Introduction
Chronic pancreatitis (CP) is a progressive inflammatory disease characterized by irreversible
morphological characteristics such as pancreatic atrophy, fibrotic tissue replacement
and pancreatic calcifications [1]. Obstructive pancreatic duct (PD) stones can be the culprit responsible for (recurrent)
pain relapses or chronic pain most likely due to pancreatic ischemia caused by an
increased intraductal and parenchymal pressure [2]. In current practice, patients with obstructive PD stones are treated using an endoscopy-first
approach [3]
[4]. Extracorporeal shock wave lithotripsy (ESWL) followed by endoscopic extraction
of stone fragments is recommended as first-line treatment for stones larger than 5 mm
[4]. ESWL involves careful targeting of the pancreatic stone with shock waves generated
by a strong electromagnetic lithotripter [5]. Pancreatoscopy-guided intraductal lithotripsy is a relatively new promising technique
which may serve as an alternative treatment for ESWL [6]. With pancreatoscopy-guided intraductal electrohydraulic lithotripsy (EHL), fragmentation
of stones is achieved under direct visualization by the absorption of shockwave pulses
generated by a bipolar probe in an aqueous medium [7]. We recently evaluated the efficacy and safety of pancreatoscopy-guided EHL as first-line
therapy in consecutive patients with obstructive chronic calcifying pancreatitis (PELSTONE
study) [8]. When PD cannulation was achieved, pancreatoscopy was technically successful in
92 % of patients defined as complete (100 %) or partial ductal clearance (50 % to
99 %) based on post-EHL pancreatoscopic imaging and fluoroscopic pancreatogram. At
6-month follow-up compared with baseline, a significant improvement in Izbicki Pain
Score and reduction in opioid usage was observed. However, the long-term clinical
outcomes of pancreatoscopy-guided EHL as first-line treatment of obstructing PD stones
are unclear and, since CP is a chronic disease, a longer clinical follow-up for such
studies is required. Therefore, the aim of the present study is to evaluate the long-term
clinical success of pancreatoscopy-guided EHL as first-line treatment in patients
with symptomatic CP due to obstructive distal PD stones and to compare outcomes to
a historical cohort of patients who underwent ESWL as a primary treatment.
Patients and methods
Study design and population
An observational retrospective long-term follow-up study of patients who underwent
pancreatoscopy-guided EHL was conducted at the Erasmus MC University Medical Center
Rotterdam, the Netherlands, an academic tertiary referral center for pancreaticobiliary
diseases. In this study, we report and primarily focus on the long-term outcomes of
pancreatoscopy-guided EHL as first-line treatment for patients with CP and symptomatic
obstructive PD stones. In addition, to put these outcomes into perspective, we describe
the long-term outcomes of patients who underwent ESWL followed by ERP as primary treatment
(historical cohort), which is the recommended treatment in current guidelines.
For the EHL cohort, we included patients who were technically successful treated with
pancreatoscopy-guided EHL as first-line treatment and who participated in the previous
PELSTONE study [8]. The EHL technique and protocol we used have been described in detail previously
[8]. In short, in all patients a pancreatic sphincterotomy was performed to facilitate
introduction of the pancreatoscope (SpyGlass DS Direct Visualization System, Boston
Scientific Corp, Natick, Massachusetts, United States). If a stricture was present
that precluded the passage of the pancreatoscope, a balloon dilatation was attempted.
When the stone was visualized with the pancreatoscope, a 1.9F EHL probe (Nortech AUTOLITH
system, Northgate Technologies, Inc., Elgin, Illinois, United States) was introduced
and EHL was performed. Depending on characteristics of the stone (i. e., size and
hardness), generator settings of the AUTOLITH system were adjusted. Adjustments could
be made in power settings varying from low to high and number of shots given per second
(i. e., 10 or 15 shots). After lithotripsy was performed, residual stone fragments
< 5 mm were extracted using retrieval balloons, baskets or both. Patients with concomitant
PD strictures were not excluded from the EHL- nor ESWL cohort. PD strictures were
treated endoscopically in both cohorts by exchanging stents on a regular basis (i. e.,
every 3 months) and insert an increasing number of stents (7Fr or 10F diameter) with
each consecutive procedure to further dilate the stricture, during a fixed 1-year
stenting period.
