Keywords
Reflux disease - Benign strictures - Endoscopy Upper GI Tract - Dilation, injection,
stenting - Malignant strictures
Introduction
Benign esophageal strictures can be challenging to treat and 30% to 40% of them recur
despite rigorous endoscopic dilations (EDs) [1]. They are defined by any abnormally stenotic segment of the esophagus and are called
as refractory when there is a failure to maintain luminal patency after at least five
EDs [2]. Clinically, esophageal strictures are manifested by dysphagia, commonly described
by patients as difficulty to swallow. By far the most common cause of benign esophageal
strictures is gastroesophageal reflux disease (GERD, peptic stricture), accounting
for at least 80% of cases [3]
[4]. Beyond that, most cases of benign esophageal strictures derive from eosinophilic
esophagitis, from endoscopic therapy, radiation injury, anastomotic formations after
surgical interventions, drug-induced esophagitis, and corrosive substance ingestion
[5].
In the last decades new technological advances in endoscopic therapy of esophageal
strictures have shown promising results with notable improvement in stricture management,
low recurrence rates and fewer complications. The techniques most utilized for benign
strictures management include through the scope balloons or bougies [1]. Studies comparing the efficacy of bougies and endoscopically-directed balloons
for the dilation of benign strictures have shown a comparable efficacy and complication
rates of both procedures [6]
[7]
[8]
[9]. The goal of endoscopic intervention for patients with nonmalignant esophageal strictures
is relief of dysphagia by increasing the diameter of the esophageal lumen. Due to
a large inter-individual variability, there is no general correlation between the
maximum luminal diameter and clinical response. However, data and clinical experience
have suggested that dilation to a lumen diameter of 15 to 17 relieves patients from
dysphagia [10].
Unfortunately, there is a paucity of data concerning the evaluation of the optimal
number of dilations as well as the optimal frequency of endoscopic sessions and evidence-based
recommendations are lacking. This lack of published data is particularly striking
because endoscopic bougienage has gained great popularity and relevance in treating
benign esophageal strictures. The goal of our study was to compare two different concepts
of ED concerning the frequency of interventions in two endoscopic centers with regard
to endoscopic results and clinical response. Both centers differed in the time intervals
between two EDs with one of them showing a higher frequency of dilations whereas the
second center was characterized by a longer period of time between two bougienages.
Patients and methods
In this retrospective study, adult patients aged 18 and over who were treated at the
participating hospitals (Center 1: Sana Klinikum Offenbach; Center 2: University Hospital
Frankfurt) for esophageal dilatation using the bougienage technique with Savary-Gilliard
dilators between April1, 2014 and March 1, 2020 were included in the study. Possible
patients were identified by systematically searching the patient chart database of
the participating hospitals for bougienage related Operation Procedure codes (OPS)
5–429.7 and 5–429.8.
Medical records of the resulting cases were systematically reviewed. The diagnosis
of a benign esophageal stricture was based on typical radiologic, endoscopic appearance
and on negative biopsies for malignancy. Esophageal stricture was defined by obstruction
of the esophageal lumen by at least 50% as a result of benign disease and complaint
of dysphagia. Stricture diameter was determined by the diameter of the first bougie
or balloon used in an ED session. Size of dilation was determined from the first to
the last bougie or balloon used in one ED session. Patients treated by balloon dilatation
were excluded from analysis.
Extracted patient data included baseline characteristics (gender, age), stricture
characteristics (etiology, localization, length, complexity), ED characteristics (procedure
date, number of interventions, pre- and post-dilation diameter), adverse events (AEs)
related to ED and duration of follow-up. For single stricture characteristics, data
were not always available for all patients. Thus medians, ranges, and percentages
were always calculated based on the corresponding available data, which were in Center
1 as follows: stricture length, n=141; stricture complexity, n=188. Corresponding
available in Center 2 were as follows: stricture length, n=39; stricture complexity,
n=44.
The primary endpoint was defined as the number of Savary dilations until freedom from
dysphagia was achieved. Beyond that, we assessed the number of therapeutic episodes
until long-term freedom from dysphagia was achieved. Further clinical endpoints were
the time span until freedom from dysphagia was observed and the duration of freedom
from dysphagia, which was defined as the time span between the last ED, which was
necessary to achieve freedom from dysphagia, and the time point of the first ED, which
was carried out due to recurrence of dysphagia. For conducting regression analysis,
reaching freedom from dysphagia by a low number of ED sessions (≤4) was defined as
clinical endpoint.
Concerning endoscopic endpoints, we assessed the maximal post-dilation diameter. Beyond
that, we analyzed the difference in pre-dilation and post-dilation diameter and the
number of patients who achieved and did not achieve a dilation diameter of 15 mm.
The time as well as the number of ED sessions until a dilation diameter of 15 mm or
– in cases of not reaching a dilator size of 15 mm – until the alternative maximal
dilation diameter was achieved was recorded in both groups. Clinical endpoints comprised
the time as well as the number of ED sessions and the number of treatment episodes
until permanent freedom from dysphagia was achieved. One therapy episode was defined
by the temporal sequence of endoscopic interventions, which were no more than 3 months
apart.
