Dig Dis Sci DOI 10.1007/s10620-014-3098-2
ORIGINAL ARTICLE
Efficacy and Safety of Endoscopic Submucosal Dissection for Superficial Squamous Esophageal Neoplasia: A Meta-Analysis Joon Sung Kim • Byung-Wook Kim In-Soo Shin
•
Received: 26 December 2013 / Accepted: 25 February 2014 Ó Springer Science+Business Media New York 2014
Abstract Background and Aims Although endoscopic submucosal dissection (ESD) has grown popular in resecting lesions in the stomach, the application of ESD to the esophagus has been limited by greater technical difficulty. An increasing number of series have recently reported the application of ESD to esophageal lesions. The aim of the present systemic review and meta-analysis was to evaluate the efficacy and safety of ESD for esophageal lesions. Methods Comprehensive literature searches (1999–2012) were performed on studies that reported ESD for the removal of esophageal neoplasia. Primary outcome measures were pooled estimates of complete resection rate and en bloc resection rate. Secondary outcome measures were pooled estimates of complication rates. Results A total of 15 studies provided data on 776 ESDtreated lesions. The pooled estimate of complete resection rate was 89.4 % (95 % CI 86.2–91.9 %). The pooled estimate of en bloc resection was 95.1 % (95 % CI 92.6–96.8 %). The pooled estimates of complications of ESD such as bleeding, perforation, and stenosis were 2.1, 5.0, and 11.6 %, respectively. Conclusions ESD appeared to be an extremely effective technique to achieve complete resection of esophageal
J. S. Kim B.-W. Kim (&) Division of Gastroenterology, Department of Internal Medicine, Incheon St. Mary’s Hospital, The Catholic University of Korea, 665, Bupyeong-dong, Bupyeong-gu, Inchon 403-720, Republic of Korea e-mail: [email protected] I.-S. Shin College of Education, Jeonju University, Jeonju, Republic of Korea
neoplasia. The very low rate of complications also shows the potential safety of this approach. Keywords Endoscopic submucosal dissection Esophageal neoplasia Meta-analysis
Introduction Squamous cell carcinoma (SCC) of the esophagus is detected more frequently at early stages due to the development of techniques for endoscopic diagnosis [1]. Endoscopic resection (ER) has been accepted as an effective procedure for superficial neoplasms of the esophagus because of its minimal invasiveness and benefits in terms of patients’ quality of life. This is based on a large number of retrospective studies of surgically resected esophageal squamous cell carcinomas which showed that non-invasive carcinoma and intramucosal invasive carcinoma limited to the lamina propria without vessel infiltration have little risk of lymph node or distant metastases [2–8]. Among the ER methods, endoscopic submucosal dissection (ESD) by en bloc resection with tumorfree lateral and vertical margins is considered to be the ideal method. Although ESD has grown popular in resecting lesions in the stomach, the application of ESD to the esophagus has been limited by greater technical difficulty. Recently, several studies have recently reported the application of ESD to esophageal lesions [9–25]. However, most of these studies were retrospective and single-center studies that included only a relatively small number of cases. Such small sample sizes prevent reliable estimates of the efficacy of esophageal ESD. The safety of this procedure also needs to be validated since the frequency of post-ESD complications would be expected to be small due to small sample sizes. Therefore, we decided to perform a systematic review and meta-analysis to assess the
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efficacy and safety of ESD for esophageal lesions. This metaanalysis and systematic review was written in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations for reporting on systematic reviews [26].
Methods Search Method A comprehensive literature search was performed to identify all relevant studies that performed ESD for esophageal lesions. Several databases were searched including MEDLINE (through PubMed), EMBASE, and the Cochrane Library for the period 1999–2012. The medical terms ‘‘endoscopic submucosal dissection,’’ ‘‘esophagus,’’ ‘‘esophageal,’’ were used in the search. We also searched the reference of screened articles to identify any additional studies. All human studies published in English were considered.
Fig. 1 Flow diagram of studies included in this meta-analysis
single- or multicenter study, enrollment period, number of patients included, number of lesions included, mean age, sex, mean tumor size, location of tumor, device used for ESD, type of solution injected into the submucosa, duration of ESD, and the primary and secondary endpoints.
Study Selection
Statistical Analysis
Potential studies were initially screened by the two authors (JSK and BWK) based on the title and abstract. All studies that were published during the period January 1999–July 2012 and in which patients underwent ESD for the removal of esophageal dysplasia or esophageal squamous cell carcinoma were included. Cases in which ESD was performed for submucosal tumors or adenocarcinoma of the esophagus were not included in this analysis. Exclusion criteria were case reports (\10 cases), non-human studies, review articles, editorials, commentaries, and book chapters. The primary outcome of this study was pooled estimates of complete resection rate and en bloc resection rate. Complete resection was defined as complete en bloc resection with vertical and lateral margins free of neoplasia at histology. En bloc resection was defined as en bloc resection at endoscopy, irrespective of histology. The secondary outcomes included pooled estimates of complication rates such as bleeding, perforation, and stenosis.
