- Endoscopic Full Thickness Resection Using a Clip Non-exposed Method for Gastrointestinal Tract Lesions

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ENDOSCOPIC FULL THICKNESS RESECTION USING A CLIP NON-EXPOSED METHOD FOR GASTROINTESTINAL TRACT LESIONS: A META-ANALYSIS

Key words: subepithelial lesions, endoscopic full-thickness resection, difficult adenomas, clip-assisted, full-thickness resection device, OTSC

Abbreviations:

EFTR: endoscopic full-thickness resection

OTSC: over the scope clip

SELs: subepithelial lesions

ESD: endoscopic submucosal dissection

EMR: endoscopic mucosal resection

ABSTRACT

Background: Endoscopic full-thickness resection (EFTR) allows for treatment of epithelial and sub-epithelial lesions (SELs) unsuitable to conventional resection techniques. This meta-analysis aimed to assess the efficacy and safety of clip-assisted method for non-exposed EFTR using FTRD or over-the-scope clip of gastrointestinal (GI) tumors. Methods: A comprehensive literature search was performed. The primary outcome of interest was the rate of histologic complete resection (R0). Secondary outcomes of interest were the rate of en bloc resection, FTR, adverse events, and post-EFTR surgery. Random-effects model was used to calculate pooled estimates.Results: 10 studies with 357 patients and 358 lesions were included in the analyses. Indications for EFTR were difficult/residual colorectal adenoma, adenoma at a diverticulum or appendiceal orifice and early cancer (n=294), colorectal SELs (n=34), and upper GI lesions (n=30). Median size of lesions was 14 mm. There were 5 failed EFTR attempts. Pooled overall R0 resection rate was 86% (95% CI: 73-96). The pooled overall FTR rate was 87% (95% CI: 76-95). The pooled overall en bloc resection rate was 96% (95% CI: 92-99). The pooled estimates for perforation and bleeding were 1% and 1%, respectively. Following EFTR, a total of 32 patients underwent surgery for any reason [pooled rate 7% (95%CI 4-10)]. The pooled rates for post-EFTR surgery due to invasive cancer, for non-curative endoscopic resection and for adverse events were 4%, < 0.1% and < 0.1%, respectively. No mortality related to EFTR was noted. Conclusions: EFTR appeared to be safe and effective intervention for GI lesions that are not amenable to conventional endoscopic resection. This technique should be considered as an alternative to surgery in selected cases.

INTRODUCTION

Advanced endoscopic resection procedures like endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) are established techniques for the treatment of gastrointestinal (GI) neoplasia. For large colorectal polyps, endoscopic resection is successful in avoiding the need for surgery in up to 90% of cases with low rates of adverse events (1.5% for endoscopic perforation and 6.5% for bleeding)¹. However, the efficacy of endoscopic resection is mired in the setting of non-lifting lesions associated with fibrosis and scaring or in lesions located in a difficult area such as in a diverticulum or the appendiceal orifice². Moreover, subepithelial lesions (SELs) such as neuroendocrine tumors in the GI tract can be difficult to manage endoscopically. For example, although EMR is feasible in duodenal SELs < 1.5 cm, it is associated with low rate of complete resection. ESD is a feasible option with higher chances of complete resection rate with increased risk of perforation ³.

Recently, endoscopic full-thickness resection (EFTR) has emerged as an option to remove difficult superficial mucosal lesions and SELs⁴that are not amenable to standard resection techniques. EFTR enables full-thickness resection including the muscularis propria layer and provides a complete basis for pathological diagnosis ³. There are two approaches: (1) the tumor is resected first and defect closure is performed in a second step (exposed EFTR); or (2) creating serosa-to-serosa apposition underneath the tumor before resection (non-exposed EFTR) ⁵.

