A prospective randomized trial comparing the pocket-creation method and conventional method of colorectal endoscopic submucosal dissection

Journal Pre-proof A prospective randomized trial comparing the pocket-creation method and conventional method of colorectal endoscopic submucosal dissection Takeshi Yamashina, Daiki Nemoto, Yoshikazu Hayashi, Hisashi Fukuda, Masahiro Okada, Takahito Takezawa, Aizawa Masato, Hirotsugu Sakamoto, Yoshimasa Miura, Keijiro Sunada, Alan Kawarai Lefor, Kazutomo Togashi, Hironori Yamamoto PII:

S0016-5107(20)30210-8

DOI:

https://doi.org/10.1016/j.gie.2020.02.034

Reference:

YMGE 12006

To appear in:

Gastrointestinal Endoscopy

Received Date: 10 December 2019 Accepted Date: 20 February 2020

Please cite this article as: Yamashina T, Nemoto D, Hayashi Y, Fukuda H, Okada M, Takezawa T, Masato A, Sakamoto H, Miura Y, Sunada K, Lefor AK, Togashi K, Yamamoto H, A prospective randomized trial comparing the pocket-creation method and conventional method of colorectal endoscopic submucosal dissection, Gastrointestinal Endoscopy (2020), doi: https://doi.org/10.1016/ j.gie.2020.02.034. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Copyright © 2020 by the American Society for Gastrointestinal Endoscopy

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A prospective randomized trial comparing the pocket-creation method and conventional method of colorectal endoscopic submucosal dissection Takeshi Yamashina1,2, Daiki Nemoto3, Yoshikazu Hayashi1, Hisashi Fukuda1, Masahiro Okada1, Takahito Takezawa1, Aizawa Masato3, Hirotsugu Sakamoto1, Yoshimasa Miura1, Keijiro Sunada1, Alan Kawarai Lefor4, Kazutomo Togashi3 and Hironori Yamamoto1

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Department of Medicine, Division of Gastroenterology, Jichi Medical University,

Shimotsuke, Japan 2

Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan

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Department of Coloproctology, Fukushima Medical University Aizu Medical Center,

Aizuwakamatsu, Japan 4

Department of Surgery, Jichi Medical University, Shimotsuke, Japan

Corresponding author: Hironori Yamamoto, MD, PhD Address: 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan E-mail: [email protected]; Tel: +81-285-58- 7347; Fax: +81-285- 40-6598

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Abstract Background and Aims: Colorectal endoscopic submucosal dissection (ESD) is recognized as a challenging procedure. Previously, we reported that a new ESD strategy using the pocket-creation method (PCM) is useful for colorectal ESD, but there has been no prospective randomized study to evaluate the efficacy of the PCM. The aim of this study was to evaluate the efficacy and safety of PCM for colorectal ESD compared with the conventional method (CM). Methods: This was a prospective randomized controlled trial at 3 institutions in Japan. Patients with superficial colorectal neoplastic lesions >20 mm predicted to be intramucosal were randomly assigned to undergo ESD using the PCM or CM. Primary outcome was the ESD completion rate defined as completion of colorectal ESD with an en bloc resection using the assigned ESD method without changing to other methods or assisted by other devices. Results: We analyzed 59 patients with 59 colorectal tumors in the PCM group and 55 in the CM group. ESD completion rate was significantly higher in the PCM group compared with the CM group (93% [55/59] vs 73 % [40/55]; P = 0.01). En bloc resection rates, R0 resection rates, procedure time and dissection speed were not significantly different comparing the 2 groups. The incidence of adverse events was similar in the 2 groups. Conclusions: Use of the PCM allows the endoscopist to complete the procedure with the intended method more often than the CM with similar clinical outcomes. UMIN000024394

Introduction Endoscopic resection of colorectal polyps reduces the risk of developing colorectal cancer and the number of cancer deaths (1). Endoscopic polypectomy and endoscopic mucosal resection

