Endoscopic submucosal dissection in the colorectum : Feasibility in the Canadian setting

1Division of Gastroenterology & Hepatology, Endoscopy Unit University of Calgary, Calgary, Alberta; 2Division of Research and Development of Minor Invasive Treatment, Cancer Center, School of Medicine, Keio University; 3Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan Correspondence: Dr Marietta Iacucci, Division of Gastroenterology, Department of Medicine, University of Calgary, 2500 University Drive Northwest, Calgary, Alberta T2N 1N4. Telephone 403-592-5015, fax 403-592-5090, e-mail miacucci@ucalgary.ca Received for publication September 15, 2013. Accepted September 16, 2013 what is Endoscopic submucosal dissEction? Endoscopic submucosal dissection (ESD) is a novel technique designed for the en bloc removal of early stage gastrointestinal tumours via minimally invasive endoscopic methods. Initially developed in Japan in the mid-1990s for gastric and esophageal lesions, its use has subsequently expanded to lesions in the colorectum, and is becoming increasingly accepted and used worldwide. In western countries, larger sessile colonic lesions are currently being removed using a ‘raise and snare’ technique known as endoscopic mucosal resection (EMR), while large and more difficult polyps are often referred for laparoscopic surgery despite many of them being benign tumours (1). Although it is the procedure of choice for sessile lesions in the west, EMR still presents many drawbacks. Due to piecemeal resection, it often does not provide accurate histological assessment and is associated with a high rate of local recurrence, which is then difficult to treat due to the local fibrosis from the initial EMR. For flat tumours, the more specialized ESD offers the benefits of resecting tumours en bloc, even with large lesions that progress to the submucosal layers, and provides more accurate histology and higher rates of cure (2-4). Indeed, studies by Hotta et al (5) and Saito et al (6) compared recurrence rates for large colorectal tumours removed using EMR and ESD. Tumours removed using traditional EMR showed a dramatically higher recurrence rate (23.5%) compared with a recurrence rate of only 0.7% for those removed en bloc using ESD. Attempts are being made to expand its applications to both esophageal and colonic neoplasms, opening a wide number of indications for use for this novel and exciting technique. The present review provides an overview of the uses and challenges of ESD in colorectal neoplasms, and examines its feasibility and opportunities in the Canadian setting. application in colonic nEoplasms The absolute indications for ESD in the colon are laterally spreading nongranular-type tumours ≥ 2 cm in size and laterally spreading granular-mixed type tumours ≥4 cm – lesions that cannot be resected in en-bloc fashion (7). Not surprisingly, indications for colorectal ESD and therapeutic applications have been developed mostly in Japan and are based around the Japanese Society of Gastroenterology classification system, which divides neoplasms based on morphology from sessile (stage 1) to laterally spreading (stage 4) (8). While firm criteria for ESD vary among centres, smaller lesions are generally treated with snare or endoscopic resection, while larger lesions with higher risks and superficial submucosal invasion are treated using a submucosal dissection. The National Cancer Centre of Japan approved ESD for laterally spreading tumours >2 cm for nongranulating lesions and >3 cm for granular type lesions (8,9). In addition, ESD is used for large sessile lesions and any intramucosal tumours that do not lift with fluid injection. Other indications include lesions with biopsy-induced scars and sporadic circumscribed lesions in inflammatory bowel disease (IBD), in which en bloc resection technique is exceedingly difficult (Figure 1).