Over-the-scope clip (OTSC) – assisted EFTR is a “close-then-cut” non-exposed EFTR technique that, in theory, could be a safer method than “cut-then-close” EFTR because it avoids contamination of GI luminal content into the peritoneum and prevents bleeding before full thickness resection. OTSC-assisted EFTR has been reported using over the scope clips followed by resection of the pseudopolyp using a snare resection or a needle knife, or using a dedicated full-thickness resection device (FTRD; Ovesco Endoscopy, Tuebingen, Germany) which consists of OTSC preloaded into a cap with an integrated snare. The FTRD has recently being approved by the FDA in the United States to perform colorectal EFTR ^2,5.

A number of studies on efficacy and safety of clip-assisted EFTR have been published to date with variable results. Therefore, the aim of our study was to perform a meta-analysis to summarize the current scientific evidence on efficacy, safety and clinical outcomes of patients with GI neoplasia treated with clip-assisted non-exposure EFTR.

METHODS

Information sources

We conducted a comprehensive electronic literature search for studies of clip-assisted EFTR using “close-then-cut” technique for treatment of GI lesions. Relevant original publications were identified The following electronic databases were searched: inMEDLINE, PubMed, E, Cochrane Library, Scopus, and Web of Science, Central Register for the period July, 1966 to December 2017. Terms used for the search are reported in online supplementary material. Additional publications were identified through searching the reference lists of retrieved papers. We contacted the authors when further information from selected papers was needed.

Eligibility criteria

Studies were included if they met the following criteria: (1) Original articles that assessed the use of EFTR for upper or lower GI neoplasia and provided outcomes of interests. GI neoplasia included mucosal or SELs of the esophagus, stomach, duodenum and colo-rectum; (2) All available studies performed in humans that used the FTRD or OTSC to perform EFTR of GI neoplasia; (3) studies included more than 5 patients and (4) studies that were published in English. Exclusion criteria were: (1) studies using the non-clip assisted FTR technique; (2) studies of EFTR performed in animals; (3) review papers; (4) studies written in languages other than English; (5) case reports with less than 5 patients and (6) abstracts.

Study selection

We report our results according to the MOOSE statement for meta-analyses of observational studies ⁶. The initial search strategy was performed by a librarian (MT). All titles and abstracts of papers retrieved in the pre-specified search were screened by two reviewers (OIBG, YH). Full-length publications of selected articles were screened for final inclusion. Any disagreement was resolved by a third reviewer (SN). Data from the included studies was extracted into a data extraction sheet.

Data collection process and listed items

From each series, the reviewer abstracted the following information: (1) country; (2) publication year; (3) enrolment period; (4) setting (single center/multicenter); (5) study design (prospective/retrospective); (6) number of patients included; (7) number of patients excluded; (8) reasons for exclusion; (9) total of patients included; (10) total number of EFTR attempted; (11) gender distribution; (12) site distribution (gastric/duodenal/colonic) of the lesions; (13) size of lesions; (14) device used for EFTR; (15) total procedure time (16) outcome of endoscopic resection at endoscopy (rate of success/failure); (17) rate of complete endoscopic resection (en-bloc resection); (18) rate of complete histological resection (R0 resection); (19) rate of FTR (defined as presence of all layers of the wall including serosa within the resected specimen or presence of muscle layer in the resected specimen, depend on the studies); (20) rate of total adverse events; (21) rate of intra-procedural or (22) post-procedural bleeding; (23) rate of perforation; (24) rate of surgery for adverse events; (25) rate of surgery for non-curative endoscopic resection of precancerous lesions; (26) rate for surgery due to invasive cancer; (27) duration of post-procedural follow-up; (28) number of patients with follow-up data; (28) rate of lost at follow-up; (29) performance of biopsies from scar.

Risk of bias in individual studies

Information on the methodological quality of each included study was recorded and quality assessment was performed using the Newcastle-Ottawa Scale (NOS) ⁷. Representativeness of the study cohorts, ascertainment of exposure, demonstration that outcome of interest was not present at start of study, assessment of outcome and adequate length of endoscopic follow-up was assessed for each study.

