Introduction
The primary approach for managing malignant gastric outlet obstruction (GOO) is palliation
of symptoms [1 ]. Historically, the surgical gastrojejunostomy (SGJ) was the standard of care and
most common intervention performed, with a more recent transition toward less invasive
procedures like enteral self-expandable metal stents (SEMS) or decompressive venting
gastrostomy [2 ]
[3 ]
[4 ]. However, patients with malignant GOO are not always optimal surgical candidates
due to sequelae associated with cancer and GOO. These patients often suffer from malnutrition,
electrolyte abnormalities, and poor wound healing. Their poor nutritional status renders
them poor operative candidates. Moreover, the invasive nature of SGJ poses a risk
for serious complications including bleeding, gastroparesis, perioperative infections,
and increased morbidity which can delay recovery and subsequent chemotherapy treatments
[5 ]. Therefore, alternative approaches for the management of GOO have been developed.
An endoscopic approach using enteral SEMS has shown better short-term outcomes and
decreased complication rates compared to SGJ in palliative management of malignant
GOO [3 ]
[5 ]
[6 ]. However, one of the main drawbacks is the lack of long-term benefit due to recurrent
obstruction as a result of tumor ingrowth/overgrowth [3 ]. The development and availability of lumen apposing metal stents (LAMS) has allowed
for the emergence of endoscopic ultrasound-guided gastroenterostomy (EUS-GE). EUS-GE
is a novel procedure that has become increasingly accepted as a treatment approach
for malignant GOO [7 ]
[8 ]. The procedure entails the deployment of a LAMS across a fistulous tract created
between the gastric and the enteral lumen under EUS guidance, allowing for direct
access of the small bowel from the gastric lumen and a bypass of the GOO [9 ]. Studies have demonstrated the safety, efficacy, and feasibility of EUS-GE in patients
with malignant GOO [10 ]
[11 ]
[12 ].
With various options for palliation of symptoms associated with malignant GOO, the
selection of the optimal treatment approach remains controversial. EUS-GE, being a
less invasive endoscopic procedure, has the potential of offering a long-term palliative
benefit in patients with malignant GOO as opposed to enteral SEMS [13 ]
[14 ]. Few studies comparing the outcomes of EUS-GE and SGJ in this patient population
have been performed [15 ]
[16 ]
[17 ]
[18 ]
[19 ]
[20 ]. The aim of our study was to perform a systematic review and meta-analysis of the
available literature that directly compared outcomes including clinical success, technical
success, adverse events (AE), and recurrence or reintervention rates, between EUS-GE
and SGJ for malignant GOO symptom palliation as new data emerges on this novel endoscopic
procedure.
Materials and methods
This systematic review was performed in accordance with Cochrane Handbook for Systematic
Reviews of Interventions [21 ]. It is reported in accordance with Preferred Reporting Items for Systematic Reviews
and Meta-Analyses (PRISMA) guidelines [22 ].
Data sources and search strategies
A comprehensive search of several databases from inception to January 31, 2021, limited
to English language and excluding animal studies, was conducted. The databases included
Ovid MEDLINE and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and
Daily, Ovid Embase, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane
Database of Systematic Reviews, and Scopus. The search strategy was designed and conducted
by an experienced librarian with input from the study’s principal investigator. Controlled
vocabulary supplemented with keywords was used to search for studies describing EUS-GE,
SGJ and GOO. The actual strategy listing all search terms used and how they are combined
is available in Appendix 1 .
The keywords used in the search included a combination of EUS guided gastroenterostomy,
gastrojejunostomy (GJ), laparoscopic, open, surgical GJ, malignant gastric outlet
obstruction. Two authors (SB, AG) independently reviewed the titles and abstracts
of studies identified in the primary search and excluded studies that did not address
the research question, based on pre-specified exclusion and inclusion criteria. The
full text of the remaining articles was then reviewed to determine whether it contained
relevant information. Any discrepancy in article selection was resolved by consensus
and in discussion with a co-author (RK). The bibliographic sections of the selected
articles, as well as the systematic and narrative articles on the topic, were manually
searched for additional relevant articles.
