Keywords
pancreatitis - stent - stricture
Introduction
The stents currently used in management of benign biliary and pancreatic diseases
are either plastic stents made up of polyethylene or fully covered self-expanding
metallic stents (FCSEMS). These stents are not ideal stents and several attempts are
being made to improve upon the conventionally available stents. An ideal stent for
benign biliary and pancreatic disease would be the one that has adequate radial expansile
force for a sufficient period of time, provides drainage for a sufficient period of
time, and does not elicit a tissue response or epithelial hyperplasia that may contribute
to the formation of a new stricture.[1]
[2] Apart from these necessary requirements, biodegradability of the stent with biocompatible
breakdown products would be an added advantage, making it an ideal stent. A biodegradable
stent (BDS) with the above-mentioned properties has a potential to replace conventional
plastic and FCSEMS biliary and pancreatic stents for managing benign diseases like
postcholecystectomy biliary strictures, bile leaks, and benign fibrotic pancreatic
duct strictures.
The main advantage of BDSs is avoidance of repeated endoscopic retrograde cholangiopancreatography
(ERCP) for stent removal and thus saving treatment costs and decreasing patient’s
discomfort.[2] This spontaneous degradation is an attractive option in patients who are expected
to have poor compliance to regular follow-up, especially in developing countries like
ours and the problem of difficult removal of impacted stents in situ because of prolonged
indwelling times can be avoided. Also inadvertent stent migration would be of less
concern if the stent is biodegradable. A major problem with FCSEMS is an inability
to place them across the hilum and cystic duct because of risk of occlusion of the
ducts. However, BDS has a meshed design and therefore they can be deployed across
the hilum and cystic duct without fear of occlusion.[1]
[3] The initial data on the use of biodegradable stents look promising but studies on
efficacy of these stents are still limited and there are teething problems, like reduced
expansile force and fragmentation of the stent during degradation causing duct obstruction
that are yet to be resolved.
Initially, BDS was used in animal models and the results on biocompatibility and degradation
were encouraging. The initial BDS was made with biodegradable polymers that were similar
to the materials used in biodegradable surgical sutures. These materials had proven
biocompatibility and reliable degradation times and have been in use for a long time.
These biodegradable synthetic polymers include polyglycolic acid, polylactic acid,
and their copolymers, poly-p-dioxanone (PDX), and copolymers of trimethylene carbonate
and glycolide.[4] A biodegradable stent made up of polylactide (PLA) and loaded with barium sulfate
powder for radio-opacity was evaluated in the bile ducts of pigs and the authors reported
that the stent can be deployed endoscopically, is self-expanding, can be visualized
on fluoroscopy and remains functionally patent for more than 6 months.[5] There was no bile duct integration or proliferative changes but stent migration
and occlusion were important concerns. PLA BDS was also evaluated in the pancreatic
duct of a swine model.[6] The authors reported that this novel biodegradable pancreatic stent appeared to
be safe for use in the pancreatic duct (PD). Other biodegradable polymers have also
been evaluated but studies have shown that BDS made up of PDX is the best as they
offer good expansion force and patency that is very similar to that provided by FCSEMS
and importantly, have controlled degradation.[7]
Studies evaluating clinical use of BDS are limited and majority of published work
on safety and efficacy of BDS is on its use through the percutaneous route. Petrtýl
et al in 2010, studied two patients with postbilioenteric anastomotic strictures who
were successfully treated with percutaneous placement of PDX stents.[8] Mauri et al reported their experience with percutaneous placement of PDX stents
in 10 patients with benign biliary strictures and reported that stent placement was
successful in all patients with no major procedure related complications. Also, stent
degradation occurred within 6 months and stricture resolution was documented at a
median follow-up of 16.5 months with none of the patients requiring any further intervention.[9] The same investigators in 2015 published further data on percutaneous placement
of 7- to 12-mm diameter PDX stents in 107 patients with benign biliary strictures
refractory to bilioplasty. Technical success rate was 98% with an acceptable stent
migration rate of 2%. At a median follow-up of 23 months, stricture recurrence was
seen in 18% and the estimated stricture recurrence rates were 26 and 29%, at 2 and
3 years, respectively.[10] Although, the technical, as well as clinical success rates of these studies were
impressive, up to 30% patients treated with BDS developed episodes of transient cholangitis
that was hypothesized to be due to transient bile duct obstruction by stent fragments
during the process of stent degradation.
