Department of Gastroenterology and Digestive Oncology, Paris Descartes University, Hôpital Européen Georges Pompidou, Paris, France.
Medical Oncology Department, Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Barcelona, Spain.
Lancet Oncol. 2014 Jul;15(8):862-73. doi: 10.1016/S1470-2045(14)70227-X. Epub 2014 Jun 11.
Since the 1990s, fluorouracil-based adjuvant chemotherapy has significantly reduced the risk of tumour recurrence in patients with stage III colon cancer. We aimed to assess whether the addition of cetuximab to standard adjuvant oxaliplatin, fluorouracil, and leucovorin chemotherapy (FOLFOX4) in patients with stage III colon cancer improved disease-free survival (DFS).
For this open-label, randomised phase 3 study done in nine European countries, we enrolled patients through an interactive voice response system to the central randomisation centre, with a central stratified permuted block randomisation procedure. We randomly assigned patients with resected (R0) stage III disease (1:1) to receive 12 cycles of FOLFOX4 twice a week with or without cetuximab. Patients were stratified by N-status (N1 vs N2), T-status (T1-3 vs T4), and obstruction or perforation status (no obstruction and no perforation vs obstruction or perforation or both). A protocol amendment (applied in June, 2008, after 2096 patients had been randomly assigned to treatment-restricted enrolment to patients with tumours wild-type at codons 12 and 13 in exon 2 of the KRAS gene (KRAS exon 2 wild-type). The primary endpoint was DFS. Analysis was intention to treat in all patients with KRAS exon 2 wild-type tumours. The study is registered at EudraCT, number 2005-003463-23.
Between Dec 22, 2005, and Nov 5, 2009, 2559 patients from 340 sites in Europe were randomly assigned. Of these patients, 1602 had KRAS exon 2 wild-type tumours (intention-to-treat population), 791 in the FOLFOX4 plus cetuximab group and 811 in the FOLFOX4 group. Median follow-up was 3·3 years (IQR 3·2-3·4). In the experimental and control groups, DFS was similar in the intention-to-treat population (hazard ratio [HR] 1·05; 95% CI 0·85-1·29; p=0·66), and in patients with KRAS exon 2/BRAF wild-type (n=984, HR 0·99; 95% CI 0·76-1·28) or KRAS exon 2-mutated tumours (n=742, HR 1·06; 95% CI 0·82-1·37). We noted heterogeneous responses to the addition of cetuximab in preplanned subgroup analyses. Grade 3 or 4 acne-like rash (in 209 of 785 patients [27%] vs four of 805 [<1%]), diarrhoea (113 [14%] vs 70 [9%]), mucositis (63 [8%] vs 10 [1%]), and infusion-related reactions (55 [7%] vs 30 [4%]) were more frequent in patients treated with FOLFOX4 plus cetuximab than in those patients who received FOLFOX4 alone.
The addition of cetuximab to FOLFOX4 did not improve DFS compared with FOLFOX4 alone in patients with KRAS exon 2 wild-type resected stage III colon cancer. This trial cannot conclude on the benefit of cetuximab in the studied population, but the heterogeneity of response suggests that further investigation of the role of FOLFOX4 plus cetuximab in specific patient subgroups is warranted.
Fédération Francophone de Cancérologie Digestive (FFCD), Merck KGaA, and Sanofi-Aventis.
自 20 世纪 90 年代以来，氟尿嘧啶为基础的辅助化疗显著降低了 III 期结肠癌患者的肿瘤复发风险。我们旨在评估在 III 期结肠癌患者中，西妥昔单抗联合标准辅助奥沙利铂、氟尿嘧啶和亚叶酸（FOLFOX4）化疗是否能改善无病生存（DFS）。
这是一项在 9 个欧洲国家进行的开放性、随机 3 期研究，我们通过中央随机化中心的交互式语音应答系统招募患者，采用中央分层随机分组方案进行分层。我们将 R0 期 III 期疾病（1:1）的患者随机分配接受 12 个周期的 FOLFOX4 每周两次，联合或不联合西妥昔单抗。患者按 N 状态（N1 与 N2）、T 状态（T1-3 与 T4）、梗阻或穿孔状态（无梗阻和穿孔与梗阻或穿孔或两者兼有）分层。在 2008 年 6 月应用了一项方案修正案（应用于 2096 名患者后），仅限于 KRAS 基因外显子 2 密码子 12 和 13 野生型（KRAS 外显子 2 野生型）的肿瘤患者。主要终点是 DFS。所有 KRAS 外显子 2 野生型肿瘤患者均进行意向治疗分析。该研究在 EudraCT 注册，编号为 2005-003463-23。
2005 年 12 月 22 日至 2009 年 11 月 5 日，欧洲 340 个地点的 2559 名患者被随机分配。这些患者中有 1602 名患者的 KRAS 外显子 2 野生型肿瘤（意向治疗人群），791 名患者接受 FOLFOX4 联合西妥昔单抗治疗，811 名患者接受 FOLFOX4 治疗。中位随访时间为 3.3 年（IQR 3.2-3.4）。在实验组和对照组中，意向治疗人群的 DFS 相似（风险比[HR] 1.05；95%CI 0.85-1.29；p=0.66），在 KRAS 外显子 2/BRAF 野生型（n=984，HR 0.99；95%CI 0.76-1.28）或 KRAS 外显子 2 突变型肿瘤（n=742，HR 1.06；95%CI 0.82-1.37）患者中也是如此。我们在预先计划的亚组分析中注意到西妥昔单抗添加的反应存在异质性。3 级或 4 级痤疮样皮疹（785 名患者中的 209 例[27%]与 805 名患者中的 4 例[1%]）、腹泻（113 例[14%]与 70 例[9%]）、黏膜炎（63 例[8%]与 10 例[1%]）和输注相关反应（55 例[7%]与 30 例[4%]）在接受 FOLFOX4 联合西妥昔单抗治疗的患者中比单独接受 FOLFOX4 治疗的患者更常见。
与单独使用 FOLFOX4 相比，西妥昔单抗联合 FOLFOX4 并未改善 KRAS 外显子 2 野生型 III 期结肠癌患者的 DFS。该试验不能确定西妥昔单抗在研究人群中的获益，但反应的异质性表明，需要进一步研究 FOLFOX4 联合西妥昔单抗在特定患者亚组中的作用。
法国消化肿瘤学联合会（FFCD）、默克公司和赛诺菲-安万特公司。