Study selection
Studies considered in this meta-analysis were cohort studies that met the following
inclusion criteria: 1) Study population consisting of majority of the patients with
malignant GOO; 2) Comparison of cohorts who underwent SGJ versus EUS-GE; 3) Reported
outcomes which included technical success, clinical success, AE, and recurrence and/or
reintervention rates; and 4) Sample size of 10 patients or more. We excluded: 1) studies
that did not directly compare outcomes of EUS-GE and SGJ; 2) studies that were in
non-English language or on animal; and 3) letters to the editor, case reports, editorials,
and review articles. If multiple publications were identified from the same cohort,
then most recent and / or most appropriate comprehensive report was included.
Data extraction and quality assessment
After relevant studies were identified, two authors abstracted the data on study characteristics,
relevant outcomes of interest into a standardized form. The risk of bias and study
quality was independently assessed by two authors (SB, AG) using the Newcastle-Ottawa
scale (NOS) for cohort studies [23 ]. Using the scale, the studies were assigned scores under three broad perspectives:
(1) Selection (4 questions); (2) comparability of study groups; and (3) ascertainment
of the outcome of interest (3 questions). All questions received a score of one except
for comparability which could get a maximum of 2. Studies with a total score ≥ 8,
5 to 7, and ≤ 5 were considered high, medium, and low-quality studies, respectively.
Any discrepancies in data abstraction and quality assessment were resolved by joint
assessment of the original articles by two authors (SB, RK).
Outcomes assessment
The primary outcome of the current meta-analysis was to compare rates of technical
success and clinical success of EUS-GE vs SGJ. Secondary outcomes were AE and recurrence
and/or reintervention rates of EUS-GE vs SGJ.
Technical success was defined as successful creation of a gastroenterostomy during
the procedure and clinical success was defined as ability tolerate at least liquid
diet after the procedure. Recurrence was defined as recurrence of symptoms due to
GOO and reintervention was defined as any repeat procedure done due to patients’ recurrence
of symptoms or as a consequence of failure or AE from the primary procedure. AEs were
defined as complications or adverse outcomes related to procedure or stent. AEs were
defined and classified based on American Society of Gastrointestinal Endoscopy lexicon
or Clavein-Dindo classification [24 ]
[25 ].
Statistical analysis
We used meta-analysis techniques to calculate the pooled rates of outcomes using random
effects model described by DerSimonian and Laird [26 ]. Odds ratios comparing the outcome of interest between two procedures was calculated.
The pooled odds ratios comparing the rates of outcomes between the two groups with
95 % confidence intervals and heterogeneity was measured.
Heterogeneity was calculated using Cochran’s Q statistical test and I2 statistic. The Q-statistic provides a test of the null hypothesis that all studies
in the analysis share a common effect size. If all studies shared the same effect
size, the expected value of Q would be equal to the degrees of freedom (the number
of studies minus 1). When the expected value of Q exceeds the degrees of freedom,
the null hypothesis is rejected and variations across the studies and heterogeneity
is accepted to exist. I2 statistic estimates the proportion of total variation across studies that is related
to heterogeneity rather than by chance. Values of < 30 %, 30 % to 60 %, 61 % to 75 %,
and > 75 % were considered suggestive of low, moderate, substantial, and considerable
heterogeneity, respectively [27 ]. P < 0.05 was considered to be statistically significant. If there were ≥ 10 studies
included in the meta-analysis, we planned to assess for publication bias qualitatively,
by visual inspection of a funnel plot and quantitatively, by the Egger test. All statistical
analyses were performed by using Comprehensive Meta-Analysis (CMA) software, version
3 (BioStat, Englewood, New Jersey, United States).
Results
A total of 213 studies were identified by our search criteria. After removing duplicates,
202 studies were screened based on titles and abstracts. One hundred and seventy-nine
studies were excluded due to various reasons which include irrelevance to topic, editorials
and review articles, inadequate data, and case reports. After above exclusions 23
studies were reviewed. Five studies were excluded due to overlapping cohorts and 12
studies were excluded due to lack of specific data of interest.
Six studies that directly compared EUS-GE and SGJ fulfilled our inclusion criteria
and were included in this meta-analysis [15 ]
[16 ]
[17 ]
[18 ]
[19 ]
[20 ]. [Fig. 1 ] illustrates the study identification and selection process.
Fig. 1 Flowchart summarizing study selection process.
