Objective: To identify the prognostic factors in metastatic colorectal cancer (mCRC) patients treated with cetuximab and establish a prognostic nomogram and validate its accuracy. Methods: A retrospective case-control study was conducted. Patients were selected as following criteria: patients with metastatic colorectal cancer(mCRC), which primary site confirmed by pathology and metastatic lesions confirmed by CT or MRI with at least one measurable and evaluable target lesion; patients' expected survival longer than 3 months; Eastern Cooperative Oncology Group (ECOG) score between 0 to 2; patients have signed informed consent; both KRAS and NRAS genes were wild-type; and at least 2 cycles of cetuximab combined with chemotherapy as the first-line regimen. Patients who met the following criteria were excluded: patients with incomplete clinicopathological and follow-up data; patients with severe diseases of vital organs such as heart, brain, lung, kidney, or other advanced malignant tumors; patients without informed consent. According to the above criteria, clinicopathological data of 95 patients with mCRC admitted in the Department of Medical Oncology, the Second Affiliated Hospital, Zhejiang University School of Medicine for first-line treatment with cetuximab from January 2010 to January 2017 were analyzed retrospectively. The Cox proportional hazards model was used to analyze the clinicopathological factors to determine the independent prognostic factors for progression-free survival(PFS). The R software was adopted to establish a prognostic nomogram model. Then, the nomograms of 6-month, 12-month and 18-month progression-free survivals (PFS) were drawn, and compared with the reality. The internal validation and accuracy of the nomogram were determined by the Bootstrap method and also the calculated concordance index (C-index). Results: The median follow-up time was 16.5 (2-43) months and the median PFS was 8.5 months. PFS at 6-,12- and 18-month was 73.7%, 35.8%, and 17.9%, respectively. ECOG score of 1-2 (HR=5.733, 95% CI:2.408-13.649, P<0.001), primary tumor was located in the ileocecal region (HR=5.880, 95% CI:1.645-21.023, P=0.006), Ki-67 index ≥45% (HR=3.574,95% CI:1.403-9.108,P=0.008), baseline D-dimer level ≥345 mg/L (HR=2.536,95% CI:1.531-7.396, P=0.012), NLR≥2.8 (HR=5.573,95% CI:2.107-14.740,P=0.001) and the combined treatment for FOLFOX (HR=0.465, 95% CI: 0.265-0.817, P=0.008) were independent risk factors for PFS of mCRC patients (all P<0.05). These independent risk factors were taken into account to construct a nomogram prediction model. The bootstrap method was used to perform internal validation, and the C-index of the nomogram prediction model in this study was 0.67 (95% CI: 0.64~0.71). The 6-, 12- and 18-month PFS predicted by the nomogram were consistent with the actual values. Conclusion: The nomogram model constructed by ECOG score, primary tumor site, Ki-67 index, baseline D-dimer level, baseline NLR and chemotherapy regimen may predict the prognosis of mCRC patients treated with cetuximab more accurately and individually, which can assist clinicians in making treatment decisions.
目的： 建立西妥昔单抗治疗转移性结直肠癌（mCRC）患者的预后列线图预测模型并进行验证。 方法： 采用回顾性病例对照研究方法。患者入选标准：病理证实为结直肠腺癌，通过CT或MRI检查证实存在转移灶，且有至少一处可测量评价的靶病灶的病例；预计生存期≥3个月；美国东部肿瘤协助组（ECOG）评分0~2分；签署知情同意书；KRAS和NRAS基因检测均为野生型，均接受至少2个周期的西妥昔单抗联合化疗，且该治疗方案作为一线方案。排除标准：临床病理学及随访资料不完整者，合并心、脑、肺、肾等重要器官严重疾病或合并其他晚期恶性肿瘤者以及未签署知情同意者。根据以上标准，回顾性收集2010年1月至2017年1月期间，浙江大学医学院附属第二医院肿瘤内科收治的接受西妥昔单抗一线治疗的95例mCRC患者的临床及病理学资料。应用Cox回归模型对可能影响无复发生存率（PFS）的临床病理学因素进行单因素及多因素分析，确定独立预后因素；应用R软件建立列线图预测模型，绘制校准曲线并与实际观察情况比较。用Bootstrap法进行内部验证，计算一致性指数（C-index）评估模型准确性。 结果： 全组中位随访16.5（2~43）个月，中位PFS为8.5个月，6个月、12个月及18个月PFS分别为73.7%、35.8%和17.9%。ECOG评分1~2分（HR=5.733，95% CI：2.408~13.649，P<0.001）、肿瘤原发部位为回盲部（HR=5.880，95% CI：1.645~21.023，P=0.006）、Ki-67指数≥45%（HR=3.574，95% CI：1.403~9.108，P=0.008）、基线D-二聚体水平≥345 mg/L（HR=2.536，95% CI：1.531~7.396，P=0.012）以及中性粒细胞淋巴细胞比值（NLR）≥2.8（HR=5.573，95% CI：2.107~14.740，P=0.001）是影响本组mCRC患者PFS的独立危险因素，联合治疗方案为FOLFOX（HR=0.465，95% CI：0.265~0.817，P=0.008）是影响本组mCRC患者PFS的独立保护性因素（均P<0.05）。将以上影响本组mCRC患者PFS的独立因素，构建列线图预测模型。使用bootstrap方法执行内部验证，本研究列线图预测模型的一致性指数（C-index）为0.67（95% CI：0.64~0.71）。校正曲线表明预测的6个月、12个月及18个月PFS率与实际观察情况符合。 结论： 将ECOG评分、肿瘤原发部位、Ki-67指数、基线D-二聚体水平、基线NLR以及化疗方案构建的列线图模型，可较准确个体化地预测西妥昔单抗治疗mCRC患者的预后，可以辅助临床医生进行治疗决策。.
Keywords: Cetuximab; Colorectal neoplasms, metastatic; Nomogram; Prognosis.