结肠癌（NCCN 2017.V1）终于回答左右半结肠癌之争

来源：丁香园 作者：赖明军

关于原发瘤部位在 mCRC 治疗决策中的作用，也就是业界统称的「左右半之争」是 2015-2016 年度 CRC 领域最热门的话题之一。2017 版 NCCN 指南更新了 RAS 野生型 mCRC 一线靶向治疗的推荐，将抗 EGFR 靶向治疗（西妥昔单抗和帕尼单抗）在一线治疗中的使用「仅限于原发瘤位于左侧结肠者」，并在指南最后面的讨论部分专门增加了一个章节「原发肿瘤部位的价值」来阐述此事。越来越多的证据表明在转移性结直肠癌（mCRC）中，原发瘤的部位可能不但是预后因素，也是 EGFR 抑制剂的疗效预测因素。来自意大利三个中心的 75 例右半 mCRC 患者，一线或后线治疗中接受西妥昔单抗，帕尼单抗或西妥昔单抗 / 伊立替康治疗，根据原发瘤部位分析了疗效。最后结果发现，原发灶在右半的患者没有一例出现客观缓解的，与之相对，原发瘤在左半的患者，客观缓解率为 41%，右半和左半的中位 PFS 分别是 2.3 个月和 6.6 个月。

原发瘤部位对 EGFR 单抗疗效预测的最强有力证据来自 CALGB/SWOG 80405 研究。该研究结果显示对于全 RAS 野生型 mCRC 患者，原发瘤位于右侧（回盲部到肝曲）时，一线治疗接受含贝伐单抗 (Bev) 的治疗患者相较西妥昔单抗 (Cet) 治疗者，具有更长的 OS；而当原发瘤位于左侧时（脾曲到直肠），接受西妥昔单抗治疗者较贝伐单抗治疗者具有更长的 OS。与贝伐单抗相比，左半患者接受西妥昔单抗治疗后 OS 被延长了（39.3 个月对 32.6 个月），但在右半患者中却缩短了（13.6 月对比 29.2 月）。

上述这些以及其他数据提示，原发瘤起源于右侧的 mCRC 患者，如果有任何获益的话，西妥昔单抗和帕尼单抗带来的获益也是微乎其微的。关于整个结肠中各种分子亚型的非随机分布，专家组相信原发瘤部位是反映这个特征的一个替代指标，正在进行的对这些研究中标本组织的进一步分析将有助于了解左右半的生物学特征差异，来更好解释目前我们已经观察到的 EGFR 靶向药物在左右半 mCRC 患者中的疗效差异。

附录文献：

The Role of Primary Tumor Sidedness （from NCCN Colon 2017 V1 Discussion）

A growing body of data has shown that the location of the primary tumor can be both prognostic and predictive of response to EGFR inhibitors in metastatic colorectal cancer.675-682 For example, outcomes of 75 patients with metastatic colorectal cancer treated with cetuximab, panitumumab,

or cetuximab/irinotecan in first-line or subsequent lines of therapy at 3 Italian centers were analyzed based on sidedness of the primary tumor.676 No responses were seen in the patients with right-sided primary tumors compared with a response rate of 41% in those with leftsided primaries (P = .003). The median PFS was 2.3 and 6.6 months in patients with right-sided and left-sided tumors, respectively (HR, 3.97; 95% CI, 2.09-7.53; P < .0001).

The strongest evidence for the predictive value of primary tumor sidedness and response to EGFR inhibitors is in the first-line treatment of patients in the phase III CALGB/SWOG 80405 trial.682,683 The study showed that patients with all RAS wild-type, right-sided primary tumors (cecum to hepatic flexure) had longer OS if treated with bevacizumab than if treated with cetuximab in first line (HR, 1.36; 95% CI, 0.93–1.99; P = .10), whereas patients with all RAS wild-type, left-sided primary tumors (splenic flexure to rectum) had longer OS if treated with cetuximab than if treated with bevacizumab (HR, 0.77; 95% CI, 0.59–0.99; P = 0.04).683 OS was prolonged with cetuximab versus bevacizumab in the left-sided primary group (39.3 months vs. 32.6 months) but shortened in the right-sided primary group (13.6 months vs. 29.2 months).

