Primary percutaneous placement of metal stents for palliative biliary drainage in patients with a primary malignant perihilar stricture

Perihilar cholangiocarcinoma (pCCA) is the most common malignancy of the bile
ducts. Unfortunately, most patients are ineligible for curative-intent
resection because of metastatic disease, locally advanced (i.e. unresectable)
disease, or co-morbidity precluding a major liver resection. In the palliative
setting, the median overall survival is only 6-10 months.

The key to successful palliative treatment is adequate biliary drainage to
improve the patient*s wellbeing and to allow for palliative systemic therapy.
Discussion remains whether palliative biliary drainage is best achieved
percutaneously or endoscopically. Regardless of a percutaneous or an endoscopic
approach, biliary drainage for pCCA has a high risk of post-drainage
cholangitis and most patients require multiple reinterventions to improve
biliary drainage. As a result of these complications, 90-day mortality was 35%
after initial palliative drainage in 186 patients with (suspected) unresectable
pCCA in the Netherlands. Notably, the majority of patients with 90-day
mortality have no metastatic disease, suggesting that mortality is mainly
caused by insufficient biliary drainage and/or drainage-related complications.
Failure of current management of biliary obstruction in unresectable pCCA is
also reflected by the very low percentage (<10%) of patients who receive
palliative systemic chemotherapy.

Endoscopic biliary drainage with plastic stents in one or more segments of the
liver is the most common technique in the Netherlands. The main problem of this
approach is that the stents cause bacterial colonization of the previously
sterile intrahepatic bile ducts, because the stents cross the ampulla.
Cholangitis often develops, especially if undrained segments become colonized.
Percutaneous transhepatic biliary drainage is the alternative approach.
External biliary drainage can be accomplished without passing the tumor and the
ampulla. The drawback of external-only drainage is that patients typically
dehydrate and develop metabolic disturbance. The bile fluids can be
readministered with a nasoduodenal feeding tube. However, such a tube impacts
the quality of life. Moreover, cholangitis can still develop from skin bacteria
gaining access to the biliary tree with external biliary drainage. Also,
external drainage suffers from a high risk of catheter dislodgement. Therefore,
percutaneous biliary catheters are typically internalized: that is, side holes
in the intrahepatic part of the catheter collect the bile and deliver the bile
via the tip of the catheter which is positioned beyond the ampulla in the
duodenum. The downside of an internalized percutaneous biliary catheter is the
same as an endoscopic plastic stent: the ampulla is crossed and biliary
bacterial colonization occurs. Percutaneously placed catheters are typically
flushed with normal saline to avoid clogging of the side holes. However,
flushing has the theoretical downside of causing colonized bile to end up in
undrained segments and cause cholangitis.

The only method to avoid colonization of the bile ducts is percutaneous
placement of uncovered self-expandable metal stents (SEMS) that do not cross
the ampulla. After stent placement, the tract is sealed (e.g., with glue)
without leaving a catheter.

We hypothesize that direct SEMS placement in patients with unresectable pCCA
minimizes post-drainage cholangitis and mortality, requires fewer
reinterventions, and increases the rate of patients receiving palliative
chemotherapy.

To proof feasibility and safety of direct SEMS placement for palliative
treatment of perihilar cholangiocarcinoma.

In preparation of the design of a phase-II study, we aim to perform a
proof-of-concept pilot study at Erasmus MC, including 10 patients. The expected
inclusion period is 1 year. When all patients have been included in the pilot
cohort and feasibility and safety have been determined, an expansion cohort
will be added which includes UMC Utrecht, as second participating center in
order to perform a multicenter phase-II trial. Following the first 10 patients
in the pilot cohort, another 27 patients will be included in the expansion
cohort to assess the effectiveness and further assess safety of direct SEMS
placement for palliative treatment of a primary malignant perihilar stricture.
In total 37 patients will be included and analyzed in this study.

Nine months (July 1st, 2022) after approval for the first expansion cohort of
27 patients, we have included 20 additional patients in Erasmus MC. For the
first 30 patients (10+20), the outcomes are compared with our historical cohort
for endoscopic biliary drainage (see protocol, table 1.). Because of these
favorable results, we are currently designing a multicenter randomized
controlled trial (RCT) to compare this intervention with the standard of care
(i.e. endoscopic biliary drainage). Six additional centers will participate in
this trial. To avoid any aspect of learning curve regarding the intervention
within the RCT, each participating center is required to perform the study
intervention in 5 patients in this phase II study, before accruing patients in
the RCT. Therefore, a second expansion cohort of 30 patients (i.e. 5 patients
per center for 6 centers) is required.
A total of 67 patients (10+27+30) will be included and analyzed for the study
endpoints. The expected inclusion period of the additional 30 patients, in six
participating centers, is one year.

Seven months (June 1st, 2023) after approval for the second expansion cohort of
30 patients, we have included 23 additional patients in Erasmus MC. Because of
the favorable results (see table 1), the growing awareness of this study among
other hospitals, and the waiting period for the initiation of the RCT, an
expansion cohort will be added. Therefore, a third expansion cohort of 50
patients is required.

A total of 117 patients (10+27+30+50) will be included and analyzed for the
study endpoints. The expected inclusion period of the additional 50 patients,
in six participating centers, is one year.

Percutaneous transhepatic biliary drainage, by bridging significant ductal
strictures by self-expandable fenestrated metal stents without cannulation of
the ampulla.

The percutanous intervention is an alternative approach to the standard of
care, which is endoscopic biliary drainage. Complications due to the
transhepatic biliary drainage, i.e. bleeding, infection and bile leakage are
uncommon (<5%).
We hypothesize that direct SEMS placement in patients with unresectable
perihilar cholangiocarcinoma minimizes post-drainage cholangitis and mortality,
requires fewer reinterventions, and increases the rate of patients receiving
palliative chemotherapy.