Characteristics and quality of included studies
A total of six retrospective comparative studies were included in the analysis [15 ]
[16 ]
[17 ]
[18 ]
[19 ]
[20 ]. Three studies were international multicenter studies [16 ]
[18 ]
[20 ] and three were single center [15 ]
[17 ]
[19 ]. The three single-center studies were conducted in the United States [15 ]
[17 ]
[19 ]. The International multicenter studies included centers from the United States,
Japan, Belgium, France, and Spain. While all the studies compared the outcomes between
EUS-GJ vs SGJ, one study also compared outcomes of enteral stenting for the treatment
of GOO [20 ]. Study characteristics of each included study have been summarized in [Table 1 ]. Overall outcomes of EUS-GE and SGJ of all the studies included in the meta-analysis
has been illustrated in [Fig. 2 ].
Table 1
Characteristics of studies involved in meta-analysis comparing EUS-GE vs SGJ.
Study/
Center/
Study type/
Intervention
Total patients (N)
Mean age (y)
Type of surgery
Khashab et al/
Multicenter/
Retrospective cohort/
EUS-GE
30
70
Open-GJ
SGJ
63
68
Perez-Miranda et al/
Multicenter/
Retrospective cohort/
EUS-GE
25
63.9
Lap-GJ
SGJ
29
75.8
Widmer et al/
Single center/
Retrospective cohort/
EUS-GE
10
63
Open-GJ & lap-GJ
SGJ
14
68
Marya et al/
Multicenter/
Retrospective cohort/
EUS-GE
172
62.4
Unspecified
SGJ
39
63.9
Bondi et al/
Single center/
Retrospective cohort/
EUS-GE
18
64
Unspecified
SGJ
34
61.3
Kouanda et al/
Single center/
Retrospective cohort/
EUS-GE
36
70.4
Open-GJ
SGJ
14
71.5
EUS-GE – endoscopic ultrasound-guided gastroenterostomy; SGJ – surgical gastrojejunostomy;
Lap −laparoscopic.
Fig. 2 Study outcomes of endoscopic ultrasound-guided gastroenterostomy vs surgical gastrojejunostomy.
Primary outcomes
The technical success rate of EUS-GE was inferior compared to SGJ with OR = 0.195
(95 %CI: 0.054–0.702; P = 0.012; Q = 1.909; I2 = 0) and this was statistically significant. The calculation of heterogeneity was
minimal with Q value within degrees of freedom and I2 was 0 ([Fig. 3 ]).
Fig. 3 Forest plot for EUS-GE vs SGJ technical success. Pooled OR = 0.195 (95 %CI:0.054-.702).
Prediction interval = 0.032 to 1.197 [The true effect size (OR) in 95 % of all populations
falls in this interval]
The Odd’s ratio for the rate of clinical success between EUS-GE and SGJ trended toward
favoring EUS-GE, but statistically insignificant (OR = 1.566; 95 %CI: 0.585–4.197;
P = 0.372; Q = 9.37; I2 = 46.68 %), However, a wide confidence interval of 0.6 to 4.2 demonstrates uncertainty
regarding this outcome. Heterogeneity was moderate ([Fig. 4 ]).
Fig. 4 Forest plot for EUS-GE vs SGJ clinical success. Pooled OR = 1.566 (95 %CI: 0.584–4.197). Prediction Interval = 0.108 to 22.685 [The
true effect size (OR) in 95 % of all populations falls in this interval]
Secondary outcomes
The rate of AEs was lower in the EUS-GE group compared to the SGJ group (OR = 0.295;
95 % CI: 0.172–0.506; P < 0.005; Q = .40: I2 = 0) and was statistically significant. Heterogeneity was minimal ([Fig. 5 ]).
Fig. 5 Forest plot for EUS-GE vs SGJ adverse events. Pooled OR = 0.295 (95 %CI: 0.172–0.506). Prediction interval = 0.137–0.634 [The true
effect size (OR) in 95 % of all populations falls in this interval].
Among the five studies which reported recurrence and/or reintervention rates, there
was no statistically significant difference in the overall recurrence/reintervention
rates between EUS-GE vs SGJ (OR = 0.587; 95 %CI: 0.174–1.979; P = 0.390, Q = 8.87; I2 = 54.91). Heterogeneity was moderate ([Fig. 6 ]).
Fig. 6 Forest plot for EUS-GE vs SGJ recurrence/reintervention rates. Pooled OR = 0.587 (95 %CI:0.174–1.979). Prediction interval = 0.022 to 15.360 [The
true effect size (OR) in 95 % of all populations falls in this interval].