Meta-analysis was performed by calculating pooled estimates of primary and secondary endpoints. Pooled results were derived by using the fixed effects model, unless significant heterogeneity was present, in which case the random effects model was applied. The fixed effects model assumes that primary studies have a common effect size, while the random effects model attempts to estimate the distribution of mean effect size based on the assumption that each primary study has a different population. Forest plots were constructed for visual display of individual studies and pooled results. The width of the point estimates in the forest plots indicated the assigned weight to that study. Heterogeneity between studies was evaluated using the Cochran Q test and the inconsistency index (I2). Funnel plots, Egger’s test, and Duval and Tweedie’s trim-and-fill methods were used to investigate whether publication bias or other small study effects may have adversely affected the results for the primary and secondary endpoints. Statistical analyses were executed by the aid of Comprehensive Meta-Analysis software, version 2 (Biostat Inc., Englewood, NJ), with inputs confirmed by both authors.
Data Collection A data extraction manual was developed in advance, and information was collected independently by the two authors using the predefined extraction manual. Disagreement was resolved by discussion and consensus by the two authors. From each report, researchers independently abstracted information including year of publication, whether the study was retrospective or prospective, country where the study was performed, whether the study was a
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Results Study Selection A flow diagram of this systematic review is shown in Fig. 1. In summary, 68 studies were identified by our
Dig Dis Sci Table 1 Main characteristics of included studies Reference
Year of publication
Study design
Type of publication
Country
Enrollment period
Type of study
Urabe et al. [23]
2011
Retrospective
Full article
Japan
2007–2009
Single center
Oyama et al. [18]
2005
Retrospective
Full article
Japan
2000 –2004
Single center
Ono et al. [17]
2009
Retrospective
Full article
Japan
2002 –2008
Single center
Ishii et al. [12]
2010
Retrospective
Full article
Japan
2006–2008
Single center
Farhat et al. [9]
2011
Retrospective
Full article
France
–
Multicenter
Takahashi et al. [25]
2010
Retrospective
Full article
Japan
1994–2007
Single center
Teoh et al. [21]
2010
Retrospective
Full article
Hong Kong
2002–2007
Single center
Repici et al. [19]
2010
Prospective
Full article
Italy
2005–2008
Single center
Lee et al. [14]
2012
Retrospective
Full article
Taiwan
2007–2010
Single center
Kikuchi et al. [13]
2012
Retrospective
Full article
Japan
2005–2011
Single center
Toyonaga et al. [22] Tamiya et al. [20]
2010 2010
Prospective Retrospective
Full article Full article
Japan Japan
2008 2003–2007
Single center Single center
Nonaka et al. [16]
2010
Retrospective
Full article
Japan
2007–2009
Single center
Yamashina et al. [24]
2012
Retrospective
Full article
Japan
2001–2011
Single center
Mizuta et al. [15]
2009
Retrospective
Full article
Japan
2003–2008
Single center
literature search. Twenty-three studies were excluded after initial screening of title and abstracts. Full text of the 45 remaining articles was reviewed and 26 non-pertinent articles were removed. Four studies were excluded due to suspicion of cohort overlap between studies. The remaining 15 published papers were included in the systematic review. Study Characteristics The main characteristics of the studies are listed in Table 1. A total of 13 studies were performed in Asian countries (11 in Japan, one in Hong Kong, and one in Taiwan), and two were performed in Europe (one in Italy and one in France). All but one of the included studies were single-center studies, and all but two were retrospective. The enrollment period ranged from 1994 to 2009. Participants A total of 776 lesions from 609 patients were enrolled in the selected studies (Table 2). The median of the mean ages across the included studies was 66.3 years (range 47.6–67.5 years). The median of the male sex rate was 84.5 % (range 72–100 %). ESD Interventions Multiple cutting devices such as flush knife, flex knife, hook knife, and IT knife were used in the studies. Similarly, multiple solutions such as glycerol and hyaluronate were used to inject the submucosal layer in most of the
