1016/s1470-2045(13)70447-9
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发表时间：
2013-11-01
期刊：
影响因子：
51.1
通讯作者：
Gruenberger, Thomas
中科院分区：
文献类型：
--
作者：
Nordlinger, Bernard;Sorbye, Halfdan;Gruenberger, Thomas
背景：EORTC组间试验40983的既往结果显示，对于最初可切除的结直肠癌肝转移患者，与单纯手术相比，FOLFOX 4（亚叶酸、氟尿嘧啶和奥沙利铂）围手术期化疗可延长无进展生存期（PFS）。在这里，我们提出了长期follow-up.Methods后的总生存数据，随机，对照，平行组，3期研究招募来自欧洲，澳大利亚和香港的78家医院的患者。年龄在18-80岁、经组织学证实的结直肠癌和多达4处肝转移的合格患者被随机分配（1：1）至围手术期FOLFOX 4或单纯手术。围手术期FOLFOX 4包括6个14天周期的奥沙利铂85 mg/m2，亚叶酸200 mg/m2（DL型）或100 mg/m2（L型），第1-2天加推注，氟尿嘧啶400 mg/m2（推注）和600 mg/m2（连续22小时输注），术前和术后。患者通过最小化、调整中心和风险评分以及既往辅助化疗至结直肠癌初次手术进行集中随机分配，试验为开放标签。在所有随机分配的患者中，按意向治疗分析总生存期。该试验在ClinicalTrials.gov注册，编号NCT 00006479。结果在2000年10月10日至2004年7月5日期间，364名患者被随机分配到治疗组（每组182名患者，其中每组171名患者合格，每组152名患者接受切除术）。在中位随访8.5年（IQR 7.6-9.5）时，围手术期化疗组有107例（59%）患者死亡，而单纯手术组有114例（63%）患者死亡（HR 0.88，95% CI 0.68-1.14; p=0.34）。在所有随机分配的患者中，围手术期化疗组的中位总生存期为61.3个月（95% CI 51.0-83.4），单纯手术组为54.3个月（41.9-79.4）。5-围手术期化疗组总生存率为51.2%（95%CI 43.6-58.3），单纯手术组为47.8%（40.3-55.0）。围手术期化疗组中有2例患者和单纯手术组中有3例患者死于手术并发症，围手术期化疗组中有1例患者可能死于手术方案治疗的毒性反应。Interpretation我们发现，对于结直肠癌可切除肝转移患者，加用FOLFOX 4围手术期化疗与单纯手术相比，总生存率无差异。然而，既往观察到的PFS获益意味着FOLFOX 4围手术期化疗仍应作为该患者人群的参考治疗。
Background Previous results of the EORTC intergroup trial 40983 showed that perioperative chemotherapy with FOLFOX4 (folinic acid, fluorouracil, and oxaliplatin) increases progression-free survival (PFS) compared with surgery alone for patients with initially resectable liver metastases from colorectal cancer. Here we present overall survival data after long-term follow-up.Methods This randomised, controlled, parallel-group, phase 3 study recruited patients from 78 hospitals across Europe, Australia, and Hong Kong. Eligible patients aged 18-80 years who had histologically proven colorectal cancer and up to four liver metastases were randomly assigned (1:1) to either perioperative FOLFOX4 or surgery alone. Perioperative FOLFOX4 consisted of six 14-day cycles of oxaliplatin 85mg/m(2), folinic acid 200 mg/m(2) (DL form) or 100 mg/m2 (L form) on days 1-2 plus bolus, and fluorouracil 400 mg/m(2) (bolus) and 600 mg/m(2) (continuous 22 h infusion), before and after surgery. Patients were centrally randomised by minimisation, adjusting for centre and risk score and previous adjuvant chemotherapy to primary surgery for colorectal cancer, and the trial was open label. Analysis of overall survival was by intention to treat in all randomly assigned patients. This trial is registered with ClinicalTrials.gov, number NCT00006479.Findings Between Oct 10, 2000, and July 5, 2004, 364 patients were randomly assigned to a treatment group (182 patients in each group, of which 171 per group were eligible and 152 per group underwent resection). At a median follow-up of 8.5 years (IQR 7.6-9.5), 107 (59%) patients in the perioperative chemotherapy group had died versus 114 (63%) in the surgery-only group (HR 0.88, 95% CI 0.68-1.14; p=0.34). In all randomly assigned patients, median overall survival was 61.3 months (95% CI 51.0-83.4) in the perioperative chemotherapy group and 54.3 months (41.9-79.4) in the surgery alone group. 5-year overall survival was 51.2% (95% CI 43.6-58.3) in the perioperative chemotherapy group versus 47.8% (40.3-55.0) in the surgery-only group. Two patients in the perioperative chemotherapy group and three in the surgery-only group died from complications of protocol surgery, and one patient in the perioperative chemotherapy group died possibly as a result of toxicity of protocol treatment.Interpretation We found no difference in overall survival with the addition of perioperative chemotherapy with FOLFOX4 compared with surgery alone for patients with resectable liver metastases from colorectal cancer. However, the previously observed benefit in PFS means that perioperative chemotherapy with FOLFOX4 should remain the reference treatment for this population of patients.