Endoscopic Ultrasound and Endoscopic Retrograde Cholangiopancreatography for Malignant Distal Biliary Obstruction

Study Overview
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Brief Summary
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The purpose of this study is to compare the rates of adverse events between patients undergoing Endoscopic Ultrasound- guided biliary drainage and Endoscopic Retrograde Cholangiopancreatography for distal malignant biliary obstruction.

Detailed Description
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The current curative treatment for patients with occlusion of the distal common bile duct by pancreatic cancer is pancreaticoduodenectomy (Whipple procedure). Unfortunately, more than 80% of patients have locally advanced or metastatic disease that requires neoadjuvant or palliative treatment. The goals of biliary drainage in the setting of locally advanced or metastatic pancreatic cancer are to palliate obstructive jaundice and lower serum bilirubin prior to systemic chemotherapy. In addition to resolving jaundice and associated pruritus, biliary drainage improves anorexia, indigestion and quality of life (1, 2). Endoscopic approach by means of retrograde cholangiopancreatography (ERCP) and biliary stent placement is the preferred treatment option for palliation of malignant obstructive jaundice. Endoscopic biliary drainage is safer than surgical bypass, with endoscopic placement of a plastic or metal stent having a lower relative risk of complications (3). When performed by experts, ERCP has favorable (80-90%) short-term (<90 days) success rates in the setting of malignant distal biliary obstruction (1-3). The rate of ERCP-associated adverse events (AEs) is 5-27% (4-7) and include pancreatitis, bleeding, infection, perforation and rarely death. In a recent audit of 524 consecutive patients with an intact papilla who underwent ERCP at a tertiary endoscopy unit, 49 (9.4%) had a previously failed attempt at an outside facility and more than 80% of these failures were in the setting of a distal malignant stricture (8). Cancer in the pancreatic head or uncinate process can cause extensive ampullary inflammation that precludes successful biliary cannulation using standard techniques. In such circumstances, advanced techniques such as needle-knife sphincterotomy, dual wire technique, trans-papillary pancreatic sphincterotomy and cannulation over a pancreatic duct stent are performed to access the bile duct (9, 10). While the technical success rate for advanced techniques in expert hands is more than 85%, the procedure is associated with an AE rate of about 10-20% (9-11). When ERCP is technically unsuccessful, patients are usually referred for interventional radiology-guided percutaneous transhepatic biliary drainage (PTBD). PTBD is usually a multi-step procedure that involves the initial placement of an external drainage catheter followed by internal trans-papillary stent placement. When the distal bile duct is severely strictured or when the intra-hepatic biliary system is non-dilated, PTBD is unsuccessful and is encountered in about 5-15% of patients with pancreatic cancer (12). The rate of short and long-term PTBD-related AEs is 5-10% and 20-30%, respectively (12-14). While most short-term AEs are due to infection and bleeding, the long-term AEs are due to stent dysfunction requiring frequent readmissions (12-14). More recently, EUS-guided biliary drainage (EUS-BD) has emerged as a novel alternative to PTBD and ERCP for biliary decompression when advanced cannulation techniques fail. EUS-BD is a minimally invasive technique where the extra-hepatic common bile duct (choledochoduodenostomy) or intrahepatic bile duct (hepatogastrostomy) is punctured under EUS-guidance and after transmural dilation a stent is deployed for biliary drainage. The potential advantages of EUS-BD are three-fold. Firstly, EUS-BD can be performed from multiple routes in the stomach and duodenum. Thus, duodenal stenosis is not a limitation to biliary access. Secondly, as biliary access is gained distant from the major duodenal papilla, the risk of post-procedure pancreatitis is low. Thirdly, as the deployed stent does not traverse the tumor, its patency could be longer. In a recent study of 95 patients with failed ERCP or inaccessible papilla, direct EUS-guided biliary drainage was successful in 86% of patients with an AE rate of 10.5% that included pancreatitis, bleeding, perforation, bile leak and infection (15). Most AEs were managed conservatively without the need for aggressive treatment measures. In another small, randomized trial of 25 patients with inoperable malignant biliary obstruction, there was no difference in clinical success, AEs, and costs between patients randomized to EUS-BD or PTBD (16). In a recent retrospective study of 208 patients with malignant obstructive jaundice treated by ERCP or EUS-BD directed biliary metal stent placement, there was no difference in the rates of technical success (>90% in both cohorts) or AEs (8.65% in both cohorts) between groups (17). However, patients who underwent ERCP had a 5% incidence of post-procedure pancreatitis compared to 0% in the EUS-BD cohort. Given these promising outcomes, EUS-BD is currently practiced as a complimentary therapy that allows biliary drainage when technical failure is encountered at ERCP. EUS-BD and PTBD have been shown to be comparable in effectiveness after failed ERCP, however patients who underwent PTBD had higher rates of adverse events and required additional interventions (19). PTBD and EUS-BD have shown to be equally effective treatment options (16). The effectiveness of treatment outcomes between EUS-BD and ERCP needs to be evaluated. Since the treatment outcomes and safety profile of EUS-BD is comparable to ERCP and because EUS-BD is successful in more than 85% of patients with a failed ERCP, EUS-BD could be a first-line treatment option and not just a rescue measure for patients with malignant distal biliary obstruction.