The clinical experience with endoscopic insertion of BDS is limited due to challenges
in development of endoscopic delivery devices for BDS. However, the development of
an endoscopic implantation device for deployment of PDX BDS has led on to studies
evaluating its clinical utility. Siiki et al published the first successful endoscopic
biodegradable biliary stent placement in a patient with postcholecystectomy cystic
duct stump leak. An 8-mm custom made braided PDX self-expandable stent was successfully
deployed using a novel insertion device.[11] Further, successful stent placements in benign biliary strictures and iatrogenic
biliary leaks were reported by the same investigators (n = 13). 8- to 10-mm PDX stents (Ella CS, Hradec Králové, Czech Republic) with radiopaque
markers at both ends were placed using 10.5 French insertion devices. Stent deployment
was successful in all patients even though some of the stents had to be adjusted into
position using grasping forceps or extraction balloons postdeployment. On radiological
follow-up, all the stents degraded within 6 months. Stricture resolution was seen
in 83% patients at a median follow-up of 21 months and resolution of bile leak was
seen in all the treated cases. The adverse events documented were cholangitis and
pancreatitis, in one patient each.[12] Same group also reported a prospective nonrandomized trial comparing BDS (n = 8) with plastic stents (n = 24) for management of iatrogenic bile leaks. Clinical success rates were similar
(BDS 100% vs. plastic stents 75%, p = 0.059). One patient in BDS group developed cholangitis but overall adverse events,
length of hospital stay, and readmission rates were similar between the two groups.[3]
BDS has also been studied for treating benign pancreatic diseases. Cahen et al published
the first endoscopic placement of biodegradable pancreatic stents. PDX stents (Ella-DV
biliary stent, ELLA-CS, Hradec Králové, Czech Republic) with 6-mm diameter and length
of 3 to 4 cm were placed in 19 patients with pancreatic duct strictures. Stent placement
was successful in all patients with no major periprocedural adverse events. Stricture
resolution was seen in 58% at 6 months of follow-up and two stents got occluded necessitating
balloon clearance of stones and sludge. Stent degradation occurred in a predicted
manner within 6 months.[13] Despite these encouraging results, progressive decrease in radial force with stent
degradation that may be insufficient to dilate and remodel benign strictures, and
duct obstruction due to stent fragments are a matter of concern. Therefore, there
is a need to further improve upon the design of BDS before they can be put into routine
clinical use.
In this news and views we discuss, an interesting study by Anderloni et al that has
evaluated a new type of biodegradable biliary and pancreatic stent (the Archimedes
stent, Amg International GmbH, Winsen, Germany) in benign biliary and pancreatic diseases.[14] The Archimedes stent has a helicoidal shape that is presumed to facilitate bile
or pancreatic juice flow through the outer surface of the stent while supporting the
duct opening, and are available in a wide range of lengths and outer diameters. Importantly,
these stents are made up of varying combinations of polymeric mixtures so that they
have different degradation times: (1) fast (12 days): polymeric mixture of PDX, polyethylene
glycol (PEG), and barium sulfate; (2) medium (20 days): polymeric mixture of PDX and
barium sulfate; and (3) slow (11 weeks): blend of poly (lactidecocaprolactone-co-trimethylene
carbonate) and barium sulfate. This varying degradation times can be of use in differing
clinical indications. The stent degradation occurs via hydrolysis of polyester polymers
and stent migration is minimized by proximal and distal flaps. These stents have a
central channel for a 0.035̋ guidewire and are available in three outer diameters:
2 (6 F), 2.6 (8 F), and 3.4 mm (10 F), and in lengths ranging from 4 to 12.5 cm. An
important advantage of this novel stent is that it does not require a special delivery
device and can be inserted over the guidewire like conventional plastic stents.