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(EMR) are commonly used techniques for the resection of colorectal polyps. Colorectal polyps should be resected completely, however, the en bloc resection rate when performed with a snare tends to decrease as the polyp size increases resulting in an increased rate of local recurrence after piecemeal resection (2). As a consequence, recurrence occurs in >15 % of patients when the polyp exceeds 10 mm, which has become a significant problem in clinical practice (3–5). Endoscopic submucosal dissection (ESD) facilitates the excision of large superficial colorectal neoplastic lesions in an en bloc fashion and provides a specimen allowing accurate pathological diagnosis regardless of the lesion (6–9). However, technical difficulties with colorectal ESD continue to limit the widespread use of this technique. Several devices and methods have been developed to reduce the difficulties associated with colorectal ESD such as scissors forceps-type endo-knife (10, 11), traction using a clip line (12, 13) and balloon-assisted endoscopy (14). We reported previously that a new ESD strategy using the pocket-creation method (PCM) is useful for gastrointestinal ESD (15–21). In order to overcome various difficulties, the PCM evolved from a tunneling method (22–24) originally used to prevent endoscopic instability. The main point of the PCM is the creation of a large submucosal pocket under the tumor with a minimal mucosal incision maintaining a thick submucosal layer by preventing leakage of the solution injected into the submucosa and facilitating submucosal dissection. The 2 main advantages of PCM are stable submucosal dissection resulting in a negative vertical margin and minimizing the technical

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difficulties associated with colorectal ESD. We hypothesized that the PCM facilitates ESD and improves the completion rate of resection of colorectal lesions. To date, there has been no prospective randomized study to evaluate the efficacy of the PCM for colorectal ESD. The aim of this prospective study was to evaluate the efficacy and safety of the PCM for colorectal ESD.

Material and methods Trial design This is a randomized controlled parallel clinical trial conducted at 3 Japanese institutions. The trial complied with the Declaration of Helsinki and the trial protocol was approved by the Ethics Committees of all 3 participating institutions: Jichi Medical University Hospital (No. B16-008 on 11 October 2016), Osaka Red Cross Hospital and Fukushima Medical University Aizu Medical Center. This trial was registered in the University Hospital Medical Network Clinical Trials Registry (UMIN-CTR) as UMIN 000024394. The manuscript was prepared according to the Consolidated Standards of Reporting Trials (CONSORT) 2010 Statement (25).

Patients

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According to Japanese guidelines for colorectal cancer (26), patients with superficial colorectal neoplastic lesions >20 mm predicted to be intramucosal or carcinoma with slight submucosal invasion were enrolled. The lesion size was measured endoscopically before study enrollment. The tumor invasion depth was estimated based on the macroscopic appearance, findings on narrow-band imaging (NBI) or blue-light imaging (BLI) and pit pattern classification in magnifying chromoendoscopy. EUS was also performed when necessary to evaluate suspected submucosal invasion. Patients were excluded if they had lesions invading at the appendiceal orifice or ileocecal valve, local recurrence after endoscopic resection, ulcerative colitis, Crohn’s disease, hematological abnormalities or severe organ failure. Patients were excluded if they had lesions measuring >50 mm on preoperative colonoscopy because this is an independent risk factor for the occurrence of adverse events (27) and the total dissection time was significantly longer than for lesions 20 mm to 50 mm in diameter (17). Nonexpert endoscopists are not trained to resect these challenging lesions and we excluded these lesions to enhance patient safety while including nonexpert endoscopists in this study. In case of multiple lesions, only the most proximal lesion was registered in the trial to avoid operator selection bias for a lesion treated with CM or PCM. All patients provided written informed consent after receiving a thorough explanation for endoscopic procedures as well as study participation.

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Operator All procedures were performed by 7 endoscopists; 4 expert endoscopists and 3 nonexpert endoscopists. The 4 expert endoscopists had experience with at least 100 colorectal ESD cases using tip-type endo-knives, such as the FlushKnife (DK2618JN15; Fujifilm, Tokyo, Japan) or DualKnife (KD-650Q; Olympus, Tokyo, Japan). The 3 nonexpert endoscopists had experience with 80 or fewer colorectal ESD cases using tip-type endo-knives. The colorectal ESD procedures performed before this study are shown in Table 1. The minimum requirements for nonexpert endoscopists to begin colorectal ESD with PCM or CM include competence in total colonoscopy, polypectomy, EMR without supervision and experience of at least 20 gastric ESD procedures.

