The introduction of colorectal endoscopic submucosal hydrodissection at a Western Center: results and learning curve

Background Colorectal endoscopic submucosal dissection (CR-ESD) is an evolving technique in Western countries. The use of hydrodissection has been established as an effective technique for safe resection. However, it is unknown if the adoption of this technique can help a novice perform ESD safely without prior experience or formal tutorial. Here we aimed to determine the results of the introduction of endoscopic submucosal hydrodissection for the treatment of complex colorectal polyps and establish the learning curve for this technique, at a European tertiary hospital. Methods This study included data from 80 consecutive CR-ESDs performed for complex colorectal polyps, by a single endoscopist within a structured training program. The main outcome was en bloc resection rate, while secondary outcomes included complications (perforation and bleeding), knife en bloc (KEB) resection rate, knife-snare en bloc resection rate, conversion rate to endoscopic piecemeal mucosal resection (EPMR), complete resection rate, curative resection rate. To explore the impact of experience, procedures were divided into 4 groups of 20 each, with outcomes measures compared between these. Results The overall en bloc resection rate was 75%. KEB resection was obtained in 15%, 25%, 50%, and 80% cases in the consecutive periods (period 1 vs 4, p<0.001; periods 1, 2 and 3 vs 4, p<0.001). Conversion rate to EPMR was obtained in 40%, 25%, 25% and 5% respectively (period 1,2 and 3 vs 4; p=0.031). Curative resection was achieved in 55%, 75%, 70% and 95% respectively (p=0.037). Series results were 75% R0 resection, 23.7% conversion to EPMR, and 1.2% incomplete resection. Complications included perforations (7.5%) and bleeding (3.75%), there was no significant difference in the 4 periods of training. Multivariate analysis revealed factors more likely to result in non-en bloc versus en bloc resection were polyp size > 35 mm 70% vs. 23.4%; OR 13.2 This study was a clinical service evaluation of the outcomes associated with the introduction of CR ESD within a single institution. A prospectively maintained database of consecutive CR-ESDs performed between July 2013 and December 2015 was created. All procedures were performed on lesions that met established clinical criteria for resection [9]; 1) sessile lesions > 2 cm, 2) laterally spreading tumors nongranular type (LST-NG) > 2 cm, and 3) mixed type and homogenous LST tumors granular type (LST-G) > 3 cm. Additionally, CR-ESD was considered for lesions with recurrence on a scar, those suspected of mild (<1000 um) submucosal infiltration or lesions for which previous endoscopic mucosal resection (EMR) had failed. We did not exclude any lesions exclusively because of their size or location. All performed procedures were included in the database. CR ESD was not performed where there was suspicion of deep tumor infiltration, non-acceptance by the patient, and lack of coverage by the medical insurance company. In these cases, standard therapy was offered. Patient outcomes were monitored a follow up months post procedure. Patients our institution the any post procedural We ensured that any complications encountered captured our analysis two follow-up visits, 4 and 16 weeks after the procedure. In this study of prospectively collected data, we analyzed 80 colorectal lesions in 68 patients who were treated by CR-ESD at our institution between July 2013 and December 2015. To identify evidence of improvement in the development of this technique at our hospital, we compared results of our first 80 CR-ESDs divided into 4 groups of 20 cases CRC: colorectal cancer; ESD: Endoscopic submucosal dissection; EMR: Endoscopic mucosal resection; EPMR: Endoscopic piecemeal mucosal resection; KEB resection: Knife en bloc resection; KSEB resection: Knife-Snare en bloc resection; LST-NG: laterally spreading tumors nongranular type; LST-G: laterally spreading tumors granular type; SPMC: sodium picosulfate and magnesium citrate; CR-ESD: colorectal endoscopic submucosal dissection; LGD: low-grade intraepithelial neoplasia; HGD: high-grade intraepithelial neoplasia.


