Tech Coloproctol DOI 10.1007/s10151-015-1383-5
REVIEW
Endoscopic submucosal dissection versus local excision for early rectal cancer: a systematic review and meta-analysis S. Wang1 • S. Gao2 • W. Yang3 • S. Guo4 • Y. Li2
Received: 30 March 2015 / Accepted: 16 August 2015 Ó Springer-Verlag Italia Srl 2015
Abstract Endoscopic submucosal dissection (ESD) and local excision (LE) are minimally invasive procedures that can be used to treat early rectal cancer. There are no current guidelines or consensus on the optimal treatment strategy for these lesions. A systematic review was conducted to compare the efficacy and safety of ESD and LE. A metaanalysis was conducted following all aspects of the Cochrane Handbook for systematic reviews and preferred reporting items for systematic reviews and meta-analysis (PRISMA) statement. To perform the statistical analysis, the odds ratio (OR) was used for categorical variables and the weighted mean difference (WMD) for continuous variables. Four studies, involving a total of 307 patients, were identified. The length of hospital stay was longer in the group of patients undergoing LE [weighted mean difference (WMD) -1.94; 95 % CI -2.85 to -1.02; p \ 0.0001]. The combined results of the individual studies showed no significant differences as regards en-bloc resection rate (OR 0.82; 95 % CI 0.25–2.70; p = 0.74), R0 resection rate (OR 1.53; 95 % CI 0.62–3.73; p = 0.35), overall complication rate (OR 0.67; 95 % CI 0.26–1.69; p = 0.40), and tumor size (WMD 0.57; 95 % CI -3.64 to
& Y. Li [email protected] 1
The Affiliated Cancer Hospital of Shanxi Medical University, Taiyuan, China
2
Department of Colorectal Surgery, Shanxi Cancer Hospital and Institute, 3 Zhigongxin Street, Taiyuan 030013, Shanxi, China
3
Department of Gastroenterology, Shanxi Cancer Hospital and Institute, Taiyuan, China
4
Department of Molecular Biology, Shanxi Cancer Hospital and Institute, Taiyuan, China
4.78; p = 0.79) between ESD and LE. When adopting the fixed effect model which takes into account the study size, ESD was associated with a lower recurrence rate than LE (OR 0.15; 95 % CI 0.03–0.87; p = 0.03), while with the random-effect model the difference was not significant (OR 0.18; 95 % CI 0.02–2.04; p = 0.17). Over the last decade improvements in technology have improved the technical feasibility of rectal ESD. In specialized centers with highly experienced endoscopists, ESD can provide high-quality en-bloc excision of rectal neoplasms equivalent to traditional local excision. Keywords Endoscopic submucosal dissection Local excision Early colorectal cancer Systematic review Meta-analysis
Introduction Most early colorectal neoplasms can be removed by conventional polypectomy. However, if the colorectal neoplasm is too large or cannot be removed en bloc using conventional endoscopic techniques, the alternative is local excision (LE) which can be performed by means of direct transanal resection (TAR) and transanal endoscopic microsurgery (TEM). The indications for LE include benign rectal neoplasms, early T1 rectal cancers, and rectal carcinoid tumors [1]. TAR is regarded as a method of choice for palliation in patients with primary, or recurrent rectal carcinoma and for villous adenoma [2]. TEM is known for excellent exposure of the rectum and low complication rates compared with conventional surgical techniques and has consequently emerged as an accepted treatment option for selected rectal neoplasms [3–5]. Local excision may be optimal for cases of early colorectal
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cancer and is associated with a better functional outcome (notably less anorectal or bladder dysfunction [6, 7]. These local procedures have proven to be safe and effective in the treatment of rectal lesions [8–12]. With endoscopic submucosal dissection (ESD), developed in Japan in the mid-1990s, early-stage gastrointestinal tumors including large lesions and lesions with a positive non-lifting sign are resected en bloc [13–24]. The ESD technique was introduced for noninvasive colorectal neoplastic lesions (adenoma, intramucosal cancer, and superficial submucosal cancer), especially in the rectum as an alternative of TAR as early as 1998 [25, 26]. But colorectal ESD is more difficult to perform than gastric ESD. With the recent introduction of various new endoscopic instruments and the skills and experience acquired by colorectal surgeons, more and more cases of early colorectal cancer are detected and cured by ESD. The use of colorectal ESD (CR-ESD) has been spreading largely because of the high en-bloc resection rate, precise histological assessment, efficient elimination of tumor residue and low recurrence rate associated with the technique [27]. The primary indication for CR-ESD is noninvasive lesions diagnosed as adenoma, mucosal, or submucosal colorectal cancer [28]. More recently, CR-ESD has also been used for removing laterally spreading tumors (LSTs) in the colon and rectum, especially those identified by high-magnification chromoendoscopy [25, 29–31]. ESD and LE both offer opportunities to conserve the anal sphincter in cases of malignancy, with low morbidity. In treating rectal cancer the aim is to achieve en-bloc R0 excision. However, the ESD technique is generally regarded as a particularly difficult procedure in the colon and rectum, and LE involves expensive equipment and a steep learning curve. However, CR-ESD allows intraoperative management by utilizing conscious sedation (for instance with midazolam or pentazocine hydrochloride). General anesthesia with endotracheal intubation is required with other minimally invasive techniques but not with CR-ESD. However, there are neither guidelines nor a consensus statement to indicate which treatment strategy is optimal for early colorectal cancer. A systematic review and metaanalysis of ESD versus LE would be of vital importance. The aim of the present study was to perform a systematic review of the literature and evaluate the short-term outcomes for ESD versus LE.
Materials and methods The inclusion criteria and analysis of data were based on preferred reporting items for systematic reviews and metaanalyses (PRISMA) recommendations [32].