ESD procedure All procedures were carried out with a therapeutic-type video-colonoscope (EC-580RD/M: Fujifilm, Tokyo, Japan or PCF-Q260AZI: Olympus Medical Systems, Tokyo, Japan). The video-colonoscope insertion and ESD procedure were carried out with a CO2 insufflation regulation unit (UCR; Olympus or GW-1; Fujifilm) in all patients. When a target lesion was found, it was removed using either the PCM or the conventional method (CM). We used a FlushKnife-BTS 1.5 mm (DK2620J-B15S-, Fujifilm) for both methods of ESD. A water-jet fluid solution was usually used with a mechanical water pump (OFP-2; Olympus, or JW-2,

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Fujifilm). In all cases, the small-caliber tip transparent (ST) hood (DH-15GR; Fujifilm or ST Hood Short Type; DH-28GR, Fujifilm) was mounted on the tip of the videocolonoscope. The VIO 300D (ERBE Elektromedizin, Tübingen, Germany) was used as the power source for electrical mucosal incisions (Endo-Cut I; effect 1; duration 1-4; interval 1), submucosal dissection (swift coagulation; effect 4; 25-30 W) and coagulation (soft coagulation; effect 4; 80W). Sodium hyaluronate solution (0.4%) (MucoUp; Seikagaku Corp, Tokyo, Japan) was used for submucosal injections. In both groups, endoscopists were allowed to change to other methods or get assistance from other devices with the consent of the assistant endoscopist only when it was necessary for patient safety. Changes in technique were considered when the endoscopist was faced with technically difficult situations including (1) the submucosal space being too narrow caused by severe fibrosis, which makes access to the submucosal layer difficult; (2) an unstable approach to the lesion, with difficulty in controlling the endoscope as a result of an adverse effect, such as respiratory or paradoxical movement; (3) total procedure time exceeding 3 hours; (4) perforation detected during the procedure or the muscularis propria was injured twice; or (5) hemorrhage could not be controlled, and the endoscopist or assistant judged it dangerous to continue. We included “severe fibrosis” and “unstable approach” in criteria (1) and (2) to change methods according to technical difficulty associated with colorectal ESD described in previous studies (28–31). The criteria (3), (4) and (5) were

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defined to ensure safety for participants. After resection, specimens were fixed on a board and the size was measured again.

Conventional method (CM) CM ESD was carried out as previously reported (15, 21) (Figure 1). First, sodium hyaluronate solution was injected into the submucosal layer under and around the lesion. An initial mucosal incision was made for at least one-quarter of the circumference approximately 5 mm from the distal side of the tumor. Then, submucosal dissection was performed from the distal to the proximal edge of the tumor to both ends of the incision line. After dissecting all initially incised areas of mucosa, consciously avoiding being pocket-like, additional mucosal incisions and submucosal dissection were repeated toward the proximal side.

Pocket-creation method (PCM) The PCM was performed as previously described (15–21) (Figure 2). Initially, a submucosal injection was performed in the same method described for the CM. An initial mucosal incision was made approximately 20 mm in length approximately 10 mm from the distal side of the tumor. Submucosal dissection proceeded to create a pocket in the submucosal layer by inserting the tip of the endoscope under the mucosal tumor. The major difference with the CM is the completion of the submucosal dissection under the tumor with a minimal mucosal

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incision when performing the PCM. After creation of a submucosal pocket under the tumor, the pocket is opened in a step-by-step manner, with repetition of the mucosal incision and subsequent submucosal dissection, up to the proximal margin of the tumor. Finally, the upper remaining area is opened in the same manner to complete the en bloc resection.

Randomization and blinding Randomization was stratified according to location (colon or rectum), operator and tumor morphology (laterally spreading tumor granular type [LST-G] (including protruded lesion) or laterally spreading tumor nongranular type [LST-NG]). After that, research coordinators not involved in clinical practice randomly assigned eligible patients in a 1:1 ratio to the PCM (PCM group) or CM (CM group), with the minimization method (32). The research coordinator informed operators and assistants by e-mail to which study arm the patient was assigned a few days before the procedure or on the day of the procedure. The allocation table was known only to the research coordinator. Patients and pathology staff were blinded to the treatment allocated pending the outcome of the histopathologic examination.

