Open Access
Endosc Int Open 2016; 04(10): E1030-E1044
DOI: 10.1055/s-0042-114774
Original article
© Georg Thieme Verlag KG Stuttgart · New York

Colorectal endoscopic submucosal dissection: a systematic review and meta-analysis

Emmanuel Akintoye
1   Department of Internal Medicine, Wayne State University School of Medicine, Detroit, Michigan, United States
,
Nitin Kumar
2   Developmental Endoscopy Lab, Brigham and Women’s Hospital, Boston, Massachusetts, United States
,
Hiroyuki Aihara
3   Division of Gastroenterology, Brigham and Women’s Hospital, Boston, Massachusetts, United States
,
Hala Nas
1   Department of Internal Medicine, Wayne State University School of Medicine, Detroit, Michigan, United States
,
Christopher C. Thompson
3   Division of Gastroenterology, Brigham and Women’s Hospital, Boston, Massachusetts, United States
› Author Affiliations
Further Information

Corresponding author

Christopher C. Thompson, MD, MHES, FACG, FASGE
Division of Gastroenterology
Brigham and Women’s Hospital
75 Francis St. ASBII
Boston, MA 02115

Publication History

submitted30 March 2016

accepted after revision29 July 2016

Publication Date:
30 September 2016 (online)

 

Background and study aims: Endoscopic submucosal dissection (ESD) is an advanced endoscopic technique that allows en-bloc resection of gastrointestinal tumor. We systematically review the medical literature in order to evaluate the safety and efficacy of colorectal ESD.

Patients and methods: We performed a comprehensive literature search of MEDLINE, EMBASE, Ovid, CINAHL, and Cochrane for studies reporting on the clinical efficacy and safety profile of colorectal ESD.

Results: Included in this study were 13833 tumors in 13603 patients (42 % female) who underwent colorectal ESD between 1998 and 2014. The R0 resection rate was 83 % (95 % CI, 80 – 86 %) with significant between-study heterogeneity (P < 0.001) which was partly explained by difference in continent (P = 0.004), study design (P = 0.04), duration of the procedure (P = 0.009), and, marginally, by average tumor size (P = 0.09). Endoscopic en bloc and curative resection rates were 92 % (95 % CI, 90 – 94 %) and 86 % (95 % CI, 80 – 90 %), respectively. The rates of immediate and delayed perforation were 4.2 % (95 % CI, 3.5 – 5.0 %) and 0.22 % (95 % CI, 0.11 – 0.46 %), respectively, while rates of immediate and delayed major bleeding were 0.75 % (95 % CI, 0.31 – 1.8 %) and 2.1 % (95 % CI, 1.6 – 2.6 %). After an average postoperative follow up of 19 months, the rate of tumor recurrence was 0.04 % (95 % CI, 0.01 – 0.31) among those with R0 resection and 3.6 % (95 % CI, 1.4 – 8.8 %) among those without R0 resection. Overall, irrespective of the resection status, recurrence rate was 1.0 % (95 % CI, 0.42 – 2.1 %).

Conclusions: Our meta-analysis, the largest and most comprehensive assessment of colorectal ESD to date, showed that colorectal ESD is safe and effective for colorectal tumors and warrants consideration as first-line therapy when an expert operator is available.


Introduction

Endoscopic submucosal dissection (ESD) is an advanced endoscopic technique that allows complete resection of early-state lesions in the gastrointestinal tract with the aim to achieve accurate histological diagnosis and prevent tumor recurrence [1]. Initially developed for gastric tumors, the procedure has become widely used as standard of care for resection of colorectal tumors in Asian countries (notably in Japan). The main steps involved in the procedure include injecting fluid into the submucosa to elevate the tumor; cutting through surrounding mucosa to gain access into the submucosa layer; and dissecting the submucosa beneath the tumor to enhance complete resection [2]. Given the relatively burdensome maneuverability of the colon in addition to its thin wall, colorectal ESD is associated with greater technical difficulty, increase procedure time and potential high risk of perforation [3]. These concerns have led to the procedure being adopted more slowly in western countries than foregut ESD. Endoscopic mucosal resection (EMR) is the most widely used minimally invasive technique for noninvasive colorectal tumors in the western world. However, accumulating evidence suggests that with adequate training, ESD could be equally as safe as the other minimally invasive alternative in addition to offering superior efficacy and lower rate of tumor recurrence [2] [4]. Nevertheless, these reports from several clinical trials and observational studies have yielded mixed results. In order to summarize the literature and assess for potential sources of heterogeneity, we conducted a systematic review and meta-analysis of available literature on the safety and efficacy of colorectal ESD.


Patients and methods

We followed the recommendations of the Meta-analysis of Observational Studies in Epidemiology (MOOSE) during all stages of the design, implementation, and reporting of this meta-analysis (Stroup 2000) [5].

Search strategy

We performed a comprehensive literature search of MEDLINE, EMBASE, Ovid, CINAHL, and Cochrane for studies published up to October 2014. Our search query for MEDLINE was (“endoscopic submucosal dissection”[tiab] OR “endoscopic submucosal resection”[tiab] OR “submucosal dissection”[tiab] OR “ESD”[tiab]) AND (“colon”[Mesh] OR “colorectal neoplasms”[Mesh] OR “colorectal”[tiab] OR colo*[tiab] OR “large bowel”[tiab] OR hindgut[tiab]). Similar search terms were adapted for the other databases ([Table S1]).

Table S1

Search query.