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Study selection criteria Inclusion criteria were as follows: the studies (1) included a comparison of ESD and LE for rectal cancer (2) had to report all end-points of interest (see below) and (3) were published in English (4) if there were many related clinical studies from the same research institution, only the best quality study or a study published recently were included. We excluded review articles, case reports, position papers, editorials, commentaries and book chapters. We also excluded those studies that did not include a detailed description of the treatment procedure. Search strategy The databases including MEDLINE, EMBASE, PubMed, the Cochrane Library, Google Scholar and OVID were searched for literatures published between January 1970 and October 2014. The search terms included ‘‘early rectal carcinoid’’, ‘early rectal cancer’, ‘rectum cancer’, ‘rectal neoplasms’, ‘local excision’, ‘endoscopic submucosal dissection’, ‘transanal excision’, ‘transanal endoscopic microsurgery’, ‘rectal minimally invasive surgery’ and all information about end-points of interest. The bibliography of the retrieved papers, reviews and meta-analyses were scanned for additional sources. Study selection and data extraction Two authors (Wang and Gao) assessed titles or abstracts of all identified studies independently and excluded all those that were irrelevant. Full-text articles of potentially relevant studies were obtained. A third researcher (Li) arbitrated in the event of any disagreement. The decision for inclusion in the analysis was made by consensus. Original data were initially screened based on paper titles and abstracts. The full texts were then reviewed and the following data were collected: year of publication, institutional affiliations of the main author, country where the study was conducted, type of study (prospective or retrospective), study setting (monocentric or multicentric), number of patients and number of lesions selected for ESD or LE, mean age of patients, gender distribution of patients, clinical indications for ESD and LE, authors’ definition of complete resection, mean tumor size, en-bloc complete resection rate, pathological complete resection rate, average follow-up period (months), rate of overall morbidity, rate of bowel perforation, mean operation time and recurrence rate. Multiple papers by the same author were considered to be one study.
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Planned methods of analysis Statistical analysis was conducted using the statistical software REVIEW MANAGER Version 5.3 (The Nordic Cochrane Centre, The Cochrane Collaboration, 2014). The odds ratio (OR), weighed mean difference (WMD), and 95 % confidence interval (95 % CI) were calculated for each included study. A two-sided p value of\0.05 was considered statistically significant. Statistical analysis for dichotomous variables was performed using the OR as the summary statistic. Statistical analysis for continuous variables was performed calculating the WMD. The Mantel–Haenszel method was used to combine the OR or WMD for the outcomes of interest by using random-effect model. Heterogeneity among the studies was tested using the v2 test and calculating I2 value. A v2 test result with a p value of \0.05 was considered to be statistically significant. If I2 = 0 %, there was no heterogeneity. If I2 [ 50 %, heterogeneity was present. If the data on continuous outcomes were reported as medians and range, we estimated the mean and standard deviation (SD) according to Hozo’s methods [33].
Results Search results and characteristics of studies A systematic literature search revealed 946 references from electronic databases. Evaluation of the 650 abstracts
identified 5 studies that potentially could be included in the meta-analysis. Following full-text analysis, one of those studies were excluded. Finally, 4 studies, all of which were originally published as full papers, met the inclusion criteria for the present meta-analysis, (see Fig. 1). The principal characteristics of the included studies and clinical characteristics of the tumors are reported in Tables 1 and 2. The 4 studies were conducted in 4 countries (Brazil, Korea, China, Japan) and were published in 2014, 2012, 2011, 2011, respectively. The studies were monocentric and retrospective. A total of 216 patients were enrolled in the studies. The number of patients ranged from 24 to 85. All patients in 2 studies had assessed the precise depth of the lesions by endoscopy prior to ESD or LE because of the possibility of surgical intervention in the event of a major complication. The remaining 2 studies did not specify whether a preoperative evaluation of each patient was performed. Complete resection was defined according to pathologic evaluation criteria in all included studies. Multiple cutting devices were used in the studies: for instance the Flush knife, needle knife, flex knife and Dual Knife or Insulated Tip Knife (Olympus Medical System, Tokyo, Japan) in ESD, and TEM400 (ERBE Elektromedizin, Tubingen, Germany), the Ultracision harmonic scalpel (Ethicon Endo-Surgery, Cincinnati, OH, USA), needle diathermy, tissue handling forceps, needle holder, injection needle, and clip applicator, a binocular stereoscopic eyepiece and rectoscope 4 cm in diameter in LE. The efficacy and safety indicators of ESD and LE are reported in Table 3.
Fig. 1 Flow chart of the study selection process and exclusion criteria, constructed using the preferred reporting items for systematic reviews and metaanalyses (PRISMA) guidelines (32)
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Tech Coloproctol Table 1 Principal characteristics of the included studies Study
Year
Country
Monocentric/ multicentric
No. of tumors
ESD or LE indication
Definition of R0 resection
Fabio et al.
2014
Brazil
Monocentric
24
Patients with larger lesions or lesions located more proximally in the rectum were preferably sent for an ESD. The lesions were assessed by magnifying colonoscopy, ESD was considered to be indicated for lesions C20 mm with pit pattern types III-L, IV, and Vi. Before TEM, the lesions were assessed by rectal endosonography. TEM was indicated for lesions restricted to the submucosal layer
Differentiated adenocarcinoma, no lymphatic or vascular invasion, intramucosal or superficially submucosal tumors (Sm1\1000 lm from the muscularis mucosae), and vertical and lateral tumor-free margins
Park et al.
2012
Korea
Monocentric
63
Patients who met any of the following criteria were excluded: (1) case referred because of incomplete resection or indeterminate pathological results from another hospital; (2) synchronous lesions requiring two sessions of treatment; (3) having co-morbid disease that influenced hospital stay; or (4) undergoing neoadjuvant chemotherapy. There were no significant differences between the two groups regarding and tumor characteristics such aa pit pattern and aspect
The lateral and basal resection margins and free of tumor
Shinsuke et al.
