Effect of oxaliplatin, fluorouracil, and leucovorin with or without cetuximab on survival among patients with resected stage III colon cancer: a randomized trial.
Effect of oxaliplatin, fluorouracil, and leucovorin with or without cetuximab on survival among patients with resected stage III colon cancer: a randomized trial.
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DOI：
10.1001/jama.2012.385
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发表时间：
2012-04-04
影响因子：
120.7
通讯作者：
Goldberg, Richard M.
中科院分区：
文献类型：
--
作者：
Alberts, Steven R.;Sargent, Daniel J.;Nair, Suresh;Mahoney, Michelle R.;Mooney, Margaret;Thibodeau, Stephen N.;Smyrk, Thomas C.;Sinicrope, Frank A.;Chan, Emily;Gill, Sharlene;Kahlenberg, Morton S.;Shields, Anthony F.;Quesenberry, James T.;Webb, Thomas A.;Farr, Gist H., Jr.;Pockaj, Barbara A.;Grothey, Axel;Goldberg, Richard M.
亚叶酸钙、氟尿嘧啶和奥沙利铂(FOLFOX)是切除的III期结肠癌的标准辅助治疗。将西妥昔单抗加入FOLFOX对转移性野生型KRAS患者有益，但对突变KRAS结肠癌患者没有好处。目的：评估在改良的第六版FOLFOX方案(MFOLFOX6)中加入西妥昔单抗对切除III期野生型KRAS结肠癌患者的潜在益处。在2004年2月10日至2009年11月25日期间，北美多个机构的2686名年龄在18岁或以上的患者参加了一项随机试验，这些患者接受了切除手术并征得知情同意。主要的随机比较是使用和不使用西妥昔单抗的12个双周周期的mFOLFOX6。集中确定KRAS突变状态。在对1863名(2070名计划中的)具有野生型KRAS的肿瘤患者中发生的48%的预测事件(246/515)进行计划中期分析后，试验停止。共有717名突变的KRAS患者和106名不明原因的KRAS患者入选。2070名野生型KRAS患者提供了90%的能力来检测风险比(HR)为1.33(双侧α=0.05)，并在预期复发的25%、50%和75%后进行了计划的中期疗效分析。野生型KRAS突变患者的无病生存。次要终点包括总存活率和毒性。中位(范围)随访28(0-68)个月。试验表明，加入西妥昔单抗没有任何好处。在野生型KRAS患者中，单用mFOLFOX6的三年无病存活率为74.6%，在加入西妥昔单抗的患者中为71.5%(HR，1.21；95%CI，0.98-1.49；P=.08)；在突变的KRAS患者中，mFOLFOX6的三年无瘤存活率为67.1%，65.0%(HR，1.12；95%CI，0.86-1.46；P=.38)，在任何评估的亚组中都没有显著的好处。在所有患者中，西妥昔单抗的3级或更高的不良事件(72.5%比52.3%；优势比[OR]，2.4；95%CI，2.1-2.8；P<；.001)和未能完成12个周期(33%比23%；OR，1.6；95%CI，1.4-1.9；P<；.001)显著增加。在70岁或70岁以上的患者中观察到毒性增加和所有结果中更大的有害差异。在III期切除结肠癌的患者中，与单独使用mFOLFOX6相比，西妥昔单抗与辅助剂mFOLFOX6联合使用并不能提高无病生存率。
Leucovorin, fluorouracil, and oxaliplatin (FOLFOX) is the standard adjuvant therapy for resected stage III colon cancer. Adding cetuximab to FOLFOX benefits patients with metastatic wild-type KRAS but not mutated KRAS colon cancer. To assess the potential benefit of cetuximab added to the modified sixth version of the FOLFOX regimen (mFOLFOX6) in patients with resected stage III wild-type KRAS colon cancer. A randomized trial of 2686 patients aged 18 years or older at multiple institutions across North America enrolled following resection and informed consent between February 10, 2004, and November 25, 2009. The primary randomized comparison was 12 biweekly cycles of mFOLFOX6 with and without cetuximab. KRAS mutation status was centrally determined. The trial was halted after a planned interim analysis of 48% of predicted events (246/515) occurring in 1863 (of 2070 planned) patients with tumors having wild-type KRAS. A total of 717 patients with mutated KRAS and 106 with indeterminate KRAS were accrued. The 2070 patients with wild-type KRAS provided 90% power to detect a hazard ratio (HR) of 1.33 (2-sided α =.05), with planned interim efficacy analyses after 25%, 50%, and 75% of expected relapses. Disease-free survival in patients with wild-type KRAS mutations. Secondary end points included overall survival and toxicity. Median (range) follow-up was 28 (0–68) months. The trial demonstrated no benefit when adding cetuximab. Three-year disease-free survival for mFOLFOX6 alone was 74.6% vs 71.5% with the addition of cetuximab (HR, 1.21; 95% CI, 0.98–1.49; P=.08) in patients with wild-type KRAS, and 67.1% vs 65.0% (HR, 1.12; 95% CI, 0.86–1.46; P=.38) in patients with mutated KRAS, with no significant benefit in any subgroups assessed. Among all patients, grade 3 or higher adverse events (72.5% vs 52.3%; odds ratio [OR], 2.4; 95% CI, 2.1–2.8; P < .001) and failure to complete 12 cycles (33% vs 23%; OR, 1.6; 95% CI, 1.4–1.9; P < .001) were significantly higher with cetuximab. Increased toxicity and greater detrimental differences in all outcomes were observed in patients aged 70 years or older. Among patients with stage III resected colon cancer, the use of cetuximab with adjuvant mFOLFOX6 compared with mFOLFOX6 alone did not result in improved disease-free survival.
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