Analysis Of The Occurrence Of NSCLC Brain Metastasis With EGFR-TKIs And Related Biological Factors

PART ?: The effect of Initial Gefitinib versus Erlotinib on Central Nervous System Progression in Advanced Non–Small Cell Lung Cancer with EGFR MutationsBackground:Brain metastasis occurred in about 10% of NSCLC patients at their first rank and in 40-55% of patients during the whole course of disease,especially the lung adenocarcinoma patients with epidermal growth factor receptor(EGFR)mutations showed brain metastasis rate as high as 349% of EGFR wild-type patients.The central nervous system(CNS)brain metastasis confers an even worse quality of life and prognosis.Conventional chemotherapy drugs are difficult to effectively pass through the blood brain barrier.NSCLC multiple brain metastasis treated with whole brain radiotherapy(WBRT)had an overall survival(OS)of 3-6 months and 1-year survival rate of only 10-20%.The concurrent chemotherapy with WBRT can improve the effective rate but can not prolong OS of NSCLC brain metastases patients.With continuous improvement of systemic treatment for NSCLC,the possible therapeutic strategies on preventing and controlling brain metastasis to improve overall disease control and quality of life becomes more critical.Evidence from multiple prospective phase III clinical trials had shown significantly better clinical efficacy in EGFR-mutation advanced NSCLC patients initially treated with first-generation EGFR inhibitor(gefitinib or erlotinib)compared with upfront chemotherapy,with objective response rate(ORR)of 71%-83% and progression-free survival(PFS)of 9-13 months.Recently published data showed that erlotinib and gefitinib could efficiently pass through the blood brain barrier and target to brain metastases of NSCLC patients with positive EGFR mutation.For brain metastases of NSCLC patients with EGFR sensitive mutation,gefitinib as the first-line treatment attained the intracranial objective reaction rate(i ORR)of 87.8%,but erlotinib as second-line treatment reached i ORR of 75%.Two retrospective analysis by Heon et al.showed there was a lower rates of CNS progression in EGFR-mutant advanced NSCLC patients treated with first-line gefitinib/ erlotinib compared with chemotherapy.These results indicated that,for the NSCLC patients with brain metastasis via molecular screening,gefitinib and erlotinib may have a vital role in prevention and treatment of CNS metastases that have not been sensitive to conventional chemotherapeutic agents.However,the difference of contributing effects of erlotinib and gefinitib on the risk of CNS progression in EGFR-mutant advanced NSCLC patients remain undefined.Because the cerebro-spinal fluid(CSF)concentration of erlotinib and gefitinib was only(2.77+0.45)% and(1.13+0.36)% of blood concentrations,indicating that the brain may be a susceptible site for progression of NSCLC targeted by EGFR inhibitors.However,a CNS-specific pharmacokinetics resistance,absence from classical genetic mechanisms of acquired resistance(eg,EGFR T790 M mutation,c-MET amplification),as a result of low CSF-to-plasma concentration ratio of either erlotinib or gefitinib has been described when lesions of the body were well controlled but CNS progression appeared.Hence,the difference of CSF-to-plasma concentration ratio between erlotinib and gefitinib may affect CNS progression in advanced NSCLC patients with EGFR mutations.In addition,our group recently reported the inconsistency rate of EGFR mutation in primary lung foci and brain metastasis is 16.14%.That is,16.14% of EGFR mutation in primary lung lesion may be wild type in established brain metastasis.Combined with a stronger antitumor effect of erlotinib than gefinitib using the recommended dose,plasma concentration of erlotinib can inhibit the growth of NSCLC with wild/ mutant-type EGFR,while gefinitib can not inhibit the wild-type EGFR and all mutant EGFR NSCLC cells.Perhaps erlotinib and gefitinib may cause differential regression of established brain metastases from NSCLC.The platform for EGFR mutation screening in NSCLC patients has been set up in three affiliated hospitals of Third Military Medical University and First Affiliated Hospital of Chongqing Medical University since 2009.Therefore,we collected the information of the advanced NSCLC patients with EGFR sensitive mutation from patient records,patients himself and Cancer Foundation of China(CFC),comparing the risk of CNS progression in those initially treated with erlotinib to the risk in similar patients treated with gefitinib.In particular,we sought to determine whether significantly different at time to neurological progression(n TTP)in EGFR-mutant advanced NSCLC patients had brain metastases at the time of diagnosis treated with gefitinib and erlotinib by delaying