Introduction
Gastric outlet obstruction is a clinical condition characterized by nausea and vomiting,
postprandial fullness, as well as epigastric abdominal pain and weight loss as a pathophysiologic
consequence of a mechanical obstruction within the gastrointestinal tract. Previously
termed pyloric stenosis, gastric outlet obstruction is the preferred or standard terminology
as mechanical obstruction may occur in the distal stomach, pylorus, or duodenum. The
condition itself is typically classified based upon etiology with benign and malignant
causes. Although the primary etiology over time has changed from peptic ulcer disease
and other benign entities to a more common association with underlying malignancy,
gastric outlet obstruction has a significant effect on patient morbidity and overall
quality of life [1]
[2]
[3]
[4]
[5].
Traditionally, surgical gastrojejunostomy has been the primary treatment for both
benign and malignant gastric outlet obstruction although the procedure itself is associated
with a high complication rate that approaches more than 40 % [6]
[7]. Although surgical gastrojejunostomy is currently the standard of care for palliative
treatment, the procedure is further limited by prolonged recovery times delaying chemotherapy
for malignancy-related obstructions, delayed gastric emptying and gastroparesis, as
well as substantial procedure-associated costs [7]. Given the significant morbidity of this surgical procedure, less-invasive endoscopic
alternatives have been developed including endoscopic ultrasound-guided gastroenterostomy
(EUS-GE).
EUS-GE has recently emerged as a procedure to treat patients with gastric outlet obstruction
as an alternative to surgery or to standard endoscopy when endoscopic enteral stent
placement is not possible [7]
[8]. Although EUS-GE was first described by Fritscher-Ravens et al. in the early 2000 s,
it was only after the recent availability of a bi-flanged lumen-apposing metal stent
(LAMS) that EUS-GE was clinically adopted. EUS-GE performed with placement of a LAMS
has emerged as another treatment option that may provide long-term luminal patency
without associated morbidity and complication rates of a surgical approach [9]
[10]. While this novel procedure is designed to facilitate sustained luminal patency
in patients with gastric outlet obstruction while avoiding the morbidity of a surgical
procedure, the efficacy and safety is EUS-GE remains less clear.
The primary aim of this study was to perform a systematic review and meta-analysis
to evaluate the efficacy and safety of EUS-GE for treatment of benign and malignant
gastric outlet obstruction.
Methods
Literature search
A comprehensive search of the literature was performed to identify articles that examined
the EUS-GE procedure. Systematic searches of PubMed, EMBASE, Web of Science, and the
Cochrane Library databases were performed from 2001 through April 1, 2019. The following
search terms included: “endoscopic ultrasound-guided gastroenterostomy (EUS-GE),”
“endoscopic ultrasound-guided gastrojejunostomy (EUS-GJ),” “endoscopic ultrasound-guided
gastroduodenostomy (EUS-GD),” “endoscopic ultrasound and gastric outlet obstruction,”
and “endoscopic ultrasound and pyloric obstruction.” All relevant articles irrespective
of year of publication, type of publication, or publication status were included.
Titles and abstracts of all potentially relevant studies were screened for eligibility.
The reference lists of studies of interest were then manually reviewed for additional
articles by cross-checking bibliographies. Two reviewers (TRM and RG) independently
screened the titles and abstracts of all the articles according to predefined inclusion
and exclusion criteria. Any differences were resolved by mutual agreement and in consultation
with the third reviewer (TR). In the case of studies with incomplete information,
contact was attempted with the principal authors to obtain additional data.
Study selection criteria
This study was prospectively submitted in PROSPERO, an international database of prospectively
registered systematic reviews in health and social care. The Preferred Reporting Items
for Systematic Reviews and Meta-Analyses (PRISMA) statement outline and Meta-Analysis
of Observational Studies in Epidemiology (MOOSE) reporting guidelines for reporting
systematic reviews and meta-analyses was used to report findings [11]
[12]. Only studies investigating use of the EUS-GE modality for treatment of gastric
outlet obstruction were included. Only human subject studies were considered in the
analysis. A study was excluded if deemed to have insufficient data, as were review
articles, editorials, and correspondence letters that did not report independent data.
