Introduction
Chronic pancreatitis (CP) is a fibro-inflammatory disease of the pancreas that often
is a result of heavy and prolonged alcohol use. It can also occur as a final consequence
of pancreaticobiliary obstruction, cystic fibrosis, autoimmune pancreatitis, or other
rheumatologic diseases [1]. In a single-center study, CP had a sex- and age-adjusted prevalence of 42 cases
per 100,000 person years [2]. It results in more than 122,000 outpatient visits and in more than 56,000 hospitalizations
yearly in the United States alone [2]. CP manifests as both exocrine and endocrine insufficiency. It is characterized
by strictures and progressive fibrosis with destruction of the islet and acinar cells
[3]. Severe episodes of pain are the presenting complaint in 30 % to 85 % of patients
[4], causing disability, early retirement, opiate addiction, and recurrent hospitalizations
[5], Symptomatic pancreatic duct strictures are commonly managed endoscopically with
plastic stents. However, up to 68 % of treated patients still experience pain 5 years
post-intervention. The Dutch multicenter trial showed that conventional endoscopic
management with plastic stents and balloon dilation had a lower rate of success than
longitudinal pancreaticojejunostomy [6]. Fully covered self-expanding metal stents (FCSEMS) have been used successfully
to treat benign biliary strictures, and have also been reported to be useful in management
of pancreatic duct strictures [3]. The aim of this study was to investigate the feasibility, safety, and efficacy
of FCSEMS in refractory pancreatic duct strictures.
Patients and methods
A retrospective review of patients with moderate to severe chronic pancreatitis who
had undergone endoscopic retrograde cholangiopancreatography (ERCP) with FCSEMS placement
between February 2010 and June 2016 at five tertiary care centers was performed. Patients
were included if they had refractory pain despite prior treatment with a conventional
therapy that included at least three balloon dilations, repeat plastic stent placements
with upsizing of the stents, or stone lithotripsy. Patients with malignant strictures
were excluded.
Technical success was defined as successful placement of the FCSEMS during the ERCP.
Clinical success was defined as improvement in stricture diameter as well as symptomatic
pain relief seen by improvement in pain scores on the visual analogue scale (VAS).
Adverse events (AEs), including infection, stent occlusion, stent migration, and bleeding
were noted. AEs were graded according to the American Society for Gastrointestinal
Endoscopy lexicon severity grading system [5]
[7]. As this was a retrospective study, clinical success and AEs were documented by
each institution in various forms by either phone or office visit. All patients gave
informed consented for the procedure and all centers received approval by their respective
institutional review board.
Endoscopic technique
Endoscopists who performed the endoscopic procedures all had extensive experience
in endoscopic management of chronic pancreatitis, each having done more than 1000
ERCPs. Side-viewing endoscopes (TJF-180, TJF-160, Olympus America, Center Valley,
Pennsylvania, United States) were used for all procedures. Pancreatic sphincterotomy
was performed on all patients before FCSEMS placement. The pancreatic stricture was
dilated with either a 4-mm or 6-mm balloon dilator (Hurricane, Boston Scientific,
Natick, Massachusetts, United Sates), then, over a 0.035-inch guide- wire, an 8-mm-diameter
or 10-mm-diameter FCSEMS (Wallflex, Boston Scientific Corp, Natick, Massachusetts,
United States) was placed in the main PD across the stricture ([Fig. 1]); the length of the stent was determined by the length of the stricture. Biliary
sphincterotomy was performed at the same time if no prior one was performed. The FCSEMSs
were removed after a period of at least 3 weeks with snare or rat-tooth forceps and
pressure injection was performed to confirm pancreatic drainage after stent removal.
Fig. 1 a PD cannulation with a guidewire. b Balloon dilation of the pancreatic duct. c Placement of the FCSEMS into the PD with an anchoring double pigtail stent
Outcome measures
Primary endpoints were technical success, clinical success, and procedure-related
morbidity. Secondary endpoints were pain relief at the end of follow-up, resolution
of the pancreatic stricture on fluoroscopy during ERCP and AEs. Pain scores were collected
prior to the procedure and in follow-up on most patients, as well as doses of analgesic
medications at each office visit or over phone. Pain scores were recorded as VAS if
available at each office visit.
Statistical analysis
Descriptive statistics were calculated for all demographic and clinical variables
and reported as mean ± standard deviation, median (interquartile range), or as a proportion
where appropriate. Univariate analysis was performed using χ2 test and Fisher exact
test for categorical variables and Student’s t test, Wilcoxon or Mann-Whitney U test as required for continuous variables. All variables
were tested for normality using the Shapiro-Wilk test. All statistical analysis was
conducted using STATA 13.0 (StataCorp LP, College Station, Texas, United States).
P < 0.05 was considered significant.
Results
A total of 33 patients (75 % male, mean age 53.9 ± 13.1 years) with chronic symptomatic
pancreatitis underwent ERCP with a FCSEMS (Wallflex, Boston Scientific, Natick, Massachusetts,
United States) placement with a mean follow-up time of 14 months (range: 6 – 24).
