Abstract: Background　The treatment of patients with brain metastasis（BM） from lung adenocarcinoma（LAC） with epidermal growth factor receptor（EGFR） mutation is a hot and controversial issue，as no standard treatment modality currently exists. Objective　To analyze the clinical factors associated with intracranial failure following BM treatment in BM patients from LAC with EGFR mutation. Methods　In this study，we retrospectively enrolled 282 patients with a confirmed diagnosis of BM from LAC with EGFR mutation from the Fourth Hospital of Hebei Medical University between January 2011 and June 2018. Baseline characteristics were obtained，containing age，gender，smoking history，Karnofsky Performance Status Scale score，extracranial disease control status，number of involved extracranial organs，number and symptoms of BMs，timing of BM development，treatment modality for BMs，treatment strategy for the primary lung tumor，and Lung-molGPA. At four weeks after the end of whole-brain radiation therapy（WBRT） or targeted oral therapy using tyrosine kinase inhibitors（TKIs），we assessed the intracranial response，and delivered a follow-up to patients，during which the overall survival-BM（OS-BM），intracranial progression-free survival（iPFS） and time of intracranial control were recorded. We plotted Kaplan-Meier curves for OS-BM and iPFS. We used multivariate Logistic regression analysis to explore clinical factors associated with intracranial failure and to further investigate the associated factors between two subgroups divided by the median time to intracranial failure〔early failure subgroup（≤10.0 months） and late failure subgroup（>10.0 months）〕. Results　（1） Baseline characteristics：the median follow-up time was 28.4 months（range，3.0 to 94.8 months）. The median OS-BM was 45 months，and the 3-year OS-BM rate was 28.5%. The median iPFS time was 24 months，and the 3-year iPFS rate was 38.4%. （2）Group analysis of intracranial failure：in all，48.9% of the patients developed intracranial failure. BM symptoms and related treatment modality as well as Lung-molGPA were significantly different for those who developed intracranial failure as compared to those who did not in the baseline characteristics（P<0.05）. Other baseline data showed no intergroup differences（P<0.05）. Multivariate Logistic regression analysis showed that BM treatment modality was associated with intracranial failure〔OR=1.992，95%CI（1.308，3.437），P=0.004〕. The patients receiving WBRT combined with TKIs or not had a higher 3-year iPFS rate as compared to those receiving TKIs alone（51.6% vs 26.7%）（χ2=10.769，P=0.001）. （3）Subgroup analysis of intracranial failure：early failure subgroup（n=71） had a lower 3-year OS-BM rate than late failure subgroup（n=67）（5.9% vs 42.1%）（χ2=51.888，P<0.001）. By the multivariable analyses，the number of involved extracranial organs was associated with early intracranial failure〔OR=0.336，95%CI（0.126，0.894），P=0.029〕. The 3-year iPFS rate was 4.2% in patients with ≥4 involved extracranial organs，and 14.0% in those with ≤3（χ2=4.993，P=0.025）. Conclusion　For patients with EGFR-mutated LAC with BM，BM treatment modality was associated with intracranial failure. Compared to the use of TKIs alone，using WBRT in combination with TKIs or not may delay the time to develop intracranial failure with an around 50% reduced risk. In addition，the number of involved extracranial organs was associated with early intracranial failure. The higher the number（≥4），the earlier intracranial failure occurred.

Key words: Adenocarcinoma of lung, Neoplasm metastasis, Treatment failure, Epidermal growth factor receptor mutation, Brain metastasis, Intracranial failure, Whole brain radiotherapy, Molecular targeted therapy

摘要： 背景　EGFR基因突变阳性肺腺癌脑转移患者的治疗仍是目前的研究热点和有争议的问题，没有标准的治疗模式。目的　探讨EGFR基因突变阳性肺腺癌脑转移患者经脑转移治疗后发生颅内失败的相关因素。方法　回顾性收集2011年1月至2018年6月河北医科大学第四医院确诊为EGFR突变阳性肺腺癌脑转移患者282例，整理282例患者的一般资料，包括年龄、性别、吸烟状况、卡氏评分、颅外控制情况、颅外转移器官数目、脑转移数目、脑转移症状、脑转移时间、脑转移治疗方案、肺原发灶治疗情况及肺癌专用诊断评估预后分级（Lung-molGPA）。全脑放疗结束4周或口服靶向药物4周评价颅内疗效并开始进行随访，记录脑转移后生存时间（OS-BM）、颅内无进展时间（iPFS）、颅内控制时间。采用Kaplan-Meier法绘制脑转移后生存曲线和颅内无进展生存曲线，治疗后颅内失败相关影响因素分析及亚组分析采用多因素Logistic回归分析。结果　（1）基本信息：282例EGFR基因突变阳性肺腺癌脑转移患者随访时间为3.0~94.8个月，中位随访时间为28.4个月。282例患者3年生存率为28.5%，中位OS-BM为45个月；3年颅内无进展生存率为38.4%，中位iPFS为24个月。（2）颅内失败患者分析：48.9%（138/282）的患者发生颅内失败；发生颅内失败患者的脑转移症状、脑转移治疗方式、Lung-molGPA与未发生颅内失败患者比较，差异均有统计学意义（P<0.05）；多因素Logistic回归分析显示，脑转移治疗方式是发生颅内失败的影响因素〔OR=1.992，95%CI（1.308，3.437），P=0.004〕；脑转移治疗方式中全脑放疗联合或不联合靶向药物治疗患者3年颅内无进展生存率为51.6%，高于单纯靶向药物治疗患者的26.7%（χ2=10.769，P=0.001）。（3）颅内失败患者亚组分析：以中位颅内失败时间10.0个月为界限，分为早失败组71例和晚失败组67例；早失败组3年生存率为5.9%，低于晚失败组的42.1%（χ2=51.888，P<0.001）；多因素Logistic回归分析显示，颅外转移器官数目是脑转移治疗后颅内早失败的影响因素〔OR=0.336，95%CI（0.126，0.894），P=0.029〕；颅外转移器官数目≥4个患者3年颅内无进展生存率为4.2%，低于颅外转移器官数目≤3个患者的14.0%（χ2=4.993，P=0.025）。结论　EGFR突变阳性肺腺癌脑转移患者脑转移治疗后颅内失败影响因素为脑转移治疗方式，应用全脑放疗联合或不联合靶向药物治疗较单纯靶向药物治疗可以延缓颅内失败时间，约降低50%的颅内失败风险。颅外转移器官数目与脑转移治疗后颅内较早发生失败相关，颅外转移器官数目≥4个的患者发生颅内失败会更早。

关键词: 肺腺癌, 肿瘤转移, 治疗失败, EGFR基因突变, 脑转移, 颅内失败, 全脑放疗, 分子靶向治疗