Medline

(“endoscopic submucosal dissection”[tiab] OR “endoscopic submucosal resection”[tiab] OR “submucosal dissection”[tiab] OR “ESD”[tiab]) AND (“colon”[Mesh] OR “colorectal neoplasms”[Mesh] OR “colorectal”[tiab] OR colo*[tiab] OR “large bowel”[tiab] OR hindgut[tiab])

Embase

(‘endoscopic submucosal dissection’/exp OR ‘endoscopic submucosal resection’:ab,ti OR ‘submucosal dissection’:ab,ti OR submuco* NEAR/2 dissection OR ‘ESD’:ab,ti) AND (‘colon’/exp OR ‘large intestine tumor’/exp OR colorectal:ab,ti OR colo*:ab,ti OR ‘large bowel’:ab,ti OR hindgut:ab,ti) AND [embase]/lim NOT [medline]/lim

Ovid

(endoscopic submucosal dissection OR endoscopic submucosal resection OR submucosal dissection OR endoscopic dissectionOR ESD) AND (colon OR colorectal OR colo* OR large bowel OR hindgut)

CINAHL

(endoscopic submucosal dissection OR endoscopic submucosal resection OR submucosal dissection OR endoscopic dissectionOR ESD) AND (colon OR colorectal OR colo* OR large bowel OR hindgut)

Cochrane

(endoscopic submucosal dissection OR endoscopic submucosal resection OR submucosal dissection OR endoscopic dissectionOR ESD) AND (colon OR colorectal OR colo* OR large bowel OR hindgut)


Study selection

One investigator (EA) screened all titles and abstracts for relevance to our study. Two investigators (EA, NK) reviewed full text of these articles and applied our predefined inclusion/exclusion criteria independently and in duplicate ([Fig. 1]). Hand searching of reference list of the articles was also done in order to retrieve other articles that might have been missed by our search strategy. We included all studies reporting clinical outcome(s) after colorectal ESD. Our exclusion criteria were: animal studies; case reports; commentaries or general reviews; or overlapping publications (based on study period) from the same center. However, review paper and overlapping publications from the same center were included in the initial screening for further assessment of the full-text and reference list after which, for the overlapping publications, only the most updated and comprehensive publication was retained. For the multicenter studies, we excluded all overlapping individual studies from the contributing centers if their sample size is comparable or less than that contributed to the multicenter study. Otherwise, we excluded the multicenter study if there are more updated studies from individual centers that provided more information. In the few cases where an abstract provided a more updated and comprehensive reporting of outcomes than the full-text journal article(s) from the same center, the abstract was selected for our main analysis. Articles in foreign language were translated via Google translator and, when possible, a native speaker of the foreign language was solicited to double-check the data.

Zoom
Fig. 1 Screening and selection process.

Data extraction

Data from each study were extracted using a standardized data extraction sheet. These included publication information such as author name, year of publication, type of publication (e. g. abstract, journal); characteristics of study cohort such as country, name of medical center, study design, number of patients, year of data collection, demographics, setting (single/multi center); characteristics of tumor such as anatomical location, number of tumors, average tumor size, macroscopic or microscopic detail; ESD procedural details such as duration of procedure and number of failed procedure; and number of patients with clinical success and adverse outcomes.


Endpoints

We assessed both measures of efficacy and adverse outcomes associated with colorectal ESD. Our primary measure of efficacy was complete (R0) resection defined as en bloc (i. e. one-piece) resection with histologically confirmed tumor-free lateral and vertical margins. In addition, we evaluated endoscopic en bloc (i. e. without histological confirmation) and curative resection rate as secondary endpoints. Curative resection was defined as resections with both tumor-free lateral and vertical resection margins, minimal submucosal invasion (< 1000 μm), and with no lymphovascular invasion or poorly differentiated component. Adverse outcomes included viscus perforation, major bleeding requiring intervention, and tumor recurrence. Immediate adverse outcomes refers to those occurring within 24 hours of the procedure while delayed refers to those occurring after 24 hours of the procedure. For all endpoints, the rates were evaluated as percentage of number of tumors operated.


Statistical analysis

Proportions from each study were pooled together using logistic-normal random effect model. Study-specific confidence intervals were based on the exact method while confidence intervals for the pooled estimates were based on the Wald method with logit transformation and back transformation. Heterogeneity between studies were assessed via visual inspection of the forest plot and chi-square statistic of the likelihood ratio test comparing the random effect model with its corresponding fixed effect model; and, for the efficacy measures, evaluation for potential sources of heterogeneity such as type of article , study design, setting, year of data collection (categorized based on start year into < 2005, 2005 – 2009, ≥ 2010), continent, average age, sex distribution, number of tumors, average tumor size, histology (carcinoid vs non-carcinoid), and duration of the procedure were assessed via meta-regression. Evaluation for publication bias was assessed via visual inspection of the funnel plot and Egger’s test. Since traditional method of funnel plot (log of estimate vs 1/standard error [1/SE]) has been shown to be an inaccurate method for assessing publication bias in meta-analysis of proportion, funnel plot was constructed using study size rather than 1/SE has proposed in the literature [6] [7]. Due to huge difference in the outcome of ESD between Asian and Western countries, we performed a supplementary analysis of Asian and non-Asian studies separately.

In a sensitivity analysis, we limited our studies to full-text journal publications. The result from the sensitivity analysis was compared to that of the main analysis.

Analyses were performed using STATA (Version 13; StataCorp, College Station, TX), all tests were two-sided and significance level was set at 0.05.



Results

Of the 1090 citations retrieved through database searching, 603 were excluded because they reported no clinical outcome after ESD procedure in human ([Fig. 1]). Full text review was performed on 487 studies using our predefined inclusion and exclusion criteria, after which 112 studies were retained. In order to avoid potential study overlap, we additionally excluded 8 abstracts that provided no indication of the source of data such as country, state, city, or medical center. Overall, 104 articles including 58 full-text journal article and 46 abstracts published between 2007 and 2014 were retained for data synthesis. Seventy-five of these studies were from Asia while 29 were from the Western world.