Background
Endoscopic submucosal dissection (ESD) for treatment of colorectal neoplasms has been established as a safe and effective technique within in Eastern countries [1,2]. In the West, this is an emerging technique [3]. In part this is due to the lower frequency of gastric lesions in Western populations, which due to their relative technical simplicity act as good training cases. In the West colorectal lesions are the most frequent indication for ESD [4,5].Although classically considered to be lesions at high risk for colorectal cancer (CRC), evidence suggests that complex polyps are generally benign. Most early colorectal neoplasms can be treated endoscopically, thereby avoiding the mortality and morbidity associated with major surgery. ESD has become an accepted technique, as it can provide en bloc resection and retrieval of a more adequate specimen than piecemeal resection [6]. The main aims of this study were to evaluate the efficacy and safety of the implementation of endoscopic submucosal hydrodissection by a single endoscopist for the treatment of complex colorectal polyps at a European tertiary hospital, and to evaluate the learning curve.

Study design, patients, and indications
This study was a clinical service evaluation of the outcomes associated with the introduction of CR ESD within a single institution. A prospectively maintained database of consecutive CR-ESDs performed between July 2013 and December 2015 was created. All procedures were performed on lesions that met established clinical criteria for resection [9]; 1) sessile lesions > 2 cm, 2) laterally spreading tumors nongranular type (LST-NG) > 2 cm, and 3) mixed type and homogenous LST tumors granular type (LST-G) > 3 cm.
Additionally, CR-ESD was considered for lesions with recurrence on a scar, those suspected of mild (<1000 um) submucosal infiltration or lesions for which previous endoscopic mucosal resection (EMR) had failed. We did not exclude any lesions exclusively because of their size or location. All performed procedures were included in the database.
CR ESD was not performed where there was suspicion of deep tumor infiltration, nonacceptance by the patient, and lack of coverage by the medical insurance company. In these cases, standard therapy was offered.
Patient outcomes were monitored for a follow up period of 36 months post procedure.
Patients were instructed to attend our institution in the event of any post procedural symptoms. We ensured that any complications encountered were captured by our analysis with two follow-up visits, 4 and 16 weeks after the procedure.
In this study of prospectively collected data, we analyzed 80 colorectal lesions in 68 patients who were treated by CR-ESD at our institution between July 2013 and December 2015. To identify evidence of improvement in the development of this technique at our hospital, we compared results of our first 80 CR-ESDs divided into 4 groups of 20 cases with increasing experience. This pragmatical approach was decided in order to facilitate the observation of the evolution of the learning curve, more easily that with only two groups Endoscopist and endoscopic protocol All procedures were performed by a single endoscopist (F.R-Z), who, as an expert in therapeutic colonoscopy, having personally performed more than 200 EMRs and 2000 polypectomies. ESD was implemented after the endoscopist had acquired the necessary technical skills by training in an isolated animal model for over one year, attending national training courses. He observed multiple colorectal ESD online resources. The intent was to perform standard untutored ESD in all cases.
The patients underwent bowel preparation at home with 2 sachets of sodium picosulfate and magnesium citrate (SPMC). All procedures were carried out in an operating room. The dissection was performed under general anesthesia controlled by an anesthesiologist.
The insufflation was achieved with CO 2 , except for 31 (39%) procedures that were carried out with room air. To facilitate visualization of the resection area, a disposable distal cap attached to the tip of the endoscope, with a conical shape (DH28GR, 29CR, Fujifilm, Japan) or a straight shape (D-201-11804, Olympus, Japan), was used. Two different types of hemostatic forceps, (Coagrasper, Olympus, Japan and bipolar Hemostat Y, Pentax, Japan), were used to control bleeding. Any perforations were closed using clips (Resolution Clip, Boston Scientific, United States).
To diagnose recurrences, we followed up the scar for 3 years after the procedure. At least 3 biopsies were taken from the scar area during the follow-up colonoscopies.

Definitions and outcomes
The definitions used related to ESD are included in Table 1. The primary outcome of this study was en bloc resection rate. Secondary outcomes were: complication rate (bleeding and perforation),knife en bloc (KEB) resection (figure 1) rate, knife-snare en bloc (KSEB) resection (figure 2) rate, conversion rate to endoscopic piecemeal mucosal resection (EPMR), complete resection rate, curative resection rate.