studies. The median of the mean operation time of the included studies was 90.9 min (range 49.7–180 min). Outcomes Primary Outcomes Twelve studies including 574 lesions provided information on complete resection (Table 3). Pooled estimates of complete resection was 89.4 % (95 % CI 86.2–91.9 %, I2 45.4) using the fixed effects model (Fig. 2). No evidence of publication bias was observed, as indicated by a symmetric funnel plot and a non-significant Egger’s test (P = 0.07) (Fig. 3). We found three missing studies based on the trimand-fill method and the adjusted effect size was 87.3 % (95 % CI 84–90 %). Fourteen studies including 714 lesions provided information on en bloc resection. Pooled estimates of en bloc resection was 95.1 % (95 % CI 92.6–96.8 %, I2 20.8) using the fixed effects model (Fig. 4). Secondary Outcomes All of the studies provided information on post-ESD complications such as bleeding and perforation. Pooled estimates of bleeding and perforation were 2.1 % (95 % CI 1.2–3.8 %, I2 0.0) and 5.0 % (95 % CI 3.5–7.2 %, I2 19.5) using the fixed effects model. Fourteen studies provided information on stenosis after ESD. Pooled estimates of stenosis was 11.6 % (95 % CI 8.2–16.2 %, I2 6.0) using the random effects model. No case of mortality, either directly or indirectly related to ESD, was reported in any of the studies. One of the patients was diagnosed with perforation
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Dig Dis Sci Table 2 Clinical characteristics of included studies
Reference
No. of patients
Urabe et al. [23] Oyama et al. [18]
* Cervical esophagus was included as upper location, and abdominal esophagus was included as lower location
Median size of tumor
Table 3 Endoscopic submucosal dissection (ESD) success and complication rates
59 –
Age, mean
Sex, male (%) 85
Tumor size, mean, mm
Location (upper, mid, lower)
Device for ESD
–
7/47/25*
Hook knife, IT knife
79
65
102
–
–
28
–
Hook knife
–
23
7/59/41*
Flex knife, splash needle
22
5/21/11
Flex knife
–
–
–
Ono et al. [17]
84
107
–
Ishii et al. [12]
35
37
67
Farhat et al. [9]
27
27
–
Takahashi et al. [25]
116
116
67
88
30
14/76/26
Hook knife
Teoh et al. [21]
18
22
68
72
–
4/14/4*
Hook knife
Repici et al. [19]
20
20
64
80
32
4/13/3
Hook knife, IT knife
Lee et al. [14]
22
26
48
100
33.7
4/15/7*
IT knife
Kikuchi et al. [13]
62
62
–
84
–
8/42/12*
Flex knife, flush knife
Toyonaga, et al. [22]
11
12
–
–
–
Flush knife, flush knife BT
Tamiya et al. [20]
58
58
66
30
3/34/21*
Hook knife
Nonaka et al. [16]
25
27
–
21
15/9/3*
Flash knife, flex knife
Yamashina et al. [24]
39
39
65
82
52
5/10/24
Flex knife
Mizuta et al. [15]
33
42
85
–
6/20/16*
IT knife, flex knife
Reference Urabe et al. [23]
77 95 107
80 –
–
90 –
6.8
En bloc resection
Oyama et al. [18] Ono et al. [17]
Complete resection 77 – 94
Bleeding
Perforation
Stenosis
1
6
0
0
7
0
4
15
4
Ishii et al. [12]
37
35
0
0
9
Farhat et al. [9]
24
21
2
3
0
Takahashi et al. [25]
116
113
0
3
20
Teoh et al. [21]
21
18
0
1
2
Repici et al. [19]
20
18
0
0
1
Lee et al. [14] Kikuchi et al. [13]
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No. of lesions
23 –
Toyonaga et al. [22]
12
Tamiya et al. [20]
58
Nonaka et al. [16] Yamashina et al. [24]
27 39
Mizuta et al. [15]
40
21
1
1
3
56
2
0
2
12
0
0
0
0
4
0 0
1 0
3 11
0
5
7
– 24 36 –
–
Dig Dis Sci
Fig. 2 Forest plot of the included studies analyzing the rate of complete resection Fig. 3 Forest plot of the included studies analyzing the rate of en bloc resection
during ESD and received urgent operation. Except for this patient, all of the perforations were treated conservatively without surgery. Subgroup Analysis Meta-regression of complete resection based on publication year, sample size, median size of tumor, and geographic location (Japan vs. other countries) was performed. Only geographic location significantly affected complete resection rate on meta-regression (P = 0.00384). Subgroup analysis by grouping studies that were from Japan and studies that were from other countries found pooled estimates of complete resection to be 91.9 % (95 % CI 88.8–94.2 %, I2 34.2) and 81.6 % (95 % CI 72.3–88.3 %,
I2 0.0), respectively. Significant heterogeneity existed for the pooled estimates of stenosis, and we investigated this by performing a meta-regression based on median tumor size of the studies. The rate of stenosis tended to increase as the median tumor size increased but without statistical significance (P = 0.08).
