Application Of Stereotactic Ablation Radiotherapy In Early Stage Non-small Cell Lung Cancer And Pulmonary Oligometastases

Background and Objective:Lung cancer is a primary malignant tumor and is the leading cause of death in the world.Non-small cell lung cancer(NSCLC),accounts for 75%-80% of all lung cancers.Although the prognosis of lung cancer is poor in history,early-stage NSCLC(ES-NSCLC)usually has a better prognosis.With the popularity of medical imaging technology,especially low-dose spiral CT,the detection rate of early lung cancer has greatly increased.However,there are some patients with cardiovascular and other basic diseases,cannot operate or refuse surgery.Although there are serious complications with those patients,but most of them still die of cancer,so tumor treatment is very necessary.These non-surgical patients are considered to be "medically inoperable" or refuse surgical resection and need a local treatment instead of surgery.Stereotactic ablation radiotherapy(SABR),also known as stereotactic radiotherapy(SBRT)is a new radiotherapy technology in recent years,which has the characteristics of small target area,high single dose,less irradiation times,particularly accurate target location and treatment parameters,and large dose gradient between the target area and the surrounding normal tissue.The target focus can be given a higher dose of radiotherapy while reducing the dose of the surrounding normal tissue as much as possible.At present,the National Comprehensive Cancer Network(NCCN)guidelines recommend SABR as the standard treatment for early inoperable NSCLC.For advanced malignant tumors,it has been found that it is a continuous process from local progression to extensive metastasis,in which there is an intermediate state,and the early metastatic state with a small number and location of metastasis may only have limited metastatic ability called "oligo-metastatic".Studies have shown that local treatment of metastatic foci(surgery,radiotherapy,intervention)can improve the progression-free survival and overall survival of advanced tumor patients with oligo-metastasis.Clinicians have been concerned that patients with oligo-metastases should not be limited to medical treatment,local treatment should be actively intervened.However,there are few reports on the prognostic factors and failure modes of SABR in early non-small cell lung cancer and patients with pulmonary oligo-metastases.The purpose of this study is to study the role of SABR in the treatment of pulmonary malignant tumors in the following two different levels: 1)the analysis of the efficacy,prognosis and failure mode of SABR in early non-small cell lung cancer;2)the application of SABR in patients with pulmonary oligo-metastases.The purpose of this study is to provide some evidence support for selecting patients,dose division and follow-up treatment of patients treated with SABR.Part I: Analysis of the efficacy and failure patterns of stereotactic ablation radiotherapy in early stage non-small cell lung cancer.Objective:To evaluate the long-term survival efficacy,prognostic factors and failure patterns of stereotactic ablation radiotherapy(SABR)in early stage non-small cell lung cancer(NSCLC).Methods:Patients with early stage non-small cell lung cancer treated by SABR in Henan Cancer Hospital from January 2011 to December 2018 were analyzed retrospectively.Overall survival(OS),cancer-specific survival(CSS),local recurrence free survival(LRFS),regional recurrence-free survival(RRFS)and distant metastasis-free survival(DMFS)were calculated by Kaplan-Meier method.Univariate analysis was performed by Log-rank method,and multivariate prognostic analysis was performed by Cox regression model to determine the prognostic value of neutrophil-lymphocyte ratio(d NLR).And to explore the main failure patterns and adverse reactions of early stage non-small cell lung cancer(NSCLC)after SABR radiotherapy.Results:There were 109 patients,including 85 males and 24 females,with a median age of 73 years(range 33-86 years).The median BED10 dose of SABR was 100Gy(range 100-119Gy).The median follow-up time for all patients was 44 months(1)The results of recurrence: 45 cases had recurrence and metastasis,32 cases(29%)had distant metastasis(DM),17 cases(16%)had local recurrence(LR),and 10 cases(9%)had regional lymph node recurrence(RR).There were 8 cases had local recurrence only(primary focus and the same lobe),4 cases had RR,20 cases had distant metastasis(DM),1 case had LR with RR and 7 cases had LR with DM.4 cases had RR with DM,only 1 case had LR with RR wit DM.(2)Survival prognosis results:the median OS was 78 months,the median CSS was 78 months,and the median PFS was 44 months.1-year OS,CSS,PFS,RRFS,DMFS is 95.4%,97.2%,86%,94.4%,99.1% and 89.7%,respectively.For 3 years,75.6%,79.1%,61.8%,83.8%,91% and68.8%,respectively,and for 5 years,55.6%,60.7%,45.7%,77.7%,83.2% and59.4%,respectively.Univariate analysis showed that ECOG score,age,smoking history and d NLR were the influencing factors of OS(P = 0.03,0.02,0.04,0.001),while age,smoking history and d NLR were the factors affecting CSS(P = 0.02,0.03,0.001).The time from diagnosis to radiotherapy(TTF)is the factor affecting LRFS(P= 0.03),and the factor affecting RRFS is radiotherapy technology(P = 0.007).Multivariate analysis showed that d NLR was a prognostic factor for OS and CSS(P =0.001,0.001).