Additional endpoints included AEs, which were defined as events which were related
to ED and required consecutive endoscopy or hospitalization. Hemorrhage was defined
as observed esophageal bleeding after ED session. Esophageal perforation was defined
as a rupture of the esophageal wall after bougienage. Retrosternal pain was defined
as retrosternal non-cardiac chest comfort. The presence of ulcer was defined as a
discrete postinterventional break in the esophageal mucosa.
This study was approved by the local ethics committee of the Goethe University Frankfurt
(vote #2021–97). Patients were excluded if they were younger than 18 years old or
pregnant. Owing the retrospective, anonymous nature of the study, no informed consent
from individual patients had to be obtained.
Procedure
Due to the retrospective nature of the study, endoscopic procedures were not standardized.
Nevertheless, both participating centers complied with the guidelines for ED in clinical
practice [5]
[11]. During the endoscopic procedure, patients received conscious sedation, deep sedation
or general anesthesia with an endotracheal tube, depending on the treating physicians’
discretion. ED was performed using wire-guided bougies (mainly Savary-Gilliard bougies,
Cook Medical, Bloomington, Indiana, United States) in both centers. There is no general
correlation between maximum diameter and clinical response and accordingly no consensus
on the definition of an endpoint for dilation therapy. However, a case series of 321
patients showed that reaching a diameter of 15 mm was associated with clinical response
and freedom from symptoms in 98% of cases [12].
Accordingly, international guidelines also recommend weekly or two-weekly dilatation
sessions until easy passage of a ≥15-mm dilator is achieved [5]. Thus, successful therapeutic bougienage was defined when the dilator of 15mm was
effectively passed and complete resolution of dysphagia was noted by the patient.
Follow-up was conducted until patients were permanently symptom-free and did not require
further dilations.
Statistical analysis
Statistical analyses were performed using IBM SPSS 26.0 statistical software package
(SPSS/IBM, Munich, Germany). Characteristics of the cohort were examined by descriptive
statistics (percentages, means, standard deviation, etc.). Categorial variables were
compared using the chi-square or Fisher exact test, as appropriate, and expressed
as frequencies and percentages. Variables showing P<0.05 in the univariate model were analyzed in a multivariate logistic regression
model. Odds ratio (ORs) and 95% Cis were calculated for the independent predictive
factors of SVR. P ≤0.05 was considered statistically significant. Statistical analysis was performed
using SPSS Version 22 and R (Version 4.0.4).
Results
The main baseline patient characteristics of the overall study population, including
demographic and clinical features are listed in [Table 1]. Between April 2014 and March 2020, bougienage was used as the primary treatment
of benign esophageal stricture in 238 patients (194 patients in Center 1 and 44 patients
in Center 2). All of these patients presented with solid food dysphagia and an upper
gastrointestinal endoscopy was performed in all cases, which ensured the diagnosis
of benign esophageal stenosis. The majority of benign esophageal strictures of Center
1 derived from GERD (30.9%) and iatrogenic from endoscopic therapy (endoscopic mucosal
resection [EMR]), argon plasma coagulation [APC] or radiofrequency ablation [RFA];
27.8%). Benign esophageal strictures at Center 2 were primarily characterized by radiogenic
(50.0%) and peptic nature (16.0%). One hundred seventeen patients in Center 1 (60%)
and eight patients (18%) in Center 2 were treated with high-dose proton-pump inhibitor
(PPI) therapy after endoscopic dilatation to reduce recurrence rate. Standard-dose
PPI therapy was administered to 54 patients (0.5%) at Center 1 and 2 patients (5%)
at Center 2, respectively. Post-therapeutic stenoses after EMR were treated with high-dose
PPI therapy according to a specific protocol consisting of 3×40 mg PPI over 3 weeks
followed by therapy with 2×40 mg PPI until the patient presented again.
Table 1 Baseline characteristics.
|
Characteristics
|
Center 1*
|
Center 2*
|
P
|
|
APC, argon plasma coagulation; EMR, endoscopic mucosal resection; RFA, radiofrequency
ablation; SD, standard deviation.
*Center 1: University Hospital Frankfurt; Center 2: Sana Klinikum Offenbach.
