The Role Of Local Ablation Thepray For Advanced EGFR-mutant NSCLC Patients With Oligometastatic Disease Or Oligoprogressive Disease

BackgroundLung cancer is one of the most malignant tumors with the highest morbidity and mortality in the world.In China,the incidence of lung cancer is increasing year by year,and it has become the first cause of cancer death in urban population.Lung cancer is divided into Small Cell Lung Cancer(SCLC)and Non-small Cell Lung Cancer(NSCLC),of which NSCLC accounts for about 80%.Due to the lack of specific symptoms of early lung cancer,65%to 70%of NSCLC patients have been diagnosed at an advanced stage and have lost the chance of surgery.Stage IV NSCLC is a broad concept,which is a heterogeneous combination from a therapeutic point of view,including both oligometastasis(number of metastases ?5 lesions)and extensive metastases.The oligometastatic state is a mildly invasive stage of tumor,and it is a transitional stage between the local primary lesion and the extensive metastases.Oligometastases can be multiple metastases of a single organ or multiple metastases of multiple organs.The number of metastases is usually considered to be within 5,because lesions within 5 are considered to be treated by radical treatment such as(surgery or radiotherapy)to obtain a longer survival time.In China,the rate of epidermal growth factor receptor(EGFR)sensitive mutations in non-selective NSCLC patients is about 30%,while which in adenocarcinoma patients can reach 50%,and in non-smoking adenocarcinoma patients can even be as high as 60%to 70%.The progression-free survival(PFS)of advanced NSCLC patients with EGFR sensitive mutation can reach 9.5 months to 13.7 months after treated by first-line EGFR tyrosine kinase inhibitors(TKIs)including gefitinib,erlotinib and ectinib.EGFR TKIs have become the first-line treatment for advanced NSCLC patients with EGFR-sensitive mutation.In 2015,the International Lung Cancer Research Association(IASLC)conducted the eighth edition of NSCLC new staging adjustment.Oligometastasis was classified as Mlb,and the prognosis was similar to M1a,which was significantly better than patients with extensive metastasis(Mlc).Moreover,The new staging emphasizes the predominance of local therapy(eg,surgical resection,stereotactic radiotherapy,etc.)in oligometastatic NSCLC.However,there are sparse studies on local therapy in oligometastatic NSCLC patients with EGFR-sensitive mutations.The role of local treatment in such patients remains undetermined.This study retrospectively analyzed the role of local ablative therapy in EGFR-mutant NSCLC patients with oligometastatic disease or oligoprogressive disease.This study consists of two parts.Part 1Consolidative local ablative therapy improves survival in patients with synchronous oligometastatic NSCLC harboring EGFR activating mutation treated with first-line EGFR-TKIsIntroduction:Studies have shown that patients with oligometastatic NSCLC can benefit from local ablation therapy(LAT),but this is mainly for patients with undefined genetic status.The aim of the current study was to investigate whether consolidation local ablative therapy can improve the survival of patients with stage IV EGFR-mutant NSCLC who have oligometastatic disease treated with first-line EGFR-TKI therapy.Materials and Methods:Patients with stage IV EGFR-mutant NSCLC and no more than five metastases at diagnosis in 2 months were enrolled.All patients were treated with first-line EGFR-TKIs.Consolidation LAT included radiotherapy or surgery.Overall survival(OS)and progression-free survival(PFS)were estimated by Kaplan-Meier curves.Results:From October 2010 to May 2016,145 patients were enrolled,including 51(35.2%)who received consolidation LAT to all oligometastatic sites(All-LAT group),55(37.9%)who received consolidation LAT to either primary tumor or oligometastatic sites(Part-LAT group),and 39(26.9%)who did not receive any consolidation LAT(Non-LAT group).The median PFS in All-LAT,Part-LAT,and None-LAT group were 20.6 months,15.6 months,and 13.9 months,respectively(P<0.001).The median OS in All-LAT,Part-LAT,and None-LAT group were 40.9 months,34.1 months,and 30.8 months,respectively(P<0.001).The difference was significant between All-LAT group and Part-LAT or Non-LAT group but was not significant between Part-LAT and Non-LAT group.The median OS was significantly improved with consolidation LAT for primary tumor(40.5 versus 31.5 months,P<0.001),brain metastases(38.2 versus 29.2 months,P=0.002),adrenal metastases(37.1 versus 29.2 months,P=0.032).Adverse events(Grade?3)due to radiotherapy included pneumonitis(7.7%)and esophagitis(16.9%).Conclusion:The current study demonstrated that Consolidative LAT to all sites was a feasible option among patients with EGFR-mutant oligometastatic NSCLC during first-line EGFR-TKI treatment,with significantly improved PFS and OS compared with consolidation LAT to partial sites or observation alone.Part 2Local ablation therapy can prolong the therapy of EGFR-TKIs in EGFR-mutant NSCLC patients with oligoprogressive disease after first-line EGFR-TKIs treatment Introduction:EGFR-TKIs are the standard first-line treatment for patients with EGFR-mutant non-small cell lungs with a median PFS of 10 to 14 months.Oligoprogressive NSCLC patients with EGFR mutation is a special type.The effect of local ablative therapy for oligoprogressive EGFR mutation non-small cell lung cancer(NSCLC)remains undetermined.This study aimed to investigate the survival benefit of addition of LAT to EGFR-TKIs in EGFR-mutant NSCLC patients with oligoprogression during TKI therapy.Materials and Methods:Patients with stage IIIB/IV EGFR mutant NSCLC who had oligoprogressive disease during the first-line EGFR-TKI therapy and accepted local ablative therapy from March 2011 to February 2016 were identified.The primary research point were progression-free survival 1(PFS 1),defined as time of initiation of TKI therapy to Response Evaluation Criteria in Solid Tumours(RECIST)1.1 defined progress disease(PD)or death and PFS2,defined as time of initiation of TKI therapy to off-TKI PD.The second research piont inclued overal survival(OS)and safety.Results:A total of 206 patients were included.The median follow-up time was 42 months(20.0-69.6 months).The median PFS1,median PFS2 and median OS for the related cohort were 10.7 months(95%CI,10.1-13.3 months),18.3 months(95%CI,17.4-19.2 months)and 37.4 months(95%CI,35.9-38.9 months)respectively.Survival rates of 1 year,2 years and 3 years were 94.1%,78.9%,and 54.7%,respectively.Multivariate analysis revealed that female,EGFR exon 19 mutation,one metastatic lesion,partial or complete response to prior EGFR TKIs therapy in 6 months were the independent prognostic factors.No unexpected toxicities were observed.Conclusion:The current study suggested that the addition of LAT to EGFR-TKI could prolonged the therapy of EGFR-TKIs in EGFR-mutant NSCLC patients with oligoprogressive disease after first-line EGFR-TKIs treatment,which provided survival benefit in this cohort.