(3)Toxicity reaction: rib fracture occurred in 2 patients,51 patients had grade 1 radiation pneumonia,and no grade 3 or more radiation pneumonia,esophagitis and other adverse reactions was found.Conclusion:ES-NSCLC treated with SABR can achieve better OS,CSS and PFS.d NLR is an independent prognostic factor of OS and can be considered in clinical application.The most common failure mode is distant metastasis,followed by local recurrence.The most common site of distant metastasis is lung metastasis,followed by brain and bone,so regular reexamination is necessary after SABR treatment of ES-NSCLC.Part II:The application of stereotactic ablation radiotherapy in pulmonary oligo-metastasesObjective: SABR is a new local therapy for pulmonary metastases,to evaluate the safety and efficacy of SABR in pulmonary oligo-metastases.Methods: The patients with advanced malignant tumor with lung metastasis who underwent SABR in Henan Cancer Hospital from January 2011 to December 2018 were retrospectively analyzed.OS,LRFS and DMFS were calculated by KaplanMeier method.Log-rank method was used to analyze the factors that may affect survival,such as primary tumor,number of metastatic tumors,BED,age,sex,smoking history,focus location,pathological type,ECOG score and the time from primary tumor to confirmed pulmonary metastasis(disease-free interval,DFI).Cox regression model was used for multivariate analysis.Then explore the failure mode and toxicity of SABR in the treatment of pulmonary oligo-metastases.Results: There were 214 patients with advanced malignant tumor with pulmonary oligo-metastases,including126 males and 88 females,with a median age of 59.5 years(range 18-84 years).Of the 214 metastases,88(41.12%)originated from lung cancer,31(14.48%)from esophageal cancer,27(12.61%)from cervical cancer,28(13.08%)from colorectal cancer,10(4.7%)from breast cancer,7(3.3%)from head and neck tumors,and 23(10.74%)from other tumors such as malignant melanoma,sarcoma and liver malignant tumor.172(80.37%)metastatic lesions were located in the peripheral and 42(19.63%)in the central.The median maximum diameter of the tumor was 1.7cm(1-4.2cm);SABR dose BED < 100 Gy in 70 cases,BED ≥ 100 Gy in 144 cases.From the date of SABR treatment as the starting point,the median follow-up time was 40 months(range 1-72 months).1)failure patterns: 191(89.25%)lesions had progressed,34(15.89%)metastases had LR,and 157(73.36%)had DM,including 94 intrapulmonary metastases,13 brain metastases,22 lymph node metastases,19 bone metastases and 9 other metastases.The most common failure mode was DM,and the most common site of distant metastasis was lung metastasis,followed by lymph node and bone metastasis.2)Survival results: of the 159 patients,107(67.30%)died during the follow-up period,of which 1 case died of cerebral hemorrhage,1 case died of traffic accident,and the remaining 105 cases died of malignant tumors and or complications.The median OS is 31 months.The 1-year OS,LRFS,DMFS of the whole patients was 73.8%,90.1% and 52.5% respectively,the 3-year OS,LRFS,DMFS was 53.8%,76% and 24.3%,and the 5-year OS,LRFS,DMFS was 11.9%,69.8% and 10.1%,respectively.3)Prognostic factor results: the number of metastatic lesions was a factor affecting LRFS.The 1-year,3-year and 5-year LRFS of < 2 and ≥ 2 metastatic tumors were 91%,85.4%,78.8%,88.4%,57.7% and 51.9%,respectively.Although there was no significant difference in LRFS between BED < 100 Gy group and ≥ 100 Gy group and metastatic primary organs(lung cancer VS others),the survival analysis showed that the local control rate of BED ≥ 100 Gy group was significantly better than that of BED < 100 Gy group(P < 0.066),and the LRFS of primary lung cancer group was better than that of other tumor sources group(P < 0.074).The number of metastatic lessions was also a factor affecting DRFS.The 1-year,3-year and 5-year DRFS of < 2 and ≥ 2 metastatic tumor were 62.9%,29.9%,17.2%,36.2%,15.6% and 0,respectively.DFI was the factor affecting OS.The 1-year,3-year and 5-year OS of the DFI < 2 years group were 75.9%,60.5% and 27.7% respectively,and the 1-year,3-year and 5-year OS of the ≥ 2 years group were 73.2%,38.5% and 10%,respectively.The results of Cox multivariate analysis showed that DFI was an independent prognostic factor for OS(P=0.045 HR 0.638 95% CI 0.407-0.999),the number of metastatic lesions was an independent prognostic factor for LRFS(P=0.007 HR2.552 95%CI 1.292-5.041)and an independent prognostic factor for RRFS(P=0.001 HR1.693 95%CI 1.232-2.326).4)Toxicity reaction: the main manifestations were self-relieving fatigue and asymptomatic grade 1 radiation pneumonia.One patient with esophageal cancer had 5 lung metastases developed grade 3 radiation pneumonia when 4 months after SABR treatment,and 1 case had fracture in the long-term adverse reactions.No grade 2 pneumonia and other radiation-related adverse reactions in the rest of the patients.Conclusion: Pulmonary metastases have fine local control when treated by SABR and the adverse reactions are low.For advanced malignant tumors with lung oligo-metastases,especially those with metastases from lung cancer or confirmed after 2 years of treatment,SABR should be given actively,and the radiation dose with BED ≥ 100 Gy should be chosen as far as possible.The main failure mode after SABR treatment is distant metastasis,so it is very necessary and important for patients with advanced malignant tumor receive standardize treatment in the whole course.