2011
Japan
Monocentric
85
1998–2002 the indications for TAR were lesions unsuitable for conventional EMR or tumors spreading to the dentate line. Starting from 2003, TAR was performed for only eight lesions in this study, From 2003 onwards, ESD as the standard treatment for large noninvasive rectal tumors and those spreading to the dentate line
En-bloc and negative resection margin
Sophie et al.
2011
China
Monocentric
44
The indications for ESD included early neoplasms 2 cm or larger that were deemed not feasible for en-bloc resection with conventional polypectomy or endoscopic mucosal resection and those without endoscopic signs of massive submucosal invasion (including excavated/depressed morphology or Kudo’s pit pattern type V). The indications for LE included benign rectal neoplasms, early T1 rectal cancers, and rectal carcinoid tumors
Negative resection margin
ESD Endoscopic submucosal dissection, LE local excision, TEM transanal endoscopic microsurgery, TAR transanal resection, EMR endoscopic mucosal resection
R0 resection rate and en-bloc resection rate R0 resection was defined as tumor-free margins on histopathological examination and no lymphovascular
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invasion. In the 4 studies [1, 34–36], the R0 resection rate of the ESD group ranged from 67.3 to 96.7 % and that of the LE group from 42.4 to 93.3 %. The forest plot in Fig. 2 summarizes the results of these studies. The overall
Tech Coloproctol Table 2 Clinical characteristics of carcinoid tumors treated by ESD or LE Study
Treatment
No. of patients
Mean age ± SD (year)
Male/ female
Mean size of tumor ± SD (mm)
Endoscopic evaluation before ESD or LE
Instruments
Fa´bio et al.
ESD
11
62.3 ± 4.6
Yes
13
61.5 ± 9.5
Not mentioned
64.6 ± 57.9
LE
Needle knife or Flush knife TEO equipment and operative rectoscope etc.
Park et al.
ESD
30
58.6 ± 8.3
14/16
25.4 ± 11.0
Yes
LE
33
59.5 ± 11.0
17/16
27.8 ± 15.0
Shinsuke et al.
ESD
52
61 ± 11
Flex knife or Needle knife Multifunctional TEM400 and Ultracision harmonic scalpel etc. B-knife and an insulation-tipped knife
LE
33
64 ± 13
Sophie et al.
ESD
14
65.3 ± 14.7
LE
30
66 ± 14.4
43.9 ± 30.7
Not mentioned
40 ± 21
5/9
29 ± 10
17/13
26 ± 12
No
39 ± 24
Not mentioned No
Dual knife or insulated tip knife anal retractor, electrocautery and rectoscope etc.
ESD endoscopic submucosal dissection, LE local excision, TEO transanal endoscopic operations, TEM transanal endoscopic microsurgery
Table 3 Efficacy and safety of ESD or LE Study
No. of tumors
Fabio et al.
11/13
No. of en-bloc and R0 resections, n (%)
Mean procedural time ± SD (min)
Mean hospital stay ± SD (day)
No. of recurrences
No. of complications
10 (90.9)/11 (84.6)
133 ± 94.8/150 ± 66.3
3.8 ± 3.3/4.8 ± 1.7
1/2
5/5
84 ± 51.2/116 ± 58.5
3.6 ± 1.2/6.6 ± 3.5
0/0
1/2
131 ± 100/63 ± 54
4.9 ± 0.8/7.0 ± 3.0
0/5
4/3
78 ± 176.7/50 ± 589.2
2.5 ± 4.3/4 ± 29.5
0/0
1/10
9 (81.8)/11 (84.6) Park et al.
30/33
29 (96.7)/33 (100) 29 (96.7)/32 (97)
Shinsuke et al.
52/33
46 (88)/28 (33) 35 (67)/14 (42)
Sophie et al.
14/30
12 (85.7)/30 (100) 12 (85.7)/28 (93.3)
ESD endoscopic submucosal dissection, LE local excision, SD standard deviation
Fig. 2 Forest plot showing the R0 resection rate of endoscopic submucosal dissection (ESD) compared with that of local excision (LE)
pooled OR was 1.53 (95 % CI 0.62–3.73; p = 0.35). There were no statistically significant differences between ESD and LE in R0 resection rate. Figure 3 shows that ESD did not differ significantly from LE in en-bloc resection rate. The overall pooled OR was 0.82 (95 % CI 0.25–2.70; p = 0.74).
Intra-operative outcomes There were no statistically significant differences between ESD and LE in the size of the operative specimen (Fig. 4). The overall pooled WMD of the size of tumor in ESD versus LE was 0.57 (95 % CI -3.64 to 4.78; p = 0.79).