A total of 13 833 tumors in 13 603 patients (42 % female) with average age 66 years (range: 25 – 92 years) underwent colorectal ESD between 1998 and 2014 ([Table S2]). The majority of these procedures were performed in Asian countries of Japan and South Korea with only a few experiences in the western world ([Fig. 2]). Average tumor size was 31 mm (range: 2 mm – 158 mm), and the procedure was completed in an average time of 75 min (range: 5 min – 600 min).

Table S2

Characteristics of studies included in the meta-analysis of colorectal endoscopic submucosal dissection.

Article

Data period, yr

Country

Patients, n

Age, mean (range), yr

Female, %

Tumor, n

Tumor size, mean (range), mm

Procedure length, mean (range), min

Kawaguti 2014 [15]

2008 – 2011

Brazil

  11

62

NA

  11

65

133

Santos 2013 [16]

2010 – 2011

Brazil

   7

54 (45 – 60)

43

   7

26 (20 – 50)

163 (80 – 242)

Wang 2014 [17]

NA

China

  17

NA

NA

  17

9.4 (7 – 25)

NA

Zhao 2012 [18]

2002 – 2008

China

  10

NA

NA

  10

NA

(16 – 35)

Hon 2011 [19]

2000 – 2010

China

  14

65

64

  14

29

78 (25 – 180)

Rahmi 2014[1] [20]

2010 – 2012

France

  45

67

47

  45

35 (10 – 100)

110 (30 – 280)

Farhat 2011[1] [21]

2008 – 2010

France

  85

NA

NA

  85

NA

NA

Probst 2012 [22]

2004 – 2011

Germany

  76

64 (38 – 85)

43

  82

45.5

176

Repici 2013 [23]

2010 – 2011

Italy

  40

65 (43 – 83)

33

  40

47 (33 – 80)

86 (40 – 190)

Fusaroli 2009 [24]

NA

Italy

   8

64

63

   8

42

110

Trecca 2014 [25]

2012 – 2013

Italy

  14

(50 – 82)

57

  14

3 (1.5 – 5.5)

123 (60 – 240)

Niimi 2010 [26]

2000 – 2008

Japan

 290

65 (29 – 88)

68

 310

29 (6 – 100)

NA

Nishiyama 2010 [27]

2001 – 2008

Japan

 282

69 (30 – 91)

48

 296

27 (4 – 75)

NA

Tamegai 2007 [28]

2003 – 2005

Japan

  70

63

46

  71

33 (13 – 80)

61 (7 – 164)

Hotta 2012 [29]

2000 – 2010

Japan

 215

69

37

 219

30 (6 – 100)

101 (20 – 595)

Ishi 2010 [30]

2005 – 2009

Japan

  33

66 (42 – 89)

39

  33

35 (20 – 80)

121 (22 – 240)

Imaeda 2012 [31]

2008 – 2010

Japan

  13

69 (42 – 90)

31

  13

33 (20 – 80)

60 (20 – 150)

Tanaka 2007 [32]

2003 – 2005

Japan

  70

66 (36 – 85)

33

  70

28

71 (15 – 180)

Onozato 2007 [33]

2002 – 2006

Japan

  30

70 (51 – 89)

47

  30

26 (8 – 60)

70 (8 – 360)

Sohara 2013 [34]

2006 – 2011

Japan

 129

66 (44 – 80)

33

 129

32 (2 – 92)

60 (7 – 300)

Hori 2014 [35]

2006 – 2010

Japan

 242

70 (62 – 75)

32

 247

35 (23 – 46)

60 (40 – 120)

Ohya 2009 [36]

2008 – 2009

Japan

  45

71 (58 – 83)

NA

  45

35 (13 – 98)

60 (12 – 200)

Fujihara 2013 [37]

2010 – 2012

Japan

  68

71 (37 – 88)

43

  68

35

105 (45 – 250)

Okamoto 2013 [38]

2010 – 2012

Japan

  30

69 (63 – 76)

43

  30

36 (28 – 45)

61 (58 – 72)

Akahoshi 2010 [39]

NA

Japan

  10

66 (55 – 74)

40

  10

NA

155

Shono 2011 [40]

2007 – 2010

Japan

 137

67 (40 – 90)

42

 137

29 (20 – 150)

79 (20 – 100)

Izumi 2014 [41]

2006 – 2011

Japan

 199

66 (35 – 90)

40

 199

35 (20 – 110)

Motohashi 2011 [42]

NA

Japan

  12

NA

NA

  12

(22 – 42)

45 (30 – 110)

Mizushima 2014[1] [43]

2009 – 2013

Japan

 122

68 (38 – 91)

41

 134

27 (5 – 65)

64 (8 – 189)

Takeuchi 2014[1] [44]

2007 – 2010

Japan

 808

67

43

 816

NA

78 (50 – 120)

Kita 2007 [45]

1998 – 2005

Japan

 166

NA

NA

 166

33

102

Homma 2012[1] [46]

2009 – 2010

Japan

 100

71 (30 – 88)

48

 102

32 (12 – 120)

54 (15 – 270)

Sato 2014 [47]

2009 – 2013

Japan

 147

72 (37 – 89)

42

 151

32 (20 – 85)

72 (15 – 340)

Shiga 2014 [48]

2009 – 2013

Japan

  80

68.1

33

  80

35

109

Sakamoto 2014 [49]

NA

Japan

1017

66

43

1017

38

103

Nagai 2012 [50]

2007 – 2011

Japan

 139

(39 – 89)

35

 140

NA

70 (15 – 350)

Ohata 2013 [51]

2007 – 2012

Japan

 608

67

NA

 608

36

69.5

Nawata 2014 [52]

2010 – 2013

Japan

 150

69 (36 – 91)

39

 150

30 (18 – 123)

43 (6 – 235)

Yoshida 2014 [53]

2010 – 2013

Japan

 371

70 (35 – 92)

NA

 371

30 (6 – 100)