Case series and reported studies with fewer than 10 patients were excluded. Multiple
published work from similar authors was evaluated for overlapping enrollment times
to preserve independence of observations. Participants included patients of any age
in whom presence of gastric outlet obstruction was suspected or confirmed based upon
prior imaging studies.
Procedure characteristics
All patients included in this study for analysis underwent EUS-GE for treatment of
gastric outlet obstruction. Multiple EUS-GE procedures (i. e., unassisted and assisted
techniques) were also analyzed including: direct EUS-GE, balloon-assisted, EUS-guided
double-balloon-occluded gastrojejunostomy bypass (EPASS), nasobiliary drain, and Natural
Orifice Transluminal Endoscopic Surgery (NOTES). All sizes of available LAMS were
included as well as both cautery-enhanced lumen-apposing metal stent (CE-LAMS) and
non-cautery-enhanced lumen-apposing metal stent (NCE-LAMS). Both EUS-GJ and EUS-GD
were included.
Outcome measures
The primary outcome measurement in this study was the feasibility, efficacy, and tolerability
of EUS-GE in patients with gastric outlet obstruction. Efficacy and safety of the
device were measured by immediate technical success rate (i. e., ability to perform
the procedure without issue), clinical success as defined by individual study authors,
and serious adverse events (AEs) reported during follow-up. Clinical success was also
measured by level of oral intake or relief of symptoms (i. e., early satiety, nausea,
vomiting) using the validated gastric outlet obstruction scoring system (GOOSS) [13]. This GOOSS is designed to provide an objective grade to determine patients’ ability
to eat before and after gastric outlet obstruction procedure (i. e., EUS-GE). Other
measured outcomes included baseline patient characteristics (i. e., mean age, gender,
benign or malignancy etiology of gastric out obstruction, and prior gastrointestinal
treatment), procedural-related characteristics (i. e., EUS-GE technique, timing of
procedure, and other AEs), and duration of follow-up.
Statistical analysis
This meta-analysis was performed by calculating pooled proportions. After appropriate
studies were identified through systematic review, the individual study proportion
was transformed into a quantity using the Freeman–Tukey variant of the arcsine square
root transformed proportion. Then the pooled proportion was calculated as the back
transform of the weighted mean of the transformed proportions, using inverse arcsine
variance weights for the fixed effects model and DerSimonian–Laird weights for the
random effects model [14]
[15]
[16]
[17].
Measured outcomes comparing the pre- and post-procedure GOOSS were also obtained.
From this, standardized mean difference was calculated and transformed to the natural
logarithm before pooling, and the variance was calculated. Fixed-effects models were
applied to pre- and post-EUS-GE data to determine effect size and corresponding 95 %
confidence intervals (CIs). Tabular and graphical analyses were performing using Comprehensive
Meta-Analysis software, version 3 (BioStat, Englewood, New Jersey, United States).
Additional analyses were performed with the aid of the Stata 13.0 software package
(Stata Corp LP, College Station, Texas, United States).
Risk of bias and quality assessment
Risk of bias and quality of observational studies was evaluated using the Newcastle-Ottawa
Quality Assessment Scale [18]. Domains assessed were selection of cohort, ascertainment of exposure/comparator,
and assessment of outcome. Based upon this, criteria score ≥ 5 was consistent with
high quality, 3 to 4 medium quality, and ≤ 2 was considered low quality. Quality of
randomized clinical trials (RCTs) was assessed using the JADAD score [19]. Two authors (TRM and RG) independently extracted data and assessed risk of bias
and study quality for each of the articles. Any disagreements were resolved by discussion
and consensus, and in consultation with the third reviewer (TR).
Investigations of heterogeneity
Heterogeneity was assessed for the individual meta-analyses using the chi squared
test and the I
2 statistic [20]. Significant heterogeneity was defined as P < 0.05 using the Cochran Q test or I
2 > 50 %, with values > 50 % indicating substantial heterogeneity. To assess for publication
bias, a funnel plot was created and visually inspected for asymmetry and quantitatively
using Egger regression testing [21]
[22].