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Fig. 3 Forest plot showing the en-bloc resection rate of endoscopic submucosal dissection (ESD) compared with that of local excision (LE)
Fig. 4 Forest plot showing the tumor size for endoscopic submucosal dissection (ESD) compared with that of local excision (LE)
Fig. 5 Forest plot showing the mean length of hospital stay for endoscopic submucosal dissection (ESD) compared with that of local excision (LE)
Recovery outcomes The mean hospital stay after ESD was significantly shorter than after LE (Fig. 5). The overall pooled WMD of the mean duration of hospital stay in ESD versus LE was -1.94 (95 % CI -2.85 to -1.02; p \ 0.0001)]. Safety Figure 6 shows that ESD did not differ significantly from LE in overall complications, with OR 0.67 (95 % CI 0.26–1.69; p = 0.40). No heterogeneity was present (v2 = 2.63, p = 0.45, I2 = 0 %). Recurrence rate Figure 7 shows that ESD was associated with a lower recurrence rate than LE, with OR 0.15 (95 % CI 0.03–0.87;
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p = 0.03) when the fixed effect model was adopted. Figure 8 shows that ESD did not differ significantly from LE as regards recurrence rate, with OR 0.18 (95 % CI 0.02–2.04; p = 0.17), heterogeneity was (v2 = 1.55, p = 0.21, I2 = 36 %), when the random model was adopted. In summary, 8 patients with ESD developed a local recurrence within 1 year and 6 patients with local recurrence in the TAR group underwent additional treatment: 3 with ESD, 2 with 2 TAR sessions, and 1 with low anterior resection. Curative resections were obtained in all 6 cases of local recurrence. Sensitivity analysis We excluded the trials in which precise depth of the lesions were not established by endoscopy prior to ESD or LE before tumor resection. This exclusion for R0 resection rate led to a reduction before sensitivity analysis (v2 = 3.49,
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Fig. 6 Forest plot indicating rates of overall complications in endoscopic submucosal dissection (ESD) and local excision (LE)
Fig. 7 Forest plot showing tumor recurrence after endoscopic submucosal dissection (ESD) or local excision (LE), while fixed effect model was adopted
Fig. 8 Forest plot showing tumor recurrence after endoscopic submucosal dissection (ESD) or local excision (LE), while random-effect model was adopted
p = 0.32, I2 = 14 %) versus after sensitivity analysis (v2 = 0.00, p = 0.95, I2 = 0 %) in statistical heterogeneity, en-bloc resection rate (v2 = 3.51, p = 0.32, I2 = 15 % vs. v2 = 0.75, p = 0.39, I2 = 0 %), overall complications (v2 = 2.63, p = 0.45, I2 = 0 % vs. v2 = 0.37, p = 0.54, I2 = 0 %), and increased statistical heterogeneity for tumor size (v2 = 2.39, p = 0.50, I2 = 0 % before sensitivity analysis and v2 = 1.37, p = 0.24, I2 = 24 % after sensitivity analysis), mean duration of hospital stay (v2 = 4.62, p = 0.20, I2 = 35 % before sensitivity analysis and v2 = 4.53, p = 0.03, I2 = 78 % after sensitivity analysis). The pooled OR and WMD still supported the
original results without any change in statistical significance except for the duration of hospital stay. In this case, ESD had equal mean duration of hospital stay (WMD -1.79, 95 % CI -4.44 to -0.86; p = 0.19) despite considerable heterogeneity (v2 = 4.53, p = 0.03, I2 = 78 %) after sensitivity analysis. After exclusion of the studies in which data on continuous outcomes were expressed as median and range, the SD were calculated using the method of Hozo. These analyses produced an increase in the degree of heterogeneity with equal mean duration of hospital stay in statistical significance (v2 = 4.62, p \ 0.20, I2 = 35 %
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before analysis of sensitivity and v2 = 4.60, p \ 0.10, I2 = 57 % after analysis of sensitivity) despite marked heterogeneity. When only the ESD versus TEM studies were considered, the results of sensitivity analysis were the same as in excluded the trials in which precise depth of the lesions were not performed by endoscopy prior to ESD or LE before tumor resection.
Discussion Although currently rectal lesions are diagnosed earlier than in the past and can be treated with a variety of different techniques, we found no randomized controlled studies comparing ESD with LE. In patients with rectal cancer ESD has achieved a 80–90 % en-bloc resection rate as reported in literature [37, 38]. From this systematic review and meta-analysis, we can see there were no statistically significant differences between ESD and LE in R0 resection rate and en-bloc resection rate. A previous study comparing ESD with TEM showed an advantage of TEM as regards achievement of R0 resection and en-bloc resection. With ESD there was an en-bloc resection rate: 88 versus 99 % with TEM. Even more significantly, an R0 resection was achieved for 74 % of patients using ESD compared with 89 % using TEM [39]. The sensitivity analysis in which only the ESD versus TEM studies were considered, showed there were slight differences in the overall R0 resection rate (92.7 % using ESD compared with 93.5 % using TEM, p = 0.85) and enbloc resection (95.1 % using ESD compared with 95.7 % using TEM, p = 0.92), favouring TEM over ESD, although these differences were not statistically significant. With regard to the time until recovery, the mean duration of hospital stay was significantly shorter after ESD than after LE. Furthermore, we compared several procedure-related variables between the 2 groups. General anesthesia or spinal anesthesia was obligatory for patients undergoing LE, whereas conscious sedation was sufficient for those undergoing ESD, which could reduce complications related to general or spinal anesthesia. Consequently shorter hospital stays could be anticipated for patients undergoing ESD if complications do not occur. All sensitivity analysis about mean duration of hospital stay showed an increase in the degree of heterogeneity with equal mean duration of hospital stay. However, the marked heterogeneity between the studies leads to the conclusion that there is no evidence for one procedure being better than the other. The average lesion size was comparable between the ESD and LE groups. The degree of safety of ESD and LE
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was also similar. However, ESD appeared to be associated with a lower recurrence rate than LE. This meta-analysis has certain limitations. First of all, the findings are mostly based on retrospective studies. This exposes the data to bias, even where other aspects of the methodology were satisfactory. On the other hand, associated with the high degree of heterogeneity regarding anastomotic technique and postoperative care, it could have resulted in bias. Nevertheless, the present paper reflects the current state of the literature on the subject. Owing to a lack of long-term cancer-specific data, it was not possible to compare survival or cost.
Conclusions Our results provide valuable information regarding the role of rectal ESD versus LE and can set the stage for further prospective studies. Indeed, further prospective randomized trials with a larger sample size and a longer follow-up period are needed to validate the benefits of rectal ESD and LE. Acknowledgments The present study was supported by grants from the Development Center for Medical Science and Technology, Ministry of Health, P. R. China (No. W2013R02) and Shanxi Cancer Hospital and Institute (No. 201102). Compliance with ethical standards Conflict of interest of interest.
The authors declare that they have no conflict
Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent required.
