Precision Radiotherapy And Targeted Therapy Intervention On Clinical High-risk Prognostic Factors Of Brain Metastases In Lung Cancer

Background:Brain metastasis(BM)and leptomeningeal metastasis(LM)are considered the fatal progressive events of advanced malignant tumors.At present,no treatment for BM and LM has been standardized.About 30%to 50%of non-small cell lung cancer(NSCLC)patients develop brain metastases.Targeted therapy represented by epidermal growth factor receptor-tyrosine kinase inhibitors(EGFR-TKI)has yielded significant benefits for survival of some patients with driver gene mutation-positive.However,the incidence of brain metastasis is increasing on a yearly basis.Whole-brain radiotherapy and stereotactic radiosurgery(WBRT and SRS,respectively)remain the most important local treatment modalities.Establishing a prognostic stratification system based on individual characteristics is the key strategy for guiding precision combination therapy.At the same time,the analysis of neurocognitive impairment in patients with BM is also the focus of this paper.Methods:Based on the clinical actuarial requirements,the high-risk factors and prognostic indicators of brain metastases from lung cancer were retrospectively analyzed.A survival predictive nomogram after SRS for brain metastasis was established.The efficacy and safety of osimertinib in the treatment of leptomeningeal metastases were evaluated using a systematic review and meta-analysis.Based on real-world data,we explored the value of SRS combined with external ventricular drainage in rescuing critically ill patients with BM and further analyzed the changes in neurocognitive function in patients with BM.Results:Based on the retrospective analysis of 80 cases of NSCLC-LM,it was found that WBRT could significantly prolong the survival time of EGFR wild-type patients(8.0 versus 2.1 months;P=0.002).Younger ages(P=0.048)and WBRT(P=0.025)were favorable prognostic factors for EGFR wild-type patients.Next,356 BM patients were included in the study,and a nomogram for opverall survival(OS)was developed by incorporating four independent prognostic factors:(1)Karnofsky Performance Score,(2)cumulative tumor volume,(3)gene mutation status,and(4)serum lactate dehydrogenase.The nomogram was validated in a separate cohort and demonstrated good calibration and good discriminative capability(C-index=0.780,area under the curve[AUC]=0.784).The prognostic accuracy of the nomogram(0.792)was considerably enhanced when compared with classical prognostic indices.Subsequently,a meta-analysis was conducted on the treatment of NSCLC-LM with osimertinib.Based on 11 studies(353 patients),the pooled rate of objective response and disease control rates(ORR and DCR,respectively)were 42%and 90%,respectively,and the pooled one-year OS was 59%.The most common adverse events were rash(53%),diarrhea(45%),and paronychia(35%).On this basis,we reviewed the critical BM cases in the real world.We found that fractional SRS combined with external ventricular drainage(EVD)in treating brain metastases with obstructive hydrocephalus can rapidly relieve neurological symptoms and improve patients’quality of life.We further included 74 patients with BM from lung cancer and found that a significant difference between the results of the mini-mental state examination(MMSE)and the neurocognitive assessment(Kappa<0.4).The multivariate analysis revealed that over 60 years of age and recursive partitioning analysis score of≥2 were independent risk factors for neurocognitive impairment.Finally,this paper also reviews the value of various radiotherapy methods in LM.Conclusion:This study discusses the position and role of radiotherapy and targeted therapy of brain metastasis in lung cancer in the era of precision medicine and provides a positive basis for clinical practice.WBRT presents clear survival advantages for patients with wild-type EGFR,and molecular biological stratification of LM patients for WBRT is highly recommended.This study developed and validated an individualized prognostic nomogram by integrating physiological,volumetric,clinical chemistry,and molecular biological surrogates.The study also highlighted and confirmed the meaningful efficacy and a manageable safety profile of osimertinib for the treatment of LM patients from EGFR mutant advanced NSCLC.FSRS combined with EVD is an effective rescue method for critically ill patients with brain metastases complicated by hydrocephalus.Old age and RPA grade are independent risk factors for neurocognitive impairment.