Official Title
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Randomized Trial Comparing Endoscopic Ultrasound-guided Biliary Drainage (EUS-BD) and Endoscopic Retrograde Cholangiopancreatography (ERCP) for Malignant Distal Biliary Obstruction

Conditions
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Pancreatic Cancer, Pancreatic Neoplasms, Pancreatic Adenocarcinoma

Intervention / Treatment
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* Procedure: EUS-BD
* Procedure: ERCP


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥ 18 years of age. Has jaundice due to malignant distal (more than 3cm distal to liver hilum) biliary obstruction. The subject (or when applicable the subject's LAR) is able to understand and willing to sign an informed consent form prior to the initiation of any study procedures. Exclusion Criteria: Age <18 years Females who are pregnant or lactating. Pregnancy in females of childbearing potential will be determined by routine preoperative urine HCG testing. Coagulopathy which cannot be corrected (INR >1.6, thrombocytopenia with platelet count <50,000/ml) Has surgically altered gastrointestinal anatomy such as but not limited to (Billroth II/Roux en-Y, gastric bypass). Liver metastasis involving >30% of liver volume. Liver cirrhosis with portal hypertension and/or ascites.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: EUS-BD<br>EUS-BD is a minimally invasive technique where the common bile duct (choledochoduodenostomy) is punctured under EUS-guidance and after transmural dilation, a stent is deployed for biliary drainage. | Procedure: EUS-BD<br>* EUS-BD is a minimally invasive technique where the common bile duct (choledochoduodenostomy) is punctured under EUS-guidance and after transmural dilation, a stent is deployed for biliary drainage.<br>* Other names: Endoscopic Ultrasound-guided biliary drainage;|
| Active Comparator: ERCP<br>At ERCP, the common bile duct will be selectively cannulated using a sphincterotome and guide wire technique. Once biliary access is obtained a stent will be deployed to facilitate biliary drainage. | Procedure: ERCP<br>* During the ERCP, a small catheter and guidewire is inserted into the bile duct and the stent can be deployed into the duct.<br>* Other names: Endoscopic Retrograde Cholangiopancreatography;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rates of perforation | As defined by evidence of air or luminal contents outside the GI tract | 1 week | 
| Rates of pancreatitis | Defined as typical pain with amylase/lipase >3 times normal | 1 week | 
| Rates of bile leak | Not caused by pancreatitis or perforation | 1 week | 
| Rates of bleeding | As defined by A lexicon for endoscopic adverse events: report of an ASGE workshop PMID: 20189503 | 1 week | 
| Rates of infection (cholangitis) | As defined by >38C >24 hours with cholestasis | 1 week | 
| Rates of peritionitis | As defined by A lexicon for endoscopic adverse events: report of an ASGE workshop PMID: 20189503 | 1 week | 
| Rates of cholecystitis | As defined by A lexicon for endoscopic adverse events: report of an ASGE workshop PMID: 20189503 | 1 week | 
| Rates of pneumoperitoneum | As defined by A lexicon for endoscopic adverse events: report of an ASGE workshop PMID: 20189503 | 1 week | 
| Rates of fever | Defined as temperature >38C | 1 week | 
| Rates of abdominal pain | Defined as pain described by the patient not caused by pancreatitis or perforation | 1 week | 
| Rates of death attributable to the procedure. | As defined by A lexicon for endoscopic adverse events: report of an ASGE workshop PMID: 20189503 | 1 week | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Technical Success | Defined as successful placement of a stent for malignant distal biliary obstruction in the desired location as determined at ERCP and EUS in the index session. | 1 day | 
| Treatment success | Clinical success is defined as decrease in direct bilirubin by 50% at 2 weeks | 2 weeks | 
| Procedural duration | Defined as the time between procedure onset and completion of the procedure (stent deployment). The duration will be calculated in minutes from the time the echoendoscope or duodenoscope is positioned and the stent is deployed. | 1 day | 
| Reintervention | Need for additional intervention (endoscopic, surgical or radiological) to relieve jaundice in the presence of dilated biliary system | 6 months |