In this pilot study, 38 patients (11 females [28.9%]; median age 68.05 ± 10.74 years),
underwent placement of 53 biodegradable stents. Out of 53 stents, 34 were biliary
stents placed for varied etiologies like iatrogenic bile duct strictures, strictures
secondary to chronic pancreatitis, postampullectomy, in severe cholangitis, primary
sclerosing cholangitis (PSC), and preoperative drainage of malignant biliary strictures
and 19 were pancreatic stents placed for prevention of post-ERCP pancreatitis (PEP)
or in pancreatic ductal strictures secondary to chronic pancreatitis. The authors
used 35 (66%) slow-degrading stents, 6 (11.3%) medium-degrading stents, and 12 (22.6%)
fast degrading stents. The type of stent used depended on the clinical indication,
fast degrading stents were used for prevention of PEP, and slow degrading stents were
used in patients with benign strictures. Unlike previous stents where only the radiopaque
markers could be seen on radiography, here radiopaque barium sulfate was incorporated
into the stent material, and the entire stent could be visualized on fluoroscopy.
The primary outcome of the study was to evaluate the degradation time of the stents.
The secondary outcome of the study was to evaluate technical features related to stent
performance at the time of stent positioning, particularly, loadability, pushability,
and fluoroscopic visibility.
The authors reported technical success in all the patients. Stent loadability and
pushability were excellent in the majority and fluoroscopic visibility was either
good or excellent in 94% of the cases. Importantly, the safety profile was also excellent
and there were no episodes of cholangitis. Though the study did not aim at evaluating
clinical efficacy, none of the patients needed any further treatment during the follow-up
period, and the subgroup with biliary strictures had significant reduction in bilirubin
levels. Five (9.4%) stents prematurely migrated and this happened in patients where
the stents were placed for indications other than strictures. Stent degradation, assessed
at predefined intervals was as expected, 100% of fast stents degraded in 4 weeks,
medium stents in 6 weeks, and slow stents in 6 months. The authors concluded that
the biodegradation of the new biodegradable biliary and pancreatic stent is reliable
and as expected. Moreover, the stent insertion was technically successful in a variety
of benign biliary and pancreatic diseases.
Commentary
BDS is a dream that the pancreaticobiliary endoscopists have been chasing for a long
time. Various technical issues have hampered the widespread use of BDS. The novel
Archimedes stent used in the current study has many advantages compared with previously
studied biodegradable stents. Foremost is the ease of deployment which is similar
to conventional plastic stents. Moreover, multiple stents may be placed in a single
sitting for the treatment of biliary and pancreatic strictures. Stents with different
degradation times opens new avenues for use of biodegradable stents, including in
the preoperative biliary drainage of malignant strictures and prevention of PEP. A
cause of concern with previous stents were reports of cholangitis in up to 30% of
cases due to stent fragmentation during degradation of the BDS. In the current study,
none of the patients developed cholangitis on follow-up. The spiral design of the
Archimedes stent along with the polymeric stent material might have contributed to
better stent patency and more uniform degradation preventing duct obstruction.
There were initial concerns whether BDS could provide adequate radial force to cause
biliary stricture remodeling and stricture resolution. Though PLA stents had less
radial force, PDX stents, especially those with 10-mm diameter have been found to
have almost similar expansion force like FCSEMS.[7] A recent systematic review and meta-analysis comparing BDS (three studies) with
multiple plastic stents (six studies) for benign biliary strictures reported that
BDS is not inferior to multiple plastic stents in resolving and maintaining long-term
biliary duct patency.[15] However, patients in BDS group had higher incidence of postprocedural cholangitis.
The Archimedes stents used in this study did not have this adverse effect of cholangitis.
Extrapolation of these results suggest that these stents may be as effective as FCSEMS
for management of benign strictures with added advantage of biodegradability.
Conclusion
In conclusion, BDS does hold promise in the treatment of benign biliary or pancreatic
diseases with the major advantage being avoidance of ERCPs for stent removal or stent
exchange. They have been confirmed to have good biocompatibility and current evidence
shows acceptable rates of clinical efficacy and safety. Larger control trials with
long-term follow-up are needed before these stents can be advocated as a replacement
for conventional plastic stents or FCSEMS.