|
|
Patients, n (%)
|
194
|
44
|
|
|
Patient age at diagnosis(years), mean ± SD
|
70 ± 1.0
|
61 ± 3.2
|
0.06
|
|
Male gender, n (%)
|
143 (73.7)
|
22 (65.6)
|
0.51
|
|
Localization of esophageal stenosis, n (%)
|
|
Proximal esophageal stricture
|
42 (21.6)
|
25 (56.8)
|
<0.001
|
|
Mid-esophageal stricture
|
43 (22.2)
|
7 (15.9)
|
0.27
|
|
Distal esophageal stricture
|
77 (39.7)
|
11 (25.0)
|
0.04
|
|
Elongated stricture
|
26 (13.4)
|
1 (2.3)
|
0.39
|
|
Characterization of esophageal stricture, n (%)
|
|
Simple, n (%)
|
35 (19)
|
4 (9)
|
0.14
|
|
Complex, n (%)
|
153 (81)
|
40 (91)
|
0.14
|
|
Multiple, n (%)
|
7 (4)
|
1 (2)
|
1.00
|
|
Short (<2 cm) (%)
|
59 (42)
|
14 (35)
|
1.00
|
|
Long (≥2 cm) (%)
|
82 (58)
|
26 (59)
|
0.76
|
|
Stricture length, median (range)
|
3 (0.5–23)
|
2 (1–5)
|
0.04
|
|
Cause of esophageal stricture, n (%)
|
|
Peptic
|
70 (36.0)
|
10 (22.7)
|
0.31
|
|
Post-radiation
|
19 (9.8)
|
22 (50.0)
|
<0.001
|
|
Eosinophilic esophagitis
|
4 (2.1)
|
1 (2.3)
|
0.57
|
|
Anastomotic stenosis
|
14 (7.2)
|
3 (6.8)
|
0.99
|
|
Corrosive
|
2 (1.0)
|
1 (2.3)
|
0.26
|
|
Post-therapeutic after EMR-/APC therapy or RFA
|
54 (27.8)
|
2 (4.5)
|
<0.001
|
|
Pseudodiverticulosis
|
8 (4.1)
|
0 (0)
|
0.41
|
|
Desquamative esophagitis
|
1 (0.5)
|
0 (0)
|
0.56
|
|
Papillomatosis
|
1 (0.5)
|
0 (0)
|
0.56
|
|
Others
|
3 (1.5)
|
4 (9.1)
|
0.006
|
|
Cause not defined
|
9 (4.6)
|
2 (4.5)
|
0.65
|
Post-radiation strictures derived in both centers from radiotherapy treatment of solid
organ malignancies. In most cases, patients were treated for esophageal or head and
neck cancer (Center 1: esophageal cancer, n=8, head and neck cancer, n=7; Center 2:
esophageal cancer, n=5; head and neck cancer, n=15), followed by lung cancer (Center
1: n=3; Center 2: n=0), lymphoma (Center 1: n=1; Center 2: n=1) and multiple endocrinological
neoplasia (Center 2: n=1).
The centers differed in their endoscopic bougienage regime: Cohort 1 was characterized
by a higher frequency of interventions and a shorter period of time between ED sessions:
median duration between two interventions were 2 days (1–28) in Cohort 1 compared
to 10 days (1–41) in Cohort 2 (P<0.001).
Follow-up was available in all of the patients until permanent freedom from dysphagia
was achieved. Median duration of follow-up from the beginning of ED using bougienage
to the last follow-up, which was marked by freedom from symptoms, were 155 days (range
0, 1792) in Center 1 and 186 days (range 0, 4107) in Center 2.
Clinical response
Concerning the clinical response, significantly fewer ED sessions were necessary using
the therapeutic regimen at Center 1 until patients presented permanently symptom-free
([Table 2]; [Fig. 1]
a). In line with these findings, the time until patients were permanently free of dysphagia
was shorter and the time span in which patients presented free of dysphagia was longer
in patients in Cohort 1 compared to those in Cohort 2 (99 vs. 95; P=0.88; 162 vs. 191, P=0.35; [Table 2];[Fig. 1]
b,c). Only the number of therapy episodes required to achieve permanent freedom from
symptoms was significantly higher in patients treated in Center 1 (2 vs. 1, P=0.01; [Table 2]; [Fig. 1]
d).
Fig. 1 Comparison of endoscopic concepts of both centers regarding a
the number of interventions until freedom from dysphagia is achieved, b the duration of freedom from symptoms until dysphagia recurred, c the time span until freedom from dysphagia is achieved and d the number of therapy episodes until freedom from
dysphagia is achieved. The length of the box thus represents the IQR within which
50% of
the values were located. The line through the middle of each box represents the median.
The error bars show the minimum and maximum values (range).
Table 2 Effect of bougienage on clinical and endoscopic endpoints.
|
Endpoints
|
Center 1*
|
Center 2*
|
P
|
|
*Center 1: University Hospital Frankfurt; Center 2: Sana Klinikum Offenbach.
|
|
Clinical endpoints
|
|
Time span until freedom of dysphagia was achieved (months), median (range)
|
155 (0–1792)
|
186 (0–4107)
|
0.35
|
|
No. of Savary dilations until freedom from dysphagia was achieved, median (range)
|
3 (1–41)
|
9 (1–57)
|
<0.001
|
|
No. of therapy episodes containing Savary dilations until long-term freedom of dysphagia
was achieved, median (range)
|
2 (1–16)
|
1 (1–9)
|
0.011
|
|
Time span to recurrence of dysphagia, median (range)
|
99 (1–1042)
|
95 (5–1003)
|
0.88
|
|
Endoscopic endpoints
|
|
Predilator size, median (range)
|
9 (5–15)
|
7 (5–12)
|
<0.001
|
|
Maximum dilator, median (range)
|
16 (10–18)
|
14 (9–16)
|
<0.001
|
|
Difference in dilation diameter, median (range)
|
8 (3–15)
|
7 (0–10)
|
0.30
|
|
Dilator size of 15 mm is achieved, n (%)
|
158 (81.4)
|
22 (50.0)
|
<0.001
|
|
Time span until dilator size of 15 mm was achieved (days), median (range)
|
2 (0–1743)
|
73 (0–750)
|
<0.001
|
|
No. of Savary dilations until dilator size of 15 mm was achieved, median (range)
|
2 (1–27)
|
8 (2–28)
|
<0.001
|
|
Dilator size of 15 mm is not achieved, n (%)
|
36 (18.6)
|
22 (50.0)
|
|
|
Time span until maximal dilator size was achieved (days), median (range)
|
41 (0–706)
|
60 (0–648)
|
0.001
|
|
No. of Savary dilations until maximal dilation size was achieved, median (range)
|
2 (1–22)
|
4 (1–12)
|
0.03
|
Endoscopic outcome
Evaluating the effectivity of higher- versus lower-frequency ED at both centers with
regard to endoscopic outcomes, Cohort 1 reached significantly larger maximum dilation
diameters (Cohort 1: 15, Cohort 2: 14; P<0.001; [Fig. 2]
a). Accordingly, reaching a dilator size of 15 mm as one further endoscopic outcome
was observed significantly more frequently in Cohort 1 (81.4% vs. 50%, P<0.001; [Table 2]). Moreover, the time as well as the required total number of EDs until a dilator
size of 15 mm was achieved were also significantly shorter and lower in Cohort 1 compared
to Cohort 2 (62 vs. 213 days, P<0.001; 3 vs. 9 ED, P<0.001; [Table 2]; [Fig. 2]
b,c). In 22% of patients from Center 1 and 50% of patients from Center 2, a dilator size
of 15 mm could not be achieved. Comparing those subgroups with each other, the alternative
maximal dilator size in Cohort 1 was also larger than in Cohort 2 (14 vs. 12; P=0.114; [Table 2]). Moreover, the time span and the total number of ED required to achieve the alternative
maximum dilator size were significantly shorter and lower in patients from Center
1 as well (2 vs. 60 days, P<0.001; 2 vs. 4 ED, P=0.03; [Table 2], [Fig. 3]
a,b).