Discussion This systematic review and meta-analysis showed that ESD is an effective procedure for removing esophageal squamous cell neoplasia. Twelve studies provided data on complete resection and 14 studies provided data on en bloc resection. Complete resection was achieved in 89.4 % of
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Dig Dis Sci Fig. 4 Funnel plot for the detection of bias within the studies for complete resection
the lesions, and en bloc resection was achieved in 94.8 % of the lesions. These results are in concordance with previous systemic reviews of ESD for gastric and colonic lesions, which reported complete resection rates as 92 and 88 %, respectively [27, 28]. ESD for treating esophageal neoplasms is considered to be more difficult than ESD for gastric lesions. The esophageal lumen is narrower, and the esophageal wall moves continuously with respiration and heartbeat. In addition, the esophageal wall is thinner than that of the stomach, and risk of perforation is regarded to be greater for esophageal ESD. In our analysis, pooled estimates of bleeding and perforation rates were 2.1 and 5.0 %, respectively. Both of these complications were successfully treated conservatively without surgery in most cases, and there was no mortality associated with the procedure. Meta-analysis of ESD for early gastric cancer reported bleeding rates of 7 % and perforation rates of 4.5 % [27]. Meta-analysis of ESD for colonic neoplasia reported bleeding rates of 2 % and perforation rates of 4 % [28]. Our pooled analysis suggests that complication rates after esophageal ESD are similar to complications rates after gastric and colonic ESD. Pooled analysis revealed postoperative esophageal stricture as the major complication after ESD. Resecting areas larger than three quarters of the circumference of the esophageal lumen is considered an important risk factor for postoperative stricture [29]. Several treatment options such as balloon dilatations, placement of biodegradable stents, systemic administration of steroids, and local injection of steroids have been suggested to prevent postoperative stricture [30–33]. All of the strictures in our study were treated successfully with repeated endoscopic balloon dilatation or bougination. Although balloon dilatation is regarded as a risk factor for perforation, no perforation was associated with repetitive dilatation in our analysis.
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Endoscopic mucosal resection (EMR) has been shown to be as effective and less invasive for removing small localized superficial esophageal neoplasia [34–37]. However, it is difficult to achieve en bloc resection for lesions larger than 20 mm by the EMR method, which may lead to imprecise histological evaluation and a high frequency of local recurrence [38]. ESD allows en bloc resection regardless of size of the lesions and thus precise histological assessment of the specimen. Meta-analysis comparing the effect of EMR and ESD for gastric lesions showed considerable advantages of ESD regarding en bloc resection rate, histologically complete resection rate, and local recurrence [27, 39]. However, ESD had the disadvantage of higher complication rates and longer resection time. Two studies included in our review compared EMR and ESD for the resection of superficial esophageal neoplasm. In these studies, en bloc resection rate was significantly better in the ESD group than in the EMR group, and local recurrence rate was significantly lower in the ESD group compared with the EMR group. ESD was found to be a more effective method than EMR. Further high-quality trials and studies are needed to confirm these results. The indications of ESD for the studies included in our analysis were mostly esophageal dysplasia or early esophageal squamous cell neoplasia. Recently, there have been reports showing promising results of ESD for esophageal adenocarcinoma [40, 41]. However, most of the studies published regarding ESD of the esophagus were performed for squamous carcinoma of the esophagus. This is probably because the incidence of esophageal adenocarcinoma is extremely low in Japan where ESD is widely performed. Further studies are needed to investigate the efficacy and safety of ESD for adenocarcinoma of the esophagus. There are several limitations to our present study. First, significant heterogeneity existed among the studies
Dig Dis Sci
regarding rate of stenosis and the random effects model was used. The different median size of the lesions among the studies might have been the cause of heterogeneity, but we were not able to explain this by meta-regression. Second, most of the studies included in this analysis were from Japan, so our results need further confirmation in other countries. Meta-regression and subgroup analysis found eradication rates to be higher from Japan compared with studies from other countries. Third, there was poor standardization of the ESD technique, and different cutting devices, accessories, and injection material were used in our studies. Fourth, there were only two prospective studies included in our analysis. Most of the studies were retrospective studies, and this may have affected the results. In conclusion, this systematic review provides estimates of the efficacy and safety of esophageal ESD. Considering the high mortality and postoperative morbidity rates of esophagectomy [42], the high rate of complete resection rate and low complication rates suggest that endoscopic resection could be considered an alternative treatment in superficial squamous esophageal neoplasia patients with low risk of lymph node metastasis. Benign stricture of the esophagus was the most serious postoperative complication that occurred after ESD and was treated successfully with balloon dilatation. Standardization of techniques and equipment may be needed before ESD can be widely accepted for the treatment of superficial squamous esophageal neoplasms. Conflict of interest
None.