Statistical Analysis
Because this study meant to evaluate the results during the introduction of the technique in the initial 80 cases, that has been considered as the initial phase of learning curve, a power calculation was not performed.
The statistical analysis was carried out as per lesion analysis. The Kolmogorov-Smirnov test with Lilliefors correction was used to evaluate whether the data followed a normal distribution. Categorical variables are presented as frequencies and percentages.
Continuous variables are expressed as the mean (±SD). The χ2 -based proportion test with Yates correction or Fisher's exact test was used to evaluate differences among categorical variables; for continuous variables, either a 2-tailed t test (when the normality and homogeneity of variance assumptions were met) or the nonparametric Mann-Whitney U test was used. For all statistical tests, differences with a confidence interval (CI) of 95% and a p < 0.05 were considered significant. Statistical analysis was performed using the IBM SPSS version 24.0 program.

Results
Eighty CR-ESDs were carried within 68 patients. The mean patient age was 64.9 years (range: 36-87 years, with a male preponderance (57.5%) The most frequent lesion location was the proximal colon (66.25%). The mean lesion size was 31.3± 12 mm. Table 2 summarizes the characteristics of the patients and lesions for the four periods. Table 3 summarizes the outcomes and complications of the ESD procedure.
Perforations and hemorrhages occurred in 7.5% and 3.75% of the cases, respectively. No significant differences in complications were noted depending on stage of training. All perforations were intraprocedural. Submucosal dissection of the lesions were carried out with the knife, and the perforations were successfully closed with clips, except for one perforation in the cecum in the 3rd period. In this patient, the resection was completed with a polypectomy snare; emergency surgery was performed with caecectomy, which included the whole resection area, thus, avoiding a right hemicolectomy. Hemorrhages occurred in one case in each of the initial three periods (p = 1.0). All of these were cases of delayed bleeding, which resolved endoscopically and were related to the reintroduction of the antiplatelet agent or anticoagulant drug.
One patient (1.25%) required surgery because of incomplete resection. Surgery was needed as further treatment in another patient (1.25%) due to < 1 mm submucosal invasion with vascular invasion. The follow-up time was 36 months. No recurrence was seen in either patient.
No complications occurred as a consequence of general anesthesia. We also searched for clinicopathological features that might be associated with non-en bloc resection (

