Tisseel® as a Reinforcement of Esophagojejunal Anastomoses

Study Overview
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Brief Summary
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Background: The dehiscence of esophagojejunal anastomoses is one of the most serious complications after total gastrectomy in patients with gastric cancer. Any method of avoiding this problem will affect not only the postoperative course but also the prognostic of disease. Methods: This is a prospective, randomized and multicenter trial, within the Spanish EURECCA Esophagogastric Cancer Group, to investigate the efficacy of Tisseel® in reducing the rate of esophagojejunal anastomosis leakage in patients with gastric cancer. The rate of anastomosis leak will be measured with clinical, radiological and analytic parameters. Objective: Analyze the efficacy of Tisseel® as a reinforcement in reducing the rate of anastomotic esophagojejunal anastomoses.

Detailed Description
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Introduction The dehiscence of the esophagojejunal anastomosis is one of the most serious complications after a total gastrectomy not only in the short term but it has been shown to be an independent risk factor for survival. The rate of esophagojejunal anastomosis leakage after cancer gastrectomies is described to be between 1-12.3%. Any method to prevent this complication would be of vital importance to improve the evolution of these patients. Likewise, when the dehiscence has been established, early detection could contribute to an early intervention, avoiding more serious consequences and, therefore, improving the short and long term prognosis. Little progress has been made during recent decades in the prevention of anastomotic leakage in high-risk digestive tract anastomosis. Some authors have tried the use of new methods of suture, reinforcements or patches in the anastomosis. Fibrin adhesives were introduced more than 30 years ago, in order to favor hemostasis and tissue adhesion. Numerous studies have demonstrated their effectiveness in reducing surgical bleeding in cardiovascular surgery but its role as a sealant in gastrointestinal anastomosis is more debated. There have been some experimental studies that have shown a possible protective effect of this material in enteric anastomoses. With the evolution of bariatric surgery and with the high volume of surgeries handled, several studies have been published that assess the effect of fibrin sealants on gastrojejunal anastomoses. In esophagogastric surgery, the number of published studies is reduced and there are only 2 studies that assess the effect of fibrin sealants on esophagojejunal anastomosis. The results of these studies seem to indicate that the application of fibrin sealants in this anastomosis could have a favorable effect in reducing the number of anastomotic dehiscences. There are different definitions for the concept of anastomotic dehiscence. The dehiscence of the esophago-jejunal anastomotic can be defined as any clinical and / or radiological evidence of dehiscence of the anastomosis. Although early diagnosis is key to avoiding major consequences, in clinical practice, the diagnosis of anastomotic dehiscence is often delayed. Direct observation of the debit of surgical drainage, fever or persistent ileus or clear symptoms of peritonitis are indirect signs that make us suspect a possible anastomotic dehiscence. The possibility of having a parameter that allows us to diagnose early a problem in the suture would allow us to act earlier and, therefore, improve the prognosis of these patients in the short and long term. In colorectal surgery, serological parameters such as procalcitonin or C-reactive protein have been studied as early predictors of anastomotic dehiscence. In esophagogastric surgery, publications are scarce and all of them analyze results in esophagogastric anastomoses. Furthermore, the determination of amylases in drainage has also been used for the detection of postoperative fistula. It is a simple and low cost method and is a parameter widely used in pancreatic surgery for the detection and evolutionary control of pancreatic fistulas. It has also been shown to be useful in esophageal surgery and in bariatric surgery. However, in gastric cancer it has only been used for the diagnosis of pancreatic fistula as a complication in total gastrectomies with associated splenectomy. Finally, the use of radiology with oral contrast routinely in the postoperative period of esophagogastric surgery has been shown to have a low sensitivity for the early detection of anastomotic dehiscence. CT with oral contrast seems to have greater sensitivity and positive predictive value in esophageal surgery for this purpose, but the need to perform a postoperative test to evaluate the anastomosis without clinical evidence of dehiscence is unclear. For all these reasons, we believe that a multicenter randomized study will contribute to improve the clinical results of esophagogastric surgery and the knowledge of the diagnosis of complications, by studying the efficacy of Tisseel® in reducing the rate of anastomotic leakage, but also analyzing the role of drain amylases, serum CRP (C-reactive protein), procalcitonin and white blood cell levels in the early detection and prediction of anastomotic leak, and the role of CT with oral contrast as a routine assessment of anastomotic integrity. Objective Analyze the efficacy of Tisseel® in reducing the rate of anastomotic leakage diagnosed in the postoperative period using clinical and / or radiological parameters. Methods This is a prospective, randomized and multicenter trial, within the Spanish EURECCA Esophagogastric Cancer Project, to investigate the efficacy of Tisseel® in reducing the rate of esophagojejunal anastomosis leakage in patients with gastric cancer. Participation study will be offered to all centers that are currently part of the Spanish EURECCA Esophagogastric Cancer Group. Those hospitals that show their desire to participate must sign the Letter of Commitment. In the same way, the study must sign off by European Medicine Agency and Spanish Agency of Medicines. Once the patient is included in the study the surgeon performs a total gastrectomy as usual procedure. Once the esophagojejunal anastomosis is done the patient is randomized (Tisseel® vs no product). Surgeon dispenses Tisseel® all over the anastomosis following data sheet if applicable. The rest of the surgical procedure is as usual. In the postoperative period the investigator collects the data commented in following sections. The evidence of an anastomotic leak will be tested with analytical and radiological parameters: Blood samples will be taken from patients at: Immediate preoperative (blood count, procalcitonin and C-reactive protein) Days 1, 3, 5 and 7 postoperative (blood count, procalcitonin and C-reactive protein). A sample of surgical drainage will be collected for the determination of amylases on days: 1,3,5, and 7 postoperative or until drainage is withdrawn. An abdominal CT with oral contrast will be performed within the first 5 postoperative days. The date and the result will be collected.