Risk of bias and study quality assessment
Risk of bias and quality assessment of the involved retrospective cohort studies were
done using NOS. Four studies were deemed to be high quality [16 ]
[17 ]
[19 ]
[20 ] and two were deemed medium quality [15 ]
[18 ]. The quality assessment of each study has been detailed in Supplementary Table 1 . Assessment of publication bias was performed despite the limited number of studies
using a funnel plot and Egger’s regression test and adjustments based on Duval and
Tweedie’s trim and fill technique were also performed [28 ]
[29 ]. Analysis using these techniques did not show evidence of significant publication
bias. (Supplemental Fig. 5, Supplement Fig. 6, Supplement Fig. 7 ). Sensitivity analysis for each outcome by removing one study at a time was done
and the results are shown in Supplemental Fig. 1, Supplemental Fig. 2, Supplemental Fig. 3, and Supplemental Fig. 4 .
Discussion
Malignancy is the most common cause of GOO [30 ]. Malignant GOO carries an overall poor prognosis in patients who cannot be offered
surgical cure and for these patients with unresectable disease, the management of
GOO involves reducing their symptom burden, improving nutritional status, and improving
the patient’s quality of life [31 ]. Choosing an appropriate treatment needs to factor in the patient’s medical co-morbidities,
expected prognosis, and chances of technical success. Palliative care in terminal
patients with malignant GOO should ideally be as least invasive as possible, provide
long-term symptom relief, cause the least morbidity, and improve quality of life.
Additionally, interventions should not prolong length of hospitalization and allow
for palliative chemotherapy without complications or delay in recovery. With the available
endoscopic procedures, surgery is reserved for patients deemed surgical candidates
and with an expected prognosis that can justify the surgical risk [4 ]. With higher rate of AEs and morbidity associated with surgery, a less invasive
endoscopic procedure that can offer comparable outcomes with less complications would
be an ideal option. EUS-GE may be able to provide a more ideal intervention in this
patient population, but supporting data is dearth. This led us to perform this systematic
review and meta-analysis of the available literature and data on this subject.
Our study showed that technical success rates of EUS-GE were inferior to SGJ (OR = 0.195;
95 %CI: 0.054–0.702; P = 0.012). However, clinical success rates were comparable between EUS-GE and SGJ
with odds ratio favoring EUS-GE, however this did not achieve statistical significance
(OR = 1.566; 95 %CI: 0.585–4.197; P = 0.372). Lower technical success of EUS-GE compared to SGJ could be due to several
reasons: EUS-GE is a new and technically challenging procedure which needs significant
expertise. Its rate of technical success may improve with more experience and utilization.
The EUS-GE procedure is not standardized and five different techniques to achieve
EUS-GE have been described [9 ]. Involvement of malignant GOO in the small bowel, especially in the region of the
ligament of Treitz, can render the procedure technically challenging and even prove
impossible as this small bowel section is typically adjacent to stomach [16 ]. Being a newer, non-standardized procedure, the studies involved may have reflected
the early experience in the technique and the learning curve effect may have contributed
to lower technical success as well.
The adverse event rates of EUS-GE were significantly lower compared to SGJ (OR = 0.295;
95 %CI: 0.172–0.506; P < 0.005). Also, among the five studies that reported recurrence and/or reintervention
rates, there was no statistically significant difference between these two groups
[15 ]
[16 ]
[17 ]
[19 ]
[20 ]. Therefore, if technically feasible, EUS-GE can provide long-lasting clinical success
encompassing symptom improvement and diet tolerance while also posing lower adverse
event rates compared to SGJ in patients with malignant GOO. Two studies performed
cost analysis on procedural costs between EUS-GE versus SGJ [17 ]
[18 ]. As per the study by Perez-Miranda et al, the procedural costs were calculated to
be $ 4,515 for EUS-GE vs $ 14,778 for SGJ (P < 0.001) [18 ]. Similarly, in the study by Kouanda et al, the procedural costs were $ 19,785 vs
$ 42,716, respectively (P < 0.001) [17 ]. Differences in calculated costs are likely due to different techniques used as
one study used Medicare reimbursement rates while the other used charge rate billed
to payor. Nevertheless, in both studies EUS-GE is associated with significantly lower
costs than SGJ.