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ORIGINAL ARTICLE
Efficacy and Safety of Endoscopic Submucosal Dissection for Superficial Squamous Esophageal Neoplasia: A Meta-Analysis Joon Sung Kim • Byung-Wook Kim In-Soo Shin
•
Received: 26 December 2013 / Accepted: 25 February 2014 Ó Springer Science+Business Media New York 2014
Abstract Background and Aims Although endoscopic submucosal dissection (ESD) has grown popular in resecting lesions in the stomach, the application of ESD to the esophagus has been limited by greater technical difficulty. An increasing number of series have recently reported the application of ESD to esophageal lesions. The aim of the present systemic review and meta-analysis was to evaluate the efficacy and safety of ESD for esophageal lesions. Methods Comprehensive literature searches (1999–2012) were performed on studies that reported ESD for the removal of esophageal neoplasia. Primary outcome measures were pooled estimates of complete resection rate and en bloc resection rate. Secondary outcome measures were pooled estimates of complication rates. Results A total of 15 studies provided data on 776 ESDtreated lesions. The pooled estimate of complete resection rate was 89.4 % (95 % CI 86.2–91.9 %). The pooled estimate of en bloc resection was 95.1 % (95 % CI 92.6–96.8 %). The pooled estimates of complications of ESD such as bleeding, perforation, and stenosis were 2.1, 5.0, and 11.6 %, respectively. Conclusions ESD appeared to be an extremely effective technique to achieve complete resection of esophageal
J. S. Kim B.-W. Kim (&) Division of Gastroenterology, Department of Internal Medicine, Incheon St. Mary’s Hospital, The Catholic University of Korea, 665, Bupyeong-dong, Bupyeong-gu, Inchon 403-720, Republic of Korea e-mail: [email protected] I.-S. Shin College of Education, Jeonju University, Jeonju, Republic of Korea
neoplasia. The very low rate of complications also shows the potential safety of this approach. Keywords Endoscopic submucosal dissection Esophageal neoplasia Meta-analysis
Introduction Squamous cell carcinoma (SCC) of the esophagus is detected more frequently at early stages due to the development of techniques for endoscopic diagnosis [1]. Endoscopic resection (ER) has been accepted as an effective procedure for superficial neoplasms of the esophagus because of its minimal invasiveness and benefits in terms of patients’ quality of life. This is based on a large number of retrospective studies of surgically resected esophageal squamous cell carcinomas which showed that non-invasive carcinoma and intramucosal invasive carcinoma limited to the lamina propria without vessel infiltration have little risk of lymph node or distant metastases [2–8]. Among the ER methods, endoscopic submucosal dissection (ESD) by en bloc resection with tumorfree lateral and vertical margins is considered to be the ideal method. Although ESD has grown popular in resecting lesions in the stomach, the application of ESD to the esophagus has been limited by greater technical difficulty. Recently, several studies have recently reported the application of ESD to esophageal lesions [9–25]. However, most of these studies were retrospective and single-center studies that included only a relatively small number of cases. Such small sample sizes prevent reliable estimates of the efficacy of esophageal ESD. The safety of this procedure also needs to be validated since the frequency of post-ESD complications would be expected to be small due to small sample sizes. Therefore, we decided to perform a systematic review and meta-analysis to assess the
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efficacy and safety of ESD for esophageal lesions. This metaanalysis and systematic review was written in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations for reporting on systematic reviews [26].
Methods Search Method A comprehensive literature search was performed to identify all relevant studies that performed ESD for esophageal lesions. Several databases were searched including MEDLINE (through PubMed), EMBASE, and the Cochrane Library for the period 1999–2012. The medical terms ‘‘endoscopic submucosal dissection,’’ ‘‘esophagus,’’ ‘‘esophageal,’’ were used in the search. We also searched the reference of screened articles to identify any additional studies. All human studies published in English were considered.
Fig. 1 Flow diagram of studies included in this meta-analysis
single- or multicenter study, enrollment period, number of patients included, number of lesions included, mean age, sex, mean tumor size, location of tumor, device used for ESD, type of solution injected into the submucosa, duration of ESD, and the primary and secondary endpoints.
Study Selection
Statistical Analysis
Potential studies were initially screened by the two authors (JSK and BWK) based on the title and abstract. All studies that were published during the period January 1999–July 2012 and in which patients underwent ESD for the removal of esophageal dysplasia or esophageal squamous cell carcinoma were included. Cases in which ESD was performed for submucosal tumors or adenocarcinoma of the esophagus were not included in this analysis. Exclusion criteria were case reports (\10 cases), non-human studies, review articles, editorials, commentaries, and book chapters. The primary outcome of this study was pooled estimates of complete resection rate and en bloc resection rate. Complete resection was defined as complete en bloc resection with vertical and lateral margins free of neoplasia at histology. En bloc resection was defined as en bloc resection at endoscopy, irrespective of histology. The secondary outcomes included pooled estimates of complication rates such as bleeding, perforation, and stenosis.