Outcomes The primary outcome of this study was the ESD completion rate. En bloc resection rate, R0 resection rate, procedure time, dissection speed and adverse events were evaluated as

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secondary outcomes. ESD completion was defined as completion of colorectal ESD in 3 hours with an en bloc resection using the assigned ESD method without changing to other methods or other devices and without perforation during the procedure. En bloc resection was defined as endoscopically assessed 1-piece removal of the lesion by at least 2 or more endoscopists, and an R0 resection was defined as an en bloc resection with histologically confirmed negative resection margins in each institution by at least 2 or more pathologists. The procedure time was measured from the time of initial mucosal incision until removal of the tumor. Postoperative bleeding was defined as overt bleeding within 14 days after ESD requiring endoscopic hemostasis (33). Perforation during the procedure was defined as a visible lumen in the endoscopic image or evidence of air or luminal contents outside the gastrointestinal tract on abdominal x-ray or abdominal CT scan after ESD. Adverse events were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE version 4.0) (34). Subgroup analyses were performed for location (colon and rectum), morphology (LST-G and protruded, and LST-NG), size (<30 mm and ≥30 mm) of lesions, operators’ experience (expert and nonexpert) and at which institution it was removed (A, B or C).

Sample size

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Previous studies reported that the en bloc resection rate for ESD of colorectal polyps >20 mm was 70% to 95% (28, 35–37). We estimated that the completion rate of colorectal ESD would be 80%. Next, we estimated that the completion rate using the PCM alone would be 98% by referring to a previous study from our institution that was reported at 98% to 100% (14, 15). We estimated that ≥116 lesions would be required to detect a significant difference between the groups with a significance level of 0.05 (2-sided) and a power of 80%. We determined that 120 lesions would be required, considering some protocol deviations and dropouts.

Statistical analysis The primary outcome was analyzed according to the intention-to-treat (ITT) principle. The chi-square test or Fisher exact test was used for analysis of categorical data. Quantitative data were compared using the Mann–Whitney U test. P<0.05 (2-sided) was considered significant. All statistical analyses were carried out using SPSS version 24 (SPSS, Chicago, Ill, USA).

Results Baseline data One hundred fourteen patients were included in the final analysis and baseline characteristics are presented in Table 2, including 67 men and 47 women with a median age (range) of 70

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(42–91) years. There were no significant differences between the groups with regard to operators, estimated tumor size, tumor location, or morphological type.

Participant flow and recruitment From November 2016 to May 2018, 121 patients with 121 colorectal tumors were enrolled in the trial and randomly assigned to the PCM group (n = 61) or the CM group (n = 60). After randomization, ESD was not performed in 7 patients, including 2 in the PCM group and 5 in the CM group. In the PCM group, one patient withdrew from the study before ESD and one lesion was diagnosed as non-neoplastic just before ESD. In the CM group, one lesion was diagnosed as a deeply invasive submucosal cancer and one was invading at the appendiceal orifice just before ESD. These 2 patients were referred to a surgeon for colectomy. The other 3 lesions were treated by EMR because they could be removed en bloc. A flow diagram of the participants is shown in Figure 3.

Treatment results and outcomes ESD was performed in 114 patients included in the ITT analysis for the primary outcome. Seven cases in the CM group were changed to the PCM and 2 cases in the PCM group were changed to CM during the procedure. There was one case assisted by clip line in the PCM