59 (6 – 385)

Toyonaga 2010[1] [54]

2002 – 2008

Japan

 512

NA

NA

 512

29 (4 – 158)

57 (11 – 335)

Kim 2013 [55]

2005 – 2011

S.Korea

  44

47

27

  44

6

9.4

Lee 2010 [56]

2003 – 2009

S.Korea

  46

49

54

  46

6.2 (2 – 15)

18.9

Park 2012 [57]

2007 – 2011

S.Korea

  30

59

53

  30

25

84

Lee 2013 [58]

2005 – 2011

S.Korea

  26

NA

15

  26

6.2

22

Kim 2013 [59]

2007 – 2011

S.Korea

 115

63 (31 – 87)

38

 115

29 (10 – 64)

65 (6 – 220)

Lee 2013 [60]

2006 – 2011

S.Korea

 974

61 (25 – 86)

NA

1000

24 (3 – 145)

49 (3 – 321)

Sohn 2008 [61]

2003 – 2006

S.Korea

  41

53 (32 – 78)

46

  42

4.4 (2 – 10)

7.8 (2 – 22)

Moon 2011 [62]

2007 – 2009

S.Korea

  35

49 (32 – 74)

29

  35

4.7 (1 – 9)

36 (7 – 82)

Jung 2013 [63]

2009 – 2011

S.Korea

  82

59

46

  82

27

52

Choi 2013 [64]

2008 – 2011

S.Korea

  31

48

35

  31

5.2

15

Byeon 2011 [65]

2004 – 2010

S.Korea

 233

61

37

 237

30

44.6

Spychalski 2014 [66]

2013 – 2014

Poland

  70

67 (38 – 84)

57

  70

34 (15 – 75)

106 (30 – 225)

Thorlacius 2013 [67]

2012 – 2013

Sweden

  29

74 (46 – 85)

52

  29

28 (11 – 89)

142 (57 – 291)

Hsu 2013 [68]

2010 – 2013

Taiwan

  50

64 (46 – 82)

50

  50

33 (12 – 70)

71 (16 – 240)

Tseng 2013 [69]

2006 – 2011

Taiwan

  92

66

36

  92

37

59

Hurlstone 2007 [70]

2004 – 2006

UK

  42

68 (52 – 79)

36

  42

NA

48 (18 – 240)

Lang 2014 [71]

2006 – 2013

USA

  11

NA

NA

  11

34 (10 – 50)

106 (16 – 166)

Kantsevoy 2014 [72]

2012 – 2013

USA

   8

NA

63

8

NA

NA

Bassan 2012[2] [73]

2010 – 2011

Australia

 104

NA

NA

104

38

95

Zhong 2013[2] [74]

2006 – 2011

China

 255

NA

NA

255

NA

NA

Hon 2012[2] [75]

2009 – 2012

China

  61

NA

NA

  61

25

NA

Emura 2014[2] [76]

2008 – 2013

Colombia

  32

NA

NA

  32

33

109

Kruse 2012[2] [77]

2006 – 2011

Germany

  81

69 (47 – 90)

31

  83

NA

NA

Sauer 2014[2] [78]

2012 – 2013

Germany

  81

NA

NA

  83

35

103 (20 – 600)

Iacopini 2014[2] [79]

2009 – 2013

Italy

 112

NA

NA

 112

NA

NA

Trentino 2010[2] [80]

NA

Italy

  14

NA

NA

  14

28

NA

De Lisi 2012[2] [81]

NA

Italy

  11

71

64

  11

24 (10 – 40)

137 (45 – 270)

Petruzziello 2014[2] [82]

2011 – 2013

Italy

  15

65 (40 – 77)

33

  15

23

70

Andrisani 2014[2] [83]

2011 – 2013

Italy

  30

NA

NA

  30

29

71

Kaneko 2013[2] [84]

2001 – 2012

Japan

  16

NA

NA

  16

6.6

NA

Kudo 2013[2] [85]

2001 – 2012

Japan

 485

NA

NA

 485

NA

NA

Mizuno 2013[2] [86]

2005 – 2009

Japan

 227

NA

NA

 236

NA

NA

Osuga 2012[2] [87]

NA

Japan

  13

NA

NA

  13

NA

NA

Kashida 2012[2] [88]

NA

Japan

  74

68

38

  76

38

Kawazoe 2011[2] [89]

2006 – 2011

Japan

 114

NA

NA

 114

NA

NA

Nemoto 2014[2] [90]

2013

Japan

  33

NA

NA

  33

28 (15 – 67)

53 (26 – 247)

Hayashi 2013[2] [91]

2010

Japan

 214

NA

NA

 214

NA

NA

Inada 2013[2] [92]

2006 – 2012

Japan

 502

NA

NA

 502

31

94.9

Mitani 2013[2] [93]

2005 – 2011

Japan

 647

66 (34 – 91)

36

 748

32.9

68 (5 – 500)

Shiga 2010[2] [94]

2007 – 2010

Japan

  32

70

56

  32

27.4

70.9

Nio 2013[2] [95]

2008 – 2012

Japan

  92

NA

NA

  92

NA

NA

Sasajimi 2012[2] [96]

NA

Japan

 150

NA

NA

 150

33

86 (15 – 420)

Tanaka 2014[2] [97]

2009 – 2013

Japan

  72

NA

NA

  72

NA

NA

Yamamoto 2013[2] [98]

NA

Japan

  61

NA

NA

  61

31

65

Oyama 2010[2] [99]

NA…

Japan

 148

NA

NA

 148

31

NA

Horikawa 2012[2] [100]

2008 – 2012

Japan

  83

NA

NA

  83

NA

101

Kojima 2013[2] [101]

2007 – 2012

Japan

 233

69 (33 – 87)

41

 233

22

NA

Fukuzawa 2012[2] [102]