Meta-analysis was performed by calculating pooled estimates of primary and secondary endpoints. Pooled results were derived by using the fixed effects model, unless significant heterogeneity was present, in which case the random effects model was applied. The fixed effects model assumes that primary studies have a common effect size, while the random effects model attempts to estimate the distribution of mean effect size based on the assumption that each primary study has a different population. Forest plots were constructed for visual display of individual studies and pooled results. The width of the point estimates in the forest plots indicated the assigned weight to that study. Heterogeneity between studies was evaluated using the Cochran Q test and the inconsistency index (I2). Funnel plots, Egger’s test, and Duval and Tweedie’s trim-and-fill methods were used to investigate whether publication bias or other small study effects may have adversely affected the results for the primary and secondary endpoints. Statistical analyses were executed by the aid of Comprehensive Meta-Analysis software, version 2 (Biostat Inc., Englewood, NJ), with inputs confirmed by both authors.
Data Collection A data extraction manual was developed in advance, and information was collected independently by the two authors using the predefined extraction manual. Disagreement was resolved by discussion and consensus by the two authors. From each report, researchers independently abstracted information including year of publication, whether the study was retrospective or prospective, country where the study was performed, whether the study was a
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Results Study Selection A flow diagram of this systematic review is shown in Fig. 1. In summary, 68 studies were identified by our
Dig Dis Sci Table 1 Main characteristics of included studies Reference
Year of publication
Study design
Type of publication
Country
Enrollment period
Type of study
Urabe et al. [23]
2011
Retrospective
Full article
Japan
2007–2009
Single center
Oyama et al. [18]
2005
Retrospective
Full article
Japan
2000 –2004
Single center
Ono et al. [17]
2009
Retrospective
Full article
Japan
2002 –2008
Single center
Ishii et al. [12]
2010
Retrospective
Full article
Japan
2006–2008
Single center
Farhat et al. [9]
2011
Retrospective
Full article
France
–
Multicenter
Takahashi et al. [25]
2010
Retrospective
Full article
Japan
1994–2007
Single center
Teoh et al. [21]
2010
Retrospective
Full article
Hong Kong
2002–2007
Single center
Repici et al. [19]
2010
Prospective
Full article
Italy
2005–2008
Single center
Lee et al. [14]
2012
Retrospective
Full article
Taiwan
2007–2010
Single center
Kikuchi et al. [13]
2012
Retrospective
Full article
Japan
2005–2011
Single center
Toyonaga et al. [22] Tamiya et al. [20]
2010 2010
Prospective Retrospective
Full article Full article
Japan Japan
2008 2003–2007
Single center Single center
Nonaka et al. [16]
2010
Retrospective
Full article
Japan
2007–2009
Single center
Yamashina et al. [24]
2012
Retrospective
Full article
Japan
2001–2011
Single center
Mizuta et al. [15]
2009
Retrospective
Full article
Japan
2003–2008
Single center
literature search. Twenty-three studies were excluded after initial screening of title and abstracts. Full text of the 45 remaining articles was reviewed and 26 non-pertinent articles were removed. Four studies were excluded due to suspicion of cohort overlap between studies. The remaining 15 published papers were included in the systematic review. Study Characteristics The main characteristics of the studies are listed in Table 1. A total of 13 studies were performed in Asian countries (11 in Japan, one in Hong Kong, and one in Taiwan), and two were performed in Europe (one in Italy and one in France). All but one of the included studies were single-center studies, and all but two were retrospective. The enrollment period ranged from 1994 to 2009. Participants A total of 776 lesions from 609 patients were enrolled in the selected studies (Table 2). The median of the mean ages across the included studies was 66.3 years (range 47.6–67.5 years). The median of the male sex rate was 84.5 % (range 72–100 %). ESD Interventions Multiple cutting devices such as flush knife, flex knife, hook knife, and IT knife were used in the studies. Similarly, multiple solutions such as glycerol and hyaluronate were used to inject the submucosal layer in most of the