Discussion
The present study describes outcomes of the implementation of CR-ESD using hydrodissection by an unsupervised Western endoscopist. While few studies have described the learning curve for CR-ESD carried out by an endoscopist without prior experience in upper gastrointestinal ESD [10,11], no previous publication has described the learning curve using hydrodissection for a Western endoscopist without experience in gastric ESD or Japanese mentoring.
Based on the results of our analysis, from 60 procedure the outcomes en bloc resection can to be acceptable for an endoscopist without prior experience in gastric ESD or supervision by an international ESD expert. The overall R0 resection rate was 75%. This of resections performed only with a knife and 8.1% of resections involving use of a snare [14]. This study illustrates the reality of performing CR-ESD in a Western setting. Finishing the ESD with snare is a necessary alternative in daily practice and is often pragmatic in situations involving a high risk of complications.
The results of our series are good in regard to safety. To compare our results with those of other Western series, it should be noted that, in our study, the most frequent lesion location was the proximal colon (66.25% of the cases); only 16.25% of lesions were located in the rectum. There were 6 perforations, which corresponds to an overall perforation rate of 7.5 %; only 1 patient (1.25%) required surgery for management of the perforation. We believe these data compare favorably with previous results (Table 5). The perforation rate during the fourth period was 0 %. The frequency of this major adverse event is comparable to that in Japanese studies [1].
In our series, polyp size > 35 mm, severe fibrosis, and non-use of CO 2 were more likely to result in non-en bloc resection. Lesions larger than 4 cm and the presence of severe fibrosis are factors known to increase the difficulty of dissection [26]. In a Japanese series of 200 CR-ESDs, the use of CO 2 was introduced 3 years after commencing the technique.
The authors concluded that this change may be the principal factor responsible for the observed improvement in the learning curve [27]. In our study, we performed 38.7% of the cases without CO 2 , which was confirmed as a risk factor for non-en bloc resection in our multivariate analysis, but the cases without CO2 were performed in the first two groups, so the outcome can be considered as a potential confounder. To confirm this result, inclusion of a control group in future studies would be needed. However, such studies would not be justified, as use of CO 2 for ESD is widely recommended nowadays.
Colorectal ESD is a technique associated with low recurrence rates. Yamada et al. reported that ESD offers solid long-term clinical outcomes with extremely low recurrence rates if curative resection is achieved with en bloc resection [2]. In our study, no recurrence was seen either in cases of en bloc resection or conversion to EPMR at 36 months post procedure.
Noninvasive colorectal polyps should be removed by endoscopic techniques. There are surgical series that confirm this need. Gorgun et al. assessed patients referred for surgery because of endoscopically unresectable polyps, due either to location, size, or other factors. The authors concluded that the patients with benign polyps were overtreated and exposed to unnecessary risks and, theoretically, advanced endoscopic resection techniques could have been used to remove these lesions [28]. In Europe, a recent Dutch study showed that patients with large and complex colorectal polyps are still frequently referred for surgical treatment. These referrals should decrease, because colorectal surgery is known to be associated with significantly higher morbidity and mortality rates (34.8% and 1.4%, respectively) than endoscopic treatment [29]. Implementing ESD could reduce the need for surgery for complex polyps in the West. In Japan, the use of ESD has changed the surgical statistics. Before the introduction of ESD at the National Cancer Center Hospital (Tokyo, Japan), approximately 20% of surgeries for colonic polyps revealed evidence of intramucosal neoplasia; after the introduction of ESD, this percentage dramatically decreased to 1%, and thus, "over-surgery" was largely avoided [30]. In our study, most of the cases of CR-ESD were proposed as a means of endoscopic rescue in patients who were going to be referred for surgery for complex polyps. Even 50% of the cases had already been referred to a surgeon. We managed to endoscopically treat 97.5% of these lesions, which is in line with published results suggesting that ESD can help avoid unnecessary surgeries. Studies such as this study and others support this change in the therapy for colon cancer in the West, where the negative aspects of the technique (rate of complications, procedure time, and steep learning curve) are gradually being overcome.
Finally, it is important to address some limitations of this study. First, the retrospective design and single-site data collection represent one limitation. Second, the implementation of the technique was carried out by only one endoscopist, and the cases were not selected according to degree of difficulty; thus, the assessment of the learning curve to determine the reproducibility of the self-learning method is limited.

Conclusions
In conclusion, our results show that ESD using the ERBEJET system can be performed effectively and safely during the learning phase of an unsupervised experienced Western endoscopist. According to our experience, CR-ESD by hydrodissection under general anesthesia was safe and effective in the early phases of this technique. Accumulated experience allows one to improve the procedure, with better technical and safety results. LGD: low-grade intraepithelial neoplasia; HGD: high-grade intraepithelial neoplasia.

Ethics approval and consent to participate
The study was conducted in accordance with the ethical guidelines of the Declaration of Helsinki. All patients provided informed written consent for the endoscopic procedures and participation in the study. Our institutional ethics review board approved this study (17.03.1057-GHM).

Availability of data and materials
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests
The authors declare that they have no competing interests.

Funding
No specific grants from any funding agencies in the public, commercial, or not-for-profit sectors were received for this research.  resection of the lesion in a single piece only with use of an electrosurgical knife ( figure 1, video 1). Knife-Snare en bloc resection (KSEB resection) resection of the lesion in a single piece with use of an electrosurgical knife and a polypectomy snare to finish the procedure (the final cut) ( figure 1, video 2). Endoscopic Piecemeal Mucosal Resection (EPMR): conversion to resection of the lesion in more than one piece.
Endoscopic complete resection resection of the entire lesion, both en bloc or by EPMR. Endoscopic incomplete resection aborted resection R0 resection resection of lesion with absence of adenoma/carcinoma tissue in vertical and lateral margins (>1 mm) Curative resection post-ESD R0 resection, without submucosal invasion or with mild submucosal invasion (<1000 um), but no other histological high-risk factors (lymphatic invasion, vascular involvement, poorly differentiated cancer, or tumor budding).
Curative resection postsurveillance histological absence of adenoma/carcinoma tissue at follow-up colonoscopy