2007 – 2012

Japan

 200

NA

NA

 200

NA

100

Yamada 2013[2] [103]

2009 – 2012

Japan

  92

NA

NA

  92

34

65

Kobayashi 2012[2] [104]

2005 – 2011

Japan

  71

NA

NA

  71

29

141

Hayashi 2013[2] [105]

2010 – 2013

Japan

 247

NA

NA

 247

NA

79

Lee 2011[2] [106]

2004 – 2010

S.Korea

  45

64 (26 – 85)

36

  45

35

NA

Ko 2009[2] [107]

2004 – 2008

S.Korea

  95

NA

NA

  95

29 (12 – 86)

77

Park 2012[2] § [108]

2009 – 2011

S.Korea

  59

NA

NA

  61

20 (5 – 50)

74 (11 – 280)

Kim 2010[2] [109]

NA

S.Korea

   7

63

43

   7

2.7

NA

Rhee 2010[2] [110]

2008 – 2010

S.Korea

  78

NA

NA

  80

27

50 (11 – 152)

Joo 2010[2] [111]

2007 – 2009

S.Korea

  10

62 (50 – 75)

60

  10

43

99 (22 – 246)

Bialek 2012[2] [112]

2006 – 2012

Poland

  45

64 (49 – 85)

47

  47

26 (10 – 60)

NA

Hulagu 2011[2] [113]

2007 – 2010

Turkey

  17

NA

29

  17

NA

NA

Tholoor 2012[2] [114]

2006 – 2011

UK

  66

69

68

  66

NA

NA

George 2013[2] [115]

2004 – 2012

UK

  38

NA

NA

  38

41 (15 – 100)

NA

Gorgun 2013[2] [116]

NA

USA

   8

66 (50 – 88)

63

   8

NA

126 (62 – 196)

Omer 2012[2] [117]

2009 – 2011

USA

  66

NA

NA

  66

NA

NA

Antillon 2009[2] [118]

2006 – 2008

USA

  86

NA

NA

  86

42

NA

yr, year; n, number; mm, millimeter; min, minute; NA, not available

1 Multicenter studies


2 Abstracts


Zoom
Fig. 2 Percentage distribution of 13 603 patients who underwent colorectal endoscopic submucosal dissection between 1998 and 2014 in 15 countries. Others include Taiwan, Australia, France, Poland, Sweden, Turkey, UK, Brazil, Colombia, and USA that contributed ≤ 1 % each.

Efficacy

R0 resection rate was reported in 60 studies across which meta-analysis yielded a pooled estimate of 83 % (95 % CI, 80 – 86 %) ([Fig. 3]). There was significant between-study heterogeneity (P < 0.001) which was partly explained by difference in continent (P = 0.004), study design (P = 0.04), and duration of the procedure (P = 0.009). In addition, there was a trend toward decreasing R0 with increasing tumor size but this did not reach statistical significance (P = 0.09) ([Table 1]). Subgroup analysis based on sources of heterogeneity showed that R0 resection rate was highest in Asia (87 % [95 % CI, 84 – 90 %] in Asia vs 71 % [95 % CI, 64 – 77 %] in the West) ([Table 3]), among retrospective studies, and decreases with increasing duration of the procedure. Assessment of funnel plot asymmetry based on egger’s test also showed no significant publication bias (P = 0.57).

Zoom
Fig. 3 Meta-analysis of histologic en bloc (R0) resection rate in 60 studies involving 8312 tumors in 8111 patients that underwent colorectal endoscopic submucosal dissection. Each dot and the horizontal line through them correspond to the point estimate and confidence interval from each study respectively while the center and width of the diamond corresponds to the pooled estimate and its confidence interval respectively. Both within continent and overall pooled estimates are presented. Even though weighting (not shown) was done, it is not explicit because an iterative procedure was used in parameter estimation. ES indicates estimate.
Table 1

Potential sources of heterogeneity of histologic en bloc (R0) resection rate among 60 studies of patients that underwent colorectal endoscopic submucosal dissection.

Variable

Studies, n

Tumors, n

R0 resection rate (95 % CI), %

P value[1]

Type of article

0.23

 Full-text journal

41

6006

84 (80, 87)

 Abstract

19

2306

81 (72, 87)

Study design

0.04

 Retrospective

36

6738

85 (81, 88)

 Prospective

 7

 531

75 (62, 85)

Setting

0.11

 Single center

49

6876

84 (80, 87)

 Multicenter

 4

1079

73 (58, 83)

Start year of data collection

0.31

 < 2005

14

1586

77 (70, 83)

 2005 – 2009

30

4835

85 (81, 88)

 ≥ 2010

11

 826

86 (71, 93)

Continent

0.004

 Asia

40

7392

87 (84, 90)

 Europe

16

 806

70 (62, 77)

 South America (Brazil)

 2

  18

83 (59, 95)

 North America (USA)

 2

  96

65 (55, 73)

Average age, years[2]

0.47

 ≤ 64

14

1798

84 (77, 88)

 65 – 67

14

3563

82 (77, 87)

 > 67

14

1444

87 (78, 93)

Female, %[2]

0.33

 ≤ 36

15

1613

84 (79, 88)

 37 – 43

14

2172

88 (81, 93)

 ≥ 44

14

2066

80 (72, 86)

Number of tumors[2]

0.71

 < 40

20

 418

86 (78, 91)

 40 – 90

20

1291

80 (73, 86)

 > 90

20

6603

84 (79, 88)

Average tumor size, mm[2]

0.09

 ≤ 27

16

1844

85 (81, 89)

 28 – 34

16

2409

85 (78, 90)

 ≥ 34

16

2061

80 (70, 88)

Histology

 Carcinoid

 7

 221

85 (79, 89)

0.19

 Non-carcinoid

48

5051

82 (78, 86)

Length of the procedure, min§

0.009

 ≤ 61

15

2141

89 (84, 93)

 62 – 101

15

2954

84 (79, 88)

 > 101

15

1564

78 (68, 85)

N, number; R0, histologic en bloc resection rate

1 Potential sources of heterogeneity was assessed with metaregression. P < 0.05 indicates that the variable significantly explains part of the between study heterogeneity (i. e. an effect mofier). Differences in continent, lenth of the procedure, study design and average tumor size explains 18 %, 15 %, 8 %, and 4 % of the heterogeneity respectively.