Fig. 2 Comparison of endoscopic concepts of both centers regarding a maximum dilator size, b the time span until a
dilator size of 15 mm was achieved and c the number of
interventions until a dilator size of 15mm was achieved. The top and the bottom of
the
boxes are the first and the third quartiles, respectively. The length of the box thus
represents the IQR within which 50% of the values were located. The line through the
middle of each box represents the median. The error bars show the minimum and maximum
values (range).
Fig. 3 Comparison of endoscopic concepts of both centers regarding a the time span until the maximal alternative dilator size <15 mm was
achieved and b the number of interventions until the maximal
alternative dilator size <15 mm was achieved. The length of the box thus represents
the IQR within which 50% of the values were located. The line through the middle of
each
box represents the median. The error bars show the minimum and maximum values
(range).
Previous data have shown that reaching a dilation diameter of 16 mm after the first
three ED sessions was associated with fewer ED sessions during follow-up until freedom
from dysphagia was achieved [13]. Analyses in our study cohort showed that 122 patients of Center 1 and 10 patients
of Center 2 reached a post-dilation size of 16 mm (P<0.001). Moreover, a dilation up to 16 mm after the first three ED sessions was achieved
in one patient at Center 2 and in 83 patients at Center 1 (P<0.001).
Finally, we conducted logistic regression analysis in order to identify independent
predictors of endoscopic and clinical endpoints. At PP univariate analysis, different
bougienage concepts of both centers (P<0.001) and age (P=0.04) were significantly associated with achieving a dilator size of 15 mm. A following
multivariable analysis revealed that the different bougienage regimens of both centers
were the only independent predictive factor of reaching a dilator size of 15 mm (OR=;
P=0.003). Regarding clinical response, again the different bougienage regimens of each
center (P<0.001) and stricture localization (P=0.008) were identified as independent predictive factors of achieving freedom from
dysphagia by a low number of ED sessions (≤4) in a per protocol analysis. A consecutive
multivariate analysis revealed that again only the bougienage concept of each center
turned out to be an independent predictive factor of achieving freedom from dysphagia
by a low number (≤4) of ED sessions (P=0.002).
ED-related adverse events
A total of 62 AEs (26.1%) requiring repeat endoscopy or hospitalization were recorded
in both centers (Appendix Table 1). The most common AE after an ED session was hemorrhage in Center 1 (11.9%) and retrosternal
pain in Center 2 (20.5%). Serious AEs such as gastric perforation or esophageal ulcer
after bougienage were observed to be rare. No patients died from an ED-related cause.
Regarding the incidence of peri-intervention and post-intervention AE, no significant
difference could be observed between the centers.
Subanalyses of clinical and endoscopic outcomes depending on the localization and
etiology of esophageal strictures
Both study cohorts were heterogenous regarding the frequencies of localization and
the type of stricture. Moreover, predilator size was significantly smaller in Cohort
2 compared to that of Cohort 1 (P<0.001; [Table 2]). Thus, to better draw comparisons and to avoid selection bias, separate subgroup
analyses were carried out between 194 patients at Center 1 and 44 patients at Center
2.
Regarding the subgroup analysis of clinical endpoints among the most common esophageal
stricture types, a significant or non-significant superiority of the endoscopic treatment
regimen of Center 1 could be observed for patients with peptic strictures ([Table 3]). However, patients with radiogenic strictures were observed to respond clinically
better to the lower-frequency endoscopic treatment regimen of Center 2 ([Table 3]).