what is Endoscopic submucosal dissEction?
Endoscopic submucosal dissection (ESD) is a novel technique designed for the en bloc removal of early stage gastrointestinal tumours via minimally invasive endoscopic methods.Initially developed in Japan in the mid-1990s for gastric and esophageal lesions, its use has subsequently expanded to lesions in the colorectum, and is becoming increasingly accepted and used worldwide.In western countries, larger sessile colonic lesions are currently being removed using a 'raise and snare' technique known as endoscopic mucosal resection (EMR), while large and more difficult polyps are often referred for laparoscopic surgery despite many of them being benign tumours (1).Although it is the procedure of choice for sessile lesions in the west, EMR still presents many drawbacks.Due to piecemeal resection, it often does not provide accurate histological assessment and is associated with a high rate of local recurrence, which is then difficult to treat due to the local fibrosis from the initial EMR.For flat tumours, the more specialized ESD offers the benefits of resecting tumours en bloc, even with large lesions that progress to the submucosal layers, and provides more accurate histology and higher rates of cure (2)(3)(4).Indeed, studies by Hotta et al (5) and Saito et al (6) compared recurrence rates for large colorectal tumours removed using EMR and ESD.Tumours removed using traditional EMR showed a dramatically higher recurrence rate (23.5%) compared with a recurrence rate of only 0.7% for those removed en bloc using ESD.Attempts are being made to expand its applications to both esophageal and colonic neoplasms, opening a wide number of indications for use for this novel and exciting technique.The present review provides an overview of the uses and challenges of ESD in colorectal neoplasms, and examines its feasibility and opportunities in the Canadian setting.

application in colonic nEoplasms
The absolute indications for ESD in the colon are laterally spreading nongranular-type tumours ≥ 2 cm in size and laterally spreading granular-mixed type tumours ≥4 cm -lesions that cannot be resected in en-bloc fashion (7).Not surprisingly, indications for colorectal ESD and therapeutic applications have been developed mostly in Japan and are based around the Japanese Society of Gastroenterology classification system, which divides neoplasms based on morphology from sessile (stage 1) to laterally spreading (stage 4) (8).While firm criteria for ESD vary among centres, smaller lesions are generally treated with snare or endoscopic resection, while larger lesions with higher risks and superficial submucosal invasion are treated using a submucosal dissection.The National Cancer Centre of Japan approved ESD for laterally spreading tumours >2 cm for nongranulating lesions and >3 cm for granular type lesions (8,9).In addition, ESD is used for large sessile lesions and any intramucosal tumours that do not lift with fluid injection.Other indications include lesions with biopsy-induced scars and sporadic circumscribed lesions in inflammatory bowel disease (IBD), in which en bloc resection technique is exceedingly difficult (Figure 1).

application in dysplasia/carcinoma in ibd
The appropriate management of intraepithelial neoplasia (IEN) in IBD is evolving with advances in endoscopic technology.Lesion resectability is now the most important characteristic influencing the decision to either continue endoscopic surveillance or recommend colectomy in patients with IBD.More recent studies suggest that these lesions are heterogeneous and not all subtypes may be strongly associated with progression to malignancy.Circumscribed raised lesions and la faisabilité d'une dissection sous-muqueuse endoscopique du colorectum dans le contexte canadien La dissection sous-muqueuse endoscopique, une technique endoscopique peu effractive pour faire l'exérèse de tumeurs gastrointestinales, est de plus en plus utilisée en présence de néoplasmes coliques, afin d'éviter la résection du côlon chez certains patients.La dissection sous-muqueuse endoscopique du côlon est difficile sur le plan technique.Elle a d'abord été utilisée au Japon, mais elle est de plus en plus courante dans certains centres occidentaux, même si elle demeure limitée au Canada.Les auteurs en examinent les difficultés et les avantages, en plus de l'infrastructure de formation unique nécessaire pour l'effectuer sous supervision.Des outils précis sont nécessaires pour procéder à une dissection sous-muqueuse endoscopique, et il est essentiel de faire preuve d'une rigueur méticuleuse.Les auteurs donnent un point de vue japonais et canadien combiné sur cette technique et traitent de la formation et de l'exécution de la dissection sous-muqueuse endoscopique ainsi que de ses indications potentielles.sporadic adenomas, with a sessile or pedunculated gross appearance, may be safely removed using polypectomy, despite occurring in patients with ulcerative colitis (UC).Polypectomy may be adequate treatment for adenoma-like dysplastic lesions in chronic UC (10,11).Multiple studies have demonstrated that endoscopic surveillance is a safe and effective approach to the management of patients who have visible circumscribed neoplastic lesions resected during surveillance endoscopy.Hurlstone et al ( 12) evaluated 712 UC patients who underwent neoplasia surveillance with pancolonic chromoendoscopy and also had interval random biopsy specimens.One hundred thirtytwo circumscribed noninvase neoplasms were resected during index colonoscopy, including 46 raised lesions, 79 flat lesions and seven laterally spreading tumours, 18 of which harboured high-grade IEN.No subsequent colorectal cancer or flat IEN developed in any patients in this group throughout the study period.This underscores the importance of reconsidering colectomy as a treatment strategy in patients with flat IEN discovered in random biopsy specimens.
Indeed, in a study by Kisiel et al (13), the five-year cumulative incidence of cancer or flat dysplasia was 13%, indicating that polypectomy may be safe for the management of adenomas occurring in most UC patients.Such patients should be able to avoid colectomy but obviously would need close monitoring.
Unfortunately, resection of an adenoma-like mass in chronic UC is often difficult because it is complicated by submucosal fibrosis and ESD may not be technically feasible.This barrier may be overcome using a combination technique.ESD-assisted EMR was performed in 69 patients with selected lesions associated with UC.The endoscopic resection of adenoma-like masses was technically feasible using the combination technique and was also curable.In fact, no metachronous circumscribed IENs or cancer was detected at median follow-up of 18 months.Overall cure rates for the ESD-assisted EMR cohort was 98% (14).
ESD may represent a future endoscopic therapeutic approach in circumscribed sporadic lesions in long-standing IBD to prevent unnecessary colectomies.

