Role Of Postoperative Concurrent Chemoradiotherapy And Prognostic Value Of PD-L1 Expression For Esophageal Carcinoma Nomograms For Early Stage Non-Small Cell Lung Cancer Treated With Stereotactic Ablative Radiation Therapy And Prognostic Value Of CfDNA Fo

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Postoperative Radiotherapy Combined with Concurrent Paclitaxel-nedaplatin Chemotherapy for Esophageal Cancer:A Preliminary StudyPurpose:To investigate the safety and preliminary efficacy of postoperative intensity modulated radiotherapy(IMRT)combined with concurrent weekly paclitaxel-nedaplatin chemotherapy for patients with esophageal squamous cell carcinoma.Methods and materials:A total of 52 patients were enrolled between June 2010 and June 2013.The clinical target volume of IMRT included tumor beds and corresponding lymphatic drainage regions at high risk,and the total radiotherapy dose was 50-60Gy,2.0Gy/fraction,5 fractions per week.The concurrent chemotherapy consisted of nedaplatin 25mg/m2 on D1 and paclitaxel 45-50mg/m2 on D1 and was repeated every week during radiotherapy.Common Terminology Criteria for Adverse Events(CTCAE)4.0 was used to evaluate adverse events,and Kaplan-Meier method was applied for survival analyses.Results:All the patients had good tolerance to the treatment,and 51 patients(98%) completed radiotherapy according to the scheduled regimen.The median number of chemotherapy cycles was 4,and 42 patients(81%)completed?3 cycles of chemotherapy.Most adverse events were of grade 1-2,and grade 3 adverse events were leukopenia(29%),radiation esophagitis(10%)and anastomotic stenosis(4%).One patient(2%)experienced grade 5 gastroesophageal bleeding.Of all the patients,the median survival time was 38.7 months,and the 1-,2-,3-and 4-year overall survival rates were 83%,64%,51%and 38%,respectively.The overall recurrence rate was 46%,and the locoregional recurrence rate and distant metastasis rate were 15%and 37%,respectively.Conclusions:Postoperative IMRT combined with concurrent weekly paclitaxel-nedaplatin chemotherapy for patients with esophageal squamous cell carcinoma is safe and effective,and large-scale prospective randomized studies is needed.Part ? Role of Postoperative Concurrent Chemoradiotherapy for Esophageal Carcinoma:A meta-analysis of 2165 PatientsPurpose:This meta-analysis was aimed to evaluate the role of postoperative concurrent chemoradiotherapy(CCRT)for esophageal cancer patients after surgery.Methods and materials:We systematically searched PubMed,PMC,EMBASE,Cochrane Central Register of Controlled Trials,Chinese National Knowledge Infrastructure and Wanfang databases.Studies which compared CCRT with non-CCRT treatment for esophageal cancer patients after surgery were eligible.Outcomes of interest were odds ratios(OR)for overall survival(OS),local-regional recurrence rate,distant metastasis rate and adverse-event rate.Results:Thirteen studies with 2165 patients were included in this meta-analysis.Postoperative CCRT significantly improved OS for esophageal cancer patients.Comparing the CCRT group with the non-CCRT one,the OR and 95%confidence interval(CI)for 1-year,3-year and 5-year OS were 1.66(1.30-2.11),1.50(1.24-1.81)and 1.54(1.22-1.94),respectively.The local-regional recurrence rate was significantly reduced in the CCRT group(OR=0.58,95%CI=0.46-0.72),but no significant difference was observed in the distant metastasis rate between the CCRT and non-CCRT groups(OR=0.94,95%CI=0.68-1.30).Postoperative CCRT didn't increase the risk of pneumonitis,anastomotic stenosis or severe hematologic toxicities.Mild esophagitis in the CCRT group was increased but could be well tolerated.Conclusions:This meta-analysis based on the largest-scale of published literature confirms that post-CCRT yields significant survival benefit and improves local-regional control with tolerable toxicity for patients with esophageal carcinoma.Part ? Prognostic Value of