studies. The median of the mean operation time of the included studies was 90.9 min (range 49.7–180 min). Outcomes Primary Outcomes Twelve studies including 574 lesions provided information on complete resection (Table 3). Pooled estimates of complete resection was 89.4 % (95 % CI 86.2–91.9 %, I2 45.4) using the fixed effects model (Fig. 2). No evidence of publication bias was observed, as indicated by a symmetric funnel plot and a non-significant Egger’s test (P = 0.07) (Fig. 3). We found three missing studies based on the trimand-fill method and the adjusted effect size was 87.3 % (95 % CI 84–90 %). Fourteen studies including 714 lesions provided information on en bloc resection. Pooled estimates of en bloc resection was 95.1 % (95 % CI 92.6–96.8 %, I2 20.8) using the fixed effects model (Fig. 4). Secondary Outcomes All of the studies provided information on post-ESD complications such as bleeding and perforation. Pooled estimates of bleeding and perforation were 2.1 % (95 % CI 1.2–3.8 %, I2 0.0) and 5.0 % (95 % CI 3.5–7.2 %, I2 19.5) using the fixed effects model. Fourteen studies provided information on stenosis after ESD. Pooled estimates of stenosis was 11.6 % (95 % CI 8.2–16.2 %, I2 6.0) using the random effects model. No case of mortality, either directly or indirectly related to ESD, was reported in any of the studies. One of the patients was diagnosed with perforation
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Dig Dis Sci Table 2 Clinical characteristics of included studies
Reference
No. of patients
Urabe et al. [23] Oyama et al. [18]
* Cervical esophagus was included as upper location, and abdominal esophagus was included as lower location
Median size of tumor
Table 3 Endoscopic submucosal dissection (ESD) success and complication rates
59 –
Age, mean
Sex, male (%) 85
Tumor size, mean, mm
Location (upper, mid, lower)
Device for ESD
–
7/47/25*
Hook knife, IT knife
79
65
102
–
–
28
–
Hook knife
–
23
7/59/41*
Flex knife, splash needle
22
5/21/11
Flex knife
–
–
–
Ono et al. [17]
84
107
–
Ishii et al. [12]
35
37
67
Farhat et al. [9]
27
27
–
Takahashi et al. [25]
116
116
67
88
30
14/76/26
Hook knife
Teoh et al. [21]
18
22
68
72
–
4/14/4*
Hook knife
Repici et al. [19]
20
20
64
80
32
4/13/3
Hook knife, IT knife
Lee et al. [14]
22
26
48
100
33.7
4/15/7*
IT knife
Kikuchi et al. [13]
62
62
–
84
–
8/42/12*
Flex knife, flush knife
Toyonaga, et al. [22]
11
12
–
–
–
Flush knife, flush knife BT
Tamiya et al. [20]
58
58
66
30
3/34/21*
Hook knife
Nonaka et al. [16]
25
27
–
21
15/9/3*
Flash knife, flex knife
Yamashina et al. [24]
39
39
65
82
52
5/10/24
Flex knife
Mizuta et al. [15]
33
42
85
–
6/20/16*
IT knife, flex knife
Reference Urabe et al. [23]
77 95 107
80 –
–
90 –
6.8
En bloc resection
Oyama et al. [18] Ono et al. [17]
Complete resection 77 – 94
Bleeding
Perforation
Stenosis
1
6
0
0
7
0
4
15
4
Ishii et al. [12]
37
35
0
0
9
Farhat et al. [9]
24
21
2
3
0
Takahashi et al. [25]
116
113
0
3
20
Teoh et al. [21]
21
18
0
1
2
Repici et al. [19]
20
18
0
0
1
Lee et al. [14] Kikuchi et al. [13]
123
No. of lesions
23 –
Toyonaga et al. [22]
12
Tamiya et al. [20]
58
Nonaka et al. [16] Yamashina et al. [24]
27 39
Mizuta et al. [15]
40
21
1
1
3
56
2
0
2
12
0
0
0
0
4
0 0
1 0
3 11
0
5
7
– 24 36 –
–
Dig Dis Sci
Fig. 2 Forest plot of the included studies analyzing the rate of complete resection Fig. 3 Forest plot of the included studies analyzing the rate of en bloc resection
during ESD and received urgent operation. Except for this patient, all of the perforations were treated conservatively without surgery. Subgroup Analysis Meta-regression of complete resection based on publication year, sample size, median size of tumor, and geographic location (Japan vs. other countries) was performed. Only geographic location significantly affected complete resection rate on meta-regression (P = 0.00384). Subgroup analysis by grouping studies that were from Japan and studies that were from other countries found pooled estimates of complete resection to be 91.9 % (95 % CI 88.8–94.2 %, I2 34.2) and 81.6 % (95 % CI 72.3–88.3 %,
I2 0.0), respectively. Significant heterogeneity existed for the pooled estimates of stenosis, and we investigated this by performing a meta-regression based on median tumor size of the studies. The rate of stenosis tended to increase as the median tumor size increased but without statistical significance (P = 0.08).