colonic Esd -tEchniquEs
ESD has multiple technical challenges in the colon compared with the stomach, which relate to the anatomical features of the colon including its longer length, narrower lumen, extensive flexibility and thinner walls, longer procedure time and increased risk of perforation.Despite this, several novel techniques and technologies have been developed to aid in colonic ESD.Several keys factors are involved and are important in successful ESD.In a procedural review, Yahagi (15) reinforced the importance of appropriate bowel preparation to achieve optimal visualization.The manoeuvreability of the scope is also a very important key factor and the thinnest possible scope, often a gastroscope in the retroflex position if the lesion is rectal or proximal colon, should be used.A transparent hood or cap (Olympus, Japan) is then attached over the end of the scope, which enables tissue manipulation while maintaining visualization and lifting of the lesion and to help to control the knife during incision (Box 1).

tools required to perform Esd Electrosurgical knives:
A number of specialized electrosurgical cutting knives have been developed for ESD including the Flex knife (KD-630L; Olympus), the Hook knife (KD-260R; Olympus, Japan) the Flush knife (DK2618JN; FUJIFILM, Japan), the B-Knife (Zeon Medical, Japan) and Mucosectom (Pentax, Japan).
While developed for ESD, these cuttings tools have some technical limitations.Despite the flex knife achieving excellent treatment results, the loop-shaped tip creates some issues, resulting in difficulty with knife length adjustments, frequent intraprocedure accumulation of debris on the tip and slippage of the knife tip away from the operating field.To remedy this, newly developed electrosurgical knives for colorectal ESD have been introduced since late 2010.These include Dual Knife (Olympus, Japan), Flush Knife including Ball-Tipped (BT) type (Fujinon Optical Co, Japan), B-Knife BT type (Zeon Medical, Japan), Mucosectom 2 (thin type) (Pentax, Japan), Safe Knife V (Fujunon, Japan), Clutch cutter (Fujinon, Japan) and SB knife (Sumitomo Bakelite, Japan) and IT Knife nano (Olympus, Japan).
The Yahagi Dual knife resembles a short needle knife with a small apical disk.It has a fixed knife length: 1.5 mm for esophageal and colorectal ESD and 2 mm for gastric ESD.The small disk is useful for marking and hemostasis in a closed position, and for stabilization of the knife movement against scarred or floppy tissue in an opened position, resulting in overall improved knife manoeuvreability and durability.Combining the endoscopist's knowledge and skill with the soft and flexible properties of the Flex and the Dual knives results in relatively safe and highly effective ESD outcomes.The Flush knife is another type of needle knife that has the added advantage of allowing local injection.A new Flush knife with a BT tip (Flush knife BT type; DK2618JB; FUJIFILM] [22]) has recently been developed to improve the hemostatic function of the standard model.In addition, the ball-tip reduces the procedure time in both upper and lower gastrointestinal ESDs compared with the standard Flush knife because it facilitates scooping (16,17).