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group and 5 cases in the CM group. In the remaining cases in the PCM group without assist, there was 1 prolonged procedure resulting in a piecemeal resection and in the remaining cases in the CM group without assist, there were 2 piecemeal resections and one perforation during the procedure (Figure 4). Therefore, the primary outcome of this trial, the ESD completion rate in the PCM group (93.2% (55/59)) was significantly higher compared with the CM group (72.7% (40/55)) (P=0.005). Table 3 summarizes the clinicopathological features of the treated lesions. Removed specimen size, tumor size and histological diagnosis did not differ significantly between the 2 groups. Median procedure time and median dissection speed did not differ significantly between the PCM and CM groups (51 vs 49 min and 15.9 vs. 17.4 mm2/min). En bloc resection rate and R0 resection rate also did not differ significantly between the 2 groups (94.9 vs 94.5 % and 86 vs 87.3%). In addition to ITT analysis, we carried out per-protocol analysis which was conducted on patients only including ESD performed by the assigned method for lesions ≦ 50 mm and ≧20 mm by measurement after resection (Figure 3). This analysis also resulted in significantly higher ESD completion rate in the PCM group than the CM group (98% vs 87% p=0.037) (Table 4). In per-protocol analysis, the R0 resection rate was 94% in the PCM group, and 87% in the CM group (p=0.30) (Table 4). The reasons why ESD completion was not achieved with the intended method did not differ significantly between the 2 groups. Although in a majority of cases the reason was

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(52.6%, 10/19) inability to continue the mucosal incision and/or the submucosal dissection, only one was in the PCM group. The second most common reason was severe fibrosis (36.8%, 7/19), with 2 in the PCM group and 5 in the CM group (Table 4). The 7 cases changed to the PCM in the CM group were resected en bloc whereas the 2 cases changed to CM in the PCM group were finally resected in a piecemeal fashion using a snare because the lesions were deeply invasive (Figure 4).

Subgroup analysis Subgroup analysis showed that the PCM had a higher rate of ESD completion for lesions located in the colon (P = 0.003), lesions 30 mm or larger (P = 0.03), with LST-G or protruded morphology (P = 0.009), treatment in institution A (P = 0.001) and by nonexpert endoscopists (P = 0.003) compared with ESD using the CM. Institution C (P = 0.095) and lesions smaller than 30 mm (P = 0.08) trended toward a higher ESD completion rate with PCM than CM (Figure 5).

Adverse events Delayed bleeding after ESD occurred in one patient in each group and was managed by endoscopic hemostasis. Perforation during the procedure occurred in one patient in the CM group and none in the PCM group. The perforation was less than 1 mm and managed

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nonoperatively by endoscopic clipping. There was no delayed perforation or intraprocedural uncontrolled bleeding in either group. There were no fatal adverse events during the study period (Table 5).

Discussion In this prospective randomized controlled trial, we found that using the PCM significantly increased the rate of ESD completion by about 20% compared with the CM for colorectal lesions with no increase in procedure time or rate of adverse events. These results suggest that endoscopists benefit from using the PCM by being able to complete the resection of colorectal lesions without resorting to other endoscopic instruments, such as another endo-knife or traction using a clip line and suture to overcome difficult situations. Therefore, the PCM is likely to become a widely accepted method in routine clinical practice. Until recently, new snare polypectomy strategies without submucosal injection, cold snare polypectomy for small (≤9 mm) lesions (5, 38–40) and underwater EMR for intermediate (10–20 mm) (41, 42) lesions were reported to be safe and effective procedures for removing flat colorectal polyps. However, the en bloc resection rate with snaring tends to decrease to <50% as the polyp size increases especially for lesions over 20 mm in diameter (43, 44) which can lead to piecemeal resection which was an independent risk factor for local recurrence (2). Therefore, ESD is recommended for resection of colorectal polyps >20 mm in

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diameter (5, 26). However, colorectal ESD is thought to be technically more difficult than gastric ESD and is not in general use yet. We demonstrated that the ESD completion rate is significantly higher using the PCM than using the CM and in subset analysis, the PCM is better for nonexpert endoscopists. This suggests that the PCM operators do not necessarily need to gain specific technical skills and more experience. Nonexpert endoscopists will find colorectal ESD easy to perform with the PCM which will lead the PCM to play an important role in the future of ESD. The main point of the PCM is the creation of a large submucosal pocket under the tumor with a minimal mucosal incision which prevents leakage of the injected solution and facilitates maintenance of a thick submucosal layer. The endoscopic view with a thick submucosal layer facilitates recognition of the appropriate dissection line leading to a high-quality pathological specimen. The high-quality pathological specimen plays an important role in assessment of the risk of lymph node metastases. The PCM minimizes technical difficulties associated with colorectal ESD (1) provides good traction with the tip of the hood stretching the submucosal tissue, (2) vertical or over-a-fold location of the tumor can be easily adjusted to a tangential orientation by insertion into the pocket, (3) the tip of the endoscope in the submucosal pocket synchronizes with fluctuations due to paradoxical movement, colonic peristalsis, heartbeat or respiratory motion maintaining a stable endoscope, (4) the PCM strategy is clear and follows the same steps,

