Risk Factors Of Esophageal Fistula In Locally Advanced Esophageal Squamous Cell Carcinoma Patients Receiving Chemoradiotherapy

Backgrounds and aims: According to the statistics of National Cancer Center,esophageal carcinoma(EC)has become the third most common cancer and the fourth leading cause of cancer?related deaths in China.Radical surgery is thought to be a mainstay measure for localized EC.However,up to 30%?40% patients have lost the opportunity of radical surgery when initially diagnosed.For those people,chemoradiotherapy is an effective treatment modality and can significantly improve the treatment outcome.Despite the improvement in long?term survival rate in EC patients treated by chemoradiotherapy,it is still limited by several side effects,notably,esophageal fistula is one of the most serious complications.The esophageal fistula was caused by tumor?related and non?tumor related issues.Anatomically,the esophagus is surrounded by mediastinum,bronchus,lungs and blood vessels,which could directly invaded by advanced EC.On the other hand,chemoradiotherapy can also induce esophageal fistula due to the imbalance between tumor shrinkage and normal tissue repair system.The incidence of esophageal fistula for EC patients receiving chemoradiotherapy was reported to be 6% to 22%.The prognosis of esophageal fistula is very poor.According to the data reported,the mean survival time was only 2 to 2.5 months.The current treatment strategies for esophageal fistula are not very ideal,so prevention should be put into the first place.Associated factors about this complication,clinically significant notwithstanding,have not been well elucidated.Thus,we performed this retrospective study to determine relevant risk factors of esophageal fistula for locally advanced Chinese EC patients receiving chemoradiotherapy.Methods:PatientsThis study was approved by Institutional Review Board of The Second Hospital of Dalian Medical University,and waiver of the informed consents were permitted for this retrospective study proposal.Between September 2014 and September 2016,a total of 212 initially diagnosed EC patients in the Radiation Oncology Department of The Second Hospital of Dalian Medical University,were enrolled.The patients were selected according to the following criteria: 1)pathologically diagnosed esophageal squamous cell carcinoma patients;2)staged as ??? based on American Joint Committee on Cancer(AJCC)7th edition;3)treated by intensity modulated radiotherapy(IMRT)and chemotherapy;4)Karnofsky performance status(KPS)? 70.Patients with the following criteria were eliminated from the cohorts: 1)previously underwent esophageal surgery or thoracic radiotherapy;2)concomitant other advanced carcinoma;3)lost to follow up;4)concomitant infectious and immunodeficiency disease.Data collectionThe following information including demographics,tumor?related and treatment?related data were analyzed.Besides,pretreatment status of tumor markers,body mass index(BMI),KPS,neutrophil?to?lymphocyte ratio(NLR),platelet?to?lymphocyte ratio(PLR),albumin,smoking,and concomitant disease were also collected.Follow up and the status of esophageal fistulaEsophageal squamous cell carcinoma patients were commonly evaluated during the course of therapy and 30 days after treatment.Then,patients were followed up every 3 months,unless they had emergent symptoms which needed immediate medical intervention.At each follow?up visit,radiographic examinations including esophagus barium meal examination and contrastenhanced CT of cervical part,chest and abdomen were usually performed.The esophageal fistula was defined according to Common Terminology Criteria for Adverse Events(CTCAE)4.0 based on radiographic examinations.Results: Patient featuresIn the present study,a total of 212 patients(173 males and 39 females)were enrolled.The mean age at diagnosis was 61.3 years,ranged from 42 to 89.Of the whole study cohorts,24.06% had hypertention,7.55% had diabetes,33.02% had ulcerative tumor,and 49.53% coexisted with esophageal stenosis.All patients in this research were treated with chemoradiothrapy(77 received concurrent modality and 135 received sequential modality).TP chemo regimen was used in 144 patients and PF was performed in 71 patients.In our cohort,22 patients(10.38%)developed esophageal fistula.Among them,9 people experienced fistula formation during the period of treatment,while the other 13 patients developed after the completion of chemotherapy.The median occurrence time for this event was 5.75 months(range: 0.6-8 months).The type of esophageal fistula in our study includes esophagorespiratory(8 patients)and esophageal-mediastinum fistula(14 patients).Univariate and multivariate analysis of risk parametersIn univariate analysis,sex,age,BMI,smoking status,ulcerative tumor,esophageal stenosis,tumor location,T stage,chemo regimens,cyfra21-1,albumin,NLR,PLR were found to be significant parameters.We further performed multivariate analysis,which demonstrated that sex,age,smoking status,esophageal stenosis,T stage,N stage,fraction dose,chemo regimens,cyfra21-1 and NLR were significant risk factors.Conclusions:Our study revealed that sex,age,smoking status,esophageal stenosis,T stage,N stage,fraction dose,chemo regimens,cyfra21-1 and NLR were significantly associated with esophageal fistula.Close attention should be given to patients with above factors.However,to confirm these findings,large,prospective,multicenter studies are in need.