Development Of A Prognostic Model And Exploration Of The Clinical Target Delineation Of Adjuvant Radiotherapy For Thoracic Esophageal Squamous Cell Carcinoma After Radical Esophagectomy

BackgroundEsophageal carcinoma(EC)is a common upper digestive tract malignancy in our country.The number of new cases in China is nearly half of all cases over the world per year and esophageal squamous cell cancer(ESCC)accounts for more than 90%.Surgery remains the cornerstone of curative treatment for resectable locally advanced EC.Unfortunately,surgery alone is associated with a poor survival and its 5-year overall survival(OS)is usually less than 40%.Neoadjuvant chemoradiotherapy followed by surgery can improve the survival for locally advanced EC.However,there are still many patients chosen upfront surgery in the real world due to many reasons.Additionally,many clinical earlystage ECs may be upstaged during pathological examination after surgery.In the viewpoints of most clinicians,surgery alone is insufficient to cure these patients with poor prognosis who doesn't receive any preoperative therapy.They also agree that adjuvant radiotherapy or chemoradiotherapy should increase their chances of survival.The optimal population,target volume,dosage and combined approaches for postoperative radiotherapy(PORT)of EC is a great dispute.There is an urgent need to screen out suitable population and design more reasonable plans of adjuvant radiotherapy or chemoradiotherapy for EC.An increasing number of studies have suggested that the lower neck and upper mediastinal area should be irradiated for PORT in all thoracic EC and upper abdominal area should also be irradiated for some specific patients(lower thoracic EC,for instance).However,there is little consensus on how to delineate the clinical target volume in these high-risk areas and which patients are suitable for postoperative irradiation in the abdominal area.Here,we aimed to identify the high-risk populations based on developing a nomogram to predict the OS and explore the optimal delineation of clinical target volume based on the recurrence patterns for guiding PORT in thoracic ESCC(TESCC)after radical surgery.Part INomogram to Predict Overall Survival and Analysis on Recurrence Patterns for Thoracic Esophageal Squamous Cell Carcinoma with Radical Surgery AlonePurposesWe aimed to develop and validate a nomogram to predict the OS and analyze the patterns of recurrence in TESCCs with radical surgery alone for screening the high-risk populations and guiding their reasonable adjuvant therapies.Methods and materialsTESCCs with pathological pT1-4aN0-3M0 undergoing radical surgery without perioperative therapies from Jan 2010 to June 2017 in our hospital were enrolled in the training cohort and TESCCs in the Surveillance,Epidemiology,and End Results(SEER)(2004-2015)dataset were enrolled in the validation cohort.The nomogram was developed using independent prognosis for OS analyzed by the Cox proportional hazard regression in the training cohort and subjected to the validation cohort.The predictive accuracy and discriminative ability of the nomogram was evaluated by the area under the curve(AUC)of the receiver operating characteristic curves,calibration curves and decision curve analysis(DCA).Additionally,the distribution of all the recurrences during follow-up were analyzed in the training cohort.ResultsA total number of 706 patients(420 patients in the training cohort and 286 patients in the validation cohort)were enrolled in this study.The Cox regression analysis indicated that the pathological T stage,N stage,gender and tumor length were independent prognosis for OS.The nomogram constructed by these variables showed that the AUC for predicting 5-year OS in the training and validation cohorts were 0.711 and 0.740 respectively,which were higher than that of the AJCC TNM stage systems.Calibration curves indicated good consistency between the nomogram prediction and actual observation for OS.Risk group stratification based on the nomogram scores allowed better distinction between survival curves than AJCC TNM stage systems.Moreover,DCA suggested that the nomogram can obtain satisfactory positive net benefits.Up to the last follow-up time,recurrence occurred in 294 patients(70.0%),including hematological metastasis in 109 patients(25.5%),anastomotic recurrence in 37 patients(8.8%)and locoregional lymph node recurrence in 252 patients(60.0%).There were 89(21.2%),177(42.1%),69(16.4%)patients had lymph node recurrence in the cervical area,mediastinal area and celiac area respectively.In the mediastinal area,the recurrence sites were mainly in the upper mediastinum(147 patients accounted for 35.0%).ConclusionsWe have successfully established a novel nomogram with good risk stratification and discriminative ability for predicting OS in TESCCs with radical surgery alone.Distant metastasis and locoregional lymph node recurrence were common in these TESCCs,which indicated that aggressive adjuvant therapies should be considered for high-risk patients.The cervical area,upper mediastinal area and celiac area were the common recurrence sites of lymph nodes,so these areas should be the focus of PORT.Part ?Risk Factors and Patterns of Abdominal Lymph Node Recurrence after Radical Surgery Alone for Locally Advanced Thoracic Esophageal Squamous Cell CancerPurposesWe aimed to