In the previous study, patients were included in case of an established diagnosis
of CP according to the M-ANNHEIM criteria, and one or more PD stone(s) of ≥ 5 mm in
the head or the neck of the pancreas as shown on cross-sectional imaging (i. e., computed
tomography (CT), magnetic resonance cholangio-pancreatography (MRCP)) or endoscopic
ultrasound (EUS) [9]. Exclusion criteria included, age < 18 years, asymptomatic patients, patients suffering
from CP with stones located in the body or tail of the pancreas, previous treatment
of PD stones using ESWL, history of surgical treatment of CP and pregnancy. Moreover,
patients were not eligible for study inclusion in case endoscopic treatment was not
deemed to be possible or successful, due to for example a non-dilated PD or a completely
calcified pancreas. Patients were consented for the current study and included when
previous pancreatoscopy-guided EHL therapy had been technically successful defined
as ductal clearance confirmed with post-EHL pancreatoscopic imaging and fluoroscopic
ductal pancreatography.
For the ESWL cohort, we included patients who were successfully treated with ESWL
for obstructive PD stones ≥ 5 mm (i. e., ductal clearance confirmed with post-ESWL
pancreatoscopic imaging) followed by ERP as first-line treatment at the Erasmus MC
University Medical Center Rotterdam, between February 2012 and May 2017. These patients
were identified from the Erasmus MC endoscopy registry Endobase, the primary documentation
system for endoscopy reports which captures all relevant information about the patient
and procedure, including images and videos data, into a centralized database. ESWL
was performed on an inpatient basis. Depending on the quantity and size of the PD
stones, one to three ESWL sessions were done on consecutive days followed by an ERP
on Day 5 to remove stone fragments. Some of these ESWL patients previously participated
in the ESCAPE trial [10]. In the ESCAPE trial, patients with severe pain due to obstructive CP with a dilated
PD and who recently started using opioids because of progressive pain (strong opioids
for ≤ 2 months or weak opioids for ≤ 6 months) were included.
Written informed consent (IC) was obtained from each participant before participation
in this long-term follow-up study. The study was approved by the Medical Ethical Committee/Internal
Review Boards of the Erasmus MC University Medical Center.
Follow-up and data collection
As per routine clinical practice, patients were followed up at the out-patient clinic
every 3 months.
In case of recurrence of symptoms, cross-sectional imaging (i. e., computed tomography
[CT] or magnetic resonance imaging [MRI]/magnetic resonance cholangiopancreatography
[MRCP]) was performed to assess presence of recurrent obstructive duct stones or other
pancreaticobiliary abnormalities. Standard follow-up imaging was not performed. During
follow-up, data on demographic factors, medical history, laboratory tests (i. e.,
fecal elastase), medication use, radiological imaging, endoscopic or surgical interventions
and hospital admissions were extracted from hospital records. In addition, a follow-up
questionnaire was sent to all patients to collect information on medication use, hospital
admissions, interventions for pancreatic diseases, QoL (SF-12) and pain severity (Izbicki
Pain Score).
Study endpoints
The primary study endpoint included long-term treatment success defined as no relapse
of symptoms due to intraductal stones confirmed on imaging (i. e., CT, MRI/MRCP, EUS,
or endoscopic retrograde cholangiopancreatography) after restoration of pancreatic
outflow was achieved with first-line endoscopic treatment (i. e., pancreatoscopy-guided
EHL or ESWL followed by ERP with stone extraction).
The secondary endpoints included the long-term effects of pancreatoscopy-guided EHL
on QoL assessed by means of the 12-Item Short Form Health Survey (SF-12), pain severity
based on the Izbicki Pain Score, opioid usage, the number of hospital admissions due
to acute-on-CP or inadequate pain control and pancreatic function (i. e., exocrine-
and endocrine pancreatic insufficiency).