Strictures were located in the head, genu or proximal body in all patients. Pancreatic
stones were present in 17(51 %) patients. Prior therapy included balloon dilation
and plastic stent placement in all 33 patients (100 %), mechanical and laser lithotripsy
in 17 patients (51 %) as well as extracorporeal shockwave lithotripsy (ESWL) therapy
in eight patients (24 %). ([Table 1]). The underlying etiology for pancreatitis included alcohol (n = 19, 58 %), idiopathic
(n = 8, 24 %), divisum (n = 2, 8 %), and other (n = 4, 12 %). Four patients also had
a stent in the common bile duct (CBD): FCSEMSs in two patients and plastic stents
in the other two patients. One patient had a FCSEMS placed through his minor papilla
while the remainder was placed through the major papilla. Stents were removed after
median of 14.4 weeks (range 12 – 22).
Table 1
Basic demographics and outcomes of patients.
|
Demographics n = 33 (%)
|
|
Age, years median (range)
|
|
54 years (18 – 87)
|
|
Male sex
|
|
25 (75.8)
|
|
Prior endoscopic treatment
|
Balloon dilation
|
20 (60.6)
|
|
Plastic stent placement
|
33 (100)
|
|
ESWL
Lithotripsy
|
8 (24.2)
17 (51.5)
|
|
Etiology
|
Alcohol
|
19 (57.6)
|
|
Idiopathic
|
8 (24.2)
|
|
Divisum
|
2 (6.06)
|
|
Unknown
|
4 (12.1)
|
|
Diabetes
|
|
5 (15.1)
|
|
Exocrine Insufficiency
|
|
29 (87.8)
|
|
Outcomes
|
|
Technical success rate
|
|
33 (100)
|
|
Adverse events
|
|
Overall
|
11 (33
|
|
Immediate Stent Removal
|
2 (6.06)
|
|
Cholestasis after stent placement
|
2 (6.06)
|
|
Stent impaction
|
1 (3.03)
|
|
Worsening abdominal pain
|
6 (18.2)
|
|
Migration
|
0 (0.00)
|
|
Stent duration, weeks median (range)
|
15 (12 – 22)
|
|
Reduction in narcotic use
|
|
27 (87.1)
|
|
Need for further therapy
|
|
12 (36.4)
|
ESWL, extracorporeal shock wave lithotripsy
Technical and clinical success rates
Technical success was achieved in all 33 patients (100 %). Clinical success with successful
subjective pain relief was achieved in 31 patients (93 %). Objective long-term pain
relief with reduction in pain medication was achieved in 27 patients (87 %) ([Table 1]). Median patient pain score prior to the procedure on the VAS was 8.5 (range 7.25 – 9.75)
and post procedure was 2.5 (range 1 – 3) with a statistically significant improvement
(P < 0.001) ([Fig. 2]). After stent removal, the diameter of the narrowest MPD stricture had increased
significantly from 1 mm to 4.5 mm (P < 0.001).
Fig. 2 Tukey plot showing decrease in VAS after FCSEMS intervention. Whiskers extend to
1.5* interquartile range
No new strictures developed in anyone. Twelve patients (36 %) required further therapy,
while the remainder became stent free. Four patients were stent dependent and two
of them required eventual surgery.
Procedure-related AEs
Immediate AEs included severe abdominal pain in two patients after stent placement
requiring immediate stent removal (both with 10-mm stents), as well as overnight admission
for pain control in two patients. Four other patients developed pain that responded
to short-interval pain management. Two patients developed elevation in their liver
function tests, one of whom required biliary stent placement. No other short-term
AEs (< 30 days) occurred. There were no cases of pancreatitis, or pancreatic infection.
There were no late AEs. One patient had stent impaction at time of removal but the
stent was successfully removed endoscopically. There was no stent migration.
Discussion
CP is a disease of unrelenting pain flares, exocrine insufficiency, and diabetes.
While the exocrine and endocrine pancreatic functions can be replaced, until recently
there have been few effective interventions for chronic pain and the treatment emphasis
has been and still is on chronic pain management.