Table 3 Subanalysis of endoscopic outcomes matched for the most common causes of esophageal
stricture.
|
Characteristics and outcomes
|
Post-radiation stricture
|
Peptic stricture
|
|
Center 1*
|
Center 2*
|
P
|
Center 1*
|
Center 2*
|
P
|
|
*Center 1: University Hospital Frankfurt; Center 2: Sana Klinikum Offenbach.
|
|
Patients, n (%)
|
19 (43.2)
|
22 (11.3)
|
|
70 (36.0)
|
10 (22.7)
|
|
|
Predilator size, median (range)
|
7 (5–8)
|
6 (5–8)
|
0.22
|
8 (5–11)
|
7 (5–9)
|
0.14
|
|
Maximum dilator, median (range)
|
16 (10–17)
|
14 (9–16)
|
<0.001
|
15 (12–18)
|
13 (12–16)
|
0.003
|
|
Difference in dilation diameter, median (range)
|
9 (3–11)
|
7 (4–10)
|
0.008
|
7 (4–12)
|
6 (3–9)
|
0.18
|
|
Dilator size of 15 mm was achieved, n (%)
|
14 (74)
|
11 (50.0)
|
0.13
|
45 (75.0)
|
4 (57.1)
|
0.37
|
|
Time span until dilator size of 15 mm was achieved (days), median (range)
|
101 (0–855)
|
150 (14–750)
|
0.07
|
76 (0–1743)
|
167 (14–410)
|
0.04
|
|
No. of Savary dilations until dilator size of 15 mm was achieved, mean (range)
|
4 (1–7)
|
10 (2–28)
|
0.002
|
4 (1–21)
|
9 (3–21)
|
0.01
|
|
Dilator size of 15mm not achieved, n (%)
|
5 (26)
|
11 (50.0)
|
|
15 (25.0)
|
3 (42.8)
|
|
|
Time span until maximal dilator size was achieved (days), median (range)
|
155 (0–706)
|
60 (7–214)
|
0.13
|
21 (0–295)
|
212 (0–648)
|
0.57
|
|
No of Savary dilations until maximal dilator size was achieved, median (range)
|
3 (1–4)
|
4 (2–9)
|
0.45
|
4 (1–13)
|
4 (1–7)
|
0.21
|
Comparing clinical results at both centers among subgroups matched for the localization
of esophageal stricture, a better therapeutic response to the treatment regimen at
Center 1 could be observed for most of the defined endpoints ([Table 4]). Nevertheless, a higher number of endoscopic treatment episodes required to reach
freedom from dysphagia was observed in Cohort 1 among subgroups with an upper and
mid-esophageal stricture ([Table 4]).
Table 4 Subanalysis of endoscopic outcomes matched for localization of esophageal
stricture.
|
Characteristics and outcomes
|
Proximal esophageal stricture
|
Mid-esophageal stricture
|
Distal esophageal stricture
|
|
Center 1*
|
Center 2*
|
P
|
Center 1*
|
Center 2*
|
P
|
Center 1*
|
Center 2*
|
P
|
|
*Center 1: University Hospital Frankfurt; Center 2: Sana Klinikum Offenbach.
|
|
Patients, n (%)
|
42 (21.6)
|
27 (61.3)
|
|
43 (22.2)
|
7 (3.6)
|
|
77 (39.6)
|
11 (25.0)
|
|
|
Predilation diameter, median (range)
|
8 (5–11)
|
7 (5–12)
|
0.002
|
9 (5–15)
|
7 (5–9)
|
0.05
|
8 (6–9)
|
9 (5–13)
|
0.05
|
|
Maximum dilator, median (range)
|
15 (10–18)
|
14 (9–16)
|
0.001
|
16 (11–18)
|
13 (10–16)
|
0.001
|
15 (11–18)
|
14 (11.16)
|
0.002
|
|
Difference in dilation diameter, median (range)
|
7 (3–15)
|
7 (2–11)
|
0.55
|
7 (5–9)
|
7 (3–9)
|
0.29
|
7 (3–12)
|
6 (3–9)
|
0.52
|
|
Dilator size of 15 mm was achieved, n (%)
|
27 (64.2)
|
13 (48.1)
|
0.2
|
38 (88.4)
|
4 (57.1)
|
0.04
|
38 (19.6)
|
5 (11.4)
|
0.002
|
|
Time span until dilator size of 15 mm was achieved (days), median (range)
|
106 (0–1003)
|
143 (14–750)
|
0.006
|
30 (0–195)
|
573 (18–2107)
|
0.02
|
128 (11–4015)
|
919 (14–4015)
|
0.004
|
|
No. of Savary dilations until dilator size of 15 mm was achieved, median (range)
|
4 (1–7)
|
9 (2–28)
|
0.001
|
3 (1–10)
|
7 (6–8)
|
0.01
|
3 (1–21)
|
9 (3–21)
|
0.002
|
|
Dilator size of 15 mm not achieved, n (%)
|
15 (35.7)
|
14 (51.9)
|
|
5 (11.6)
|
3 (42.9)
|
|
39 (20.1)
|
6 (13.6)
|
|
|
Time span until maximal dilator size was achieved (days), median (range)
|
125 (0–1420)
|
281 (0–3326)
|
0.04
|
4 (0–13)
|
104 (70–152)
|
0.03
|
131 (0–706)
|
232 (0–648)
|
0.11
|
|
No of Savary dilations until maximal dilator size was achieved, median (range)
|
4 (1–22)
|
4 (1–8)
|
0.5
|
2 (1–3)
|
10 (9–12)
|
0.03
|
4 (1–10)
|
5 (1–9)
|
0.22
|
Analyzing endoscopic endpoints among subgroups with the same localization or the same
type of esophageal stenosis, considerably better results could be observed for the
endoscopic regimen at Center 1: a significantly larger maximal dilator size and a
significant or non-significant trend toward a larger dilation diameter difference
could be detected in all subgroups of Cohort 1 ([Table 5], [Table 6]). Subanalysis of predilator sizes revealed that a significant difference between
both centers could only be observed for proximal esophageal strictures ([Table 5] and [Table 6]). Among all other subgroups, the cohorts did not differ significantly regarding
predilator size.