Over-the-scope clips and FTRD

The OVESCO OTSC (Ovesco Endoscopy, Tuebingen, Germany) has been used for clip-assisted EFTR. It resembles a bear claw once deployed. The cap diameter is available in three sizes (11, 12 and 14 mm) and two depths (3 and 6 mm). There are 3 different teeth configurations: type a (blunt teeth), type t (small spikes on teeth) and type gc (spikes on elongated teeth). For EFTR in the upper GI lesions, it is recommended to use the 12/6 type t clip. For colo-rectal lesion, the 12/6 or 14/6 type t clip are considered best options ².

Another OTSC (Padlock Pro-select, Aponos Medical Corp., Kingston, NH, USA) available to perform EFTR consists of a flat star-shaped nitinol clip with 6 inner needles preloaded into a cap. This clip is available in two sizes; the standard Padlock fits a 9.5-11 mm diameter scope and the Padlock Pro-select fits an 11.5-14 mm diameter scope. An advantage of this clip design is that the wire that deploys the clip goes along the shaft of the scope, freeing the working channel of the endoscope ^2-3.

The FTRD consists of an OTSC preloaded into a cap with an integrated snare. The inner diameter of the cap of the device limits the maximum size of the lesion to be removed ⁵. Its use is recommended for epithelial lesions < 30 mm and SELs < 20 mm in the colo-rectum. The current system has an outer diameter of 21 mm making per-oral insertion and passage through the esophagus significantly more difficult than in the colo-rectum.

Outcomes

The primary outcomes of this meta-analysis were the rates of complete histological resection (R0) of upper and lower GI epithelial and SELs. Secondary outcomes were en bloc resection, FTR (defined as the presence of all layers of the wall including the serosa in the resected specimen or presence of muscle layer in the resected specimen) and adverse events related to the EFTR (bleeding, perforation, and appendicitis), the rates of surgery for any reasons, surgery due to incomplete resection, surgery due to adverse events and surgery due to invasive cancer. Subgroup analyses was also performed according to the type of OTSC device used, lesion location and indications, such as for patients with difficult colorectal adenoma due to recurrent or incomplete resected lesions or adenomas at difficult locations such as the appendiceal orifice or diverticulum and early carcinomas.

Statistical analysis

Data on the primary and secondary outcomes relevant to this study were extracted when available. The missing information was obtained by contacting the primary authors through personal communication.

For each of the study questions, cumulative data from each individual study was summarized to obtain pooled rates and the 95% confidence intervals. All analyses were done in StataMP (StataCorp. 2015. Stata Statistical Software: Release 14. College Station, TX: StataCorp LP). Given the clinical heterogeneity noted among the individual studies, random effects model were used for all analyses. ‘Metaprop’ statistical program was used in Stata to perform the meta-analyses of proportions⁸. Metaprop is most suitable for binomial data and provides methods for proportions which are close to margins by allowing the Freeman-Tukey double arcsine transformation to stabilize the variances. Subgroup analyses were performed when appropriate. The heterogeneity between the sub-groups and among the individual studies was calculated using the I² statistic, reported with the associated p-value. The I² statistic can be categorized as for low level (<25%), moderate level (25-50%) and high level of heterogeneity (>75%), respectively. A p value of <0.05 was considered statistically significant. The risk of publication bias was assessed for the primary outcome, R0 pooled resection rates of all lesions using funnel plots and funnel plot asymmetry was tested using Egger’s regression test. To further evaluate the effect of small studies with less precise estimate, we performed cumulative meta-analysis by adding studies sequentially in step-wise fashion according to the sample size, i.e. the largest study was used in step 1, the second largest study was added in step 2 and so on until all studies were added to the analysis. This also serves as sensitivity analysis by comparing summary estimate in each step to the full sample estimate, examining the drifts from center.