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allowing even nonexpert endoscopists to complete ESD without confusion. It is reasonable for nonexpert endoscopists to start ESD using the PCM approach. Although it is not mainstream yet, some institutions in Japan are starting with PCM. In this study, the 2 main reasons why ESD completion was not achieved with the intended method were “inability to continue the mucosal incision and submucosal dissection” in 9 cases and “severe fibrosis” in 5 cases. Inability to continue ESD means there was an unstable approach to the lesion due to paradoxical movement, respiratory movement or colonic peristalsis, and inability to access the submucosal layer for tangential dissection in a safe manner, for example if the lesion is on the back of folds, inner corners of flexures or at the cecum. In these situations, it is difficult to maintain the tangential approach of tip-type endo-knives to the muscularis. The PCM can change to a tangential orientation by insertion into the pocket. Even with an unstable approach to the lesion, the operator could simply cut the target tissue with minimal movement in one direction parallel to the muscularis, without having to dissect through to the edge in the pocket. Regarding severe fibrosis, some previous studies demonstrated that severe fibrosis contributed to difficult colorectal ESD because of poor lifting, hard and thin submucosa (15, 28, 31, 45, 46). When performing the CM, the injected fluid leaks out after making a wide mucosal incision and lifting of the submucosal layer is more difficult. However, when performing the PCM, the minimal mucosal incision prevents fluid leakage and the injected fluid maintains elevation of the submucosal layer for a long time which leads to safe and

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accurate dissection. It has been reported that the PCM significantly improved the therapeutic results in the presence of severe fibrosis compared with the CM (15, 46). In this study, there were 2 and 3 cases in which ESD failed to be completed resulting in piecemeal snaring in the PCM and CM groups, respectively. The 2 in the PCM group were deeply invasive lesions requiring surgical resection. The PCM might enable accurate and stable dissection without those difficulties in the 3 cases in the CM group. The 7 cases converted to PCM from the CM group were successfully resected en bloc by completion of ESD. In per-protocol analysis, ESDs performed using methods other than the assigned method, and lesions >50 mm or <20 mm by measurement after resection were excluded. This analysis also resulted in a significantly higher ESD completion rate in the PCM group than the CM group and strengthens the results of the ITT analysis of the data assessed as the primary outcome. The R0 resection rate was 94% in the PCM group, and 87% in the CM group. Although the difference did not reach statistical significance, PCM may have better potential to achieve an R0 resection. When we calculate the sample size for this study, we referred to the en bloc resection rate including data from Europe in the initial phase after the introduction of ESD. Considering the higher en bloc resection rate in East Asia, a larger study population could have been required to show superiority of PCM. In the present study, the median operating time and median dissection speed did not differ significantly between the 2 groups. Our previous reports showed that dissection speed

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was significantly faster with the PCM than with the CM for colorectal ESD (15, 21). In this study, lesions extended to the appendiceal orifice or ileocecal valve, lesions measuring >50 mm and patients with local recurrence, etc, were excluded because they would have been too difficult for nonexpert endoscopists. Although a simple comparison is difficult, previous studies included these difficult situations. We previously demonstrated that the PCM allows safe and reliable ESD even in the presence of severe fibrosis, such as large sessile colorectal tumors or LST-NG (15, 20), and these difficult cases are good candidates to demonstrate the effectiveness of the PCM. As in the situations described above, the PCM might have achieved the same results if these difficult cases had been included in this study. Future trials are warranted to confirm the validity of these results with difficult lesions. There are several acknowledged limitations to this study. First, although the group allocation was completely unknown to the patients and pathologists and we had definite criteria to change the method of ESD used, the operating endoscopists were not blinded. We invited general endoscopists from 3 institutions and we also invited nonexpert endoscopists. Endoscopists always attempt to complete ESD in practice regardless of the method used, and this reduced any bias caused by the nonblinded procedure. The en bloc resection rate and R0 resection rate using the CM in this study was consistent with that in a previous report (7, 8, 10–15, 21). Second, the decision to change the method was subjective and it could have led to bias when comparing ESD completion rate between the 2 groups. The method of ESD was