Table 5 Subanalysis of clinical outcomes matched for localization of esophageal
stricture.
|
Characteristics and outcomes
|
Proximal esophageal stricture
|
Mid-esophageal stricture
|
Distal esophageal stricture
|
|
Center 1*
|
Center 2*
|
P
|
Center 1*
|
Center 2*
|
P
|
Center 1*
|
Center 2*
|
P
|
|
ED, esophageal dilation.
|
|
Patients, n (%)
|
42 (21.6)
|
27 (61.3)
|
|
43 (22.2)
|
7 (3.6)
|
|
77 (39.6)
|
11 (25.0)
|
|
|
Time span until freedom from dysphagia was achieved (days), median (range)
|
97 (0–884)
|
74 (5–515)
|
0.33
|
170 (0–1890)
|
288 (76–838)
|
0.99
|
126 (0–2310)
|
406 (0–4107)
|
0.06
|
|
No. of ED sessions until freedom from dysphagia was achieved, median (range)
|
4 (1–36)
|
6 (1–57)
|
0.36
|
4 (1–36)
|
6 (2–57)
|
0.65
|
3 (1–41)
|
11 (6–46)
|
<0.001
|
|
No. of therapy episodes containing Savary dilations until long-term freedom from dysphagia
was achieved, median (range)
|
3 (1–14)
|
1 (1–9)
|
0.02
|
3 (1–4)
|
1 (1–9)
|
0.09
|
2 (1–16)
|
3 (1–6)
|
0.71
|
|
Time span to recurrence of dysphagia, median (range)
|
286 (0–1700)
|
113 (0–1261)
|
0.72
|
92 (16–1042)
|
185 (98–378)
|
0.14
|
111 (19–1035)
|
92 (11–1792)
|
0.33
|
Table 6 Subanalysis of clinical outcomes matched for the most common causes of esophageal
stricture.
|
Characteristics and outcomes
|
Post-radiation stricture
|
Peptic stricture
|
|
Center 1*
|
Center 2*
|
P
|
Center 1*
|
Center 2*
|
P
|
|
ED, esophageal dilation.
|
|
Patients, n (%)
|
19 (43.2)
|
22
|
|
70 (36.0)
|
10 (22.7)
|
|
|
Time until freedom from dysphagia was achieved, median (range)
|
511 (1–2310)
|
102 (14–2128)
|
0.05
|
194 (0–1890)
|
202 (8–4107)
|
0.24
|
|
No. of ED sessions until freedom of dysphagia was achieved, median (range)
|
7 (2–41)
|
6 (1–57)
|
0.63
|
6 (1–34)
|
18 (9–46)
|
0.008
|
|
No. of therapy episodes containing Savary dilations until long term-freedom of dysphagia
was achieved, median (range)
|
4 (1–16)
|
1 (1–9)
|
0.002
|
4 (1–6)
|
4 (1–14)
|
0.55
|
|
Time span to recurrence of dysphagia, median (range)
|
139 (72–566)
|
91 (14–2128)
|
0.45
|
394 (24–1418)
|
158 (24–507)
|
0.85
|
Discussion
To our knowledge, this is the first study to systematically evaluate the relevance
of the time intervals between ED sessions in endoscopic treatment of benign esophageal
strictures. Most guidelines recommend repetition of endoscopic bougienage at weekly
intervals [4]
[11]
[14]. However, trials evaluating the best interval between two endoscopic sessions are
still lacking and most recommendations are based on published reports and on practical
experience [9]
[15].
Our study compared the concepts of two different endoscopy centers, which differed
in time intervals for bougienages: Center 1 performed bougies at an average time interval
of 2 days, whereas Center 2 designed a larger break between two ED sessions and performed
bougienages only every 2 to 3 weeks, as in most prepublished articles [3]
[5].
The results of our study demonstrate that the higher-frequency treatment regimen at
Center 1 seems to be more effective in treating most types of esophageal strictures:
a significant superiority of Center 1 could not only be observed for reaching a maximal
dilator size of 16 mm after the first three ED sessions, but also for all further
endoscopic endpoints, which in turn also correlated with better clinical responses
of this cohort. Duration as well as the number of ED sessions required to achieve
freedom from dysphagia was shorter and lower in patients of Center 1. Moreover, patients
treated with high frequency ED presented symptom-free over a longer period of time
until dysphagia recurred. Only the number of therapy episodes required to achieve
permanent freedom from dysphagia was significantly lower in patients at Center 2,
which could be due to the different therapy concepts of both centers. At Center 1,
patients were often scheduled electively at regular intervals of 6 months while endoscopic
dilation treatment at Center 2 was only resumed in cases of recurring dysphagia. Thus,
a higher number of therapy episodes at Center 1 despite a significantly lower number
of ED sessions may be due to different endoscopic therapy concepts and may not necessarily
reflect an inferiority of the treatment regimen at Center 1 in this endpoint.
