Introduction
Superficial non-ampullary duodenal epithelial tumors (SNADETs) was rare and the incidence rate in autopsied cases was 0.02–0.5% (1–3). The number of reported primary non-ampullary duodenal carcinomas has increased gradually in recent years due to the development of endoscopic equipment and endoscopic techniques, and increased awareness of patients (4). Elimination of adenoma-carcinoma sequence at the early stage is essential, which is considered as one of the pathways in the carcinogenesis of duodenal carcinomas. Conventional endoscopic mucosal resection (CEMR) is widely applied for ≤20 mm SNADETs, which is an approach that required injecting a solution into the submucosa of target polyps to establish a safety cushion and removal with snare cautery. Nevertheless, because of a bending lumen and extremely thin muscle layer in the duodenum, it is associated with a higher rate of recurrence (0–37%), delayed bleeding (0–33%) and delayed perforation (3%) than gastric and colonic treatment (5, 6). Therefore, the effectiveness and safety of excising SNADETs with CEMR are limited.
Underwater EMR (UEMR) is a novel technique that was first introduced by Binmoeller et al. (7) in 2012. Instead of injecting submucosally before polypectomy in CEMR, the process involves filling the luminal space with water, which may lower the risk of intestinal perforation and disruption of deeper intestinal layers. However, the efficacy and safety of UEMR in the resection of SNADETs remain ambiguous. There were large variations across clinical trials in the en-bloc resection rate and adverse events ranging from 41 to 78% and ranging from 0 to 4%, respectively (8, 9), and the lack of stratification of the size of SNADETs in their performance attract criticism. Kato et al. (10) found that the en-bloc resection rate of UEMR for 1–9 mm SNADETs ranged from 89.1 to 93.3%, however, for 15–19 mm SNADETs was only 62.0%. Therefore, this study aimed to investigate the effectiveness and safety of UEMR for resection of ≤20 mm SNADETs.
Materials and methods
Search strategy
A comprehensive literature search was conducted in several databases, including PubMed, Embase, Scopus, and Clinical trials for studies that were published from January 1, 2012, to August 8, 2022. The search strategy was based on keywords, supplemented with standardized index terms. Keywords contained “endoscopic mucosal resection,” “Underwater EMR,” “UEMR” and phrases associated with the disease location such as “Duodenum.” The studies were searched separately by two individuals (Jixiang and Shaojie), and 1,395 citations were finally exported to the endnote. The full search strategy is available in Appendix 1. The MOOSE checklist (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) was followed and is provided in Appendix 2 (11).
Study selection
In this meta-analysis, only studies exploring the effectiveness or safety of the UEMR technique to remove SNADETs ≤20 mm were considered eligible. Studies were included regardless of sample size, study setting, and whether published as full manuscripts or abstracts, as long as the data needed for the analysis were available. Our exclusion criteria were studies that were not published in the English language. If several reports have overlap data, only the most recent or most appropriate articles were retained.
Data extraction and study quality assessment
Articles were independently screened by two people (Jixiang and Shaojie) and the data were extracted into a standardized form. Conflicts in filtering were resolved by consensus or by a neutral person (Yichong).
The quality of the cohort study was judged by the modified Newcastle-Ottawa scale (NOS), which ranges from 0 to 6 (12). We defined the good quality of a study as a score >4 on the NOS, and 2–4 as moderate, ≤2 as poor quality. Two authors (Jixiang and Jing) evaluated these trials, respectively and recorded the score in the corresponding standardized forms.
Definitions and outcomes evaluated
Pooled rate of en-bloc resection.
Pooled rate of R0 resection.
Pooled rate of adverse events.
Pooled rate of recurrence.
En-bloc resection, as opposed to resection in numerous parts, was defined as resection in a single piece. A specimen having a negative margin on microscopy was referred to as an R0 resection. Adverse events included intraoperative bleeding, perforation, and delayed bleeding perforation. Within 30 days of UEMR, the occurrence of bloody stool, hematemesis, or melena was presented as evidence of delayed bleeding. Delayed perforation was defined as abdominal computed tomography findings of air or luminal contents beyond the gastrointestinal system. Recurrence was defined as finding lesions within the 12 months follow-up period following the original resection.
Statistics analysis
The meta-analysis was carried out by measuring the pooled estimates and 95% confidence intervals (CI) following the methods suggested by DerSimonian and Laird (13) using a random-effects model. Heterogeneity was assessed by using the Cochran Q statistical test and the I2 statistics (14–16). Values of ≤30, 30–60, 61–75, and >75% were regarded as low, moderate, substantial and considerable heterogeneity, respectively (17). Publication bias was ascertained quantitatively by the Egger test (18).
In addition, subgroup analysis of the main outcomes was conducted according to factors that may have influenced the outcomes, such as the sample size and polyp size. According to the statistical program. All analyses were performed using STATA version 15.0 (StataCorp, College Station, TX, USA). If the outcomes which we are concerned about have extreme data, such as 0 or 100%, “metaprop” software commands would be used (19), otherwise used “metan,” “metaninf,” and “metanbias.”