A recent systematic review and pooled analysis by Duarte-Chavez et al. showed results
similar to our analysis [32 ]. Clinical success rates were similar in both groups while EUS-GE was associated
with lower rates of AEs and higher rates of technical success than SGJ. This study
conducted a pooled analysis of three studies comparing EUS-GE vs enteral stenting
and two studies comparing EUS-GE vs SGJ. However, in our study, we only included studies
that directly compared EUS-GE vs SGJ head-to-head. While all the studies included
in our analysis involved patients with malignant GOO, three studies also included
patients with benign etiologies. The analysis was done only among patients with malignant
GOO in four studies [15 ]
[16 ]
[17 ]
[19 ]. However, in the remaining two studies by Perez-Miranda et al and Marya et al [18 ]
[20 ], our analysis included patients with benign GOO as well, nevertheless, the majority
of patients were with malignant GOO which comprised of 85 % and 76.3 % of their study
populations respectively.
Our study has several strengths. To our knowledge, this is the first systematic review
and meta-analysis involving all studies directly comparing EUS-GE vs SGJ. Studies
were identified after a rigorous, comprehensive, and systematic search across multiple
databases and conference proceedings. A well-defined inclusion and exclusion criteria
were used with a detailed quality assessment. Heterogeneity in the analysis of technical
success and AEs were low. Half of the included studies were international multicenter
studies. There are some limitations to our study. All the involved studies were retrospective
comparative studies with inherent limitations and risk of bias. The Studies have tried
to limit selection bias by selecting all the patients within a certain time period,
however, without randomization, selection of a procedure in a particular patient might
have been biased due to various confounders. It is possible that a sicker patient
might have been assigned to receive a lesser invasive procedure, affecting the outcomes.
Three studies involved in the analysis were reported only as abstracts with limited
details regarding them; however, the outcomes of interests pertaining to our study
were clearly reported [15 ]
[19 ]
[20 ]. Also, the abstract by Marya et al. contributes to > 50 % of the total EUS-GE patients
involved in this study, however, the weight assigned to the study in the random effects
model used in the meta-analysis was only approximately 19 % to 24 %. In addition,
all the studies were conducted at tertiary referral centers with significant expertise
in therapeutic EUS, therefore the results cannot be generalizable. Heterogeneity in
the assessment of clinical success and recurrence/reintervention rates were high which
can be attributed to multiple factors, such as the low number of studies included
and small number of patients in each study. Three studies were multicenter studies
in which EUS-GE was performed by different operators internationally, which limits
the standardization of techniques, given there are multiple techniques for EUS-GE
[9 ]
[18 ]. While some studies only used electrocautery-enhanced LAMS, some studies incorporated
procedures performed both with or without electrocautery-enhanced LAMS, which could
have impacted the outcomes. Finally, SGJ is an older and more refined procedure compared
to the novel EUS-GE, which is evolving. Most of the SGJ procedures in the cohort likely
were done in a prior time period, whereas EUS-GE was done in recent years. Hence,
we can safely assume the cohorts were not entirely contemporaneous. Furthermore, some
studies used an open approach to SGJ while others used laparoscopic GJ or both and
our study lacks a direct comparison between EUS-GE and the current standard of care,
laparoscopic GJ. Three studies reported only patients with open GJ and two abstracts
did not specify the nature of surgery. Limited studies with information on laparoscopic
GJ also did not allow us to perform a subgroup analysis comparing EUS-GE vs laparoscopic
GJ.
Conclusions
Advances in endoscopic procedures have allowed for a paradigm shift in the approach
and treatment of patients with malignant GOO where the primary goal is symptom palliation.
While enteral stents were initially more commonly used than SGJ in this patient population,
symptom recurrence and reintervention was a major disadvantage. Through the advent
of LAMS, the ability to perform minimally invasive intraluminal gastroenterostomy
has led to the development of EUS-GE, which has the potential to help treat this sick
patient population and achieve long-lasting symptom relief and palliation. This study
shows that EUS-GE is similar to SGJ in delivering clinical success and avoiding reinterventions,
and better than SGJ in terms of AEs rates even in the initial learning curve period
in specialized centers. EUS-GE is rapidly evolving and with further expertise and
experience we anticipate the technical success rates to improve as well.
When expertise is available, EUS-GE is an effective and safe alternative to SGJ in
the treatment of malignant GOO, for which data are available on long-term outcomes.
Larger prospective randomized studies are required to validate our results.