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changed only after consultation with the assistant endoscopist and we think that this is an adequate measure to support the fairness of this study. The procedure times in both groups did not differ, therefore, it does not seem that endoscopists intentionally improved the ESD completion rate in either group. Third, there are various difficult situations in colorectal ESD, especially with the CM. It increases procedure options and make decision-making more difficult and delays the learning of CM. When the CM is used, endoscopists may tend to use other instruments or methods to overcome a difficult situation. This explains why it is difficult to directly compare a nonexpert endoscopist performing the CM with a nonexpert endoscopist performing the PCM. Further studies focusing on performing the CM in difficult situations are needed to evaluate the contribution of this issue to the observed results. However, the PCM simplifies the ESD strategy and makes it relatively easy to learn. In conclusion, use of the PCM allows the endoscopist to complete the procedure with the intended method more often than the CM with similar clinical outcomes.

Acknowledgments The authors thank all endoscopists and our colleagues at Osaka Red Cross Hospital, Fukushima Medical University Aizu Medical Center and Jichi Medical University who supported the study.

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Financial support: None.

Potential competing interests: Dr. Yamamoto has patents for the double-balloon endoscope and the ST hood produced by Fujifilm Corp. He also serves as a consultant for and has received honoraria, grants, and royalties from Fujifilm Corp. All other authors disclosed no financial relationships relevant to this publication.

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Figure legends Figure 1. A. First, sodium hyaluronate solution was injected into the submucosal layer under and around the lesion. B. An initial mucosal incision is made for at least one-quarter of the circumference and approximately 5 mm from the distal side. C. Then, a submucosal dissection was performed from the distal to the proximal edge of the tumor to both ends of the incision line. D. Submucosal dissection is performed by sliding the knife from the center toward the side. E. Making an additional mucosal incision in a step-by-step manner toward the proximal side. F. Dissection of the incised area in the same manner and incision and dissection of the remaining area. G. Completion of the en bloc resection. Figure 2 A. First, sodium hyaluronate solution was injected into the submucosal layer under and around the lesion. B. An initial mucosal incision approximately 20 mm in width 10 mm beyond the distal edge of the tumor after submucosal injection. C. Creation of a submucosal pocket under the tumor. D. E. Opening the downward-facing (in the direction of gravity) side of the pocket in a step-by-step manner up to the proximal side. F. Dissection of the upward-facing side in the same manner. G. Completion of the en bloc resection.

30

Figure 3. Patient flow diagram PCM, pocket creation method; CM, conventional method; ITT, intention to treat; PP, per protocol

Figure 4. Flow diagram for patient outcomes in the intention to treat analysis ITT, intention to treat; PCM, pocket creation method; CM, conventional method

Figure 5. Subset analysis of ESD completion rate PCM, pocket creation method; CM, conventional method

31

Table 1. ESD procedural experience of each endoscopist in this study period. Endoscopist

Total Colorectal ESD cases performed before this study (PCM/CM)

A*

239 (50/189)

B*

193 (71/122)

C*

139 (67/72)

D*

123 (48/75)

E

51 (16/35)

F

21 (21/0)

G

12 (12/0)

ESD, Endoscopic submucosal dissection; PCM, Pocket-creation method; CM, Conventional method. *Expert endoscopist.