PD-L1 Expression in Patients with Esophageal Squamous Cell Carcinoma Receiving Radical Surgery Followed by Adjuvant RadiotherapyPurpose:The prognostic role of programmed cell death-ligand 1(PD-L1)expression in patients with esophageal squamous cell carcinoma(ESCC)was controversial and few study focused on those receiving radical surgery followed by adjuvant radiotherapy(RSRT).Our study aimed to investigate the prognostic value of PD-L1 expression on tumor cells(TC)and tumor-infiltrating immune cells(TIC)in ESCC patients treated with RSRT.Methods and materials:ESCC patients underwent RSRT between March 1999 and December 2002 in our institution were included in the study.PD-L1 expression on TC and TIC were examined by tissue microarrays and immunohistochemistry.Kaplan-Meier method was used in the analyses of survival and cumulative recurrence rate,and log-rank test was applied in comparing the differences between groups.Cox proportional hazards regression models with univariate analyses and multivariate analyses were performed to identify significant prognostic factors.P-values<0.05 were considered statistically significant.Results:Seventy-seven patients were included in our study.The positive expression rate of PD-L1 on TC and TIC were 44.2%and 42.9%,respectively.Compared with TC PD-L1-negative group,patients in TC PD-L1-positive group had statistically significant worse disease free survival(DFS)and local-regional recurrence-free survival(LRFS)(median DFS:11.5 vs.22.8 months,P=0.029;median LRFS:11.5 vs.28.0 months,P=0.006),while had obvious though non-statistically significant worse overall survival(OS)and distant metastasis-free survival(DMFS)(median OS:21.6 vs.29.9 months,P=0.121;median DMFS:15.4 vs.24.3 months,P=0.289).PD-L1 expression on TIC was not associated with any survival-related endpoints.According to multivariate analyses,male(HR=3.402,P=0.048),pN3(HR=4.980,P=0.004)and PD-L1 positive on TC(HR=1.986,P=0.035)were independent unfavorable prognostic factors for OS;pN3(HR=2.826,P=0.044)and PD-L1 positive on TC(HR=2.333,P=0.012)were also independent unfavorable prognostic factors for PFS.Regional recurrence and distant metastasis accounted for the majority of all recurrence patterns.Patients in TC PD-L1-positive group had significantly higher cumulative local-regional recurrence rate than those in the negative group(P=0.015).Conclusions:For patients with ESCC receiving RSRT,PD-L1 expression on TC is an independent unfavorable prognostic factor,which also indicates higher risk of local-regional recurrence.Additional anti-PD-1/PD-L1 therapy or optimizing the irradiation volume and dose for this subgroup of patients may be helpful and needs to be further studied.Part ? Predicting Outcomes for Early Stage Non-Small Cell Lung Cancer Treated with Stereotactic Ablative Radiation Therapy:Development and Validation of Robust Prognostic NomogramsPurpose:To develop and validate predictive nomograms for overall survival(OS),progression-free survival(PFS),and time-to-progression(TTP)in patients with early stage non-small cell lung cancer(ES-NSCLC)treated with stereotactic ablative radiotherapy(SABR).Methods and materials:The study cohort included 714 ES-NSCLC patients treated with SABR from 2004—2015 with median follow-up of 59 months,divided into training and testing sets(8:2),with the former used for nomogram development.The least absolute shrinkage and selection operator(LASSO)was initially employed to screen for predictors of OS,PFS,and TTP;and identified predictors were subsequently applied towards Cox proportional hazards regression modeling.Significant predictors(p-value<0.05)on multivariable regression were then utilized to develop nomograms,which were validated via evaluation of concordance indexes(C-index)and calibration plots.Finally,Kaplan-Meier method and Gray's test were employed to estimate the cumulative recurrence rates and compare the differences between