For this type of study formal consent is not
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REVIEW
Endoscopic submucosal dissection versus local excision for early rectal cancer: a systematic review and meta-analysis S. Wang1 • S. Gao2 • W. Yang3 • S. Guo4 • Y. Li2
Received: 30 March 2015 / Accepted: 16 August 2015 Ó Springer-Verlag Italia Srl 2015
Abstract Endoscopic submucosal dissection (ESD) and local excision (LE) are minimally invasive procedures that can be used to treat early rectal cancer. There are no current guidelines or consensus on the optimal treatment strategy for these lesions. A systematic review was conducted to compare the efficacy and safety of ESD and LE. A metaanalysis was conducted following all aspects of the Cochrane Handbook for systematic reviews and preferred reporting items for systematic reviews and meta-analysis (PRISMA) statement. To perform the statistical analysis, the odds ratio (OR) was used for categorical variables and the weighted mean difference (WMD) for continuous variables. Four studies, involving a total of 307 patients, were identified. The length of hospital stay was longer in the group of patients undergoing LE [weighted mean difference (WMD) -1.94; 95 % CI -2.85 to -1.02; p \ 0.0001]. The combined results of the individual studies showed no significant differences as regards en-bloc resection rate (OR 0.82; 95 % CI 0.25–2.70; p = 0.74), R0 resection rate (OR 1.53; 95 % CI 0.62–3.73; p = 0.35), overall complication rate (OR 0.67; 95 % CI 0.26–1.69; p = 0.40), and tumor size (WMD 0.57; 95 % CI -3.64 to
& Y. Li [email protected] 1
The Affiliated Cancer Hospital of Shanxi Medical University, Taiyuan, China
2
Department of Colorectal Surgery, Shanxi Cancer Hospital and Institute, 3 Zhigongxin Street, Taiyuan 030013, Shanxi, China
3
Department of Gastroenterology, Shanxi Cancer Hospital and Institute, Taiyuan, China
4
Department of Molecular Biology, Shanxi Cancer Hospital and Institute, Taiyuan, China
4.78; p = 0.79) between ESD and LE. When adopting the fixed effect model which takes into account the study size, ESD was associated with a lower recurrence rate than LE (OR 0.15; 95 % CI 0.03–0.87; p = 0.03), while with the random-effect model the difference was not significant (OR 0.18; 95 % CI 0.02–2.04; p = 0.17). Over the last decade improvements in technology have improved the technical feasibility of rectal ESD. In specialized centers with highly experienced endoscopists, ESD can provide high-quality en-bloc excision of rectal neoplasms equivalent to traditional local excision. Keywords Endoscopic submucosal dissection Local excision Early colorectal cancer Systematic review Meta-analysis
Introduction Most early colorectal neoplasms can be removed by conventional polypectomy. However, if the colorectal neoplasm is too large or cannot be removed en bloc using conventional endoscopic techniques, the alternative is local excision (LE) which can be performed by means of direct transanal resection (TAR) and transanal endoscopic microsurgery (TEM). The indications for LE include benign rectal neoplasms, early T1 rectal cancers, and rectal carcinoid tumors [1]. TAR is regarded as a method of choice for palliation in patients with primary, or recurrent rectal carcinoma and for villous adenoma [2]. TEM is known for excellent exposure of the rectum and low complication rates compared with conventional surgical techniques and has consequently emerged as an accepted treatment option for selected rectal neoplasms [3–5]. Local excision may be optimal for cases of early colorectal
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cancer and is associated with a better functional outcome (notably less anorectal or bladder dysfunction [6, 7]. These local procedures have proven to be safe and effective in the treatment of rectal lesions [8–12]. With endoscopic submucosal dissection (ESD), developed in Japan in the mid-1990s, early-stage gastrointestinal tumors including large lesions and lesions with a positive non-lifting sign are resected en bloc [13–24]. The ESD technique was introduced for noninvasive colorectal neoplastic lesions (adenoma, intramucosal cancer, and superficial submucosal cancer), especially in the rectum as an alternative of TAR as early as 1998 [25, 26]. But colorectal ESD is more difficult to perform than gastric ESD. With the recent introduction of various new endoscopic instruments and the skills and experience acquired by colorectal surgeons, more and more cases of early colorectal cancer are detected and cured by ESD. The use of colorectal ESD (CR-ESD) has been spreading largely because of the high en-bloc resection rate, precise histological assessment, efficient elimination of tumor residue and low recurrence rate associated with the technique [27]. The primary indication for CR-ESD is noninvasive lesions diagnosed as adenoma, mucosal, or submucosal colorectal cancer [28]. More recently, CR-ESD has also been used for removing laterally spreading tumors (LSTs) in the colon and rectum, especially those identified by high-magnification chromoendoscopy [25, 29–31]. ESD and LE both offer opportunities to conserve the anal sphincter in cases of malignancy, with low morbidity. In treating rectal cancer the aim is to achieve en-bloc R0 excision. However, the ESD technique is generally regarded as a particularly difficult procedure in the colon and rectum, and LE involves expensive equipment and a steep learning curve. However, CR-ESD allows intraoperative management by utilizing conscious sedation (for instance with midazolam or pentazocine hydrochloride). General anesthesia with endotracheal intubation is required with other minimally invasive techniques but not with CR-ESD. However, there are neither guidelines nor a consensus statement to indicate which treatment strategy is optimal for early colorectal cancer. A systematic review and metaanalysis of ESD versus LE would be of vital importance. The aim of the present study was to perform a systematic review of the literature and evaluate the short-term outcomes for ESD versus LE.
Materials and methods The inclusion criteria and analysis of data were based on preferred reporting items for systematic reviews and metaanalyses (PRISMA) recommendations [32].