Results
Baseline study information and patient characteristics
This meta-analysis included a total of five studies including years from 2016 to 2019
[7]
[23]
[24]
[25]
[26]. A PRISMA flow chart of search results is shown in [Fig. 1]. Four studies were multicenter with two single-center trials also included. Four
included studies were retrospective in nature with an additional prospective study
analyzed. A total of 199 patients were included in this study. Forty-five percent
of patients were male. In 21.61 % of patient with gastric outlet obstruction (n = 43),
the condition was secondary to benign causes. Mean age of patients that underwent
the EUS-GE procedure for both benign and malignant gastric outlet obstruction was
64.52 ± 1.37 years with a pooled mean follow-up period of 4.32 ± 1.65 months. Further
baseline study and patient characteristics are highlighted in [Table 1].
Fig. 1 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow
chart of literature search results for EUS-guided gastroenterostomy for the treatment
of gastric outlet obstruction.
Table 1
Baseline patient characteristics of included EUS-GE studies.
|
Author
|
Year
|
Study design
|
EUS-GE technique
|
Stent size, type
|
No. patients
|
Follow-up period (mons)
|
Mean age (years)
|
No. males (%)
|
No. benign obstructions
|
No. of malignant obstructions
|
Procedure time (min)
|
Technical success
|
Clinical success
|
Serious adverse events
|
Minor adverse events
|
No. of re-interventions
|
Newcastle-Ottawa Quality Assessment
|
|
Ge et al.
|
2019
|
Single-center, retrospective comparator study
|
Direct (n = 24)
|
15 × 10 mm CE-LAMS
|
22
|
–
|
66.4
|
9
|
0
|
22
|
–
|
24/24
|
23/24
|
3/24
|
2/24
|
2/25
|
5.5
|
|
Kerdsirihair at et al.
|
2018
|
Multicenter, retrospective non-comparator study
|
Direct (n = 57)
|
15 × 10 mm CE-LAMS
|
57
|
6.5
|
65
|
28
|
9
|
48
|
39
|
53/57
|
51/57
|
1/57
|
1/57
|
8/53
|
6.5
|
|
Chen et al. (Direct)
|
2018
|
Multicenter, retrospective comparator study
|
Direct (n = 52)
|
15 × 10 mm CE-LAMS and 15 × 10 mm NCE-LAMS
|
52
|
3.8
|
62.9
|
22
|
18
|
34
|
35.7
|
49/52
|
48/52
|
1/52
|
2/52
|
3/52
|
7.0
|
|
Chen et al. (Balloon)
|
2018
|
Multicenter, retrospective comparator study
|
Balloon-assisted (n = 22)
|
15 × 10 mm CE-LAMS and 15 × 10 mm NCE-LAMS
|
22
|
3.8
|
63.3
|
11
|
7
|
15
|
89.9
|
20/22
|
20/22
|
0/22
|
2/22
|
4/22
|
7.0
|
|
Itoi et al.
|
2016
|
Single-center, prospective non-comparator study
|
PASS (n = 20)
|
15 × 10 mm CE-LAMS
|
20
|
3.3
|
|
10
|
0
|
20
|
25.5
|
18/20
|
–
|
1/20
|
1/20
|
–
|
5.0
|
|
Tyberg et al.
|
2016
|
Multicenter, retrospective non-comparator study
|
Balloon-assisted (n = 13); Ultra-slim scope (n = 5); Nasobiliary drain (n = 3); Direct
(n = 3); NOTES (n = 2)
|
15 × 10 mm and 10 × 10 mm CE-LAMS
|
26
|
1.8
|
66.2
|
11
|
9
|
17
|
–
|
24/26
|
22/26
|
3/26
|
2/26
|
1/26
|
6.0
|
CE-LAMS, cautery-enhanced lumen-apposing metal stent; NCE-LAMS, non-cautery-enhanced
lumen-apposing metal stent; PASS, EUS-guided double-balloon-occluded gastrojejunostomy
bypass.