RESULTS

Study selection

The study flow chart is shown in figure 1. A total of 413 studies were retrieved, of which 154, 114, 111, 32 and 2 studies were identified by the searches in Scopus, PubMed, EMBASE, Web of Science and Cochrane respectively. After excluding the duplicates, 248 were included. Then upon reviewing titles and abstracts, 43 studies were found to be eligible and reviewed in full text. Of these, 6 were included in the analyses, while 37 were excluded. Additionally, 4 studies were included after manually searching the references.

Characteristics of the included studies

Main characteristics of the included studies are provided in table 1. Overall, 8 (80%) studies were performed in Europe, the remaining 2 being from the US. Eight (80%) series were published in the 2017, 1 (10%) in 2015, and 1 (10%) in 2014. Median duration of the enrollment per study was 1.3 years (range: 9 months–4.4 years). Most of the studies were single center (6, 60%), 3 (30%) two-center and 1 (10%) multicenter. The majority (7, 70%) were retrospective.

Risk of bias assessment (table 2)

Selection bias:

The representativeness of each study’s cohort was appropriate, with no major selection bias identified. All study cohorts included patients who were felt to have lesions amenable to clip-assisted EFTR. These patients had undergone endoscopy that either identified lesions that were inadequately (i.e. R1 resection) or unsuccessfully (i.e. recurrent non-lifting adenoma) resected by conventional polypectomy or found lesions that would be unfeasible with conventional polypectomy. However, not all studies were explicit in their exclusion criteria.

Ascertain of exposure:

All studies utilized a medical record to access patient data, endoscopic reports, and histopathologic reports.

Outcome bias:

Regarding assessment of outcome, all studies reported R0 resection, post-EFTR histologic findings, adverse events, and technical success, which was defined by all studies as uncomplicated clip deployment and complete macroscopic removal of the lesion.

The studies included in this paper demonstrated variability in adequacy and duration of cohort follow-up. Three studies experienced loss of greater than 20% of its cohort at follow-up (22–31%), while an additional two studies experience loss of greater than 10% of its cohort at follow-up (15–17%). Follow-up was not systematically scheduled in all studies, however, all studies had a mean or median follow-up duration exceeding eight weeks, which was felt to be clinically adequate to monitor for post-procedural complications.

Patient characteristics

Study population was comprised of 357 patients with at least one GI neoplasia. The median of patients included per study was 16 (range: 6 -181 patients). Distribution of the population age and sex was available for 10 and 8 series, respectively. Medians of age and male sex were 67.5 (range: 29 – 88 years) and 61.2 % (range: 50 -78%), respectively.

The total number of GI lesions included was 358. Mean size was reported in all series, with the median being 14 mm (range: 2 – 50 mm). Distribution site within the GI tract was available for 9 series. Overall, 328/358 (91.6%) were located in the colon or rectum and 30/358 (8.4%) were in the upper GI tract.

Regarding type of lesions in colorectal EFTR group: 202/328 non-lifting/residual/recurrent adenomas, 45 adenomas at the appendiceal orifice, 30/328 were colonic SELs, 8/328 colonic adenomas involving diverticulum, and 43/328 early carcinomas. The site distribution within the colorectum was as follows: in the proximal colon 179/328, distal colon 67/328, 80/328 in the rectum and 2/328 was ileo-colon anastomosis.

For clip-assisted EFTR for upper GI lesions: 30/30 gastric and duodenal lesions were SELs. In detail, distribution within the upper GI tract was as follows: 1/30 esophagogastric junction (EGJ), 1/30 in the fundus, 2/30 were located in the gastric cardia, 7/30 in the gastric body, 3/30 in the gastric antrum, 4/30 in the duodenal bulb and 6/30 in the descending duodenum; 6/30 were not specified, of which 2 were in the stomach and 4 in the duodenum.