Figure 1) Large, laterally spreading nongranular-type tumour >2 cm
The IT knife nano electrosurgical knife features has a shorter knife length for better manoeuvreability in narrow lumens.With a smaller insulated tip and a smaller electrode in the proximal end, the knife is well suited for use in organs with a thinner submucosal layer such as the colon.The IT knife nano enables rapid dissection and is safe.hemostatic forceps and hemoclips: Aside from cutting devices, specialized hemostatic forceps (Pentax and Olympus, Japan) and endoclips are necessary to stop intraprocedure bleeding and perforation that are common in ESD.Hemostatic forceps for ESD are different from hot biopsy forceps in that they have a pointed tip, enabling precise cauterization and preventing overcauterization that can lead to delayed perforation (15).In addition, endoclips are used in the eventual case of perforation, in which defects must be closed as quickly as possible to reduce the risk of peritonitis.carbon dioxide: Carbon dioxide (CO 2 ) insufflation is preferable for longer colonoscopic procedures during ESD because it can reduce patient pain and abdominal discomfort.Saito et al (18,19) demonstrated that the use of CO 2 insufflation reduced mean operation time as well as the need for sedation.Indeed, the mean (± SD) dose of midazolam used during procedure was significantly lower in CO 2 -insufflated patients than the control group (5.6±4.9 mg and 9.7±5.9mg, respectively; P=0.005).injection solutions: Larger and difficult lesions require injecting a specialized hypertonic solution to provide a fluid cushion to protect the underlying tissues and permanently raise the lesion for resection.Hypertonic, long-term solutions that provide a sufficiently durable fluid cushion are needed for submucosal dissection.
Fluid choices vary, but have included hyaluronic acid, glycerol and normal saline (20,21).A mixture consisting of a small amount of epinephrine (0.001%) to control bleeding, indigo carmine dye (0.004%), and a glycerol solution consisting of 10% glycerine, 5% fructose and 0.9% sodium chloride is the most popular solution used in Japan.

Electrosurgical unit
The electrosurgical generators from ERBE (ICC 200 and ICC 350, ERBE, Germany), which have endocut and multiple coagulation modes, are ideal for ESD.The addition of the VIO 300 D (ERBE, Germany) with new cutting and coagulation modes -'dry cut' and 'swift coag' -can reduce bleeding during the ESD procedure (15).

challEnGEs and traininG
Training for ESD presents some future challenges that need to be addressed.To date, the majority of ESD training for western endoscopists has been performed in Japan at highly specialized centres.Several stepwise training protocols have been suggested to ensure competency before independent practice is permitted.Ohata et al (22) performed a retrospective study involving four trainees at NTT Medical Center in Tokyo, Japan, two of whom had extensive experience in gastric ESD (200 procedures) and two of whom had little experience (30 procedures).While the more experienced trainees had greater initial success, it took approximately 30 cases before the trainees' skills converged and reached an acceptable level of proficiency.A study by Hotta et al (23) examined the learning curve associated with colorectal ESD and suggested that at least 40 supervised procedures were needed to reduce risks of perforation to <5%, while 80 procedures were needed before an endoscopists was able to perform ESD in a timely manner with few complications.While the traditional model in Japan had been having trainees develop proficiency in gastric ESD before progressing to colorectal procedures, this model provides obvious barriers in a country such as Canada, where rates of gastric cancer are dramatically lower than in Japan, and where the opportunity to train under endoscopists experienced in ESD is more limited (24,25).A potential solution has been explored in European centres in the form of animal models.Berr et al (26) outlined a workshop for experienced endoscopists training in ESD.Anesthetized pigs were used to practice ESD techniques, with an overall perforation rate of 22%.Of the endoscopists who progressed to perform human ESDs in their practice, the overall perforation rates were 9.7%, suggesting an important role for initial training in animal models.In a study by Parra-Blanco et al (27), both live and dissected porcine models were used in ESD training.The authors found that the mean procedure time decreased by almost one-third comparing the first 50% of procedures performed with the latter 50%, suggesting a strong learning curve and the importance of practicing in models in which patient safety is not in danger.Certainly, animal models would play an important role in any potential training for ESD in Canada.Animal training models have, to date, been either in vivo or ex vivo (live, or killed and dissected, respectively).While live models provide obvious benefits of most closely resembling a real clinical scenario, issues pertaining to animal welfare and transport/care of live animals would likely limit Canadian training programs to ex vivo models.Typical training systems use freshly processed porcine stomachs or large intestines that are used within hours of slaughter to preserve the elastic qualities of the tissue.Samples are washed and then fluid submerged to detect pre-existing mucosal defects.An overtube is attached to the top of the esophagus or the end of the sigmoid in gastric and colonic models, respectively, and the opposite end of the system is clamped to allow air insufflation.Models can then be used to demonstrate or practice ESD technique (27,28) (Figure 2).While these models have drawbacks, including the inability to simulate active bleeding, they provide benefits such as safety and low cost (29,30).Tanaka et al (31) also showed ex vivo training models to be effective in reducing perforation rates and procedure times.The prospect of practicing ESD in a country with little opportunity for expert supervision of real-life clinical procedures makes porcine models an attractive option in western countries such as Canada.It is, however, important that centres are set up with opportunities for simulation including pig-model ESD; this may require centres of excellence and the Canadian Association of Gastroenterology to come together to provide regional and national facilities.

