Survival Comparison Of Tyrosine Kinase Inhibitor （TKI） Combined With Cranial Radiotherapy And TKI Alone In The First-line Treatment Of Oncogene-driven NSCLC With Brain Metastasis

BackgroundNon-small cell lung cancer（NSCLC）patients with EGFR mutation or ALK rearrangement have a higher incidence of brain metastasis（BM）than those with wild type.Once brain metastasis occurs,it will endanger the survival and seriously affect the quality of life.Currently,tyrosine kinase inhibitor（TKI）is the standard and first-line treatment for advanced NSCLC（including BM）harboring EGFR or ALK mutations,while cranial radiotherapy remains a major salvage treatment for BM.For TKI therapy,it is controversial whether the active addition of cranial radiotherapy can improve survival for EGFR/ALK-positive NSCLC with BM.This study aims to compare the survival efficacy of first-line TKI combined with cranial radiotherapy and TKI alone in a cohort of advanced oncogene-driven NSCLC with brain metastases.Patients and methodsThe patients with brain metastasis,NSCLC,and epidermal growth factor receptor（EGFR）or anaplastic lymphoma kinase（ALK）mutation in the medical records admitted in Radiotherapy Department of the First Hospital of Jilin University from November 2013 to November 2019 were retrospectively reviewed,and those who received first-line EGFR/ALK-TKIs with or without cranial radiation were identified.ResultsA total of 48 patients were enrolled in this study and grouped as: TKI alone（n = 19）and TKI combined with cranial radiotherapy（TKI + c RT）（n = 29）.There was baseline neurological symptoms in more patients in TKI + c RT group than that in TKI alone（62.1% vs 15.8%）.After a median follow-up of 29 months,33.3% of the patients were still alive.The median intracranial progression-free survival（i PFS）was 20.0 months in the patients who received TKI + c RT,which was significantly longer than 10.5 months in those who received TKI alone（P < 0.001）.However,no significant difference was observed in median overall survival（OS）between the two groups（24.3 vs 20.6 months,P = 0.94）.In multivariable analysis,the treatment strategies,age,and number of brain metastasis were independent factors impacting i PFS.The patients with TKI + c RT（HR0.374,95%CI 0.173-0.809,P = 0.012）,age > 60 years（HR 0.364,95%CI 0.146-0.907,P = 0.03）and four or less number of brain metastases（HR 0.301,95%CI 0.124-0.731,P = 0.008）had superior i PFS.And four or less number of brain metastases（HR 0.386,95%CI 0.161-0.926,P = 0.033）was also an independent factor for improved OS.The analysis for all subgroups showed that TKI + c RT can reduce the risk of intracranial progression in each subgroup including that with lung-mol GPA0-2（HR 0.235,95%CI 0.061-0.907）or > 2（HR 0.271,95%CI 0.107-0.683）,with brain symptoms（HR 0.192,95%CI 0.045-0.811）or without symptoms（HR 0.271,95%CI 0.097-0.754）,with greater（HR 0.279,95%CI 0.106-0.737）or less number of brain metastasis（HR 0.226,95%CI 0.066-0.772）,which was even more obvious in the subgroups over 60 years old and with neurological symptoms and extracranial metastases at the time of diagnosis（HR 0.179;HR 0.192;HR 0.209）.The incidence of adverse reactions of the patients in TKI + c RT group was 44.8%,most of which were grade 1 or2,which could be relieved after the clinical intervention.One person developed grade 2 cognitive dysfunction（3.4%）.The incidence of adverse reactions of the patients in TKI alone group was31.6%,and no grade 3 or above adverse events occurred.Conclusion1.TKI combined with cranial radiotherapy can significantly prolong intracranial progression-free survival compared with TKI alone in the first-line treatment of oncogene-driven NSCLC with brain metastases.2.The toxic effects of combined therapy were mainly manifested in skin,gastrointestinal and neurological symptoms,which can be tolerated by the patients.3.The treatment strategies,age,and number of brain metastases were independent prognostic factors for i PFS.Number of brain metastases was an independent factor impacting OS as well.4.The addition of cranial radiotherapy can reduce the risk of intracranial progression in all subgroups,especially in subgroups over 60 years old and those with neurological symptoms and extracranial metastases at the time of diagnosis.