Procedure characteristics

The information about the device used for EFTR was available in all series. Five (5) studies used the FTRD, 4 used the Padlock clip and in one study, both the Padlock and OVESCO clips were used. Overall, there were five unsuccessful attempts of EFTR. The reasons of failure were inability to advance the device through narrowed/fixed sigmoid (n=3) and inability to suction the lesion into the cap (n=2). Data on procedure time was recorded in 8 studies (80%), and was defined as time from scope in to scope out. Mean procedure time was 53.9 ± 16.3 minutes. After the procedure, in 9/10 series (90%), authors reported that patients were routinely hospitalized for observation for a median of 2 days [IQR 1.5-2.5].

Definition on FTR was reported in 8/10 (80%) series. FTR was defined as the presence of all layers of the wall including the serosa in the resected specimen in 6 studies and as the presence of muscle layer in the resected specimen in 2 studies.

Outcomes

Primary outcomes

Information regarding R0 resection was available in all series. Of the entire cohort, 272 patients achieved R0 resection. The pooled overall R0 resection rate was 86% (95% CI: 73-96; I²= 82.3%,p ≤ 0.01) (figure 2). The pooled overall R0 resection rate in the studies using the Padlock/OVESCO clip was 85% (95% CI: 46-100; I² = 87.5%, p ≤ 0.01) and 87% (95% CI: 75-96; I² = 75.1%, p ≤ 0.01) in the studies using the FTRD. In addition, the pooled R0 resection rate for difficult adenoma was 85% (95%CI 69-97; I²= 80.3%, p ≤ 0.01) (figure 3) and 76 % (95% CI 45-98; I²= 47.9%, p = 0.10) for early carcinomas (figure 4). The subgroup analysis of the R0 resection rates is available in table 3.

Secondary outcomes

Regarding en bloc resection rate, information was available in 9/10 series. Of the total cohort, 315 cases reported successful en bloc resection, with the pooled overall en bloc resection rate of 96% (95% CI: 92-99; I²= 35%, p=0.13) (figure 5). The pooled en bloc resection rate was 100% (95%CI 92-100; I²= 0%, p= 1) for upper GI SELs, 100% (95%CI 93-100; I²= 0%, p=0.99) for colorectal SELs, 97% (95%CI 92-100; I²= 44.8%, p=0.09) for difficult colorectal adenomas and 95% (95%CI 83-100; I²= 0%, p=0.67) for early carcinomas. The pooled en bloc resection rate by type of device was 100% (95%CI 97-100; I²= 0%, p =0.99) in the Padlock/OVESCO group and 92% (95% CI 86-96; I²= 41.4%, p=0.16) in the FTRD group.

Overall, FTR was achieved in 292 patients. The pooled overall FTR rate was 87% (95% CI: 76-95; I²= 73%; p ≤ 0.01) (figure 6). The pooled FTR rate was 71% (95%CI 37-97; I²=61.6%, p=0.05), 52% (95% CI 0-100; I²= 44.3%, p=0.13), 95 % (95%CI 83-100; I²= 59.9%, p=0.02) and 86% (95%CI 50-100; I²= NA, p= NA) for upper GI SELs, colorectal SELs, difficult colorectal adenomas and early carcinomas, respectively. The pooled FTR rate by device was 73% (95%CI 41-97; I²= 80.1%, p ≤ 0.01) in the Padlock/OVESCO group (Other) and 91 % (95% CI 82-98; I²= 67.1%, p=0.02) in the FTRD group.

Adverse events:

Information pertained to adverse events was reported in all studies. A total of 36 adverse events were reported. The overall pooled rate of adverse events was 8% (95% CI 3-14; I²= 44.3%, p=0.06) including bleeding (9 patients), perforation (9 patients), micro perforation (3 patients), appendicitis (4 patients), post polypectomy syndrome (3 patients) and entero-colonic fistula (1 patient) (figure 7). The pooled estimate rates for perforation and bleeding were 1% (95% CI 0-4; I²= 24.8%, p=0.22) and 1% (95%CI 0-3; I²= 0%, p=0.96), respectively. Of 45 patients with adenoma involving the appendiceal orifice, the pooled estimates of appendicitis after EFTR was 4% (95%CI 0-15; I²= 0%, p=0.70). One patient developed entero-colonic fistula after EFTR of a cecal adenoma. It was believed to occur due to entrapment of small bowel into the clip during resection. This patient was referred to surgery. No mortality related to EFTR was reported.