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Study selection criteria Inclusion criteria were as follows: the studies (1) included a comparison of ESD and LE for rectal cancer (2) had to report all end-points of interest (see below) and (3) were published in English (4) if there were many related clinical studies from the same research institution, only the best quality study or a study published recently were included. We excluded review articles, case reports, position papers, editorials, commentaries and book chapters. We also excluded those studies that did not include a detailed description of the treatment procedure. Search strategy The databases including MEDLINE, EMBASE, PubMed, the Cochrane Library, Google Scholar and OVID were searched for literatures published between January 1970 and October 2014. The search terms included ‘‘early rectal carcinoid’’, ‘early rectal cancer’, ‘rectum cancer’, ‘rectal neoplasms’, ‘local excision’, ‘endoscopic submucosal dissection’, ‘transanal excision’, ‘transanal endoscopic microsurgery’, ‘rectal minimally invasive surgery’ and all information about end-points of interest. The bibliography of the retrieved papers, reviews and meta-analyses were scanned for additional sources. Study selection and data extraction Two authors (Wang and Gao) assessed titles or abstracts of all identified studies independently and excluded all those that were irrelevant. Full-text articles of potentially relevant studies were obtained. A third researcher (Li) arbitrated in the event of any disagreement. The decision for inclusion in the analysis was made by consensus. Original data were initially screened based on paper titles and abstracts. The full texts were then reviewed and the following data were collected: year of publication, institutional affiliations of the main author, country where the study was conducted, type of study (prospective or retrospective), study setting (monocentric or multicentric), number of patients and number of lesions selected for ESD or LE, mean age of patients, gender distribution of patients, clinical indications for ESD and LE, authors’ definition of complete resection, mean tumor size, en-bloc complete resection rate, pathological complete resection rate, average follow-up period (months), rate of overall morbidity, rate of bowel perforation, mean operation time and recurrence rate. Multiple papers by the same author were considered to be one study.
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Planned methods of analysis Statistical analysis was conducted using the statistical software REVIEW MANAGER Version 5.3 (The Nordic Cochrane Centre, The Cochrane Collaboration, 2014). The odds ratio (OR), weighed mean difference (WMD), and 95 % confidence interval (95 % CI) were calculated for each included study. A two-sided p value of\0.05 was considered statistically significant. Statistical analysis for dichotomous variables was performed using the OR as the summary statistic. Statistical analysis for continuous variables was performed calculating the WMD. The Mantel–Haenszel method was used to combine the OR or WMD for the outcomes of interest by using random-effect model. Heterogeneity among the studies was tested using the v2 test and calculating I2 value. A v2 test result with a p value of \0.05 was considered to be statistically significant. If I2 = 0 %, there was no heterogeneity. If I2 [ 50 %, heterogeneity was present. If the data on continuous outcomes were reported as medians and range, we estimated the mean and standard deviation (SD) according to Hozo’s methods [33].
Results Search results and characteristics of studies A systematic literature search revealed 946 references from electronic databases. Evaluation of the 650 abstracts
identified 5 studies that potentially could be included in the meta-analysis. Following full-text analysis, one of those studies were excluded. Finally, 4 studies, all of which were originally published as full papers, met the inclusion criteria for the present meta-analysis, (see Fig. 1). The principal characteristics of the included studies and clinical characteristics of the tumors are reported in Tables 1 and 2. The 4 studies were conducted in 4 countries (Brazil, Korea, China, Japan) and were published in 2014, 2012, 2011, 2011, respectively. The studies were monocentric and retrospective. A total of 216 patients were enrolled in the studies. The number of patients ranged from 24 to 85. All patients in 2 studies had assessed the precise depth of the lesions by endoscopy prior to ESD or LE because of the possibility of surgical intervention in the event of a major complication. The remaining 2 studies did not specify whether a preoperative evaluation of each patient was performed. Complete resection was defined according to pathologic evaluation criteria in all included studies. Multiple cutting devices were used in the studies: for instance the Flush knife, needle knife, flex knife and Dual Knife or Insulated Tip Knife (Olympus Medical System, Tokyo, Japan) in ESD, and TEM400 (ERBE Elektromedizin, Tubingen, Germany), the Ultracision harmonic scalpel (Ethicon Endo-Surgery, Cincinnati, OH, USA), needle diathermy, tissue handling forceps, needle holder, injection needle, and clip applicator, a binocular stereoscopic eyepiece and rectoscope 4 cm in diameter in LE. The efficacy and safety indicators of ESD and LE are reported in Table 3.
Fig. 1 Flow chart of the study selection process and exclusion criteria, constructed using the preferred reporting items for systematic reviews and metaanalyses (PRISMA) guidelines (32)
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Tech Coloproctol Table 1 Principal characteristics of the included studies Study
Year
Country
Monocentric/ multicentric
No. of tumors
ESD or LE indication
Definition of R0 resection
Fabio et al.
2014
Brazil
Monocentric
24
Patients with larger lesions or lesions located more proximally in the rectum were preferably sent for an ESD. The lesions were assessed by magnifying colonoscopy, ESD was considered to be indicated for lesions C20 mm with pit pattern types III-L, IV, and Vi. Before TEM, the lesions were assessed by rectal endosonography. TEM was indicated for lesions restricted to the submucosal layer
Differentiated adenocarcinoma, no lymphatic or vascular invasion, intramucosal or superficially submucosal tumors (Sm1\1000 lm from the muscularis mucosae), and vertical and lateral tumor-free margins
Park et al.
2012
Korea
Monocentric
63
Patients who met any of the following criteria were excluded: (1) case referred because of incomplete resection or indeterminate pathological results from another hospital; (2) synchronous lesions requiring two sessions of treatment; (3) having co-morbid disease that influenced hospital stay; or (4) undergoing neoadjuvant chemotherapy. There were no significant differences between the two groups regarding and tumor characteristics such aa pit pattern and aspect
The lateral and basal resection margins and free of tumor
Shinsuke et al.