complications oF Esd
While ESD offers a less invasive solution to colonic neoplasms compared with surgery, it is not without complications.In a multicentre cohort study by Nakajima et al (32) in 2012, the authors compared outcomes and complications between EMR and ESD for colonic lesions >20 mm.From a total of 1845 procedures performed, perforation rates were increased to 1.6% in ESD compared with 0.8% in resections along with increased procedure times (96 min) compared with 18 min.En bloc resection rates were dramatically better for ESD (94.5%) compared with 56.9% for conventional endoscopic resection, with even higher discrepancies as lesions became larger.
In another large multicentre study by Saito et al (33), 1111 colorectal tumours treated using ESD from 1998 to 2008 were examined.The patients were from 10 specialized centres across Japan.Among the 1090 patients, total perforation rates were 4.9%, while en bloc resection and curative resection rates were 88% and 89%, respectively.
More recent studies conducted at the National Cancer Institute examining 806 colonic ESD procedures from 2004 to 2012 (34) showed an improved overall perforation risk of 2.8% and a delayed bleeding risk of 1.9%, with a similar resection rate of 87% as reported in the study by Saito et al (33).These decreasing perforation rates point to the importance of experience and, indeed, studies within Japan show higher complication rates in lower volume centres, while initial studies investigating ESD in Europe have reported slightly higher complication rates compared with more experienced endoscopists in Japan (35).

opportunitiEs For Esd in canada
Colorectal cancer screening programs are constantly expanding across Canada, thus exposing endoscopists to increasing numbers of large flat polyps encountered during colonoscopy.To date, these are generally resected in a piecemeal fashion or, occasionally, by EMR technique, both of which have been shown to increase the risk of recurrence and require frequent repeat colonoscopies to detect recurrent lesions.Some of these large lesions are referred to colorectal surgeons for resection, either transanally for low rectal lesions or by laparoscopic segmental colectomy.ESD represents a minimally invasive technique for complete resection of these lesions, with low complication rates and potentially at a lower cost than surgery.
Training programs and adequate clinical experience appear to be necessary to acquire a satisfactory and high level of skill for performing ESD.Before ESD can begin in Canada, collaborations with Japanese experts need to occur to improve the skills of Canadian endoscopists in this technique (36).
The second hurdle lies in funding.Colorectal ESD is not considered to be an advanced medical procedure that would be eligible for national health insurance coverage and the cost of this procedure has not yet been covered by the western national health insurance policies or by private payers.Further pharmacoeconomic studies need to be performed to determine the cost benefit of such an approach before Canadian patients can begin to benefit from this novel procedure.rEFErEncEs

Figure 2 ) 1 Performing colorectal endoscopic submucosal dissection step by step 1 .
Figure 2) Isolated colonic endoscopic submucosal dissection (ESD) models.a Animal training model for gastric ESD.b Animal training model for colorectal ESD