Long-term clinical success was defined as a similar or a lower Izbicki Pain Score
or reduced opiate usage, as compared to 6-month follow-up after technically successful
removal of the intraductal PD stones by pancreatoscopy-guided EHL. Exocrine pancreatic
deficiency was scored in case of a fecal elastase-1 test result < 200 µg/g or the
use of pancreatic enzyme replacement therapy. Endocrine pancreatic insufficiency was
registered when patients used oral antidiabetic medication or insulin therapy.
The primary study endpoint was also described for the historical cohort of ESWL patients.
Secondary study endpoints were only assessed for the EHL cohort.
Statistics
Statistical analyses were performed using SPSS version 25 (IBM Corp: Armonk, New York,
United States). Dichotomous or categorical outcomes were presented as numbers with
percentages and compared using the Chi-square or Fisher’s exact test. Continuous data
were expressed as means with standard deviations (SDs) or medians with interquartile
ranges (IQRs) depending on normality of distribution. Statistical comparison for continuous
data was performed using the Student’s t-test when normally distributed or the Mann-Whitney-U test when not normally distributed.
A two-sided alpha < 0.05 was considered statistically significant.
SF-12 and Izbicki Pain Score
Similar to the original PELSTONE study, regression weights that were derived from
normative data of the Dutch general population were used to compute the physical and
mental component summaries (PCS and MCS) of the SF-12 by using the orthogonal rotation
method [8]
[11]. These scores range from 0 to 100, with higher scores indicating a better quality
of life (QoL). A score of 50 represents the mean in the general population [12]. For all time points (i. e., baseline, 6-month follow-up and long-term follow-up)
the mean Izbicki Pain Score, PCS, and MCS were calculated. The mean scores at long-term
follow-up were compared to 6-month follow-up and baseline by using the Wilcoxon signed-rank
test. P < 0.05 was considered statistically significant.
Results
Study population
EHL cohort
Between December 2017 and July 2020, 24 CP patients were technically successfully
treated with pancreatoscopy-guided EHL as primary treatment for one or more obstructive
PD stone(s) in the head or neck of the pancreas [8]. Data on clinical success (i. e., Izbicki Pain Score) were missing for two patients
at 6-month follow-up and one patient died after the initial follow-up period because
of metastatic pancreatic carcinoma leaving 21 eligible patients. In total, 19 patients
provided written IC for this long-term follow-up study ([Fig. 1]). Patient demographics at baseline are provided in [Table 1]. In 17 patients the stones were located in the pancreatic head and in two patients
in the neck of the pancreas with a median of one stone (range 1 to 3), and a mean
stone size of 8.0 mm ± 2.6. At baseline, opioids were used on a daily basis in 53 %
of patients.
Fig. 1 Flowchart of patient inclusion in the study.
Table 1
Patient and disease characteristics at time of initial treatment with EHL/ESWL.
|
EHL (n = 19)
n, (%)
|
ESWL (n = 18)
n, (%)
|
|
|
60.8 ± 10.5
|
55.2 ± 9.5
|
|
|
12 (63.2)
|
10 (55.6)
|
|
|
24.0 (4.6)
|
22.5 (4.3)
|
|
ASA classifications, no. (%)[1]
|
|
|
13 (68.4)