When analyzing adverse events by type of study (prospective vs. retrospective), in the retrospective studies the pooled rate of adverse events was 5% (95% CI 1-10; I²= 0%, p=0.70) whereas in the prospective studies was 19% (95% CI 4-42; I²= N/A, p=N/A)

Need for surgery after EFTR:

Following EFTR, 32 patients underwent surgery for any reason [pooled rate 7% (95%CI 4-10; I²= 0%, p=0.64) (figure 8). This information was available from all studies. The pooled rates for post-EFTR surgery due to invasive cancer, for non-curative endoscopic resection of precancerous lesions and for adverse events was 4% (95% CI 2-7; I²=0%, p=0.80), < 0.1 % (95% CI 0 -1; I²=0%, p=1.00) and <0.1% (95% CI 0-2; I²=0%, p=1.00), respectively.

Follow up

Follow up time after EFTR was reported in all series with a median of 177 days [IQR 117.7-248.2]. Information on follow up endoscopy after EFTR was reported in 9/10 (90%) series. Overall, 274/353 (78%) patients underwent a follow up endoscopy while 71/353 (20%) patients were lost to follow up and there is no information in 8/353 (2%) patients. In the 274 patients who underwent a follow up endoscopy, 192 (70%) had spontaneous clip detachment while 16 (6%) underwent clip removal; in the remaining 66 patients (24%) the clip was left in place. Biopsy was taken in 248/274 (90%) patients who underwent endoscopy. There was recurrence/residual disease in 26/248 (10%) of the patients.

Publication bias

We evaluated the possibility of publication bias for the main outcome, R0 pooled resection rate of all lesions. The Egger’s regression (p=0.46) demonstrated no significant publication bias (figure 9). The small study effect was also evaluated by cumulative analysis. This cumulative meta-analysis method demonstrated that as less precise studies were added there was no drift in the cumulative effect estimate (online supplementary figure 1).

DISCUSSION

In this meta-analysis, we found that clip assisted non-exposure EFTR is a feasible technique for difficult GI lesions, such as difficult colorectal adenomas, early carcinomas and GI SLEs, with overall R0 resection rates of 86%, en bloc resection rates of 96% and FTR rates of 87%. Moreover, there is an acceptable rate of adverse events (8%) and a low risk of surgery due to EFTR-related adverse events (< 1 %). The above-mentioned results support this technique as a potential alternative to surgery for colorectal lesions that failed to respond to standard endoscopic resection, challenging locations such as polyps involving appendiceal orifice or a diverticulum, and superficial early carcinomas or SELs.

In this study, non-lifting from fibrosis due to difficult and recurrent adenomas or prior incompletely resected lesions was the most common indication of EFTR (in 255 of 328 cases) with pooled R0 rates of 85% for this indication. This group of patient represent a challenging situation and are commonly referred to surgical resection ¹⁸. Other endoscopic techniques to manage these lesions have been described such as ablation using soft coagulation or argon plasma coagulation, ESD, dissection-enabled scaffold-assisted resection (DeSCAR), cold snare, and underwater resection ^19-21. Success rates of these techniques vary between 59 and 100%^19-21 and require close endoscopic monitoring for recurrence if the lesion is not removed en bloc. ESD for non-lifting or recurrent lesion is technically demanding and requires extensive experiences in colo-rectal ESD expertise which limited its use in the Western countries. Clip-assisted EFTR represent a viable option for this indication with potential advantages being ability to perform complete resection and lower risk of recurrence. Further comparative studies are required to evaluate safety and efficacy of EFTR compared to other techniques.

