Clinical Study Of Gamma Knife Combined With EGFR/ALK TKIs In The Treatment Of Brain Metastasis Of Lung Adenocarcinoma

Objective This study is aim to investigate the clinical effect of gamma knife combined with EGFR / ALK TKIs in the treatment of brain metastases of lung adenocarcinoma,evaluate the effect of gamma knife and targeted treatment sequence,analyze the influencing factors affecting local control,and provide clinical guidance for improving the prognosis of patients.Materials and methods 101 patients with brain metastasis of lung adenocarcinoma diagnosed in our hospital and treated with gamma knife were analyzed retrospectively,including 55 males(54.5%)and 46 females(45.5%).The median age was 63(years old),with an average of 61.59(years old);The median maximum volume of intracranial metastases was 3.6 cm3,with an average of 7.76 cm3;The median edema index was 5.0,with an average of 9.27;There were 401 target tumors,with an average of 3.97.There were52 cases(51.5%)of brain metastasis at the first diagnosis and 49 cases(48.5%)of secondary brain metastasis;During the observation period,70 patients(69.3%)received systemic chemotherapy,and 31 patients(30.7%)did not receive systemic therapy.There were 59 cases(58.4%)in EGFR / ALK + group and 42 cases(41.6%)in EGFR / ALK-group;There were37 cases(62.7%)in gamma knife group and 22 cases(37.3%)in TKI group.The gamma knife treatment planning system uses a 45%-70% dose curve to wrap more than 95% of the focus range,with a peripheral dose of 12-18 Gy and a central dose of 22-36 Gy.Routine oral dose of small molecule TKI(including 14 cases of icotinib,12 cases of gefitinib,erlotinib1,afatinib1,osimertinib19,almonertinib2,crizotinib 5,brigatinib1 and alectinib 4).The primary endpoint was intracranial progression free survival(i PFs),and the secondary endpoints were intracranial local control rate(DCR)and objective remission rate(ORR).The tumor boundary was measured by skull enhanced MRI and the tumor volume was calculated,and the changes of tumor volume before and after treatment were compared;The intracranial progression free survival time(i PFs)and local control of patients in EGFR / ALK-mut group and EGFR / ALK-wild group were statistically analyzed and compared.The effects of pre SRS or pre TKI on long-term i PFs were evaluated in EGFR / ALK-mut group.The survival analysis of each group was evaluated by Kaplan Meier survival curve,and the statistical significance of counting data was analyzed χ 2 test or Fisher exact probability method,t-test of measurement data,nonparametric test for median comparison,Cox proportional hazards regression model for multivariate analysis.Results 101 patients are met the conditions.The overall median i PFs was 9.2 months,with an average of 10.3 months.The EGFR / ALK-mut group was 11.5 months(95% CI:8.28-14.72),and the EGFR / ALK-wild group was 7.0 months(95% CI: 5.84-8.16).The log-rank test result was p = 0.000 < 0.05.There was significant difference between the two groups.The intracranial disease control rate(DCR)in EGFR / ALK-mut group and EGFR /ALK-wild group were 94.9% and 92.9% respectively,which was not statistically significant(p = 0.691 > 0.05).The intracranial objective remission rate(ORR)in EGFR /ALK-mut group and EGFR / ALK-wild group were 74.5% and 52.3% respectively,the difference was statistically significant(p = 0.021 < 0.05).The second grouping comparison between EGFR / ALK-mut groups: 37 cases in the priority gamma knife group,the median IPFs was 12.0 months,with an average of 13.51 months,which 22 cases in the priority EGFR/ ALK-TKIs group,the median IPFs was 8.75 months,with an average of 9.53 months,and the log rank test result was p = 0.009 < 0.05,the difference was statistically significant.The number of tumors,maximum tumor volume,mutation status,Systemic chemotherapy after SRSand postoperative KPS score were included in the risk factors affecting i PFs.There was no significant difference in i PFs between points of 19,21,ALK,T790 M and combined mutation points(p = 0.754 > 0.05).The median i PFs of the first,second and third generation targeted drug therapy patients were 10.5 months,8.8 months and 12.0 months respectively.The results of nonparametric test showed that the difference was not statistically significant(p = 0.065 > 0.05).The overall adverse reaction rate of combined treatment was 11.8%.No radioactive brain necrosis was found in the follow-up cranial MRI,and there were no serious grade 4 / 5 adverse reactions.Conclusion For patients with brain metastasis of lung adenocarcinoma with EGFR / ALK positive mutation,gamma knife combined with EGFR / ALK TKIs can improve the long-term intracranial progression free survival time and intracranial remission rate of patients with brain metastasis of lung adenocarcinoma compared with gamma knife alone,but the short-term control rate of brain metastasis targeted by the first generation is equivalent to that targeted by the third generation;Priority gamma knife is associated with good long-term prognosis and less adverse reactions.It can be recommended as the first-line treatment for brain metastasis of lung cancer with positive driving gene.