Discussion
The objective of this systematic review was to assess the effectiveness and safety of underwater endoscopic mucosal resection (UEMR) for SNADETs ≤20 mm, which has not been performed before. Our analysis showed that the en-bloc resection rate of UEMR was 88.2% and the R0 resection rate was 69.1%. The pooled intraoperative bleeding rates and the delayed-bleeding rates were 2.9 and 0.9%, respectively, with only one patient happened delayed perforation and no intraoperative perforation. And the recurrence rate was 1.5%. Results indicated it was effective and safe to remove ≤20 mm SNADETs by utilizing the effect of floating force to fill the duodenal lumen with water.
Although conventional EMR is the most frequently used to treat ≤20 mm SNADA, it can be challenging due to a bending lumen in the duodenum, limited scope mobility, and the danger to inject submucosal for the muscle layer is extremely thin. Previous studies showed an R0 resection rate of 72–95.2% for EMR in small SNADETs (21, 27) compared with UEMR, but its high adverse events rate of 6.4% limited its security (10). As a new technology, UEMR can overcome these difficulties by immersion water into the intestinal, producing a natural optical magnifying effect that enhances the ability to see fine structural and microvascular details as well as the lesion’s delineation margin and enabling to improve the rate of en-bloc resection and R0 resection (30). Since polyps “float” away from the muscularis propria when filled with water without submucosal injection, this potentially decreases perforation and bleeding. For the recurrence, the guideline indicated that the risk of recurrence was related to the R0 resection which means a pathologically negative polyp border (31). In our analysis, a high R0 resection rate of 69.1% and a low recurrence rate of 1.5% were reported.
A meta-analysis of 8 studies with 258 polyps showed an 84.6% rate of en-bloc resection and a 6.9% rate of adverse events using UEMR for SNADETs (32). However, this study did not evaluate the R0 resection rate. The size of the polyps could influence the success of resection, especially when larger than 20mm, in multiple studies. Kato et al. (10) explored the en-bloc resection rate was only 30% in >20 mm SNADETs and ranged from 62.0 to 93.3% in ≤20 mm SNADETs. By comparison, all the lesions in our analysis were ≤20 mm, and we summarized all clinical outcomes of UEMR.
In the subgroup analysis according to the sample size, we found that the R0 resection rate and en-bloc resection rate were higher in the small samples subgroup (R0 resection rate 74.5 vs. 67.0%; en bloc resection rate 95.9 vs. 83.6%). The possible reason was the sampling error, small sample studies mean that they may not be representative of the whole, which makes the results calculated based on the sample unreliable. In the subgroup analysis according to tumor size, there were significant differences between the ≤10 and 10–20 mm SNADETs subgroups (R0 resection rate 83.1 vs. 48.6%; en bloc resection rate 100.0 vs. 84.0%). Thus, we surmised that tumor size was a risk factor for both R0 and en-bloc resection. This theory was supported by Li et al. (33) study, and indicated that polyp size was an independent factor determining resection outcome. In addition, since the I2 in subgroups were both 0%, lesion size was considered to be the source of heterogeneity in the R0 resection rate. Nevertheless, the cause of heterogeneity in the en-bloc resection rate was not clear.
There are several strengths to our review. Firstly, we comprised comprehensive literature searches containing ClinicalTrials.gov. with clear inclusion criteria, included studies with meticulous data extraction, rigorous assessment of study quality, and used different statistical methods according to the characteristics of the data. Secondly, according to the NOS quality evaluation system, all of the literature we included was of medium to high quality. Thirdly, we thoroughly evaluated the effectiveness and safety of UEMR for ≤20 mm polyps in non-ampullary duodenal and made subgroup analyses according to sample size and polyp size. Therefore, our findings might be more useful for clinical practice. Fourthly, heterogeneity in en-bloc resection and R0 resection was reduced by stratifying according to the size of tumors. In addition, for R0 resection, no publication bias was found and the outcome was confirmed to be stable and reliable by sensitivity analysis.
This study also has some limitations, most of which are inherent to any meta-analysis. First, all of the studies we included were cohort studies from Japan, thus, the findings of this study could not properly represent the effectiveness and safety of UEMR global. Second, even though we had conducted a comprehensive search of the literature, only 10 studies were included and four studies had a sample size of less than 50, both of which resulted in our final sample size not being sufficient. Third, because of some extremes in the data, we must use metaprop software, and the sensitivity analysis and publication bias analysis were not available. Fourth, subgroup analysis for polyp size was performed with a cut-off of 10 mm only, without more detailed stratification. To more accurately evaluate the efficacy and safety of UEMR in the resection of SNADETs, we propose that researchers further stratify the size of ≤20 mm polyps in the future. Fifth, because there have only been a few small sample clinical studies comparing UEMR, CEMR, and ESD, we decided to simply analyze UEMR’s efficacy for the removal of SNADETs in this study and not compare it to the other endoscopic resection methods. Sixth, different histological polyps may influence the efficacy and safety of the endoscopic resection (34), however, due to the lack of corresponding data in the included literature, we did not do the subgroup analysis.
Underwater endoscopic mucosal resection is an effective technique for SNADETs, and the rates of adverse events and recurrences are acceptable. Thus, the results of the meta-analysis suggest that UEMR should be recommended for optional treatment for SNADETs measuring ≤20 mm.