Epidemiology Program, Loma Linda University School of Public Health, Loma Linda, California.
Division of Surgical Oncology, Department of Surgery, Loma Linda University School of Medicine, Loma Linda, California.
JAMA Surg. 2018 Jan 1;153(1):60-67. doi: 10.1001/jamasurg.2017.3466.
Biologic therapy (BT) (eg, bevacizumab or cetuximab) is increasingly used to treat metastatic colorectal cancer (mCRC). Recent investigations have suggested that right- or left-sided primary tumor origin affects survival and response to BT.
To evaluate the association of tumor origin with mortality in a diverse population-based data set of patients receiving systemic chemotherapy (SC) and bevacizumab or cetuximab for mCRC.
DESIGN, SETTING, AND PARTICIPANTS: This population-based nonconcurrent cohort study of statewide California Cancer Registry data included all patients aged 40 to 85 years diagnosed with mCRC and treated with SC only or SC plus bevacizumab or cetuximab from January 1, 2004, through December 31, 2014. Patients were stratified by tumor origin in the left vs right sides.
Treatment with SC or SC plus bevacizumab or cetuximab.
Mortality hazards by tumor origin (right vs left sides) were assessed for patients receiving SC alone or SC plus bevacizumab or cetuximab. Subgroup analysis for patients with wild-type KRAS tumors was also performed.
A total of 11 905 patients with mCRC (6713 men [56.4%] and 5192 women [43.6%]; mean [SD] age, 60.0 [10.9] years) were eligible for the study. Among these, 4632 patients received SC and BT. Compared with SC alone, SC plus bevacizumab reduced mortality among patients with right- and left-sided mCRC, whereas SC plus cetuximab reduced mortality only among patients with left-sided tumors and was associated with significantly higher mortality for right-sided tumors (hazard ratio [HR], 1.31; 95% CI, 1.14-1.51; P < .001). Among patients treated with SC plus BT, right-sided tumor origin was associated with higher mortality among patients receiving bevacizumab (HR, 1.31; 95% CI, 1.25-1.36; P < .001) and cetuximab (HR, 1.88; 95% CI, 1.68-2.12; P < .001) BT, compared with left-sided tumor origin. In patients with wild-type KRAS tumors (n = 668), cetuximab was associated with reduced mortality among only patients with left-sided mCRC compared with bevacizumab (HR, 0.75; 95% CI, 0.63-0.90; P = .002), whereas patients with right-sided mCRC had more than double the mortality compared with those with left-sided mCRC (HR, 2.44; 95% CI, 1.83-3.25, P < .001).
Primary tumor site is associated with response to BT in mCRC. Right-sided primary tumor location is associated with higher mortality regardless of BT type. In patients with wild-type KRAS tumors, treatment with cetuximab benefited only those with left-sided mCRC and was associated with significantly poorer survival among those with right-sided mCRC. Our results underscore the importance of stratification by tumor site for current treatment guidelines and future clinical trials.
生物疗法（BT）（例如贝伐珠单抗或西妥昔单抗）越来越多地用于治疗转移性结直肠癌（mCRC）。最近的研究表明，原发肿瘤的左右侧起源影响生存和对 BT 的反应。
在一个基于人群的、接受系统化疗（SC）和贝伐珠单抗或西妥昔单抗治疗 mCRC 的患者的多样化数据集内，评估肿瘤起源与死亡率之间的关联。
设计、地点和参与者：这项基于人群的非同期队列研究使用了加利福尼亚癌症登记处的数据，纳入了所有年龄在 40 岁至 85 岁之间、诊断为 mCRC 且仅接受 SC 或 SC 联合贝伐珠单抗或西妥昔单抗治疗的患者，时间为 2004 年 1 月 1 日至 2014 年 12 月 31 日。根据肿瘤起源（左侧与右侧）对患者进行分层。
单独使用 SC 或联合使用 SC 加贝伐珠单抗或西妥昔单抗治疗。
单独接受 SC 或 SC 联合贝伐珠单抗或西妥昔单抗治疗的患者的肿瘤起源（右侧与左侧）的死亡率风险。对野生型 KRAS 肿瘤患者也进行了亚组分析。
共有 11905 名 mCRC 患者（6713 名男性[56.4%]和 5192 名女性[43.6%]；平均[标准差]年龄为 60.0[10.9]岁）符合研究条件。其中 4632 名患者接受了 SC 和 BT。与单独接受 SC 相比，SC 联合贝伐珠单抗降低了左右侧 mCRC 患者的死亡率，而 SC 联合西妥昔单抗仅降低了左侧肿瘤患者的死亡率，并且与右侧肿瘤患者的死亡率显著升高相关（危险比[HR]，1.31；95%CI，1.25-1.36；P<.001）。在接受 SC 联合 BT 治疗的患者中，右侧肿瘤起源与接受贝伐珠单抗（HR，1.31；95%CI，1.25-1.36；P<.001）和西妥昔单抗（HR，1.88；95%CI，1.68-2.12；P<.001）治疗的患者的死亡率较高相关，而左侧肿瘤起源的患者的死亡率较低。在野生型 KRAS 肿瘤患者（n=668）中，与贝伐珠单抗相比，西妥昔单抗仅在左侧 mCRC 患者中降低了死亡率（HR，0.75；95%CI，0.63-0.90；P=.002），而右侧 mCRC 患者的死亡率是左侧 mCRC 患者的两倍多（HR，2.44；95%CI，1.83-3.25，P<.001）。
原发肿瘤部位与 mCRC 对 BT 的反应相关。无论 BT 类型如何，右侧原发肿瘤部位与更高的死亡率相关。在野生型 KRAS 肿瘤患者中，西妥昔单抗治疗仅使左侧 mCRC 患者受益，并且与右侧 mCRC 患者的生存率显著降低相关。我们的研究结果强调了根据肿瘤部位对当前治疗指南和未来临床试验进行分层的重要性。
