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

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