Percutaneous Transhepatic Cholangiography Versus Endoscopic Ultrasound Guided Biliary Drainage in Advanced Biliary Tract Malignancy That Failed ERCP (PETRUS Study): A Randomized Pilot Study
Advanced biliary tract malignancy complicated by obstructive jaundice has been traditionally
managed by palliative stent placement at ERCP. In 3-12% of patients with advanced disease
tumour involvement of the small bowel or peri-ampullary region may preclude the use of ERCP
necessitating percutaneous transhepatic biliary drainage (PTBD) or surgery1. However these
techniques have been associated with high complication rates and significant morbidity2.
PTBD necessitates traversing the parietal and visceral peritoneum causing a potential for a
bile leak and bleeding into the peritoneal cavity. This procedure is also associated with
significant pain, lengthy hospital stays and an overall reduction in quality of life, and
even procedure related mortality. Indeed the Society of Interventional Radiology (SIR)
quality improvements guidelines established the procedural risk of severe major
complications including sepsis, bleeding and procedural related death at 2.5% and less
severe complications including pain and prolonged hospital admissions at 20%.
In recent years various groups have described endoscopic ultrasound guided access of the
left system allowing placement of metal or plastic stents either across the distal stricture
or deploying the stent in the stomach (hepatico-gastrostomy), with high technical success3.
Retrograde cannulation normally performed from the duodenal bulb allows access to the
biliary tract above a malignant stricture with the intent to either pass a guide wire
through the papilla and then perform a rendezvous procedure, or the placement of a covered
metal stent into the stomach (choledochoenterostomy)10. Cannulation of a dilated segment 2
or 3 sectoral duct is also possible from the proximal stomach where the endoscopist performs
all procedures in an antegrade fashion5. Currently these procedures are selectively
performed in centres by expert endoscopists from mainly tertiary care academic expert
centres including in Leuven. Collectively EUS biliary drainage is technically successful in
75-92% of cases, however reports of bile leaking and peritonitis have been described5.
Various obstacles however still exist to extend the general applicability of this technique
outside expert centres. Firstly, no randomized control trials exist comparing the safety and
efficacy of EUS biliary access to Percutaneous Transhepatic Cholangiography (PTC). Secondly,
current endoscopic techniques utilize standard endoscopic accessories not specifically
developed to be utilized within the biliary system when advanced through the gastric wall.
Thirdly, specific EUS strategies are needed to prevent or reduce complications associated
with percutaneous approaches.
Concept and preliminary experimental data
Based on the literature we hypothesize that:
- Endoscopic ultrasound guided biliary drainage is more effective than percutaneous
biliary drainage in the management of obstructive jaundice
- EUS guided biliary drainage is associated with a reduced incidence of major (bile
peritonitis, procedure related mortality, hematobilia) and minor (abdominal pain,
prolonged hospital stay) complications.
- EUS guided biliary drainage is more cost effective compared to percutaneous biliary
Aims of proposed research
Based on the current literature we propose a randomized pilot study assessing the following
specific end points
- EUS biliary drainage is as effective as percutaneous biliary drainage in achieving
resolution of cholestasis
- EUS biliary drainage is not associated with an increased risk of complications compared
to percutaneous biliary drainage.
Study population. Patients with obstructive jaundice due to locally advanced/metastatic
malignancy with dilated intrahepatic bile ducts will be recruited from the department of
Gastroenterology and Hepatology at the University Hospital of Leuven.
This population will have failed ERCP or will be considered when ERCP is not possible due to
altered surgical anatomy.
Patients will be randomized to either PTC or EUS guided biliary drainage
- Patients older than 18 years presenting with malignant obstructive jaundice
- Locally advanced primary or metastatic malignancy involving the biliary tract
- Patients in whom an ERCP have failed or where an ERCP is not possible due to surgically
altered anatomy (eg. Post-Whipple).
