Clinical Analysis Of Definitive Radiation Treatment Modality And Prognostic Factors In Patients With Inoperable Esophageal Squamous Cell Carcinoma

Part ⅠTitle:Radiation dose-effect relation in patients with esophageal squamous cell carcinomaPurpose:Despite receiving definitive chemoradiotherapy(dCRT)with radiation dose(RTD)of 50.4Gy,survival of esophageal carcinoma was dismal.The effect of RTD in cancer control and radiotoxicity,and the extent to which local-regional control(LRC)influenced survival remain vague.This study aimed at evaluating RTD-effect relationship in esophageal squamous cell carcinoma(ESCC).Materials and methods:1440 dRT/CRT-treated ESCC patients were enrolled.Restricted cubic spline regression model was applied to reveal non-linear relationship between RTD and survival/radiotoxicity.Linear regression analysis(LRA)was performed to evaluate correlations between LRC and overall survival(OS)or progression-free survival(PFS).Results:For 1440 dRT/CRT-treated ESCC patients,with RTD escalating,hazard ratios(HRs)of OS,PFS,LRC declined until RTD exceeded 60Gy,then increased.HR of treatment-related mortality were stable until RTD exceeded 60Gy,then increased.HR of LRC was lower for majority of patients treated with RTD≥60Gy,except for those with KPS<80,T1-2 lesion,or without lymph node metastasis.LRA revealed strong correlations between LRC and OS/PFS.45.5%and 44.9%of OS and PFS improvements were owing to improved LRC.Conclusion:Definitive radiotherapy with appropriate RTD could achieve well balance in LRC improvement-related survival benefit and radiotoxicity-related survival decline.RTD of 60Gy was well-tolerated,with favorable survival resulted of LRC improvement in local-advanced ESCC.Further stratification analyses based on radiation sensitivity will be helpful to determine potential beneficiaries of RTD escalation.Part ⅡTitle:Simultaneous Integrated Boost Intensity-modulated Radiotherapy with or without Concurrent Chemotherapy in Patients with Esophageal Squamous Cell Carcinoma:A Multicenter,Open Label,Randomized Phase Ⅲ Clinical TrialPurpose:Several previous phase Ⅰ/Ⅱ trials revealed simultaneous integrated boost radiotherapy(SIB-RT)with concurrent chemotherapy could achieve favorable localregional control with acceptable toxicity.The current study aimed at further assessing the efficacy and toxicity of SIB-RT with/without concurrent chemotherapy in patients with inoperable Esophageal Squamous Cell Carcinoma(ESCC)in the era of IMRT.Materials and methods:This multicenter,randomized phase Ⅲ clinical trial was conducted between December 2017 and November 2020 in 2 centers in China.Patients with inoperable clinical stage Ⅱ-Ⅲ diseases,or clinical stage Ⅳ disease with metastatic lymph nodes in supraclavicular/celiac trunk area were enrolled and randomized to receive SIB-RT concurrent with chemotherapy(SIB-RT+CT arm,N=82)or SIB-RT alone(SIB-RT arm,N=82).In both arms,planning gross tumor volume and planning target volume were administered with radiation dose of 59.92 Gy and 50.4 Gy,in 28 fractions.In SIB-RT+CT arm,concurrent chemotherapy regimen consists of weekly doses of paclitaxel and nedaplatin for 5-6 weeks.The primary endpoint was overall survival(OS).The secondary endpoints were progression-free survival(PFS),quality of life(QoL)and toxicity profiles.Results:The median follow-up time was 51.7 months.All the patients were diagnosed with lymph node metastasis,including 32.9%and 30.5%of the patients with cervical or celiac lymph node metastasis in SIB-RT and SIB-RT+CT arm.Treatment response(complete or partial response)rate was superior in SIB-RT+CT arm compared with SIBRT arm(69.5%vs.53.7%,P=0.037).Median OS was 20.5 months in SIB-RT arm and 26.5 months in SIB-RT+CT arm.The 1-,3-,and 5-year OS in SIB-RT arm and SIBRT+CT arm were 64.6%vs.76.8%,34.5%vs 38.4%,and 23.9%vs.28.8%(hazard ratio,HR,0.84,95%CI,0.58-1.20,P=0.33).The 1-,3-,and 5-year PFS in SIB-RT arm and SIB-RT+CT arm were 46.3%vs.54.9%,26.7%vs.30.2%,and 23.9%vs.27.4%(HR,0.80,95%CI,0.56-1.15,P=0.22).The improvement of EORTC QLQ-OES18 dysphagia subscale score was higher in SIB-RT+CT arm compared with SIB-RT arm(P=0.02).The incidences of grade 3 or higher leukopenia and nausea were higher in SIBRT+CT arm(P=0.001 and 0.01).There was no grade 5 adverse events in both 2 arms.Conclusion:SIB-RT should be realized as the essential treatment modality for inoperable ESCC.SIB-RT+CT remained the recommended treatment option for patients with inoperable ESCC,as it tended to achieve survival benefit and could attain superior treatment response and dysphagia relief.Part ⅢTitle:The correlation of progression-free survival and prognosis in patients with esophageal squamous cell carcinoma after definitive radiotherapyPurpose:The correlation of progression-free survival(PFS)for overall survival(OS)in esophageal squamous cell carcinoma(ESCC)remains unelucidated.This study aimed to determine the effect of PFS time on OS in ESCC patients treated with definitive RT or chemoradiotherapy(dRT/dCRT),as well as characterize the prognostic factors and survival of such patients.Materials and methods:A total of 3662 patients from 10 cancer centers were enrolled.One-,2-,and 3-year PFS(PFS 12,PFS24,and PSF36,respectively)were used as time points for analysis.At each time point,ESCC-specific mortality and OS were characterized using competing risk and conditional survival models,while correlation between PFS and OS was evaluated by linear regression.Results:At PFS12,PFS24 and PFS36,a progressive decrease in 5-year ESCC-specific mortality(35.2%to 13.4%)and increase in 5-year OS(46.6%to 62.9%)were observed.Regardless,the OS of patients remained markedly lower than those of the age-and sexmatched Chinese general population.TNM stage remained a significant prognostic factor at PFS36.Strong correlation was found between 3-year PFS and 5-year OS,which was further externally validated.Conclusion:ESCC was a tumor with a high degree of malignancy,the mortality risk of dRT/dCRT treated patients remained significantly higher than the that of the age-and sex-matched Chinese general population.Three-year PFS after dRT/dCRT was strongly correlated to long-term survival and could be used to assess the prognosis of patients in clinical trials and the subsequent clinical practice.TNM stage was a significant prognostic factor for OS,and should be the optimal prognostic tool to guide clinical decision-making and post-treatment follow-up.