32

Table 2. Baseline data of the 2 study groups

PCM Group

CM Group

(n=59)

(n=55)

Male (%)

34 (58%)

33 (60%)

Female (%)

25 (42%)

22 (40%)

70

68

(41-92)

(42-86)

Cecum

8 (14%)

9 (16%)

Ascending

19 (33%)

16 (29%)

Transverse

9 (15%)

9 (16%)

Descending

2 (3%)

1 (2%)

Sigmoid

10 (17%)

8 (15%)

Rectum

11 (19%)

12 (22%)

31 (53%)

28 (51%)

Protruded

3 (5%)

6 (11%)

LST-NG

25 (42%)

21(38%)

Male/female

Median age

(range, years)

Location

Morphology

LST-G

33

Median estimated tumor size

30

30

(18-75)

(20-80)

Expert

27 (46%)

28 (51%)

Nonexpert

32 (54%)

27 (49%)

A

27 (46%)

24 (44%)

B

19 (32%)

14 (25%)

C

13 (22%)

17 (31%)

(range, mm)

Operator

Institution

LST-G, laterally spreading tumor granular type; LST-NG, laterally spreading tumor nongranular type; PCM, pocket creation method; CM, conventional method

34

Table 3. Clinicopathological features of resected colorectal neoplasms

PCM Group

CM Group

(n=59)

(n=55)

Histological type

Adenoma

P value

0.19

21 (36%)

18 (33%)

1 (2%)

3 (5%)

Noninvasive carcinoma

27 (46%)

28 (51%)

SM 1 (＜1,000 µm)

8 (14%)

3 (5%)

SM 2 (≧1,000 µm)

2 (3%)

3 (5%)

Lympho-vascular involvement

0

0

1.0

Median resected tumor size

30

30

0.52

(18-75)

(20-80)

35

35

(20-77)

(21-97)

Serrated lesions

(range, mm)

Median resected specimen size

(range, mm)

PCM, pocket creation method; CM, conventional method

0.39

35

Table 4. ESD-related factors

PCM Group

CM Group

(n=59)

(n=55)

55/59

40/55

(93%)

(73%)

48/49

39/45

(98%)

(87%)

51

49

(15-240)

(13-170)

50

40

(15-136)

(13-170)

15.9

17.4

(3.0-66.8)

(3.1-52.1)

23.8

16.5

(6.2-66.8)

(3.1-52.1)

35

35

(20-77)

(21-97)

P value

ESD completion rate

Intention to treat analysis

Per protocol analysis

Median operation time of all cases

(range, minutes)

Median operation time of ESD completion cases

(range, minutes)

Median dissection speed (range, mm2/min)

Median dissection speed of ESD completion cases (range, mm2/min)

Median resected specimen size

(range, mm)

0.0049

0.037

0.33

0.044

0.81

0.20

0.39

36

En bloc resection

56/59

52/55

(95%)

(95%)

49/49

42/45

(100%)

(93%)

51/59

48/55

(86%)

(87%)

46/49

39/45

(94%)

(87%)

Prolonged procedure

1

0

Inability to control hemorrhage

0

0

Inability to continue the mucosal incision and

1

9

Perforation during the procedure

0

1

Severe Fibrosis

2

5

Intention to treat analysis

Per protocol analysis

1.0

0.11

R0 resection

Intention to treat analysis

Per protocol analysis

1.0

0.30

Reasons why ESD completion was not achieved (%)

submucosal dissection

ESD, endoscopic submucosal dissection; PCM, pocket creation method; CM, conventional method

37

Table 5. Adverse events

Adverse events (NCI-CTCAE grade)

Perforation

PCM Group

CM Group

(n=59)

(n=55)

0

1

(Grade 2)

Delayed bleeding

1

1

(Grade 2)

(Grade 2)

PCM, pocket creation method; CM, conventional method

ESD, endoscopic submucosal dissection; PCM, pocket-creation method; CM, conventional method; EMR, endoscopic mucosal resection; UMIN-CTR, University Hospital Medical Network Clinical Trials Registry; CONSORT, Consolidated Standards of Reporting Trials; ST, small-caliber tip transparent; LST-G, laterally spreading tumor granular type; LST-NG, laterally spreading tumor non-granular type; NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; ITT, intention-to-treat; PP, per protocol.