|
1 (5.6)
|
|
|
6 (31.6)
|
12 (66.7)
|
|
|
0 (0.0)
|
5 (27.8)
|
|
Smoking, no. (%)
|
|
|
9 (47.4)
|
14 (77.8)
|
|
|
4 (21.1)
|
0 (0.0)
|
|
|
6 (31.6)
|
4 (22.2)
|
|
Alcohol no. (%)
|
|
|
4 (21.1)
|
2 (11.1)
|
|
|
7 (36.8)
|
4 (22.2)
|
|
|
8 (42.1)
|
12 (66.7)
|
|
Etiology, no. (%)
|
|
|
12 (63.3)
|
11 (61.1)
|
|
|
7 (36.8)
|
7 (38.9)
|
|
|
0
|
|
|
|
2
|
0
|
|
|
4
|
5
|
|
|
1
|
0
|
|
|
0
|
1
|
|
Opiate usage, no. (%)
|
10 (52.6)
|
15 (83.3)
|
|
Exocrine pancreatic insufficiency, no. (%)[1]
|
12 (63.2)
|
17 (94.4)
|
|
Endocrine pancreatic insufficiency, no. (%)
|
6 (31.6)
|
9 (50.0)
|
|
Insulin usage
|
4
|
8
|
|
Oral antidiabetic medication
|
4
|
3
|
|
Sphincterotomy, no. (%)
|
|
|
19 (100.0)
|
15 (83.3)
|
|
|
6 (31.6)
|
6 (33.3)
|
|
Stricture, no. (%)
|
13 (68.4)
|
11 (61.1)
|
|
Stent placement prior to EHL/ESWL performance, no. (%)[1]
|
14 (73.7)
|
7 (38.9)
|
|
Prior balloon dilatation of stricture, no. (%)
|
9 (47.4)
|
7 (38.9)
|
|
Dilated pancreatic duct, no. (%)
|
19 (100.0)
|
18 (100.0)
|
|
Pancreatic duct diameter (mm), median (range)
|
10.0 (6–12)
|
8.5 (6–17)
|
|
Stone location based on pancreatogram, no. (%)
|
|
|
17 (89.5)
|
14 (77.8)
|
|
|
2 (10.5)
|
4 (22.2)
|
|
|
1.0 (1–3)
|
1.0 (1–3)
|
|
|
8.0 ± 2.6
|
9.0 ± 2.8
|
ASA, American Society of Anesthesiologists; BMI, body mass index; CP, chronic pancreatitis;
EHL, electrohydraulic lithotripsy; ERP, endoscopic retrograde pancreatography; ESWL,
extracorporeal shock wave lithotripsy; PD, pancreatic duct; SD, standard deviation.
1 Significant difference: P < .05.
ESWL cohort
Between February 2012 and May 2017, 51 consecutive patients underwent successful first-line
treatment with ESWL for obstructive distal PD stones at the Erasmus MC University
Medical Center of whom 17 patients previously participated in the ESCAPE trial [10]. During follow-up 15 patients died leaving 36 patients eligible for the present
study of whom 18 patients (50 %) provided written IC. Nine patients refused to participate
and nine patients who initially indicated their intention to participate did not respond
to follow-up reminders. In total, 18 CP patients treated with ESWL followed by ERP
as first-line treatment for obstructive calcifying CP were included in the present
study ([Fig. 1]). [Table 1] lists patient characteristics of the ESWL cohort. In the majority of patients (n = 14),
the stones were located in the head of the pancreas with a median of one stone (range
1 to 3) and a mean stone size of 9.0 mm ± 2.8. Daily opioid usage was observed in
83 % of patients.
Long-term treatment success
EHL cohort
Long-term treatment success after initial EHL therapy (i. e., no recurrence of symptomatic
obstructive PD stones) sustained in 12 of 19 patients (63 %) after a median follow-up
period of 35.0 months (IQR 30 to 41).
In this group, seven of 19 patients (37 %) presented with recurrent symptomatic obstructive
PD stones. Median time from the last successful ERP to recurrence was 12.0 months
(IQR 7.0 to 14.0). Based on imaging (CT/MRI/MRCP or pancreatogram during ERCP) a median
of two recurrent stones with a mean stone size of 4.3 ± 1.2 mm was present in these
patients ([Table 2]).
Table 2
Long-term outcomes of patients with symptomatic obstructive chronic pancreatitis after
initial successful treatment with EHL/ESWL.
