Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis: the New EPOC randomised controlled trial
Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis: the New EPOC randomised controlled trial
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DOI：
10.1016/s1470-2045(14)70105-6
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发表时间：
2014-05-01
期刊：
影响因子：
51.1
通讯作者：
Bridgewater, John
中科院分区：
文献类型：
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作者：
Primrose, John;Falk, Stephen;Bridgewater, John
结直肠癌肝转移的手术治疗导致5年总生存率约为40%。奥沙利铂和氟尿嘧啶联合化疗可增加无进展生存期。在这些化疗方案中添加西妥昔单抗可使具有KRAS外显子2野生型肿瘤基因型的晚期疾病患者的总生存期优势。我们的目的是评估西妥昔单抗的好处，除了标准化疗与可切除的结直肠肝transferase.Methods患者KRAS外显子2野生型可切除或次优切除结直肠肝转移瘤的患者接受化疗或不西妥昔单抗肝切除术前和后1：1的比例随机。使用最小化法进行随机化，包括手术中心、预后不良肿瘤（一种或多种：>= 4个转移灶、N2疾病或原发性肿瘤分化不良）和既往奥沙利铂辅助治疗因素。化疗方案为奥沙利铂85 mg/m2静滴2 h，氟尿嘧啶400 mg/m2静滴5 min，然后每2周重复输注氟尿嘧啶2400 mg/m2 46 h奥沙利铂130 mg/m2静脉滴注2 h，卡培他滨1000 mg/m2口服，每日2次，第1-14天，每3周重复一次（方案2）。接受奥沙利铂辅助治疗的患者可以接受伊立替康180 mg/m2静脉给药，持续30分钟，联合氟尿嘧啶替代奥沙利铂（方案3）。西妥昔单抗静脉给药，剂量为500 mg/m2，每2周一次，方案一和方案三，或负荷剂量为400 mg/m2，随后每周输注250 mg/m2，方案二。主要终点为无进展生存期。这是一项中期分析，截至2012年11月1日，当试验关闭时，符合方案定义的无效标准。研究结果：2007年2月26日至2012年11月1日，128例KRAS外显子2野生型患者随机接受单独化疗，129例接受西妥昔单抗化疗。单药化疗组117例患者和化疗+西妥昔单抗组119例患者被纳入主要分析。单纯化疗组的中位随访时间为21.1个月（95% CI 12.6-33.8），化疗+西妥昔单抗组为19.8个月（12.2-28.7）。总体中位随访时间为20.7个月（95% CI 17.9-25.6）和123/212起（58%）需要观察的事件，化疗联合西妥昔单抗组的无进展生存期显著短于单纯化疗组（14.1个月[95% CI 11.8-15.9] vs 20.5个月[95% CI 160.8-26.7]，风险比1.48，95% CI 1.04-2.12，p=0.030）。最常见的3级或4级不良事件是中性粒细胞计数低（术前单纯化疗组15例[11%] vs化疗+西妥昔单抗组6例[4%];术后4例[4%] vs 8例[8%]），栓塞事件（术前6例[4%] vs 8例[6%];术后2例[2%] vs 3例[3%]），周围神经病变（术前6例[4%] vs 1例[1%];术后2例[2%] vs 4例[4%]），恶心或呕吐（术前4例[3%] vs 6例[4%];术后4例[4%] vs 2例[2%]）和皮疹（术前2例[1%] vs 21例[15%];术后0例vs 8例[8%]）。化疗加西妥昔单抗组有3例死亡（1例间质性肺疾病和肺栓塞，1例支气管肺炎和1例肺栓塞），单独化疗组有1例死亡（心力衰竭），可能与治疗有关。解释在KRAS外显子2野生型患者中，在化疗和手术治疗可手术结直肠肝转移的基础上加用西妥昔单抗可缩短无进展生存期。需要进行转化研究以探索这种意外相互作用的分子基础，但目前不推荐在这种情况下使用西妥昔单抗。
Background Surgery for colorectal liver metastases results in an overall survival of about 40% at 5 years. Progression-free survival is increased with the addition of oxaliplatin and fluorouracil chemotherapy. The addition of cetuximab to these chemotherapy regimens results in an overall survival advantage in patients with advanced disease who have the KRAS exon 2 wild-type tumour genotype. We aimed to assess the benefit of addition of cetuximab to standard chemotherapy in patients with resectable colorectal liver metastasis.Methods Patients with KRAS exon 2 wild-type resectable or suboptimally resectable colorectal liver metastases were randomised in a 1: 1 ratio to receive chemotherapy with or without cetuximab before and after liver resection. Randomisation was done using minimisation with factors of surgical centre, poor prognostic tumour (one or more of: >= 4 metastases, N2 disease, or poor differentiation of primary tumour), and previous adjuvant treatment with oxaliplatin. Chemotherapy consisted of oxaliplatin 85 mg/m(2) intravenously