Endoscopic therapy in CP is centered on draining the MPD and PD stone fragmentation
to provide pancreatic duct decompression. Historically, pancreatic duct strictures
have been managed with placement of either single or multiple plastic stents [8]
[9]. Recurrent symptomatic strictures limit effectiveness of this approach. FCSEMS were
originally developed for palliation of malignant biliary strictures, and subsequently
used in benign biliary strictures [10]
[11]. Few studies evaluated use of FCSEMS in symptomatic benign PD strictures [9]
[12]
[13]
[14]. The most recent study included 10 patients with painful chronic pancreatitis and
refractory dominant pancreatic duct strictures treated with FCSEMS. They were followed
for a relatively long period of 19.8 months. A collaborative international study found
use of metal stents feasible, safe, and potentially effective [15]. Our study technical success rate was similarly high when compared to the other
four previous studies evaluating FCSEMS in PD strictures ([Table 2]) [12]
[13]
[14]
[15]. Prior studies have described acute pancreatitis as a complicating factor in endoscopic
management of PD strictures with rates as high as 28 %. It was thought to happen because
of PD dilation with a stent retriever or a balloon dilator [13]. We report a 0 % incidence of acute pancreatitis post-procedure in this study, highlighting
the need to offer appropriate pancreatic duct decompression. Severe abdominal pain
occurred in two patients, necessitating stent removal. Those two patients had 10-mm
stents as opposed to the 8-mm stents that were placed in other patients. The remainder
of the patients who had pain were managed with intravenous narcotics in-house during
the first week post-placement. Biliary cholestasis occurred in only 6.1 % of our patients,
compared to 15 % and 20 % reported in other studies [13]
[15]. This was treated with biliary stent placement. Our observed post-procedure pain
scores were significantly improved after FCSEMS placement, similar to other studies
[12]
[13]
[14]. In this study, the recurrence rate for treated strictures was 0 % after a median
follow-up of 8 months (range 5 – 14), which is significantly better than PD stricture
recurrence rates in prior studies that vary from 9 % to 60 % in the same follow-up
period [9]
[12]
[13]
[14]. This may be explained by the covering design of the SEMS and the absence of fins,
known to be associated with mid-term or long-term recurrence [12]. Measurements of PD after FCSEMS placement showed statistically significant improvement
inf strictures and a reduction in diameter of the dilated upstream ducts in line with
previously reported data [12]
[13]
[14]
[15]. Basis for improvement in pain with FCSEMS is unclear and may be related to overall
improved pancreatic duct drainage or better stretching of fibrostenotic strictures
themselves that cause nerve entrapment and chronic pain.
Table 2
Publications with metal stent placement for chronic pancreatitis.
|
Author
|
Patients
|
Success
|
Complications
|
Outcomes
|
|
Sauer et al. [12]
|
6
|
50 %
|
None
|
Temporary placement of FSEMSs with fins in patients with symptomatic refractory PD
stricture offered transient relief of pain
|
|
Park et al. [13]
|
13
|
69 %
|
2 cases of acute pancreatitis
5 migrations
2 incidents of cholestasis secondary to FCSEMS placement
|
Placement of FCSEMSs in patients with refractory benign pancreatic ductal strictures
may be feasible and relatively safe
|
|
Moon et al. [14]
|
32
|
100 %
|
None
|
Effective in resolving pancreatic-duct strictures in chronic pancreatitis
|
|
Giacino et al. [15]
|
10
|
90 %
|
N = 2 cholestasis
|
The diameter of the narrowest MPD stricture had increased significantly from 3.5 mm
to 5.8 mm and pain relief was achieved in nine patients
|
|
Sharaiha et al.
|
33
|
96 %
|
N = 2 abdominal pain
N = 2 cholestasis
|
Significant improvement in pain and stricture diameter
|
FCSEMS, fully covered self-expanding metal stent; PD, pancreatic duct; MPD, main pancreatic
duct
Limitations of this study include its small size and retrospective nature, which did
not allow for collection of all variables. While randomized control trials present
a better way to evaluate a device’s effectiveness against the standard of care, in
cases of rare events or rare interventions, a multicenter randomized control trial
may not be a feasible option. The multicenter nature of this study meant that we could
not systematically ensure uniform patient management, which might have been a source
of potential bias. We have a remarkably low pancreatitis rate; however, we recognize
that this may have been underreported given that we only counted those who were admitted
to the hospital. Importantly, while the stricture recurrence rate was 0 %, we did
note that some patients remained stent-dependent and two patients even required surgery.
Our 93 % clinical success rate only shows initial improvement; 36 % of patients still
needed interval ERCPs. These patients may be truly refractory to endoscopic therapy.
We think that the poor response to pain is due to the fact that the PD strictures
in some patients were distal to the metal stent and could not be treated. While VAS
is an accepted way to measure pain response, novel research indicates that the Pancreatitis
Quality of Life Instrument, a novel validated tool for evaluation of quality of life
in chronic pancreatitis, may be useful in future research studies [16].
This is the largest case series of patient with refractory PD strictures and chronic
pancreatitis treated with FCSEMS. Although the study concerns a subclass of patients
who fail conventional plastic stenting, the long-term follow-up provided is its strength.
In addition, it confirms that wide-diameter FCSEMS (8 or 10 mm) may be difficult to
tolerate in 20 % of patients and aggressive management of pain post-deployment may
be required.
Conclusion
In summary, our data confirm previous studies showing that FCSEMS placement for refractory
MPD stricture is safe and effective in the majority of patients. Smaller-diameter
(6 mm) FCSEMS are expected to be further investigated through prospective trials before
widespread adoption of this type of intervention. In our future prospective studies
in chronic pancreatitis, we will be sure to use this tool for a complete assessment
of the patients’ quality of life, pain, and emotional well-being.
