Strategies To Improve The Prognosis Of Malignant Esophageal Fistula In Esophageal Squamous Cell Carcinoma

Objective Esophageal malignant fistula is a disastrous complication during the progression of esophageal cancer before,during or after radiotherapy.Esophageal cancer may become perforating due to tumor progression,destruction of the esophageal wall,and increased intraluminal pressure during swallowing or severe coughing.Treatment(radiotherapy,chemotherapy,and brachytherapy)of esophageal cancer may also cause esophageal fistula attributed to the imbalance between tumor shrinkage and normal tissue repair.Esophageal malignant fistula frequently leads to the unaccessibility of antitumor therapy,uncontrolled and progressing cancer,uncontrolled fistula derived severe infection and massive haemorrhage,worsening nutritional and performance status,which can be solely and mutually reinforcingly causing death.Therefore,we initiated this retrospective study to explore the potential mechanism to improve the prognosis of esophageal malignant fistula by comprehensively blocking the multiple lethal cascades.Methods We enrolled 153 cases of esophageal malignant fistula patients in Cancer Hospital of Shantou University Medical College from October 1,2008-December 30,2020.Firstly,the patients were divided into 4 groups(A: never antitumor therapy;B: radiotherapy alone;C: chemotherapy alone;D: radiotherapy plus chemotherapy)in terms of the availability of antitumor therapy after the development of esophageal malignant fistula.Secondly,the patients having no antitumor therapy after the development of esophageal malignant fistula were divided into 3 groups(A: never antitumor therapy;E: esophageal malignant fistula during radiotherapy;C: esophageal malignant fistula after radiotherapy)in terms of the availability and intensity of the antitumor therapy before the development of esophageal malignant fistula.The association of overall survival with sex,ages,KPS,BMI,TNM staging,location of the primary cancer,types of the fistula,management of the fistula(fistula derived infection and the establishment of alternative nutrition intake pathway)was exhibited in the Kaplan Meier survival analysis of the groups mentioned above and by performing Cox regression analysis on the potential prognostic factors in all patients.Results Among 153 cases of esophageal fistula,male patients accounted for 88.9%.The mean age of the patients was 59.9±8.6 years.Most of the patients with esophageal fistula were in stage III-IV(95.5%),having lymph node metastasis(88.9%).The ratio of esophago-tracheal fistula to esophago-mediastinal fistula was about 4∶6.The main initial symptoms of esophageal fistula patients were cough(79.7%),chest and back pain(51.6%),fever(33.3%)and bleeding(15.7%).After the development of esophageal fistula,97 patients(63.4%)did not undego antitumor therapy,and 56 patients(36.6%)received anti-tumor therapy,including 16 patients(10.5%)in radiotherapy alone group,31 patients(20.3%)in chemotherapy alone group,and9 patients(5.9%)in radiotherapy plus chemotherapy group.The base line characteristics between patients with and without post-fistula antitumor therapy were comparable,ESCC patients having post-fistula antitumor therapy exhibited significantly favorable prognosis than those without post-fistula antitumor therapy(m OS 7.8m VS 2.1m,P<0.001).ESCC patients receiving post-fistula antitumor therapy had significantly more enteral nutrition pathway establishment(gastrojejunostomy,nasogastric feeding tube,or esophageal stent)compared with the counterparts(82.1% VS 39.3%,P<0.001).There were 97 cases(97/153,63.4%)discontinued antitumor therapy after the development of esophageal fistula,which were divided into group A: 28 cases(28/153,18.3%)without full antitumor therapy,group E: 22 cases(22/153,14.4%)with esophageal fistula during radiotherapy,group F: 40 cases(40/153,26.1%)after entire course of radiotherapy,and a group of 7 cases(7/153,4.6%)after chemotherapy.There was no significant difference in sex,ages,KPS,BMI,TNM staging,location of the primary cancer,types of the fistula,alternative enteral nutrition pathway establishment between the group A and group E as well as between the group A and group F.The patients discontinued antitumor therapy after the development of esophageal fistula did not obtain a significant favorable overall survival even if they had received antitumor therapy before the development of esophageal fistula(A vs E: 2.9m VS 2.1m,P=0.084;A vs F: 3.1m VS2.1m,P=0.207).Univariate analysis showed that age,KPS score,BMI,history of diabetes mellitus,type of fistula,albumin infusion after fistula,enteral nutritional support,and anti-tumor therapy were prognostic factors.Further multivariate analysis showed that BMI,type of fistula,enteral nutritional support after fistula,and anti-tumor therapy were independent factors that significantly affected the prognosis of patients with malignant esophageal fistula.Conclusions 1.Esophageal malignant fistula is lethal attributed to the unaccessibility of antitumor therapy,uncontrolled and progressing cancer,uncontrolled fistula derived severe infection and massive haemorrhage,worsening nutritional and performance status,which can be solely and mutually reinforcingly causing death.Blocking any of the single causing death pathway can not improve survival.2.Establishment of enteral nutrition pathway after the development of esophageal malignant fistula contributes to the management fistula derived infection and maintaining of sufficient nutrition intake and performance status,which create conditions for continuing antitumor therapy.3.Continuing antitumor therapy(including radiotherapy)can significantly improve the prognosis of esophageal malignant fistula after timely and effectively establishment of enteral nutrition pathway,through comprehensively blocking the multiple lethal cascades.