However, when interpreting these results, it must be taken into consideration that
the cohorts differed significantly in frequency of localizations and in etiologies
of esophageal strictures. Patients in Cohort 2 predominantly presented with radiation
strictures in the upper third of the esophagus, which are often remarkably fibrotic
and resistant. Compared to peptic strictures, radiation strictures are often difficult
to treat and have the tendency to be refractory or to recur despite dilatation [3]
[13]
[16]
[17]. In contrast, patients in Cohort 1 primarily suffered from peptic stenosis, which
usually represents a simple and short stricture and responds better to esophageal
dilatation [12]. In addition, predilator diameter size was significantly larger in patients in Cohort
1, which may also explain significantly larger post-dilation diameters in this cohort,
and thus, impede the correct interpretation of endoscopic results.
Thus, a separate subgroup analysis based on different localizations and on most frequent
etiologies of esophageal strictures was carried out to rule out heterogeneity of treatment
effects. Regarding endoscopic outcomes, the subgroup analyses confirmed what was already
observed: a higher frequency of endoscopic sessions, as practiced in Center 1, led
to significantly better treatment results in all subgroup analyses, also in patients
suffering from a radiation stricture ([Table 5], [Table 6]).
Analyzing the dilator diameter difference resulted in considerably larger values for
the treatment regimen of Center 1. Since the difference between pre-dilation and post-dilation
diameter enables a comparison of both treatment regimen regardless of the predilator
size, these results confirm our observations of the higher-frequency treatment regimen
being more effective regarding endoscopic endpoints.
Beyond that, clinical outcomes were compared between the referring subgroups. Comparing
patients with a mid or lower esophageal stricture as well as patients with a peptic
stricture, again a significant or non-significant superiority of the higher-frequency
endoscopic treatment regimen at Center 1 could be observed for most of the clinical
endpoints. However, the subgroup analysis of patients with a radiation stricture revealed
controversial results. Patients treated with the lower-frequency endoscopic regimen
at Center 2 achieved a better clinical response in the majority of clinical endpoints.
In contrast to other esophageal stenoses, the fibrosis driven by radiation often affects
the tissues surrounding the esophagus, creating a non-compliant mediastinum [18]
[19]
[20]
[21]. As a consequence, radiation strictures are frequently refractory to dilatation.
The treatment concept at Center 2, which is characterized by longer time intervals
between two ED sessions, may represent a better approach to effectively and gradually
treat fibrotic and refractory radiogenic strictures. Moreover, the fibrotic nature
of radiogenic strictures may also be the reason why post-dilation diameters of more
than 14 mm are often not achieved. Thus, endoscopic dilation, which is primarily focused
on clinical symptoms and on achieving freedom from dysphagia as practiced at Center
2, may be the better approach to treat those patients. Nevertheless, those contrary
results of a better clinical response in patients at Center 2 may also be driven by
a relatively small sample size of patients with radiation strictures in both subgroups
und should be further evaluated in more representative cohorts.
Beyond conducting subanalyses of different stricture localizations and etiologies,
we
performed a regression analysis in order to better analyze the influence of different
ED
regimens of both centers. With regard to the endoscopic endpoint of reaching a bougie
size of
15 mm ([Table 7]), age and the different bougienage concepts were observed to be predictors in a
univariate analysis. However, in a consecutive multivariate analysis, the different
bougienage
regimens in the cohorts were the only independent predictor of reaching a bougie size
of 15
mm. Regarding achieving the clinical endpoint of reaching freedom from dysphagia by
a low
number of ED sessions (≤4), stricture localization as well as the different bougienage
concepts of both centers were observed to be predictors in a univariate analysis.
However,
again in a consecutive multivariate analysis only the bougienage regimens of both
centers
turned out to be the only independent predictive factors of reaching freedom from
dysphagia by
a low number of EDs ([Table 8]). Because the two treatment regimens significantly differ in frequency
of ED and further bias factors such as the localization or etiology of strictures
were taken
into account by regression analysis, the results underscore the general superiority
of a
higher-frequency ED approach. Nevertheless, whether all stricture types and localizations
benefit from this approach or whether individual strictures such as radiogenic ones
should be
dilated by a lower frequency cannot be answered on the basis of this analysis and
must be
investigated prospectively.
AEs such as hemorrhage or retrosternal pain were observed to be equally frequent in
both centers. Concerning the incidence of serious AEs, gastric perforation and bougienage
ulcers were observed to be more frequent with the higher-frequency endoscopic regimen.
However, no significant difference could be detected between the regimens. Thus, it
can be assumed that higher-frequency dilatations are not associated with an increased
risk of complications.
A major limitation of our study was its retrospective design. Endoscopic procedures
including the number of dilations per session as well as the time interval between
two sessions were at physician discretion and not dictated by a predefined study protocol.
Moreover, due to the lack of standardized and systematic protocol, detailed assessment
of dysphagia by means of a scoring system was also not possible. However, both participating
centers complied with the guidelines for endoscopic dilation in clinical practice
[5]
[11]. Moreover, neither study cohort was randomized. Thus, a certain heterogeneity of
both study cohorts concerning the cohort sizes (Cohort 1: 194 patients, Cohort 2:
44 patients) as well as the frequency of localizations and etiologies of esophageal
strictures might influence the study results and lead to selection and surveillance
bias. Finally, the number of certain stenoses such as anastomotic or post-therapeutic
strictures was too small in both sub-cohorts to conduct further subanalyses. Thus,
our results refer primarily to radiogenic and peptic stenoses. Based on the overall
analysis of both centers, only assumptions can be made for further types of strictures.