The subgroup of patients with adenomas involving the appendiceal orifice (n=45) which is considered a difficult anatomic location for endoscopic resection. There have been few reports of endoscopic resection of colon polyps involving the appendiceal orifice ^22-24. In patients with no prior history of appendectomy, if the deep margin into the appendiceal lumen is not ascertained, complete resection cannot be performed. Thus, these lesions generally require surgical resection. One major concern of EFTR for these lesions are post-procedural appendicitis. In this study, risk of appendicitis following EFTR of lesions involving appendiceal lumen is 4%. However, most included studies did not report proportions of patients who had undergone prior appendectomy, thus future prospective studies are needed to assess true risk of appendicitis for those with intact appendix. Currently, clip-assisted EFTR seems to be a potential option for these lesions and should be limited to patients with prior history of appendectomy. Clip-assisted EFTR has emerged as a technique for the resection of SELs in both the upper and lower GI tract, such as neuroendocrine tumors or GIST. In the subgroup of SELs in this study, a high overall R0 resection rate was also observed (93% in upper SELs and 100% in lower SELs), making EFTR an attractive endoscopic alternative to surgery in cases whom conventional endoscopic resection seems to be at high risk for severe adverse events or unlikely to achieve complete resection. Notably, in the study by Kappelle et al ⁴, EFTR using the flat-based OTSC (Padlock clip) in the duodenum was complicated by perforation (n=1) and microperforation (n=3), whereas no adverse events were reported in other studies using this clip ^11,17. The use of the flat-based OTSC clip-assisted EFTR in the duodenum requires further technical refinements. In addition, only one study ¹⁶reported the use of the FTRD device for SELs in the upper GI tract, while the remaining studies used the OVESCO/Padlock clip ^4,11,17Due to the large diameter cap, the current FTRD system is difficult to advance through the upper esophageal sphincter or pyloric ring, increasing the risk of tears and/or perforation, therefore limiting its use in the upper GI tract. Moreover, the available FTRD system has not been approved for EFTR in the upper GI tract.

Despite the favorable risk/benefit ratio, EFTR is a technically demanding procedure and requires expertise. Advancing the device to the target lesion can be challenging due to friction and decreased visibility due to the long cap. In a small number of patients, clip-assisted EFTR was unsuccessful because the device could not be advanced through a narrow sigmoid colon. The impaired visibility once the lesion is entrapped in the cap can potentially limit complete resection ². Tumor size is a major limitation of resection with this technique. To obtain a full-thickness resection specimen and to achieve complete resection, it is critical to include the entire lesion into the cap. The maximum lesion size of colorectal polyp should not exceed 25-30 mm. However, in case of scaring or location in the rectum incorporation of the entire lesion into the cap is even more difficult. For this reason, some experts recommend limiting the size of the lesion to 20-25 mm⁹.

There are limitations to our analysis. Most studies were either single center or retrospective with inherent possibility of selection bias. Second, some information was missing or incomplete from few case series. Even though data on clip-assisted EFTR is promising, further prospective, randomized control trials are required to assess long-term efficacy and safety of this technique compared to conventional endoscopic resection techniques and/or surgery.

In conclusion, in this meta-analyses, we found that clip-assisted EFTR is an effective and safe technique for difficult mucosal and submucosal GI lesions with high complete resection rate and acceptable rates of adverse events. These findings hassle the importance of optimizing and standardizing the EFTR technique, especially when considering the widespread implementation of this procedure to remove difficult colorectal adenomas and SELs, sparing the need of surgery.