These and other data suggest that cetuximab and panitumumab confer little if any benefit to patients with metastatic colorectal cancer if the primary tumor originated on the right side.675,676,678,679 The panel believes that primary tumor sidedness is a surrogate for the non-random distribution of molecular subtypes across the colon and that the ongoing analysis of tumor specimens from the study will enable a better understanding of the biologic explanation of the observed difference in response to EGFR inhibitors. Until that time, only patients whose primary tumors originated on the left side of the colon (splenic flexure to rectum) should be offered cetuximab or panitumumab in the first-line treatment of metastatic disease. Evidence also suggests that sidedness is predictive of response to EGFR inhibitors in subsequent lines of therapy,675,676,679 but the panel awaits more definitive studies. Until such data are available, all patients with RAS wild-type tumors can be considered for panitumumab or cetuximab in subsequent lines of therapy if neither was previously given.

参考文献：

675. Brule SY, Jonker DJ, Karapetis CS, et al. Location of colon cancer (right-sided versus left-sided) as a prognostic factor and a predictor of benefit from cetuximab in NCIC CO.17. Eur J Cancer 2015;51:1405-1414. Available at: http://www.ncbi.nlm.nih.gov/pubmed/25979833.

676. Moretto R, Cremolini C, Rossini D, et al. Location of primary tumor and benefit from anti-epidermal growth factor receptor monoclonal antibodies in patients with RAS and BRAF wild-type metastatic colorectal cancer. Oncologist 2016. Available at: http://www.ncbi.nlm.nih.gov/pubmed/27382031.

677. Loupakis F, Yang D, Yau L, et al. Primary tumor location as a prognostic factor in metastatic colorectal cancer. J Natl Cancer Inst 2015;107. Available at: http://www.ncbi.nlm.nih.gov/pubmed/25713148.

678. Lee MS, Advani SM, Morris J, et al. Association of primary (1{degrees}) site and molecular features with progression-free survival (PFS) and overall survival (OS) of metastatic colorectal cancer (mCRC) after anti-epidermal growth factor receptor ({alpha}EGFR) therapy [abstract]. ASCO Meeting Abstracts 2016;34:3506. Available at: http://meetinglibrary.asco.org/content/171167-176.

679. Chen KH, Shao YY, Chen HM, et al. Primary tumor site is a useful predictor of cetuximab efficacy in the third-line or salvage treatment of KRAS wild-type (exon 2 non-mutant) metastatic colorectal cancer: a nationwide cohort study. BMC Cancer 2016;16:327. Available at: http://www.ncbi.nlm.nih.gov/pubmed/27221731.

680. Warschkow R, Sulz MC, Marti L, et al. Better survival in right-sided versus left-sided stage I - III colon cancer patients. BMC Cancer 2016;16:554. Available at: http://www.ncbi.nlm.nih.gov/pubmed/27464835.

681. Schrag D, Weng S, Brooks G, et al. The relationship between primary tumor sidedness and prognosis in colorectal cancer [abstract]. ASCO Meeting Abstracts 2016;34:3505. Available at: http://meetinglibrary.asco.org/content/167366-176.

682. Venook AP, Niedzwiecki D, Innocenti F, et al. Impact of primary (1{o}) tumor location on overall survival (OS) and progression-free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC): Analysis of CALGB/SWOG 80405 (Alliance) [abstract]. ASCO Meeting Abstracts 2016;34:3504. Available at: http://meetinglibrary.asco.org/content/161936-176.

683. Venook AP, Niedzwiecki D, Innocenti F, et al. Impact of primary (1o) tumor location on Overall Survival (OS) and Progression Free Survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC): Analysis of All RAS wt patients on CALGB / SWOG 80405 (Alliance) [abstract]. ESMO Congress 2016.