groups.Results:Significant predictors of both OS and PFS included age,gender,Charlson comorbidity index(CCI),diffusing capacity of carbon monoxide(DLCO),systemic immune-inflammation index(S?),and tumor size(P<0.01 for all).Eastern Cooperative Oncology Group(ECOG)performance status predicted for OS as well(P=0.01),while both tumor size and minimum biological equivalent dose to 95%of planning target volume(PTV D95 BED10)were predictive of TTP(P<0.01 for both).The C-indexes for the OS,PFS,and TTP nomograms were 0.73,0.68,and 0.60 in the training dataset,and 0.72,0.66,and 0.59 in the testing dataset,respectively.Tumor size>2.45cm and PTV D95 BED10<113Gy were significantly associated with both local and distant progression.Conclusions:These prognostic nomograms for OS,PFS and TTP in this study were developed and validated based on a large sample of data,which can accurately predict short-and long-term prognosis for ES-NSCLC patients treated with SABR.All these nomograms can assist in identifying high-risk patients who may benefit from additional systemic therapy,so as to achieve the risk stratification and individualized treatment for every patient.Part ? Gene Mutation-related Biomarkers in Plasm Cell-free DNA:Novel Independent Prognostic Factors for Stage p?A-N2 Non-Small Cell Lung CancerPurpose:This study aims to investigate the prognostic biomarkers of patients with stage p?A-N2 non-small cell lung cancer(NSCLC),and to analyze the correlation between gene mutation-related biomarkers in plasm cell-free DNA(cfDNA)-mutation number and max mutation frequency-and prognosis of patients with stage p?A-N2 NSCLC.Methods and materials:Clinical data of 35 patients with stage p?A-N2 NSCLC from August 2012 to January 2013 at our institution were retrospective collected.Peripheral blood was taken at different treatment period and the mutations of cfDNA were detected.DNA sequencing was performed using the HiSeq 3000 Sequencing System(Illumina,San Diego,CA).Kaplan-Meier method and log-rank test were employed in the survival analyses and the comparison between groups.Survival-related outcomes included overall survival(OS),progression-free survival(PFS),local-regional progression-free survival(LPFS)and distant metastasis-free survival(DMFS).Univariate and multivariate analysis were performed with Cox proportional hazards model.P-value less than 0.05 was considered significant.Results:A total of 35 patients were included in this study,and the median follow-up time was 61 months.Smoking(P=0.031),mutation number>2(P=0.028)and max mutation frequency>2.5%(P=0.045)were significant prognostic factors of PFS in the multivariate analysis.Survival analyses showed that compared with patients with mutation number<2,those with mutation number>2 had significantly be tter PFS(HR=0.41,P=0.022)and LPFS(HR=0.26,P=0.003),while OS(P=0.893)and DMFS(P=0.255)had no significant differences between these two groups.PFS was also significantly better in patients with max mutation frequency>2.5%than those with max mutant frequency ?2.5%(HR=0.45,P=0.047),however,the differences of OS,LRFS and DMFS was not significant between these two groups(P=0.369,P=0.158 and P=0.108,respectively).The mutation number of pre-operation group was significantly higher than that of post-radiochemotherapy group(5 vs.2.5,P=0.023)and the change of max mutation frequency was approximately significant in post-radiochemotherapy group compared with post-operation group(1.85%vs.2.6%,P=0.067).Furthermore,MET,ALK,APC,PTEN,ERBB4,NF1 and other genes,involving multiple NSCLC-driven genes and therapeutic targets,did not mutate in recurrence-free patients when compared with recurrent patients.Conclusions:Smoking,mutation number>2 and max mutation frequency>2.5%are prognostic factors for better PFS of patients with stage p?A-N2 NSCLC.Mutation number and max mutation frequency of gene mutations in cfDNA are expected to be novel prognostic predictors of ?A-N2 NSCLC patients.