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Figure 1. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram

Table 1. Main characteristics of included studies

Author	Year of publication	Country	Study Design	Multicenter/single center	Study period	Total patients	Males (%)	Age (mean)	Attempted/ failed attempt EFTR
Al-Bawardy, *et al*¹¹	2017	US	Retrospective	1 center	Jun 2014 -Oct 2015	9	7 (78)	63	9/0
Andriasani, *et al*¹²	2017	Italy	Retrospective	1 center	Jan – Sep 2016	20	12 (60)	67	20/0
Backes, *et al*¹³	2017	The Netherlands	Prospective	2 centers	Oct 2015 – Dec 2016	26	13 (50)	70	26/0
Dinelli, *et al*¹⁴	2017	Italy	Retrospective	2 centers	Unknown , 18 month period	6	4 (67)	68.5	7/0
Meier, *et al*⁹	2017	Germany	Retrospective	1 center	Jun 2015 – Aug 2016	10	6 (60)	72.5	10/0
Schmidt, *et al*¹⁵	2017	Germany	Prospective	Multicenter (9)	Feb 2015 – Apr 2016	181	99 (55)	65	181/0
Valli, *et al*¹⁶	2017	Switzerland	Retrospective	1 center	Jun 2012 – Oct 2016	60	Not reported	68	60/2
Kappelle, *et al*⁴	2017	The Netherlands	Prospective	1 center	Jan 2015 – Jul 2016	12	8 (67)	52.8	13/2
Schmidt, *et al*¹⁰	2015	Germany	Retrospective	2 centers	Jul 2012 – Jul 2014	25	Not reported	70	25/1
Sarker, *et al*¹⁷	2014	US	Retrospective	1 center	unknown , 12 month period	8	8 (67)	61.6	8/0

Table 2. Quality assessment was performed using the Newcastle-Ottawa Scale (NOS)

	Selection		Exposure	Outcome
Study	Representativeness of cohort	Demonstration that outcome of interest was not present at start of study	Ascertainment of exposure	Assessment of outcome	Was follow-up long enough for outcomes to occur	Adequacy of follow-up of cohorts
Al-Bawardy, *et al* ¹¹	Yes	Yes	Yes	Yes	Yes	No
Andriasani, et al ¹²	Yes	Yes	Yes	Yes	Yes	Yes
Backes, *et al* ¹³	Yes	Yes	Yes	Yes	Yes	No
Dinelli, *et al* ¹⁴	Yes	Yes	Yes	Yes	Yes	Yes
Meier, *et al*⁹	Yes	Yes	Yes	Yes	Yes	Yes
Schmidt, *et al*¹⁵	Yes	Yes	Yes	Yes	Yes	Yes
Valli, *et al*¹⁶	Yes	Yes	Yes	Yes	Yes	Yes
Kappelle, *et al*⁴	Yes	Yes	Yes	Yes	Yes	Yes
Schmidt, *et al*¹⁰	Yes	Yes	Yes	Yes	Yes	No
Sarker, *et al*¹⁷	Yes	Yes	Yes	Yes	Yes	Yes

Table 3. Subgroup analyses for R0 resection rates

Subgroup	Number of studies included	Number of patients	Pooled rate (95% CI)	I²	p value
Difficult colorectal polyps	8^{9,10,11,12,13,14,15,16}	255	85 (69-97)	80.3	< 0.01
Colorectal early carcinoma	5^{10,13,14,15,16}	43	76 (45-98)	47.9	0.10
Colorectal SELs	5^{10,11,14,15,17}	28	100 (87-100)	0	1
Upper GI SELs	4^4,11,16,17	28	93 (71-100)	40.1	0.17
Devices
Lower EFTR FTRD OTSC	5^{9,10,12,15,16} 4^11,13,14,17	288 38	87 (75-96) 73 (24-100)	75.1 73.6	< 0.01 0.01
Upper EFTR FTRD OTSC	1¹⁶ 3^4,11,17	5 23	60 (23-88) 98 (84-100)	N/A^* N/A^*	N/A^* N/A^*

SELs, subepithelial lesions; EFTR, endoscopic full-thickness resection; FTRD, full-thickness resection device; OTSC, over the scope clips

^* Insufficient numbers / degrees of freedom (2)

Figure 2. Pooled rates of overall R0 resection