|
EHL (n = 19)
n, (%)
|
ESWL (n = 18)
n, (%)
|
|
Main outcomes
|
|
|
18 (94.7)
|
18 (100)
|
|
|
35.0 (30–41)
|
76.5 (64.8–92.3)
|
|
|
7 (36.8)
|
11 (61.1)
|
|
|
6
|
7
|
|
|
4
|
11
|
|
|
12.0 (7.0–14.0)
|
13.0 (8.0–24.0)
|
|
|
5 (26.3)
|
11 (61.1)
|
|
|
5
|
11
|
|
|
4
|
7
|
|
|
1
|
3
|
|
|
0
|
2
|
|
|
4.3 ± 1.2
|
6.4 ± 4.1
|
|
|
2
|
2 (1–2)
|
|
Secondary outcomes
|
|
|
9 (47.3)
|
N/A
|
|
|
1.6 ± 2.5
|
N/A
|
|
|
14.6 ± 12.7
|
N/A
|
|
|
16 (84.2)
|
N/A
|
|
|
7 (36.8)
|
N/A
|
|
|
5
|
N/A
|
|
|
4
|
N/A
|
CT, computed tomography; EHL, electrohydraulic lithotripsy; ERCP, endoscopic retrograde
cholangiopancreatography; ESWL, extracorporeal shock wave lithotripsy; MRCP, magnetic
resonance cholangiopancreatography; SD, standard deviation.
In five patients with symptomatic stone recurrence an endoscopic reintervention was
performed (71 %). Endoscopic retreatment resulted in complete pain reduction in four
of five patients (80 %). A median number of three ERPs (range 3 to 5) was required
to achieve pain reduction in these four patients. In three patients the recurrent
stone(s) was successfully removed with a basket or balloon of whom one also had developed
a recurrent pancreatic stricture, which was successfully treated by progressive pancreatic
stenting. One patient was treated successfully with endoscopic dilatation of a PD
stricture and stent placement. None of the patients required retreatment with EHL.
Endoscopic retreatment was not successful in one of five patients due to a resilient
stricture in the pancreatic head impeding cannulation of the PD. This patient was
then treated surgically but died after surgery due to long-term postoperative complications
(i. e., cachexia and failure to thrive due to dumping syndrome). Finally, in two of
seven patients with recurrence (29 %) no reintervention was performed despite stone
recurrence. One patient suffered from a metastatic hepatocellular carcinoma and therefore
refrained from reintervention and the other patient was scheduled for a reintervention
which was canceled by the patient due to spontaneous regression of pain.
ESWL cohort
Of the 18 patients who were successfully treated with ESWL followed by ERP, seven
patients (39 %) reported no recurrence of symptoms after a median follow-up period
of 76.5 (IQR 64.8 to 92.3). The recurrence rate of symptomatic obstructive PD stones
in the ESWL group was 61 % (n = 11). Median time from the last successful interventional
procedure (i. e., ESWL session or ERP) to recurrence was 13.0 months (IQR 8.0 to 24.0).
Based on imaging (CT/MRI/MRCP or pancreatogram during ERCP) a median of two recurrent
stones (range 1 to 2), with a mean stone size of 6.4 ± 4.1 mm, were present ([Table 2]).
All recurrent patients underwent an endoscopic reintervention, which was clinically
successful in seven of 11 patients (64%). A median number of two ERPs (range 1 to
6) was required for the restoration of pancreatic duct outflow. Endoscopic retreatment
was not clinically successful in four patients. One patient remained symptomatic despite
technically successful endoscopic removal of the recurrent intraductal stone. In one
patient with a complete pancreas divisum, drainage via the papilla minor failed because
it was not possible to cannulate the accessory PD due to a swollen duodenal papilla.
One patient rapidly developed a new symptomatic recurrence and also suffered from
a refractory benign biliary stricture. In these three patients, endoscopic therapy
was therefore successfully followed by pancreatic surgery. The final patient developed
multiple stones recurrences during follow-up despite various endoscopic reinterventions.
This patient, however, was not considered a suitable candidate for pancreatic surgery
due to prolonged opioid usage and addiction problems.
Izbicki Pain Score
The mean Izbicki Pain scores and number of EHL patients who used opioids at the three
different time points (baseline, 6-month and long-term follow-up) are listed in [Table 3]. There was a non-significant increase in mean Izbicki Pain Score at long-term follow-up
as compared to 6-month follow-up (P = .334). However, long-term follow-up scores were still significantly lower as compared
to those at baseline (P = .001). (Supplementary Appendix, Table 1.) At long-term follow-up, a similar or reduced Izbicki Pain Score in contrast to
baseline and 6-month follow-up was reported by 79 % and 58 % of patients, respectively.