2 Indicates variables that were cut at tertiles in order to ensure comparability of number of studies between groups.


Table 3

Clinical outcomes of colorectal endoscopic submucosal dissection in Asia as compared to the western world.

Asia

Western world

Studies, n

Rate (95 % CI), %[1]

Studies, n

Rate (95 % CI), %[1]

Efficacy measures

 Histologic en bloc resection

40

87 (84, 90)

20

71 (64, 77)

 Endoscopic en bloc resection

63

94 (92, 95)

23

82 (76, 87)

Safety measures

 Immediate perforation[2]

71

3.8 (3.1, 4.6)

27

6.6 (4.6, 9.4)

 Immediate major bleeding[2]

17

0.39 (0.11, 1.3)

 7

3.3 (1.4, 7.6)

 Delayed perforation[3]

25

0.18 (0.08, 0.42)

 5

1.2 (0.29, 4.6)

 Delayed major bleeding[3]

59

1.8 (1.4, 2.4)

21

3.9 (2.5, 5.8)

 Recurrence (if R0)[4]

16

0.05 (0.01, 0.33)

 4

0

 Recurrence (if not R0)[4]

14

2.3 (1.1, 4.4)

 4

21 (11, 36)

 Recurrence (irrespective of R0 status)[4]

21

0.37 (0.13, 0.10)

11

6.5 (3.7, 11)

N, number; R0, histologically-confirmed en bloc resection

1 The rates are calculated as a percentage of the total number of tumors operated.


2 Immediate refers to adverse outcomes occurring within 24 hours of the procedure.


3 Delayed refers to adverse outcome occurring 24 hours after the procedure.


4 Average follow-up was ~20, 19, and 25 months for assessment of recurrence among tumors with R0, without R0, and irrespective of R0 status respectively (for Asian studies); and ~7, 7, and 10 months for assessment of recurrence among tumors with R0, without R0, and irrespective of R0 status respectively (for western studies).


Table 2

Rates of adverse outcomes in patients undergoing colorectal endoscopic submucosal dissection between 1998 and 2014.

Adverse outcomes

Studies, n

Patients, n

Tumor, n

Rate (95 % CI), %[1]

Immediate [2]

 Perforation

98

13291

13498

4.2 (3.5, 5.0)

 Major bleeding

24

2274

2319

0.75 (0.31, 1.8)

Delayed [3]

 Perforation

30

3887

3948

0.22 (0.11, 0.46)

 Major bleeding

80

11079

11260

2.1 (1.6, 2.6)

Recurrence [4]

 Among tumors with R0

20

2273

0.04 (0.01, 0.31)

 Among tumors without R0

18

398

3.6 (1.4, 8.8)

 Irrespective of R0 status

32

4143

4315

1.0 (0.42, 2.1)

N, number; R0, histologically-confirmed en bloc resection

1 The rates are calculated as a percentage of the total number of tumors operated.


2 Immediate refers to adverse outcomes occurring within 24 hours of the procedure.


3 Delayed refers to adverse outcome occurring 24 hours after the procedure.


4 Average follow-up was ~19 months for assessment of recurrence among tumors with and without R0; and ~23 months for the assessment of recurrence irrespective of R0 status.


Endoscopic en bloc and curative resection rates were reported in 86 and 14 studies, respectively. Across studies, meta-analysis yielded a pooled estimate of 92 % (95 % CI, 90 – 94 %) ([Fig. S2]) for endoscopic en bloc resection rate and 86 % (95 % CI, 80 % – 90 %) ([Fig. S3]) for curative resection rate, although all but one of the studies reporting curative resection were from Asia. When we performed separate analysis for Asia vs Western countries, endoscopic en bloc resection rate was 94 % (95 % CI, 92 % – 95 %) and 82 % (95 % CI, 76 % – 87 %) for Asian and Western countries, respectively.

Zoom
Fig. S1 Funnel plot of histologically confirmed en bloc (R0) resection rate in 60 studies involving 8312 tumors in 8111 patients that underwent colorectal endoscopic submucosal dissection. Each dot represents the R0 resection rate. Lack of asymmetry in the distribution of study estimates around the center of the funnel suggests no publication bias. P value for egger’s test = 0.57. ES, estimate; se(ES), standard error of estimate.
Zoom
Fig. S2 Meta-analysis of endoscopic en bloc resection rate in 86 studies involving 12 346 tumors in 12 151 patients that underwent colorectal endoscopic submucosal dissection. Each dot and the horizontal line through them correspond to the point estimate and confidence interval from each study respectively while the center and width of the diamond corresponds to the pooled estimate and its confidence interval respectively. Even though weighting (not shown) was done, it is not explicit because an iterative procedure was used in parameter estimation. ES, estimate.
Zoom
Fig. S3 Meta-analysis of curative resection rate in 14 studies involving 1805 tumors in 1784 patients that underwent colorectal endoscopic submucosal dissection. Each dot and the horizontal line through them correspond to the point estimate and confidence interval from each study respectively while the center and width of the diamond corresponds to the pooled estimate and its confidence interval respectively. Even though weighting (not shown) was done, it is not explicit because an iterative procedure was used in parameter estimation. All studies except one (Emura 2014, Colombia) were from Asia. ES, estimate.