the development of CNS metastases.Objective: To analyze the risk of central nervous system(CNS)progression in response to two epidermal growth factor receptor(EGFR)inhibitors erlotinib or gefitinib as first-line treatment for advanced non-small cell lung cancer(NSCLC)patients with EGFR sensitive mutation.Methods: A retrospective analysis was done on cerebral metastasis rate after erlotinib or gefinitib as first-line treatment for advanced NSCLC patients with EGFR sensitive mutation.Time to neurological progression(n TTP)and median progression-free survival(m PFS)were calculated.Results: The study involved 279 patients(erlotinib group: 108,gefitinib group: 171).At the time of diagnosis of advanced NSCLC,the brain metastasis occurred in 24 patients(22.2%)in erlotinib group and 22 patients(12.9%)in gefitinib group(P=0.047),of which 39 cases received treatment for brain metastases before initating systemic treatment.After a median follow-up of 22 months,27 patients(25.0%)in the erlotinib group and 60 patients(35.1%)in gefitinib group showed CNS progression.n TTP were 24 months and 16 months respectively in erlotinib group and gefitinib group(P=0.014).The 6-,12-and 18-months cumulative CNS progression rate was 0.9%,3.7% and 12.0 % in erlotinib group compared with corresponding rates 5.8%,9.4% and 17.0% in the gefitinib group(P=0.181).The HR of CNS progression was 0.695(95% CI,0.406-1.190)in the erlotinib group versus gefitinib group.Conclusions: Our data show the time to neurological progression can be effectively extend in NSCLC patients with EGFR sensitive mutation initially treated with erlotinib compared with gefitinib.If confirmed,our results indicate that erlotinib may play an important role in treatment of CNS progression from EGFR activated mutation NSCLC.PART ?:Prognosis analysis of Brain Metastasis for Advanced Non–Small Cell Lung Cancer Patients with EGFR Mutations in Response to First-Line Treatment with EGFR-TKIsBackground:Lung cancer is the leading cause of cancer-related death worldwide,non small cell lung cancer(NSCLC(non-small cell lung cancer(NSCLC)accounted for all of the lung cancer is about 80%,in NSCLC disease progression in midbrain metastasis incidence rate as high as 25% ~ 54%,and most for multiple metastases.Target on the epidermal growth factor receptor(epidermal growth factor receptor(EGFR)to the ATP competitive tyrosine protein kinase inhibitors(tyrosine kinase Inhibitors,TKIs)erlotinib erlotinib,gefitinib non erlotinib gain ESMO and NCCN recommended.It has been widely used is sensitive to the clinical treatment of first-line EGFR mutations in NSCLC.The study on prognostic factors influencing the efficacy of EGFR-TKIs is a hot topic in the field of lung cancer,and it has been reported that the efficacy of EGFR-TKIs in the treatment of NSCLC may be related to the abundance of EGFR mutation,the type of mutation,and so on.In order to further clarify the prognostic factors that influence the efficacy of NSCLC,and compare the differences in brain metastases between 19 and 21 patients with EGFR-TKIs who were treated with EGFR-TKIs.A retrospective analysis was performed on 114 patients with advanced EGFR who were treated with NSCLC who received the first line therapy and received the Chinese Cancer Foundation.Objective: To investigate the prognostic factors on the development of brain metastasis in advanced non-small cell lung cancer patients with EGFR-TKIs.Methods: Clinical data of 114 patients with non-small cell lung cancer with EGFR-TKIs(Erlotinib,Gefitinib)who got CFC gift from third military medical university daping hospital during the time from Jan 1st,2010 to Dec 1st,2013 were collected.Clinical factors of brain metastasis were analysed by single factor and multiple factors analysis(Cox's proportional hazards regression model).Brain metastases in median time to progress(m TTP)between two EGFR mutations was analysed by Kaplan-Meier method.Results: In 114 advanced NSCLC patients,14 patients had cerebral metastasis during TKIs treatment,and 24 patients(21.1%)had CNS progression.Single factor analysis showed that in the NSCLC patients with EGFR sensitive mutations,patients without bone metastasis during EGFR-TKIs treatment benefitted more in controlling brain metastasis(P=0.046).The 60 year old age and primary operation patients benefitted more on survival during EGFR-TKIs treatment(P=0.038 and P=0.034).m TTP of 19 exon and exon 21 patients were 18.3 and 13 months respectively(P=0.129).Conclusion: Bone metastasis is a risk factor for the development of brain metastasis during the treatment of TKIs in NSCLC patients.The 60 year old age and primary operation patients had lower risk of death.19 exon mutation patients may benefit more from the treatment of EGFR-TKIs in controlling brain metastasis.