(Supplementary Appendix, Table 2.)
Table 3
Izbicki pain scores, opioid use and quality of life at baseline and follow-up of the
19 patients who successfully underwent pancreatoscopy and electrohydraulic lithotripsy.
|
Baseline
|
6 months
|
Follow-up
|
|
Clinical success
|
|
|
64.2 ± 22.4
|
25.9 ± 33.0
|
35.8 ± 33.5
|
|
|
10 (53 %)
|
3 (16 %)
|
6 (32 %)
|
|
Quality of life (Short Form Health Survey)
|
|
|
39.3 ± 9.7
|
43.3 ± 10.1
|
39.9 ± 12.9
|
|
|
41.1 ± 12.4
|
46.2 ± 11.8
|
46.6 ± 11.6
|
Values are mean ± standard deviation (n/N) or n (%) (n/N).
1 Scale ranges from 0 to 100 points (increasing scores indicating more pain severity).
Questions consist of 4 items: frequency of pain, intensity of pain, use of pain medication
and disease-related inability to work.
2 These scores range from 0 to 100, with higher scores indicating a better quality
of life. A score of 50 represents the mean in the general population.
Quality of life
[Table 3] shows the mean PCS and MCS at baseline, 6-month and long-term follow-up for the
19 patients who successfully underwent pancreatoscopy with EHL. At long-term follow-up,
only physical QoL was lower compared with the normative data from the Dutch general
population, whereas mental QoL was comparable to the Dutch general population. No
significant differences were observed in the mean PCS and MCS scores at long-term
follow-up compared to 6-month follow-up and baseline. (Supplementary Appendix, Table 3.)
Hospital readmissions and pancreatic function
Data on pancreatic function and re-admission rate for the EHL cohort are presented
in [Table 2]. During long-term follow-up, nine patients were readmitted because of acute-on-chronic
pancreatitis episodes or inadequate pain control with a mean number of hospital admissions
of 1.6 ± 2.5 and hospital duration of 14.6 ± 12.7 days. Cross-sectional imaging was
performed in all patients who were readmitted during long-follow-up. Stone recurrence
on imaging was found in six of the nine patients. After the initial 6-month follow-up
post-EHL, for patients developed new-onset pancreatic exocrine insufficiency and one
patient was newly diagnosed with diabetes.
Discussion
This was the first study to assess the long-term outcomes of pancreatoscopy-guided
EHL as primary treatment for symptomatic obstructive distal PD stones located in the
head or neck of the pancreas.
After a median follow-up of 35 months, treatment success (i. e., no symptomatic stone
recurrence) sustained in more than half of patients treated successfully with EHL
(63 %). In addition, in those patients with symptomatic stone recurrence, repeat endoscopic
therapy was effective in 80 %. Overall, long-term clinical success (i. e., lower or
similar Izbicki Pain Score or reduction in opioid usage) also sustained in a small
majority of patients previously treated with EHL (58 %).
The optimal timing of endoscopy versus pancreatic surgery in symptomatic patients
with CP is still a matter of debate. According to the latest guidelines, endoscopic
treatment, including ESWL, is recommended as first-line treatment for patients with
symptomatic obstructive CP due to pancreatic strictures or intraductal stones, whereas
surgery should preferably be reserved for patients who fail endoscopic treatment [3]
[4]. As recurrences of both pancreatic strictures and stones are not uncommon in these
patients, multiple endoscopic procedures are often needed to maintain pancreatic outflow
and pain relief. Current evidence suggests that multiple endoscopic procedures and
opioid usage prior to pancreatic surgery are associated with poorer outcomes. This
may indicate that pancreatic surgery should be considered early in disease course
and not be postponed until endoscopic treatment has failed [10]
[13].
In some studies, however, physicians did not apply endoscopic treatment as outlined
in the protocol and therefore these cases should be regarded as non-compliant. Since
these patients were included in the intention-to-treat analysis and hence are discounted
in the results, this implies that there is ample room to improve the outcome of endoscopic
therapy. In the meantime, intraductal pancreatoscopy combined with lithotripsy has
become available. All this may offer new perspectives in the endoscopic treatment
of symptomatic CP patients.
