A Multicenter Prospective Randomized Controlled Study of Porcine Fibrin Sealant in Preventing Cervical Anastomotic Leakage for Esophageal or Junctional Carcinoma. (PLACE030)

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 rightapproach 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.