Procedure characteristics of included studies
Both assisted and unassisted EUS-GE techniques were included with an overall mean
procedure time for all techniques of 43.49 ± 19.69 minutes. The most commonly employed
technique was direct EUS-GE (n = 134), followed by balloon-assisted (n = 35), then
EPASS (n = 20), next ultra-slim (n = 5), afterwards nasobiliary drain (n = 3), and
finally NOTES (n = 2). All studies included the CE-LAMS device; however, one study
by Chen et al. also utilized the NCE-LAMS in 7.04 % patients (n = 14). A total of
99.50 % of patients (n = 198) had placement of a size 15 mm × 10 mm LAMS for EUS-GE,
with 10 mm × 10 mm LAMS placement in only one patient. Additional procedure-specific
characteristics are described in [Table 1].
Efficacy and clinical effectiveness of EUS-guided gastroenterostomy
The immediate technical success of EUS-GE as reported in all included studies was
92.90 % (95 % CI; 88.26 to 95.79; I2 = 0.00 %) ([Fig. 2a]). Four studies documented clinical success with a pooled success rate of 90.11 %
(95 % CI; 84.64 to 93.44; I2 = 0.00 %) ([Fig. 2b]). Clinical success as determined by the GOOSS was only reported in one study [27]. Based upon this study by Itoi et al., the mean post-GOOSS score was significantly
higher compared to the pre-GOOSS score (2.94 ± 0.23 versus 0.6 ± 0.75; P < 0.001) (Supplemental Fig. 1). The median post-GOOSS score was significantly higher than the pre-GOOSS score (0.00
versus 3.00; P < 0.001).
Fig. 2 a Immediate success rate for EUS-guided gastroenterostomy for the treatment of gastric
outlet obstruction. b Clinical success rate for EUS-guided gastroenterostomy for the treatment of gastric
outlet obstruction.
Safety of EUS-guided gastroenterostomy
Serious AEs occurred in 5.61 % (95 % CI; 2.87 to 10.67; I2 = 1.67%) of cases and were related to peritonitis, perforation, bleeding, and abdominal
pain ([Fig. 3a]). Overall, the EA rate for the EUS-GE procedure was 10.59 % (95 % CI; 6.74 to 16.25;
I2 = 27.17 %) (Supplemental Fig. 2a). Minor AEs were reported in 5.78 % (95 % CI; 3.13 to 10.41; I2 = 0.00 %) of procedures and were most commonly due to stent migration (Supplemental Fig. 2b). Need for repeat procedure or conversion to open surgical intervention was reported
in four studies. Repeat intervention was required for 11.43 % (95 % CI; 7.29 – 17.46;
I2 = 17.38 %) of EUS-GE procedures ([Fig. 3b]).
Fig. 3 a Serious adverse events for EUS-guided gastroenterostomy for the treatment of gastric
outlet obstruction. b Repeat interventions required after EUS-guided gastroenterostomy for the treatment
of gastric outlet obstruction.
Risk of bias assessment
All studies were evaluated using the Newcastle-Ottawa Quality Assessment Scale scores
with quality assessment for each study shown in [Table 1]. All included studies were considered to be of high quality with scores ≥ 5. Despite
the limited number of included studies, publication bias was assessed [28]. Based on visual inspection of the funnel plot as well as quantitative measurement
using the Egger regression test, there was no evidence of publication bias ([Fig. 4]).
Fig. 4 Funnel plot of publication bias and Eggers regression test for included studies to
assess EUS-guided gastroenterostomy for the treatment of gastric outlet obstruction.