EHL has several benefits compared with the standard treatment involving ESWL. EHL
allows for stone and stricture treatment during the same procedure, is relatively
less expensive since hospitalization is no longer needed, and there is no need to
consult a urologist because stone fragmentation is performed under direct visualization.
In the past decade, multiple studies have been performed to examine the potential
value of pancreatoscopy-guided lithotripsy as an alternative treatment for obstructive
PD stones. In a recent meta-analysis of ten studies including 302 patients (67.72 %
male; mean age 55.10 ± 3.22 years; mean stone size of 10.66 ± 2.19 mm) a pooled technical
success rate of 91 % with an overall fragmentation success of 86 % was found [6]. Most of the included studies, however, were in nature retrospective and used pancreatoscopy-guided
lithotripsy as secondary treatment after failure of ESWL. Therefore, we have prospectively
evaluated the technical and clinical success of per-oral pancreatoscopy-guided EHL
as first-line treatment in a consecutive series of patients [8]. In this study, a total of 34 patients were included of whom 25 underwent EHL, which
was followed by complete or partial stone clearance in 24 patients. Clinical success
according to the criteria of the original PELSTONE (i. e., > 50 % pain reduction or
reduction in opioid usage) was achieved in 72 % (16 of 22) of the EHL patients whose
Izbicki Pain scores were available at 6-month follow-up. The initial follow-up period
of this study, however, covered a period of only six months which is relatively short
for a benign chronic disease such as CP.
The results of this long-term follow-up study suggest that pancreatoscopy-guided EHL
is a moderately effective first-line treatment modality. However, this only applies
to a selected group of patients, as patients with a non-dilated PD were excluded from
treatment. It should be noted that also in patients with a dilated PD, pancreatoscopy
can be challenging, especially in patients with a native papilla and those with a
very distally located stone in the PD. We therefore amended our treatment strategy
by placing a pancreatic stent first for difficult and prolonged PD cannulation followed
by pancreatoscopy and EHL in 4 to 6 weeks, which has been described in detail previously
[8]. Despite these measures, the technical success of pancreatoscopy with EHL was most
limited by the inability to achieve deep cannulation of the PD. Here, when cannulation
of the PD was achieved, pancreatoscopy was technically successful in 92 % of patients.
In general, free-floating stones are technically easier to treat as compared to impacted
stones, however, in this study our experiences with treating impacted stones were
relatively good. Based on these findings we conclude that for a selected group of
patients, pancreatoscopy-guided EHL seems to be a safe and effective treatment. To
put our long-term follow-up EHL results into perspective to the current standard of
care of the treatment of large PD stones (≥ 5 mm), results were compared with a historical
cohort of patients who underwent ESWL.
The recurrence rate of symptomatic stones in the ESWL group was 61 %, which was higher
as compared to those in the EHL cohort (37 %). This could not be related to inadequate
treatment with ESWL, as only patients in whom ESWL-treatment was considered successful,
defined as restoration of PD flow followed by post-treatment self-reported pain relief,
were included. All recurrent ESWL patients underwent endoscopic therapy, which was
clinically successful in seven patients (64 %). Median follow-up times for the EHL-group
and ESWL group were 35.0 and 76.5 months, respectively. Interestingly, although the
follow-up period was longer for the ESWL group, the median time to stone recurrence
was approximately one year in both cohorts. Based on the current non-randomized comparison,
EHL seems to be a valuable and effective alternative for ESWL as first-line therapy
for symptomatic obstructing PD stones.
Our present study showed that clinical success (i. e., > 50 % pain reduction or reduction
in opioid usage) sustained in 58 % of EHL patients (11 of 19) at long-term follow-up. Stone
recurrence was only confirmed in three of the eight patients who reported increased
Izbicki Pain Scores compared with 6-month follow-up. The increase in pain scores in
non-recurrent patients could be explained by the fact that pain in CP is often multifactorial
and pathophysiological mechanisms such as alterations in pancreatic sensory nerves
and central sensitization also play an important role in patients’ experience of pain
[14]
[15].