Conclusions
In summary, our multicenter, retrospective study demonstrates that endoscopic bougienage
is generally more effective for treating non-radiogenic esophageal strictures if the
time interval between two ED sessions is kept short. Current guidelines recommend
performing endoscopic dilatations once per week. However, our results show that the
treatment concept of higher-frequency bougienages every 2 to 3 days, as practiced
at Center 1, led to significantly better clinical and endoscopic results in those
types of strictures. However, our data also showed that radiogenic strictures, in
contrast, should be treated with low-frequency ED. The clinical response was observed
to be significantly better for patients with radiogenic strictures if ED was performed
with lower frequency and longer time intervals. Nevertheless, our study is retrospective
and our data may not be generalizable to all types of strictures. Thus, prospective
studies with representative study cohorts are warranted to further evaluate these
results.
Table 7 Univariate and multivariate analysis of factors associated with achieving a dilator
size of 15 mm.
|
Parameters
|
Dilator size 15 mm achieved, n=180
|
Univariate
|
Multivariate
|
|
|
P value
|
OR (95% CI)
|
P value
|
|
Gender, n (%)
|
0.08
|
|
|
|
Males
|
137 (76)
|
|
|
|
|
Females
|
42 (23)
|
|
|
|
|
Age (years)
|
71 (20–96)
|
0.04
|
|
|
|
Stricture localization, n (%)
|
|
0.28
|
|
|
|
Proximal
|
40 (22)
|
|
|
|
|
Mid
|
42 (23)
|
|
|
|
|
Distal
|
71 (39)
|
|
|
|
|
Elongated
|
4 (2)
|
|
|
|
|
Etiology of stricture, n (%)
|
0.82
|
|
|
|
Peptic
|
59 (33)
|
|
|
|
|
Post-radiation
|
25 (14)
|
|
|
|
|
Eosinophilic esophagitis
|
4 (2)
|
|
|
|
|
Anastomotic stenosis
|
11 (6)
|
|
|
|
|
Corrosive
|
1 (0.6)
|
|
|
|
|
Post-therapeutic after ER-/APC-therapy or RFA
|
58 (32)
|
|
|
|
|
Pseudodiverticulosis
|
5 (3)
|
|
|
|
|
Desquamative esophagitis
|
0 (0)
|
|
|
|
|
Papillomatosis
|
0 (0)
|
|
|
|
|
Other
|
7 (6)
|
|
|
|
|
Center, n (%)
|
<0.001
|
(2.49–76.82)
|
0.003
|
|
1
|
158 (88)
|
|
|
|
|
2
|
22 (12)
|
|
|
|
|
Stricture length, n (%)
|
2 (1–10)
|
0.22
|
|
|
Table 8 Univariate and multivariate analysis of factors associated with low number of Savary
dilations (≤4) until freedom from dysphagia is achieved
|
Low number of EDs (≤4) until freedom from dysphagia is achieved, n=98
|
Univariate
|
Multivariate
|
|
|
P value
|
OR (95% CI)
|
P value
|
|
Gender, n (%)
|
0.77
|
|
|
|
Male
|
74 (76)
|
|
|
|
|
Female
|
23 (23)
|
|
|
|
|
Age (years)
|
70 (15–94)
|
0.78
|
|
|
|
Stricture localization, n (%)
|
0.008
|
|
0.12
|
|
Proximal
|
19 (19)
|
|
|
|
|
Mid
|
20 (20)
|
|
|
|
|
Distal
|
41 (42)
|
|
|
|
|
Elongated
|
2 (2)
|
|
|
|
|
Etiology of stricture, n (%)
|
0.13
|
|
|
|
Peptic
|
26 (27)
|
|
|
|
|
Post-radiation
|
8 (8)
|
|
|
|
|
Eosinophilic esophagitis
|
4 (4)
|
|
|
|
|
Anastomotic stenosis
|
6 (6)
|
|
|
|
|
Corrosive
|
1 (2)
|
|
|
|
|
Post-therapeutic after ER-/APC-therapy or RFA
|
40 (41)
|
|
|
|
|
Pseudodiverticulosis
|
1 (2)
|
|
|
|
|
Desquamative esophagitis
|
1 (2)
|
|
|
|
|
Papillomatosis
|
0 (0)
|
|
|
|
|
Other
|
3 (3)
|
|
|
|
|
Center, n (%)
|
<0.001
|
1.4 (2.00–9.67)
|
0.002
|
|
1
|
88 (90)
|
|
|
|
|
2
|
10 (10)
|
|
|
|
|
Stricture length, n (%)
|
1 (1–5)
|
0.22
|
|
|
Is a higher frequency of esophageal dilations more effective in treating benign esophageal
strictures? Retrospective, multicenter study
Christiana Graf, Monika Reden, Tobias Blasberg et al. Endoscopy International Open
2024; 12: E78–E89. DOI: 10.1055/a-2117-8197
In the above-mentioned article the legends of figure 1, figure 2 and figure 3 were
corrected. This was corrected in the online version on 01.02.2024.