over 2 h and fluorouracil bolus 400 mg/m(2) intravenously over 5 min, followed by a 46 h infusion of fluorouracil 2400 mg/m(2) repeated every 2 weeks (regimen one) or oxaliplatin 130 mg/m(2) intravenously over 2 h and oral capecitabine 1000 mg/m(2) twice daily on days 1-14 repeated every 3 weeks (regimen two). Patients who had received adjuvant oxaliplatin could receive irinotecan 180 mg/m(2) intravenously over 30 min with fluorouracil instead of oxaliplatin (regimen three). Cetuximab was given as an intravenous dose of 500 mg/m(2) every 2 weeks with regimen one and three or a loading dose of 400 mg/m(2) followed by a weekly infusion of 250 mg/m(2) with regimen two. The primary endpoint was progression-free survival. This is an interim analysis, up to Nov 1, 2012, when the trial was closed, having met protocol-defined futility criteria. This trial is registered, ISRCTN22944367.Findings 128 KRAS exon 2 wild-type patients were randomised to chemotherapy alone and 129 to chemotherapy with cetuximab between Feb 26, 2007, and Nov 1, 2012. 117 patients in the chemotherapy alone group and 119 in the chemotherapy plus cetuximab group were included in the primary analysis. The median follow-up was 21.1 months (95% CI 12.6-33.8) in the chemotherapy alone group and 19.8 months (12.2-28.7) in the chemotherapy plus cetuximab group. With an overall median follow-up of 20.7 months (95% CI 17.9-25.6) and 123 (58%) of 212 required events observed, progression-free survival was significantly shorter in the chemotherapy plus cetuximab group than in the chemotherapy alone group (14.1 months [95% CI 11.8-15.9] vs 20.5 months [95% CI 160.8-26.7], hazard ratio 1.48, 95% CI 1.04-2.12, p=0.030). The most common grade 3 or 4 adverse events were low neutrophil count (15 [11%] preoperatively in the chemotherapy alone group vs six [4%] in the chemotherapy plus cetuximab group; four [4%] vs eight [8%] postoperatively), embolic events (six [4%] vs eight [6%] preoperatively; two [2%] vs three [3%] postoperatively), peripheral neuropathy (six [4%] vs one [1%] preoperatively; two [2%] vs four [4%] postoperatively), nausea or vomiting (four [3%] vs six [4%] preoperatively; four [4%] vs two [2%] postoperatively), and skin rash (two [1%] vs 21 [15%] preoperatively; 0 vs eight [8%] postoperatively). There were three deaths in the chemotherapy plus cetuximab group (one interstitial lung disease and pulmonary embolism, one bronchopneumonia, and one pulmonary embolism) and one in the chemotherapy alone group (heart failure) that might have been treatment related.Interpretation Addition of cetuximab to chemotherapy and surgery for operable colorectal liver metastases in KRAS exon 2 wild-type patients results in shorter progression-free survival. Translational investigations to explore the molecular basis for this unexpected interaction are needed but at present the use of cetuximab in this setting cannot be recommended.