Another important finding of this study is that QoL was not significantly different
at long-term follow-up compared with 6-month follow-up and baseline. This finding
highlights the fact that pain is not the only factor determining QoL and our present
study confirms that treatment success does not necessarily lead to improvement of
QoL, even if pain scores did decrease. This underscores the importance of discussing
with individual patients what can potentially be expected from endotherapy at which
costs (e. g., number of procedures and potential complications). Perhaps even more
importantly, definition of treatment success should not only be looked upon as from
technical perspectives (i. e., stone removal or restoration of ductal flow), but also
from a patients’ perspectives on the impact of treatment on their lives in terms of
QoL, pain severity and social participation (i. e., holistic point of view). However,
whether current QoL assessment tools are adequate to detect the relevant clinical
difference for individual patients, especially when there are relatively few patients
in a study, remains a subject of debate. On top of that, despite extensive insights
regarding factors impacting QoL (i. e., pain, disability, current smoking, alcohol
consumption, low body mass index, use of opioids, associated comorbidities, bowel
symptoms and pancreatic dysfunction), a large proportion of variance in physical and
mental QoL scores among patients with CP still remains unexplained [16]. Therefore, it is necessary to have a better understanding of QoL and how patient-reported
outcomes can be used to assess and define treatment success. The Dutch Pancreatitis
Study Group is currently performing the COMBO trial, a nationwide stepped-wedge cluster
randomized controlled trial to investigate if patients’ education and an integrated
therapeutic approach, covering the four main domains of disease management (e. g.,
lifestyle modifications and psychological support, pancreatic function, nutritional
support, and pain management), improves QoL and pain severity as compared to current
practice [17].
Our study has several strengths, including its long-term follow-up, well-defined patient
population, comparison with a historical ESWL cohort, and clinically relevant endpoints,
including QoL. Some limitations of this study should however be acknowledged. First,
the number of patients in this retrospective analysis of a prospective cohort series
with historical controls is limited. Due to the small size of both the EHL and ESWL
cohorts, these groups could not be suitably matched. As a result, we have chosen to
describe the primary endpoint for both cohorts without performing any statistical
comparison to evaluate between-group differences. In a larger, preferably randomized
controlled, multicenter study this should be tailored according to a proper sample
calculation for which the current study may serve as input and also would circumvent
and avoid the risk of bias that is inherent to the current study approach. We, therefore,
look forward to seeing the results of this recently announced trial which directly
compares per-oral pancreatoscopy-guided lithotripsy to ESWL for treating refractory
main PD stones in CP [18]. Second, due to the non-randomized retrospective nature of the present long-term
follow-up study there is a possibility of selection bias. Third, contrary to ESWL
in the ESCAPE trial, opioid usage was not required to start treatment with EHL. Patients
not using opioids may have less disease severity and therefore the comparison might
not be optimally balanced. Finally, follow-up cross-sectional imaging after initial
successful treatment with EHL or ESWL was not routinely performed, unless in case
of symptom recurrence. The rates of stone recurrence may therefore be higher in both
cohorts than found in our present study. Furthermore, in this study ESWL and EHL were
performed according to the standard treatment protocol of the Erasmus MC University
Medical Center. In clinical practice, however, protocols may vary including the technical
success rates of EHL and ESWL depending on the local experience and available equipment.
Our results may therefore not be generalizable to non-tertiary referral centers. Besides
economic considerations, availability, and local expertise most likely will impact
the choice and hence experience with each treatment option.
Conclusions
In conclusion, at long-term follow-up, endoscopic EHL as first-line treatment for
obstructive PD stones performed in an expert treatment center is a moderately effective
treatment for symptomatic CP patients, with a sustained long-term clinical success
in more than half of the patients. Our results suggest that EHL is at least equally
effective as ESWL, which is considered the current standard of first-line care for
large PD stones. Future studies should aim at a direct comparison between EHL and
ESWL, focus on clinically relevant outcome parameters (e. g., QoL) and cost-effectiveness,
preferably within large prospective multicenter trials.
