JAMA：结肠癌手术后在化疗中添加药物不会改善其存活率

4月4日，国际著名杂志《美国医学会杂志》JAMA上的一项研究披露，在对III期结肠癌病人手术后的药物治疗方案中添加西妥昔单抗不会导致病人的无病存活率的改善。

手术切除III期结肠癌的患者的治愈机会为50%。多个试验已经确认手术后化疗在减少癌症复发风险中的裨益。根据文章的背景资料：“与先前的氟尿嘧啶和甲酰四氢叶酸的标准疗法相比，药物甲酰四氢叶酸、氟尿嘧啶和奥沙利铂（FOLFOX或略微不同的方法FLOX）在无病存活率和总体存活率上都具有明显的裨益。”

在转移性结肠直肠癌的情况下，药物西妥昔单抗和帕尼单抗，在单独使用及与化疗合并使用时提供了比单独化疗时所获得的裨益要更多。文章的作者写道：“然而，这一裨益限于那些表达有与突变形式的KRAS基因相对的野生型 [一个与任何突变衍生体相比时被用作一种标准参照的肿瘤株] KRAS基因的肿瘤的病人。”

明尼苏达州罗切斯特市梅奥诊所的Steven R. Alberts， M.D.及其同事开展了一项研究，目的是在切除了III期野生型KRAS结肠癌的病人中，对将西妥昔单抗添加到一个改良了的第6版FOLFOX治疗方案 (mFOLFOX6) 中的可能得到的裨益进行评估。病人纳入该研究始于2004年2月并在2009年11月永久性地停止，因为在第二次计划的中期分析之后显示，西妥昔单抗组的无病存活率超过仅用mFOLFOX6组的无病存活率的概率很低。

研究人员发现，在添加西妥昔单抗时，该试验没有显示裨益。仅使用mFOLFOX6疗法的野生型KRAS患者的3年无病存活率为74.6%，与其相比，添加西妥昔单抗的3年无病存活率为71.5%；以及在突变KRAS组中的67.1% 比 65.0%；在任何单个的亚组中都没有显示添加西妥昔单抗具有裨益的证据。另外，复发时间及总体存活率在治疗组之间都没有明显的差异。

文章的作者写道：“在所有的病人中，使用西妥昔单抗的患者具有3级或更高的不良反应事件发生率（72.5% 比52.3%）及无法完成12个周期的治疗（33% 比23%）。在年龄为70岁或以上的病人中观察到了毒性的增加及在所有结果中的更大的有害差异。”

研究人员补充说，在佐剂使用的情况中，mFOLFOX6加西妥昔单抗缺乏益处的原因仍不清楚。

文章的作者写道：“在这一随机化的3期试验中，在那些切除了表达野生型KRAS突变的III期结肠癌患者的mFOLFOX6疗法中添加西妥昔单抗没有改善无病或总体存活率，这与原先的在转移性结肠直肠癌患者中进行FOLFOX结合西妥昔单抗的研究的结果是截然不同的。人们需要用新的方法来发现可能在佐剂治疗中有裨益的药物，因为如在我们的试验中所显示的，在转移性癌症的情况下有前途的活性并不会转化成佐剂疗法的裨益，从而强调了进行临床试验的重要性。”（生物谷Bioon.com）

doi:10.1001/jama.2012.385
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Effect of Oxaliplatin, Fluorouracil, and Leucovorin With or Without Cetuximab on Survival Among Patients With Resected Stage III Colon Cancer

Steven R. Alberts, MD; Daniel J. Sargent, PhD; Suresh Nair, MD; Michelle R. Mahoney, MS; Margaret Mooney, MD; Stephen N. Thibodeau, PhD; Thomas C. Smyrk, MD; Frank A. Sinicrope, MD; Emily Chan, MD, PhD; Sharlene Gill, MD; Morton S. Kahlenberg, MD; Anthony F. Shields, MD, PhD; James T. Quesenberry, MD; Thomas A. Webb, MD; Gist H. Farr Jr, MD; Barbara A. Pockaj, MD; Axel Grothey, MD; Richard M. Goldberg, MD

Context 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.

Objective 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.

Design, Setting, and Participants 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.

Main Outcome Measures Disease-free survival in patients with wild-type KRAS mutations. Secondary end points included overall survival and toxicity.

Results 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.

Conclusion 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.

Trial Registration clinicaltrials.gov Identifier: NCT00079274