Discussion This systematic review and meta-analysis showed that ESD is an effective procedure for removing esophageal squamous cell neoplasia. Twelve studies provided data on complete resection and 14 studies provided data on en bloc resection. Complete resection was achieved in 89.4 % of
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Dig Dis Sci Fig. 4 Funnel plot for the detection of bias within the studies for complete resection
the lesions, and en bloc resection was achieved in 94.8 % of the lesions. These results are in concordance with previous systemic reviews of ESD for gastric and colonic lesions, which reported complete resection rates as 92 and 88 %, respectively [27, 28]. ESD for treating esophageal neoplasms is considered to be more difficult than ESD for gastric lesions. The esophageal lumen is narrower, and the esophageal wall moves continuously with respiration and heartbeat. In addition, the esophageal wall is thinner than that of the stomach, and risk of perforation is regarded to be greater for esophageal ESD. In our analysis, pooled estimates of bleeding and perforation rates were 2.1 and 5.0 %, respectively. Both of these complications were successfully treated conservatively without surgery in most cases, and there was no mortality associated with the procedure. Meta-analysis of ESD for early gastric cancer reported bleeding rates of 7 % and perforation rates of 4.5 % [27]. Meta-analysis of ESD for colonic neoplasia reported bleeding rates of 2 % and perforation rates of 4 % [28]. Our pooled analysis suggests that complication rates after esophageal ESD are similar to complications rates after gastric and colonic ESD. Pooled analysis revealed postoperative esophageal stricture as the major complication after ESD. Resecting areas larger than three quarters of the circumference of the esophageal lumen is considered an important risk factor for postoperative stricture [29]. Several treatment options such as balloon dilatations, placement of biodegradable stents, systemic administration of steroids, and local injection of steroids have been suggested to prevent postoperative stricture [30–33]. All of the strictures in our study were treated successfully with repeated endoscopic balloon dilatation or bougination. Although balloon dilatation is regarded as a risk factor for perforation, no perforation was associated with repetitive dilatation in our analysis.
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Endoscopic mucosal resection (EMR) has been shown to be as effective and less invasive for removing small localized superficial esophageal neoplasia [34–37]. However, it is difficult to achieve en bloc resection for lesions larger than 20 mm by the EMR method, which may lead to imprecise histological evaluation and a high frequency of local recurrence [38]. ESD allows en bloc resection regardless of size of the lesions and thus precise histological assessment of the specimen. Meta-analysis comparing the effect of EMR and ESD for gastric lesions showed considerable advantages of ESD regarding en bloc resection rate, histologically complete resection rate, and local recurrence [27, 39]. However, ESD had the disadvantage of higher complication rates and longer resection time. Two studies included in our review compared EMR and ESD for the resection of superficial esophageal neoplasm. In these studies, en bloc resection rate was significantly better in the ESD group than in the EMR group, and local recurrence rate was significantly lower in the ESD group compared with the EMR group. ESD was found to be a more effective method than EMR. Further high-quality trials and studies are needed to confirm these results. The indications of ESD for the studies included in our analysis were mostly esophageal dysplasia or early esophageal squamous cell neoplasia. Recently, there have been reports showing promising results of ESD for esophageal adenocarcinoma [40, 41]. However, most of the studies published regarding ESD of the esophagus were performed for squamous carcinoma of the esophagus. This is probably because the incidence of esophageal adenocarcinoma is extremely low in Japan where ESD is widely performed. Further studies are needed to investigate the efficacy and safety of ESD for adenocarcinoma of the esophagus. There are several limitations to our present study. First, significant heterogeneity existed among the studies
Dig Dis Sci
regarding rate of stenosis and the random effects model was used. The different median size of the lesions among the studies might have been the cause of heterogeneity, but we were not able to explain this by meta-regression. Second, most of the studies included in this analysis were from Japan, so our results need further confirmation in other countries. Meta-regression and subgroup analysis found eradication rates to be higher from Japan compared with studies from other countries. Third, there was poor standardization of the ESD technique, and different cutting devices, accessories, and injection material were used in our studies. Fourth, there were only two prospective studies included in our analysis. Most of the studies were retrospective studies, and this may have affected the results. In conclusion, this systematic review provides estimates of the efficacy and safety of esophageal ESD. Considering the high mortality and postoperative morbidity rates of esophagectomy [42], the high rate of complete resection rate and low complication rates suggest that endoscopic resection could be considered an alternative treatment in superficial squamous esophageal neoplasia patients with low risk of lymph node metastasis. Benign stricture of the esophagus was the most serious postoperative complication that occurred after ESD and was treated successfully with balloon dilatation. Standardization of techniques and equipment may be needed before ESD can be widely accepted for the treatment of superficial squamous esophageal neoplasms. Conflict of interest
None.
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