Study of Porcine Fibrin Sealant in Preventing Cervical Anastomotic Leakage for Esophageal or Junctional Carcinoma.

Study Overview
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Brief Summary
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The primary objective is to evaluate the efficacy and assess the role of Porcine Fibrin Sealant (Bioseal®) in preventing cervical anastomotic leakage after esophagectomy in the patients with resectable thoracic esophageal cancer and gastroesophageal junction cancer.

Detailed Description
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Esophageal cancer (EC) is the most common cancers in the world, with more than 16,910 new cases and 15,690 deaths annually worldwide. Every year in China, no matter new cases or deaths account for more than half of the world. Currently, surgery is the most important and effective treatment for esophageal cancer. According to the recommendation in Chinese Experts' Consensus on Esophageal Cancer Radical Surgery (year 2017), the right-approach esophagectomy should be adopted, in order to achieve radical lymph nodes dissection and improve the surgical outcomes. So Mckeown procedure is recommended preferentially. However, esophageal resection for cancer has been associated perioperative mortality. One of the major perioperative complications that affect morbidity and mortality in these patients is esophageal anastomotic leakage. Moreover, it was reported that the leakage incidence of cervical anastomosis after esophageal cancer resection was significantly higher than that of intrathoracic anastomosis. Therefore, how to minimize the incidence of esophageal anastomotic leaks in esophagectomy is particularly important, especially for Mckeown surgery. In recent years, the prognostic outcome of esophageal cancer has been improved due to advances in surgical technique. However, esophageal anastomotic leakage is still one of the most serious complications following esophagectomy, with an incidence around 5% to 40%. For example, a research based on Japanese national database showed that the rate of anastomotic leakage after esophagectomy was 13.3%. A recent phase 3 clinical trial, the ChemoRadiotherapy for Oesophageal Cancer Followed by Surgery Study (CROSS) reported an anastomotic leak rate of 26.1% after esophagectomy. Meanwhile, data from the investigator's center indicated that the leakage rate after esophagectomy was around 21.0%. Furthermore, anastomotic leakage following esophagectomy could seriously increase early mortality. According to the previous study, the risk of perioperative 90-day death was three times in patients with anastomotic leakage after esophagectomy than those without leaks (18.2% vs. 6.2%, P=0.003), and hospitalization was significantly increased. Bioseal® (Guangzhou Bioseal Biotech Co., Ltd., China) is a porcine-derived fibrin sealant that has been widely used in various surgical procedures to assist in hemostasis for more than a decade. This type of fibrin sealant is made from biologically porcine-derived thrombin and fibrinogen, and is designed to form a stable fibrin clot by simulating the final pathway of the coagulation cascade. The fibrin clot will form a gel-like material on the surface of the surgical wound, which can not only directly block the tissue defect, but also promote the healing of the wound by using the fibrin network as the matrix where the fibroblasts and capillary endothelial cells can proliferate to form granulation. Therefore, Bioseal® have been reported to be used as sealing agent as well as wound healing agent during surgery in some studies. In the recent years, some investigators have attempted to use the fibrin sealant to treat or prevent gastrointestinal leakage after enterectomy, gastrectomy, esophagectomy, or pancreaticoduodenectomy. The preliminary results show application of fibrin sealant may lower the chances of anastomotic leakage. Hence, it can diminish the mortality and morbidity of those patients with gastrointestinal reconstructions. In 2004, a study conducted by Nguyen both in vitro and in vivo, found that application of fibrin sealant over gastric bypass could reduce the postoperative anastomotic leakage. Among the 16 animals (pigs) undergoing laparoscopic gastric bypass, 10 cases were applied with fibrin sealant on their primary anastomosis, and no anastomotic leakage or related complications was found. Five of the other 6 cases in control group had fistula or intra-abdominal abscess. Moreover，the follow-up study in humans showed that 66 patients in whom fibrin sealant was used as reinforcement on a primary anastomosis were all free of anastomotic leakage. In China, some studies also reported fibrin sealant could prevent anastomotic leakage for patients undergoing resection of rectal carcinoma or pancreato-biliary tumors. As to esophagectomy, only few pilot studies have reported the similar attempts to prevent anastomotic leakage by using fibrin sealant. In 2007, Ling reported that application of fibrin sealant while implanting an esophageal stent under endoscopy was an effective approach for treating the postoperative esophageal anastomotic leakage. The studies conducted by Celal also showed that endoscopic treatment combined with fibrin sealant could be considered as a valuable option for the management of postoperative esophageal anastomotic leakage with a high degree of technical feasibility and safety. However, studies focusing on the role of fibrin sealant in the prevention of cervical leakage after esophagectomy are few. In 2007, a prospective clinical trial conducted by Upadhyaya enrolled 45 infant patients who underwent esophagectomy for congenital esophageal atresia (EA) with tracheoesophageal fistula (TEF). In that study, a total of 52 patients were divided into two groups. In Group A, patients received fibrin sealant as reinforcement on a primary end-to-end esophageal anastomosis. In group B, fibrin glue was not used. In the final analysis, the overall rate of postoperative leakage is 26.9% (12/45), including 9.1% (2/22) in group A and 43% (10/23) in group B (p=0.017). In 2009, Saldaña-Cortés conducted a similar research but on puerile esophagectomy for caustic injury. Results showed that the postoperative cervical anastomotic dehiscence and leakage were observed in 28.5% of patients who received fibrin sealant in the study group and 50% of those in the control group. Both of those two studies indicated that fibrin glue, when used as a sealant for cervical esophageal anastomosis, could reduce the risk of leakage. However, there is still no large-scale clinical trial investigating the use of fibrin sealant to prevent cervical anastomotic leakage after esophagectomy for esophageal cancer all over the world. The purpose of this study is to assess the role of fibrin glue (Bioseal®) in the prevention of leakage at the cervical esophageal anastomosis for esophageal cancer patients undergoing Mckeown surgery.