Discussion
This systematic review and meta-analysis demonstrates that EUS-GE is a technically
feasible and effective endoscopic procedure for management of patients with benign
and malignant gastric outlet obstruction. With an immediate technical success rate
of 92.90 % and a low 5.61 % rate of serious AEs, EUS-GE appears to be relatively safe
and well-tolerated. Given the significant morbidity of surgical gastrojejunostomy
and high incidence of recurrent gastric outlet obstruction after endoscopic luminal
stenting, EUS-GE shows promise as a fledgling procedure with the potential to become
a first-line minimally-invasive therapy for patients with benign and malignant gastric
outlet obstruction
Evolution of EUS-GE
First performed in a porcine animal model by Fritscher-Ravens et al. more than a decade
ago, EUS-GE provided a new method for stitching under flexible EUS control but required
endoscope exchange and use of special devices, thus limiting adoption in clinical
practice [8]
[10]. However, development of a lumen-apposing self-expandable fully covered metal stent
(AXIOS Boston Scientific Corp., Marlborough, Massachusetts, United States) able to
safely appose two juxtaposed luminal structures and form an endoscopic anastomosis
has brought new insights into development of EUS-GE [8]
[29].
Although early animal models were successful, translation of these findings in humans
has been challenging, represented by identification of the proper distal duodenal
or proximal jejunal loop to be accessed from the gastric body to create the anastomosis
[8]
[30]. While a variety of EUS-GE techniques are in practice, addition of EUS allows for
proper recognition of bowel structure, typically using a 19- to 22-gauge to puncture
the loop, followed by contrast injection and guidewire placement [5]
[8]. Next, EUS-GE involves exchange with a CE-LAMS device to cautery puncture and dilate
the tract, followed by distal flange deployment into the bowel lumen, withdrawal of
the endoscope and the bowel loop toward the gastric cavity where the proximal flange
is finally deployed. All included studies in this meta-analysis involved a CE-LAMS
to perform EUS-GE, though one study included both CE-LAMS and NCE-LAMS [23].
Current standard of care and other available endoscopic treatments
Surgical gastrojejunostomy is the current standard of care for treatment of gastric
outlet obstruction; however, the significant morbidity and high complication rate
associated with surgery has necessitated a search for less invasive and better tolerated
alternatives [6]
[7]
[9]. Endoscopic alternatives including placement of luminal enteral stents have been
employed and have achieved comparable technical and clinical success rates with lower
overall AE rates as compared to the traditional surgical approach [31]. Nevertheless, enteral stenting provides a less durable option for patients with
a prolonged life expectancy, plagued by frequent need for reintervention due to stent
migration or stent tumor ingrowth/overgrowth [6]
[9]
[32].
EUS-GE versus other treatments
Although evidence is limited, a recent study by Kashhab and colleagues comparing outcomes
of EUS-GE to surgical gastrojejunostomy for treatment of malignant gastric outlet
obstruction found the technical success rate was significantly higher in the surgical
cohort (100 % vs. 87 %, P = 0.009) [33]. While the surgical approach was more feasible and less technically challenging,
the clinical success rate was no different between the surgical and EUS groups (90 %
versus 87 %, P = 0.18). There was also a favorable trend with lower recurrence of gastric outlet
obstruction in the EUS-GE group (3 %) as compared to the surgical group (14 %); although
this was not statistically significant (P = 0.08). In another study by Manuel Perez-Miranda et al., technical success was nt
different between an EUS-GE cohort and patients undergoing laparoscopic gastrojejunostomy
(88 % versus 100 %, P = 0.11), although EUS-GE was associated with a significantly lower rate of AEs (12 %
versus 41 %, P = 0.0386) [34]. Both of these studies were excluded from our systematic review and meta-analysis
due to concerns regarding overlapping enrollment periods and duplication of patient
data [26]
[33]
[34].
Another study by Chen et al. compared EUS-GE with endoscopic enteral stenting and
demonstrated a significantly lower risk of recurrence and reintervention in the EUS-GE
group compared to the enteral stenting group (4.3 % vs 28.6 %, P = 0.015) [35]. Even on multivariable analysis, enteral stent placement was independently associated
with need for reintervention (OR 12.8, P = 0.027). These authors also found similar rates of technical success between the
two strategies and a trend towards favorable clinical success among the EUS-GE group. While
again not included in our meta-analysis due to concerns regarding overlapping enrollment
periods, the results suggest EUS-GE provides longer-lasting luminal patency and reduces
occurrence of stent obstruction, with a reasonable procedural risk, without the morbidity
associated with a surgical procedure [8]
[23]
[35].