Adverse outcomes

Perforation and major bleeding requiring intervention were the most common perioperative complications reported ([Table 2]). Overall, immediate and delayed perforation rates were 4.2 % (95 % CI, 3.5 % – 5.0 %) and 0.22 % (95 % CI, 0.11 % – 0.46 %), respectively, while rates of immediate and delayed major bleeding were 0.75 % (95 % CI, 0.31 % – 1.8 %) and 2.1 % (95 % CI, 1.6 % – 2.6 %). When we performed separate analysis for Asia vs Western countries, immediate and delayed perforation rates were 3.8 % (95 % CI, 3.1 % – 4.6 %) and 0.18 % (95 % CI, 0.08 % – 0.42 %) for Asia and 6.6 % (95 % CI, 4.6 % – 9.4 %) and 1.2 % (95 %, 0.29 % – 4.6 %) for Western countries, respectively, while rates of immediate and delayed major bleeding were 0.39 % (95 % CI, 0.11 % – 1.3 %) and 1.8 % (95 % CI, 1.4 % – 2.4 %) for Asia and 3.3 % (95 % CI, 1.4 % – 7.6 %) and 3.9 % (95 %, 2.5 % – 5.8 %) for Western countries, respectively ([Table 3]).

After an average postoperative follow up of 19 months, the rate of tumor recurrence was 0.04 % (95 % CI, 0.01 % – 0.31 %) among those with R0 resection and 3.6 % (95 % CI, 1.4 % – 8.8 %) among those without R0 resection ([Table 2]). Overall, irrespective of the resection status, recurrence rate was 1.0 % (95 % CI, 0.42 % – 2.1 %). For Asian studies, rates of tumor recurrence were 0.05 % (95 %, 0.01 % – 0.33 %), 2.3 % (95 % CI, 1.1 % – 4.4 %), and 0.37 % (95 % CI, 0.13 – 0.10) among tumors with R0 resection, without R0 resection, and irrespective of R0 status respectively. On the other hand, tumor recurrence rates for Western countries were 21 % (95 % CI, 11 % – 36 %) and 6.5 % (95 % CI, 3.7 % – 11 %) among tumors without R0 resection and irrespective of resection status respectively. All four Western studies that assessed recurrence among tumors with R0 resection reported no recurrence among such tumors after an average follow up of 7 months ([Table 3]).

All our estimates were comparable to those of sensitivity analysis as pre-specified ([Table S3]).

Table S3

Clinical outcomes among patients who underwent colorectal endoscopic submucosal dissection (analysis restricted to only studies published as full-text journal article).

Outcomes

Studies, n

Tumor, n

Rate (95 % CI)[1]

Efficacy measures

 R0 resection

41

6006

84 (80 – 87)

 Endoscopic en bloc resection

51

7862

93 (90 – 95)

 Curative resection

10

1614

87 (81 – 91)

Safety measures

 Immediate perforation[2]

53

8184

4 (3 – 5)

 Immediate major bleeding[2]

20

2154

0.82 (0.32 – 2.1)

 Delayed perforation[3]

22

3313

0.24 (0.11 – 0.54)

 Delayed bleeding[3]

47

7398

1.7 (1.2 – 2.4)

 Recurrence (if R0)[4]

16

1999

0.05 (0.01 – 0.35)

 Recurrence (if not R0)[4]

15

 367

3.6 (1.3 – 9.9)

 Recurrence (irrespective of R0 status)[4]

18

2391

0.58 (0.19 – 1.7)

n, number; R0, histologically-confirmed en bloc resection

1 The rates are calculated as a percentage of the total number of tumors operated.


2 Immediate refers to adverse outcomes occurring within 24 hours of the procedure.


3 Delayed refers to adverse outcome occurring 24 hours after the procedure.


4 Average follow-up was ~18, 21 and 19 months for assessment of recurrence among tumors with R0, without R0, and irrespective of R0 status, respectively.




Discussion

Our meta-analysis showed that, across multiple studies in 15 countries, ESD demonstrated an excellent treatment success in patients with colorectal tumors. Perioperatively, perforation and major bleeding were the most commonly reported serious adverse outcomes but their risk is somewhat comparable to EMR [4] [8]. In addition, the risk of tumor recurrence in patients with treatment success after a moderate duration of follow up is very low. These findings provide evidence that ESD is effective and offers a reasonable safety profile across a wide range of patients.

Treatment success was assessed in 3 ways: R0, endoscopic en bloc and curative resection rates. In this study, we considered R0 resection as primary endpoint. Across studies, there were excellent results based on this endpoint. However, there was significant heterogeneity in study estimates which were partly explained by four main factors: first, the estimates vary by continent. Difference in continent accounted for most of the heterogeneity with highest rates of clinical success being reported by studies from Asia. This, in a way, was expected because the procedure was developed in Asia and has been used for a long time in this part of the world allowing for the development of expert skill needed for the procedure as well as development of better techniques. On the other hand, the acceptance rate of the procedure had been low in other parts of the world. Second, lower rates of treatment success were reported in the prospective studies as compared to retrospective studies. However, only a few of the studies were prospective and most of these were from Europe, which further underscores the lower rates of treatment success in countries outside Asia. Third, rates of treatment success increase with decreasing length of the procedure. Because length of the procedure is expected to correlate with level of expertise and size of tumor, we presume this is an indicator of higher rates with better expertise/years of experience and smaller tumor size. This notion is further supported by difference in estimates by tumor size, the fourth sources of heterogeneity in our analysis, although this was only marginally significant.