Official Title
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Porcine Fibrin Sealant in Preventing Cervical Anastomotic Leakage After Esophagectomy for Esophageal or Junctional Carcinoma: A Phase II,Single Arm，Prospective Study.

Conditions
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Esophageal Cancer, Gastroesophageal Junction Cancer, Anastomotic Leak

Intervention / Treatment
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* Biological: Porcine Fibrin Sealant (PFS)
* Procedure: Surgery


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologic diagnosis of squamous cell carcinoma or adenocarcinoma of thoracic esophageal carcinoma or gastroesophageal junction cancer with Stage T1-4aN0-3M0, according to 8th edition of Union for International Cancer Control (UICC) staging system More than 6 months of expected survival Age ranges from 18 to 80 years Absolute white blood cells count ≥4.0×109/L, neutrophil ≥1.5×109/L, platelets ≥100.0×109/L, hemoglobin ≥90g/L, and normal functions of liver and kidney. WHO performance status (PS) of 0-1 Informed consent will be obtained before the study Exclusion Criteria: Patients who have undergone definitive chemoradiotherapy Patients with concomitant hemorrhagic disease Patients with other uncontrollable status that cannot tolerate surgery Patients with known hypersensitivity to the porcine fibrin sealant product Pregnant or breast feeding Patients cannot signed the informed consent document because of psychological quality, family and social factors Patients with concomitant peripheral neuropathy, whose CTC status is 2 or even more Have a history of diabetes over 10 years and with poorly controlled blood sugar level Patients with serious cardiac, respiratory, hepatic, renal,hematologic, immunological disease or cachexy, who cannot tolerate surgery

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A(Surgery+PFS)<br>Arm A consists of the concurrent application of Porcine Fibrin Sealant (PFS) on the gastroesophageal or coloesophageal anastomosis during Mckeown surgery . | Biological: Porcine Fibrin Sealant (PFS)<br>* 2.5ml Porcine Fibrin Sealant will be instilled over the cervical anastomose line.<br>* Other names: Bioseal®;Procedure: Surgery<br>* McKeown esophagectomy including open or minimally invasive esophagectomy will be performed for patients with resectable thoracic esophageal carcinoma or gastroesophageal junction cancer. Two-field lymphadenectomy with total mediastinal lymph node dissection is performed during surgery. At last, 2.5ml Porcine Fibrin Sealant will be instilled over the cervical anastomose line.<br>* Other names: Esophagectomy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of postoperative cervical anastomotic leakage | Cervical anastomotic leakage will be diagnosed based on a combination of clinical presentation, radiological findings, and/or endoscopic findings within the first 3 months after the operation. | within the first 3 months after esophagectomy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | Overall survival (OS) is defined as the time period from the date of enrollment to the date of death or the last follow up | At end of trial- up to 2 years in follow up | 
| Disease Free Survival | Disease-free survival (DFS) is defined as the time period from the date of R0 resection to the date of disease recurrence or death. | At end of trial- up to 2 years in follow up | 
| Postoperative Complications | Postoperative complications will be recorded after each esophagectomy | within the first 3 months after esophagectomy |