2011
Japan
Monocentric
85
1998–2002 the indications for TAR were lesions unsuitable for conventional EMR or tumors spreading to the dentate line. Starting from 2003, TAR was performed for only eight lesions in this study, From 2003 onwards, ESD as the standard treatment for large noninvasive rectal tumors and those spreading to the dentate line
En-bloc and negative resection margin
Sophie et al.
2011
China
Monocentric
44
The indications for ESD included early neoplasms 2 cm or larger that were deemed not feasible for en-bloc resection with conventional polypectomy or endoscopic mucosal resection and those without endoscopic signs of massive submucosal invasion (including excavated/depressed morphology or Kudo’s pit pattern type V). The indications for LE included benign rectal neoplasms, early T1 rectal cancers, and rectal carcinoid tumors
Negative resection margin
ESD Endoscopic submucosal dissection, LE local excision, TEM transanal endoscopic microsurgery, TAR transanal resection, EMR endoscopic mucosal resection
R0 resection rate and en-bloc resection rate R0 resection was defined as tumor-free margins on histopathological examination and no lymphovascular
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invasion. In the 4 studies [1, 34–36], the R0 resection rate of the ESD group ranged from 67.3 to 96.7 % and that of the LE group from 42.4 to 93.3 %. The forest plot in Fig. 2 summarizes the results of these studies. The overall
Tech Coloproctol Table 2 Clinical characteristics of carcinoid tumors treated by ESD or LE Study
Treatment
No. of patients
Mean age ± SD (year)
Male/ female
Mean size of tumor ± SD (mm)
Endoscopic evaluation before ESD or LE
Instruments
Fa´bio et al.
ESD
11
62.3 ± 4.6
Yes
13
61.5 ± 9.5
Not mentioned
64.6 ± 57.9
LE
Needle knife or Flush knife TEO equipment and operative rectoscope etc.
Park et al.
ESD
30
58.6 ± 8.3
14/16
25.4 ± 11.0
Yes
LE
33
59.5 ± 11.0
17/16
27.8 ± 15.0
Shinsuke et al.
ESD
52
61 ± 11
Flex knife or Needle knife Multifunctional TEM400 and Ultracision harmonic scalpel etc. B-knife and an insulation-tipped knife
LE
33
64 ± 13
Sophie et al.
ESD
14
65.3 ± 14.7
LE
30
66 ± 14.4
43.9 ± 30.7
Not mentioned
40 ± 21
5/9
29 ± 10
17/13
26 ± 12
No
39 ± 24
Not mentioned No
Dual knife or insulated tip knife anal retractor, electrocautery and rectoscope etc.
ESD endoscopic submucosal dissection, LE local excision, TEO transanal endoscopic operations, TEM transanal endoscopic microsurgery
Table 3 Efficacy and safety of ESD or LE Study
No. of tumors
Fabio et al.
11/13
No. of en-bloc and R0 resections, n (%)
Mean procedural time ± SD (min)
Mean hospital stay ± SD (day)
No. of recurrences
No. of complications
10 (90.9)/11 (84.6)
133 ± 94.8/150 ± 66.3
3.8 ± 3.3/4.8 ± 1.7
1/2
5/5
84 ± 51.2/116 ± 58.5
3.6 ± 1.2/6.6 ± 3.5
0/0
1/2
131 ± 100/63 ± 54
4.9 ± 0.8/7.0 ± 3.0
0/5
4/3
78 ± 176.7/50 ± 589.2
2.5 ± 4.3/4 ± 29.5
0/0
1/10
9 (81.8)/11 (84.6) Park et al.
30/33
29 (96.7)/33 (100) 29 (96.7)/32 (97)
Shinsuke et al.
52/33
46 (88)/28 (33) 35 (67)/14 (42)
Sophie et al.
14/30
12 (85.7)/30 (100) 12 (85.7)/28 (93.3)
ESD endoscopic submucosal dissection, LE local excision, SD standard deviation
Fig. 2 Forest plot showing the R0 resection rate of endoscopic submucosal dissection (ESD) compared with that of local excision (LE)
pooled OR was 1.53 (95 % CI 0.62–3.73; p = 0.35). There were no statistically significant differences between ESD and LE in R0 resection rate. Figure 3 shows that ESD did not differ significantly from LE in en-bloc resection rate. The overall pooled OR was 0.82 (95 % CI 0.25–2.70; p = 0.74).
Intra-operative outcomes There were no statistically significant differences between ESD and LE in the size of the operative specimen (Fig. 4). The overall pooled WMD of the size of tumor in ESD versus LE was 0.57 (95 % CI -3.64 to 4.78; p = 0.79).