identify the high-risk factors of abdominal lymph node recurrence(ALNR)for screening out suitable populations to receive prophylactic PORT in the abdominal area and determine the optimal delineation of nodal clinical target volume(CTVnd)in the abdominal area based on patterns of ALNR for guiding PORT in TESCC after radical surgery.Methods and materialsClinical data of patients with locally advanced TESCCs after radical surgery without perioperative anti-tumor therapies from June 2010 to June 2016 in our hospital was reviewed.Cox regression analyses were used to identify the independent risk factors for abdominal lymph node recurrence-free interval(ALNRFI).A nomogram was constructed based on these risk factors and the AUC value of receiver operating characteristic was used to evaluate the predictive accuracy.All the imaging data was collected for patients with ALNR.The ALNR rates in different stations based on the regional node divisions of the Japanese Classification of Gastric Cancer were analyzed.A template computed tomography(CT)in the Pinnacle treatment plan system was used to reconstruct all the ALNR and their anatomic distribution was analyzed.ResultsA total of 63(19.57%)patients with 276 lymph nodes of ALNR were identified in 322 patients.59 patients(93.7%)had the occurrence of ALNR within 2 years after surgery.Cox regression analyses indicated that pathological tumor location(p=0.016),N stage(p=0.002),status of abdominal lymph nodes(p<0.001)and status of lymphovascular invasion(p=0.007)were independent risk factors for ALNRFI.We successfully constructed a nomogram using these factors.The AUC of the nomogram for predicting 2-year ALNRFI was 0.846,which was better than that of tumor location(AUC=0.646),N stage(AUC=0.807),status of abdominal lymph nodes(AUC=0.752)and status of lymphovascular invasion(AUC=0.563).Station 16a2,station 9,station 16b1,and station 8 were the major regions of ALNR.The recurrence rates in these stations were 10.56%,9.63%,7.14%and 5.28%respectively.We proposed a detailed atlas of CTVnd in these stations for PORT based on the distribution of ALNR on the template CT images.ConclusionsPathological tumor location,N stage,status of abdominal lymph nodes and status of lymphovascular invasion were independent risk factors for ALNR in TESCC after radical surgery.We constructed a nomogram with good predictive accuracy based on these factors to predict ALNR.The CTVnd of PORT in the abdominal area should include station 8,station 9,station 16a2 and station 16b1,and our proposed atlas of CTVnd should be useful for guiding PORT in TESCC.Part ?Mapping of Cervical and Upper Mediastinal Lymph Node Recurrence for Guiding Clinical Target Delineation of Postoperative Radiotherapy in Thoracic Esophageal Squamous Cell Carcinoma after Radical SurgeryPurposesThis study aimed to map the recurrent lymph nodes in the cervical and upper mediastinal regions and explore a reasonable CTVnd for PORT in TESCC after radical surgery.Methods and materialsWe retrospectively reviewed patients with first cervical and/or upper mediastinal lymph node recurrence(LNR)after upfront esophagectomy in our hospital from June 2012 to June 2020.All these recurrent lymph nodes were plotted on template CT images with reference to surrounding structures.The recurrence frequency at different stations based on the regional node divisions of the Japan Esophageal Society was investigated and the anatomic distribution of all recurrent lymph nodes was analyzed.ResultsA total of 119 patients with 215 recurrent lymph nodes were identified.There were 47(39.5%)patients with cervical LNR and 102(85.7%)patients with upper mediastinal LNR.The high-risk regions were station 101L/R,station 104L/R,station 106recL/R,station 105 and station 106pre for upper TESCC and station 104L/R,station 106recL/R,station 105,station 106pre and station 106tbL for middle or lower TESCC.LNR in the external group of station 104L/R was not common,and LNR was not found in the narrow spaces where the trachea was in close contact with the innominate artery,aortic arch and mediastinal pleura.Additionally,LNR below the level of the cephalic margin of the superior vena cava was also not common for upper TESCC.ConclusionsThe CTVnd of PORT in the cervical and upper mediastinal regions should cover station 101L/R,station 104L/R,station 106recL/R,station 105 and station 106pre for upper TESCC and station 104L/R,station 106recL/R,station 105,station 106pre and station 106tbL for middle and lower TESCCs.Based on our results,we proposed a useful atlas for guiding the CTVnd delineation of PORT in TESCC after radical surgery.Research significanceWe successfully developed nomograms to predict OS and ALNRFI by incorporating clinicopathological factors,which are useful for screening out suitable patients to receive PORT in patients with TESCC after upfront radical surgery.In addition,we mapped the recurrent lymph nodes in the cervical,upper mediastinal and celiac regions and proposed useful atlas in these regions for guiding the CTVnd delineation of PORT.These results can provide more reliable references for decision-making of PORT in patients with TESCC after radical surgery.We hope our future clinical trials will further validate our results and provide more effective adjuvant therapy for patients with locally advanced TESCC who received upfront radical surgery.