Official Title
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The Use of Fibrin Glue Sealant (Tisseel®) as a Reinforcement of Esophagojejunal Anastomoses Will Decrease the Rate of Anastomotic Leak.

Conditions
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Gastric Cancer, Anastomotic Leak

Intervention / Treatment
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* Drug: Tisseel
* Device: No Tisseel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients over 18 years diagnosed with gastric adenocarcinoma and scheduled for a total gastrectomy with curative intent in EURECCA Esophagogastric Cancer Group who agree to participate in the study and sign the informed consent Exclusion Criteria: Patients with non-epithelial neoplasms, with metastases, not resected or undergoing palliative resections. Patients who do not sign informed consent.

Ages Eligible for Study
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Minimum Age: 18 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Tisseel®<br>Once the esophagojejunal anastomosis is done the patient is randomized (Tisseel® vs no product). In the arm Tisseel® surgeon dispenses the product all over the anastomosis. The rest of the surgical procedure is as usual. | Drug: Tisseel<br>* Reinforcement of esophagojejunal anastomoses after total gastrectomy with the product.<br>|
| Other: no Tisseel®<br>Once the esophagojejunal anastomosis is done the patient is randomized (Tisseel® vs no product). In the arm  noTisseel® surgeon performs the surgical procedure as usual. | Device: No Tisseel<br>* No reinforcement of esophagojejunal anastomoses after total gastrectomy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of esophagojejunal anastomotic leak in immediate postoperative period | Clinical or radiological (see anex 1: Score Goense) evidence of esophagojejunal anastomotic leak. | 7 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Amylases level in drainage | Amylase level (mg/L) in drainage | days 1,3,5,7 postoperatively | 
| CRP (C-reactive protein) in blood | C-reactive protein in blood (mg/L) | days 1,3,5,7 postoperatively | 
| Procalcitonin in blood | Procalcitonin in blood (mg/L) | days 1,3,5,7 postoperatively | 
| White cell levels in blood | White cell levels in blood (x109/L) | days 1,3,5,7 postoperatively | 
| Results of Computed Tomography with oral contrast. | The results will be expressed based on Goense Score Based on Score Goense (Anastomotic Leakage Prediction Score). The investigator will collect the presence of: Yes No Normal Fluid collection Air cavity Fistula Wall discontinuity Empiema Goense L, Stassen PMC, Wessels FJ, van Rossum PSN, Ruurdal JP, van Leeuwen MS, van Hillegersberg R. Diagnostic performance of a CT-based scoring system for diagnosis of anastomotic leakage after esophagectomy: comparison with subjective CT assessment. Eur Radiol 2017; 27:4426-34 | between 3th and 5th postoperative day | 
| Type of esophagojejunal anastomoses performed | The type of esophagojejunal anastomoses performed can be: mechanical (circular) mechanical (lineal) manual | day of intervention | 
| Postoperative complications | Postoperative complications (Clavien-Dindo score): Grade I Any deviation from the normal postoperative course without the need for pharmacological treatment or surgical, endoscopic and radiological interventions Grade II Requiring pharmacological treatment with drugs other than such allowed for grade I complications. Grade III Requiring surgical, endoscopic or radiological intervention IIIa Intervention not under general anesthesia IIIb Intervention under general anesthesia Grade IV Life-threatening complication requiring IC/ICU-management IVa single organ dysfunction (including dialysis) IVb multiorgandysfunction Grade V Death of a patient | 30 days after surgery | 
| 90-day mortality | Mortality at 90 days after surgery | 90 days after surgery | 
| Need for urgent surgical re-intervention | Reintervention after surgery: Yes/Not | 30 days after surgery | 
| Hospital stay | Number of days of hospital stay | 30 days after surgery | 
| Readmission | Readmission within 30 days after discharge: Yes/Not | 30 days after discharge |