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Fig. 3 Forest plot showing the en-bloc resection rate of endoscopic submucosal dissection (ESD) compared with that of local excision (LE)
Fig. 4 Forest plot showing the tumor size for endoscopic submucosal dissection (ESD) compared with that of local excision (LE)
Fig. 5 Forest plot showing the mean length of hospital stay for endoscopic submucosal dissection (ESD) compared with that of local excision (LE)
Recovery outcomes The mean hospital stay after ESD was significantly shorter than after LE (Fig. 5). The overall pooled WMD of the mean duration of hospital stay in ESD versus LE was -1.94 (95 % CI -2.85 to -1.02; p \ 0.0001)]. Safety Figure 6 shows that ESD did not differ significantly from LE in overall complications, with OR 0.67 (95 % CI 0.26–1.69; p = 0.40). No heterogeneity was present (v2 = 2.63, p = 0.45, I2 = 0 %). Recurrence rate Figure 7 shows that ESD was associated with a lower recurrence rate than LE, with OR 0.15 (95 % CI 0.03–0.87;
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p = 0.03) when the fixed effect model was adopted. Figure 8 shows that ESD did not differ significantly from LE as regards recurrence rate, with OR 0.18 (95 % CI 0.02–2.04; p = 0.17), heterogeneity was (v2 = 1.55, p = 0.21, I2 = 36 %), when the random model was adopted. In summary, 8 patients with ESD developed a local recurrence within 1 year and 6 patients with local recurrence in the TAR group underwent additional treatment: 3 with ESD, 2 with 2 TAR sessions, and 1 with low anterior resection. Curative resections were obtained in all 6 cases of local recurrence. Sensitivity analysis We excluded the trials in which precise depth of the lesions were not established by endoscopy prior to ESD or LE before tumor resection. This exclusion for R0 resection rate led to a reduction before sensitivity analysis (v2 = 3.49,
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Fig. 6 Forest plot indicating rates of overall complications in endoscopic submucosal dissection (ESD) and local excision (LE)
Fig. 7 Forest plot showing tumor recurrence after endoscopic submucosal dissection (ESD) or local excision (LE), while fixed effect model was adopted
Fig. 8 Forest plot showing tumor recurrence after endoscopic submucosal dissection (ESD) or local excision (LE), while random-effect model was adopted
p = 0.32, I2 = 14 %) versus after sensitivity analysis (v2 = 0.00, p = 0.95, I2 = 0 %) in statistical heterogeneity, en-bloc resection rate (v2 = 3.51, p = 0.32, I2 = 15 % vs. v2 = 0.75, p = 0.39, I2 = 0 %), overall complications (v2 = 2.63, p = 0.45, I2 = 0 % vs. v2 = 0.37, p = 0.54, I2 = 0 %), and increased statistical heterogeneity for tumor size (v2 = 2.39, p = 0.50, I2 = 0 % before sensitivity analysis and v2 = 1.37, p = 0.24, I2 = 24 % after sensitivity analysis), mean duration of hospital stay (v2 = 4.62, p = 0.20, I2 = 35 % before sensitivity analysis and v2 = 4.53, p = 0.03, I2 = 78 % after sensitivity analysis). The pooled OR and WMD still supported the
original results without any change in statistical significance except for the duration of hospital stay. In this case, ESD had equal mean duration of hospital stay (WMD -1.79, 95 % CI -4.44 to -0.86; p = 0.19) despite considerable heterogeneity (v2 = 4.53, p = 0.03, I2 = 78 %) after sensitivity analysis. After exclusion of the studies in which data on continuous outcomes were expressed as median and range, the SD were calculated using the method of Hozo. These analyses produced an increase in the degree of heterogeneity with equal mean duration of hospital stay in statistical significance (v2 = 4.62, p \ 0.20, I2 = 35 %
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before analysis of sensitivity and v2 = 4.60, p \ 0.10, I2 = 57 % after analysis of sensitivity) despite marked heterogeneity. When only the ESD versus TEM studies were considered, the results of sensitivity analysis were the same as in excluded the trials in which precise depth of the lesions were not performed by endoscopy prior to ESD or LE before tumor resection.
Discussion Although currently rectal lesions are diagnosed earlier than in the past and can be treated with a variety of different techniques, we found no randomized controlled studies comparing ESD with LE. In patients with rectal cancer ESD has achieved a 80–90 % en-bloc resection rate as reported in literature [37, 38]. From this systematic review and meta-analysis, we can see there were no statistically significant differences between ESD and LE in R0 resection rate and en-bloc resection rate. A previous study comparing ESD with TEM showed an advantage of TEM as regards achievement of R0 resection and en-bloc resection. With ESD there was an en-bloc resection rate: 88 versus 99 % with TEM. Even more significantly, an R0 resection was achieved for 74 % of patients using ESD compared with 89 % using TEM [39]. The sensitivity analysis in which only the ESD versus TEM studies were considered, showed there were slight differences in the overall R0 resection rate (92.7 % using ESD compared with 93.5 % using TEM, p = 0.85) and enbloc resection (95.1 % using ESD compared with 95.7 % using TEM, p = 0.92), favouring TEM over ESD, although these differences were not statistically significant. With regard to the time until recovery, the mean duration of hospital stay was significantly shorter after ESD than after LE. Furthermore, we compared several procedure-related variables between the 2 groups. General anesthesia or spinal anesthesia was obligatory for patients undergoing LE, whereas conscious sedation was sufficient for those undergoing ESD, which could reduce complications related to general or spinal anesthesia. Consequently shorter hospital stays could be anticipated for patients undergoing ESD if complications do not occur. All sensitivity analysis about mean duration of hospital stay showed an increase in the degree of heterogeneity with equal mean duration of hospital stay. However, the marked heterogeneity between the studies leads to the conclusion that there is no evidence for one procedure being better than the other. The average lesion size was comparable between the ESD and LE groups. The degree of safety of ESD and LE
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was also similar. However, ESD appeared to be associated with a lower recurrence rate than LE. This meta-analysis has certain limitations. First of all, the findings are mostly based on retrospective studies. This exposes the data to bias, even where other aspects of the methodology were satisfactory. On the other hand, associated with the high degree of heterogeneity regarding anastomotic technique and postoperative care, it could have resulted in bias. Nevertheless, the present paper reflects the current state of the literature on the subject. Owing to a lack of long-term cancer-specific data, it was not possible to compare survival or cost.
Conclusions Our results provide valuable information regarding the role of rectal ESD versus LE and can set the stage for further prospective studies. Indeed, further prospective randomized trials with a larger sample size and a longer follow-up period are needed to validate the benefits of rectal ESD and LE. Acknowledgments The present study was supported by grants from the Development Center for Medical Science and Technology, Ministry of Health, P. R. China (No. W2013R02) and Shanxi Cancer Hospital and Institute (No. 201102). Compliance with ethical standards Conflict of interest of interest.
The authors declare that they have no conflict
Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent required.
For this type of study formal consent is not
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