Clinical implications and future direction
Although these early data are promising and suggest that the procedure is safe and
effective, there is not yet enough evidence at this time to endorse EUS-GE as the
standard of care for gastric outlet obstruction [9]. Future, well-designed RCTs and prospective studies are needed to further validate
these findings. Ultimately, more comparator studies are needed to evaluate the efficacy
and tolerability of EUS-GE as compared to enteral and surgical gastrojejunostomy as
well as a comparison between various EUS-GE techniques and LAMS size. Additional limitations
to mainstream use include the notion that the EUS-GE procedure is technically demanding,
thus at present, it should be performed only by highly trained experts in interventional
EUS [8]. It is important to note EUS-GE is not devoid of morbidity and AEs may be significant
when they occur. Formal training and improved familiarity with the procedure overall
will be required prior to seeing any meaningful clinical implication. Only then will
the procedure likely see adoption into clinical practice.
Strengths and limitations
Specific limitations to this study include reliance largely on retrospectively collected
data, differences in patient population across studies, lack of long-term follow-up
periods, and inclusion of multiple EUS-GE techniques. While important to consider,
heterogeneity of studies was low based on our analyses. In addition, while clinical
success as determined by authors was reported in all studies, objective measures of
clinical success (i. e. the GOOSS) were only reported in one study [27]. As the evidence stands now, there remains limited data regarding EUS-GE with sparse
literature and numerous studies reporting redundant patient information. Several studies
in our literature search were excluded due to concerns regarding overlapping results
from the same cohort of EUS-GE individuals. Although publication bias is not typically
assessed with funnel plot asymmetry with fewer than eight to 10 studies in a meta-analysis,
qualitative and quantitative publication bias was performed as pooled results of uncontrolled,
retrospective studies carry a high risk of amplifying selection bias [28]. Despite this concern, our meta-analysis demonstrated no evidence of publication
bias.
In addition, there remains a lack of data to compare EUS-GE directly with surgical
gastrojejunostomy with only one study demonstrating similar efficacy among more complex
patients [34]. With only five studies, subgroup analysis based upon EUS-GE technique or benign
and malignant causes of gastric outlet obstruction, both of which would be highly
clinically relevant, was not possible. An additional concern with any endoscopic procedure
or technique is the learning curve or clinical expertise needed to perform an effective
procedure [16]. It is possible the technical success achieved in these studies may be not be generalizable
to centers with less familiarity or proven expertise.
Despite these limitations, this study has several strengths. Most importantly, our
meta-analysis methodologically summarizes all available data to evaluate the feasibility,
efficacy, and tolerability of the EUS-GE procedure. Overall, EUS-GE was demonstrated
to be an effective device for gastric outlet obstruction in both short- and longer-term
follow-up with impressive technical and clinical success rates and few serious AEs.
Although we were unable to provide a subgroup analysis based upon gastric outlet obstruction
etiology and EUS-GE technique, these findings provide an important step forward in
proving the effectiveness and utility of further trials. With a relatively even distribution
of benign and malignant gastric outlet obstructions included in this analysis, it
is reasonable to assume EUS-GE is an effective modality for both etiologies. These
data are pivotal to improve both symptom management and quality of life for individuals
with gastric outlet obstruction, regardless of etiology, and may suggest an increasing
role for EUS-GE.
Conclusions
Based upon our systematic review and meta-analysis, EUS-GE appears to be an effective
and safe minimally invasive alternative for treatment of benign and malignant gastric
outlet obstruction. Given the significant morbidity associated with surgical gastrojejunostomy
reaching nearly 40 %, less invasive options that provide durable and effective results
will continue to be sought. Although EUS-GE remains a technically challenging procedure
with limited evidence to date, it demonstrated high immediate technical and clinical
success rates of 92.90 % and 90.11 %, respectively, with a low serious AE profile
of 5.61 %. While surgical gastrojejunostomy will continue to be the standard of care,
this systematic review and meta-analysis suggests an increased role for EUS-GE in
management of gastric outlet obstruction.