The relatively high risk of adverse outcome associated with the procedure had been one of the factors against the acceptability of the procedure in western countries [3]. Intraoperatively, perforation was the most common serious adverse outcome. However, most of the perforations were successfully sealed with endoscopic clips with only large ones requiring surgical intervention. More than 24 hours after the procedure, major bleeding becomes the most common serious adverse event. These cases of delayed bleeding often require endoscopic re-exploration. Although the incidence of delayed perforation is very low, it is a more serious adverse event because these usually require surgery for peritonitis [9]. The relatively low risk of recurrence has been the attractive feature of ESD. After a moderate follow up, tumor recurrence was present in only 1 in 100 tumors after the procedure, and this rate was majorly influenced by those without R0 resection i. e. patients with positive lateral or vertical tumor margins. In patients with R0 resection, the risk of recurrence is very negligible: 4 in 10 000 tumors. Overall, rates of adverse events were generally better in Asia compared to the Western world.

Before the invention of ESD in the late 1990s in Japan, EMR was the most widely used minimally invasive option for noninvasive colorectal tumors in the world and it is still the most widely used in many western countries. Over the years, numerous comparative studies and reviews had shown the superior benefit of ESD in terms of complete resection and tumor recurrence as compared to EMR [4] [8] [10]. In addition, its risk of complication is comparable to other minimally invasive alternative including EMR and laparoscopic assisted colectomy (LAC) [11]. However, given the low risk of malignancy among small tumors (< 20 mm in diameter) in addition to comparable rate of recurrence between EMR and ESD for small tumors, EMR remains a suitable option in this subgroup especially when ESD cannot be performed due to lack of expertise or patient-related factors e. g. weak intestinal wall [10]. Furthermore, ESD is not recommended for invasive cancers with risk of lymph node metastasis. LAC remains the only minimally invasive option in such cases [11].

Our study has several strengths. Notably, a guideline-driven approach ensures that our analysis was systematic and comprehensive. In addition, we made attempt to gather all available data by including all comprehensive abstracts and placing no restriction on language of publication. Our moderately large number of studies enabled us to shed more light on potential sources of heterogeneity in treatment success after ESD, and the comparability of the main findings to those in sensitivity analysis further ensures the robustness of our result. Although similar studies exist in the literature [12] [13] [14], our study is the largest and most updated. In addition, we provided the most comprehensive reporting of all clinically relevant outcomes while also identifying potential sources of heterogeneity.

Limitations of this study should also be considered. First, due to rapidly evolving techniques in ESD procedure, the rates of each outcome may vary slightly by technique and our rates of adverse outcomes might have been over-estimated compared to new technique. There was also a suggestion of increasing rate of treatment success over time, indicating that newer techniques may be associated with higher success rate, although this was not statistically significant. Second, the recurrence rates were assessed after variable follow up between and within study, and since the rate of recurrence is time-dependent, cautious interpretation of average follow-up reported is warranted when applied to individual cases. Third, we could not evaluate for potential heterogeneity of clinical outcomes between mucosal and submucosal tumors as most of the studies involved a mixed population of mucosal and submucosal tumors. Further studies are needed to evaluate these 2 classes of tumors in a head-to-head comparison.


Conclusion

In conclusion, colorectal ESD appears safe and effective based on the large and broad body of current medical literature. It compares favorably with other minimally invasive options and warrants consideration as first-line therapy when an expert operator is available. However, the result is not optimal yet given that R0 resection rate is still only 86 % and there is enough room for improvement to achieve rates close to 100 %.



Competing interests: Dr. Christopher Thompson serves as consultant to the following organizations: Boston scientific; covidien; USGI Medical; Olympus; and Apollo Endosurgery


Corresponding author

Christopher C. Thompson, MD, MHES, FACG, FASGE
Division of Gastroenterology
Brigham and Women’s Hospital
75 Francis St. ASBII
Boston, MA 02115


Zoom
Fig. 1 Screening and selection process.
Zoom
Fig. 2 Percentage distribution of 13 603 patients who underwent colorectal endoscopic submucosal dissection between 1998 and 2014 in 15 countries. Others include Taiwan, Australia, France, Poland, Sweden, Turkey, UK, Brazil, Colombia, and USA that contributed ≤ 1 % each.
Zoom
Fig. 3 Meta-analysis of histologic en bloc (R0) resection rate in 60 studies involving 8312 tumors in 8111 patients that underwent colorectal endoscopic submucosal dissection. Each dot and the horizontal line through them correspond to the point estimate and confidence interval from each study respectively while the center and width of the diamond corresponds to the pooled estimate and its confidence interval respectively. Both within continent and overall pooled estimates are presented. Even though weighting (not shown) was done, it is not explicit because an iterative procedure was used in parameter estimation. ES indicates estimate.
Zoom
Fig. S1 Funnel plot of histologically confirmed en bloc (R0) resection rate in 60 studies involving 8312 tumors in 8111 patients that underwent colorectal endoscopic submucosal dissection. Each dot represents the R0 resection rate. Lack of asymmetry in the distribution of study estimates around the center of the funnel suggests no publication bias. P value for egger’s test = 0.57. ES, estimate; se(ES), standard error of estimate.
Zoom
Fig. S2 Meta-analysis of endoscopic en bloc resection rate in 86 studies involving 12 346 tumors in 12 151 patients that underwent colorectal endoscopic submucosal dissection. Each dot and the horizontal line through them correspond to the point estimate and confidence interval from each study respectively while the center and width of the diamond corresponds to the pooled estimate and its confidence interval respectively. Even though weighting (not shown) was done, it is not explicit because an iterative procedure was used in parameter estimation. ES, estimate.
Zoom
Fig. S3 Meta-analysis of curative resection rate in 14 studies involving 1805 tumors in 1784 patients that underwent colorectal endoscopic submucosal dissection. Each dot and the horizontal line through them correspond to the point estimate and confidence interval from each study respectively while the center and width of the diamond corresponds to the pooled estimate and its confidence interval respectively. Even though weighting (not shown) was done, it is not explicit because an iterative procedure was used in parameter estimation. All studies except one (Emura 2014, Colombia) were from Asia. ES, estimate.