• Resectable biliary tract malignancy with curative intent
Linear array endoscopic ultrasound (Pentax, Pentax Hitachi, Montvale, NJ) will be used to
identify the dilated left system. The Doppler mode was used to differentiate intrahepatic
bile ducts from portal and hepatic vein branches. A 19G needle (Echo-19, Cook, Limerick,
Ireland) will be used to puncture a peripherally located dilated segment 2 or 3 duct under
EUS guidance. Under fluoroscopic control a cholangiogram will be obtained and a standard
0.035 guide-wire (Hydra Jag wire, Boston Scientific, Natick, MA Boston Scientific) will be
advanced into the biliary system. Next a 6Fr cystotome (Endoflex, Voerde, Germany) will be
used to create a trans-gastric tract through the liver parenchyma to the dilated biliary
system. The guidewire will be manipulated across the stricture into the duodenal lumen. A
Hurricane biliary dilation balloon 4cm x4mm (Boston Scientific, Natick, MA Boston
Scientific) will be advanced through the tract and used to dilate the common bile duct
stricture without balloon dilation at the level of the gastric wall liver interface. A 10mmx
80mm uncovered self expandable metallic stent (SEMS) will be advanced and deployed under
fluoroscopy across the papilla and past the duodenal obstruction when present.
In patients were the left ductal system is not dilated, biliary access will be obtained from
the duodenal bulb and a covered metal stent will be deployed in the stomach
In patients with duodenal obstruction a Wallstent will be placed at the same session as part
of standard of care.
Novel research perspectives and expected outcomes
- Our research will address a very difficult clinical problem in an unique way: comparing
the standard of care biliary drainage procedure (PTC) to EUS guided biliary drainage.
- We expect to demonstrate that EUS guided biliary drainage is as effective as PTC
- We also expect to show that EUS guided biliary drainage is associated with a reduced
incidence of complications and reduced hospital stay.
- Primary endpoints
- Pain: Post-procedural pain as measured by visual analogue score (VAS) at 2, 24,
and 72 hours following the procedures
- Biochemical changes: Bilirubin decrease at 2 and 4 weeks
- Secondary endpoints
- Major complications including bile leak, bleeding, sepsis or death
- Duration of procedures in minutes
- Length of ICU and hospital stay
- Minor complications
Statistics power calculations It is assumed that 50% of the patients will experience
prolonged pain after PTC defined as pain lasting more than 48 hours and requiring
analgesics. 48 patients in total (24 per group) are then needed to detect with 80% power a
difference with EUS, expecting 10% of the patients having prolonged pain after EUS. The
sample size calculation is based on a two-sided Fisher's Exact test (with alpha=5%). To
compensate for potential dropout, 7 additional patients in total will be recruited. Therefor
the sample size will comprise of 55 patients. Exact 95% confidence intervals will be
calculated for the proportion major complications in both groups. Proportions will be
compared using a Fisher's Exact test. A Mann-Whitney U test will be used to compare the
actual VAS scores and changes in VAS scores between groups. A log-rank test will be used to
compare the length of hospital stay (LOS), censoring potential deceased patients at a value
exceeding the highest observed LOS.
P-values smaller than 0.05 will be considered significant. Statistical analyses will be
performed using SAS software, version 9.2 of the SAS System for Windowsld be given when
defining the endpoints.
Department of Internal Medicine, Division of Hepatology: Prof. Frederik Nevens, Prof. Werner
van Steenbergen, Prof. Chris Verslype, Prof. Wim Laleman, Prof. David Cassiman, Prof. Schalk
van der Merwe
Department of Interventional radiology:
Prof. Geert Maleux, Dr. Sam Heye, Dr. Johan Vaninbroukx
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Factorial Assignment, Masking: Open Label, Primary Purpose: Treatment
Pain: Post-procedural pain as measured by visual analogue score (VAS) at 2, 24, and 72 hours following the procedures
- Primary endpoints Pain: Post-procedural pain as measured by visual analogue score (VAS) at 2, 24, and 72 hours following the procedures Biochemical changes: Bilirubin decrease at 2 and 4 weeks
Schalk van der Merwe, MD, PhD
Belgium: Federal Agency for Medicinal Products and Health Products