Comparison of Efficacy and Safety of Speedboat Device and Needle Knife for Colorectal Endoscopic Submucosal Dissection: a Multicenter Randomized Study

Background/Rationale Colonoscopy screening and polypectomy have led to earlier identification and removal of precancerous lesions, which significantly decrease colorectal cancer incidence and mortality.(1, 2) While most polyps can be resected with snare polypectomy, up to 15% of them are not suitable for conventional colonoscopic removal due to a variety of reasons such as large size, difficult location, or previous resection attempts.(3) The guidelines' recommendation is to remove colorectal lesions \< 10 mm with cold snare polypectomy and consider endoscopic mucosal resection (EMR) for lesions sized 10 to 19 mm. For the treatment of nonpedunculated large-sized lesions (> 20mm), both EMR and endoscopic submucosal dissection (ESD) can be used. However, achieving en bloc resection with EMR can be difficult, and piecemeal resections are associated with reduced histopathological assessment quality and higher local recurrence rates. Thus, for lesions larger than 20 mm, ESD is recommended.(4, 5) From an oncological standpoint, colorectal polyp with high suspicion for deep submucosal invasion (invasion depth more than 1,000 μm), and the morphology presented of severely disrupted vascular structures, surgery should be the treatment of choice. While the lesion presented a high suspicion of limited submucosal invasion (invasion depth less than 1,000 μm), ESD should be preferred as the risk of lymph node metastasis was low. (3) Given the thin wall colon and narrow/angulated colonic lumen, colorectal ESD is considered a challenging procedure and carries a high risk of complications. A bunch of devices, accessories, and techniques were created to overcome this difficulty as well as to shorten the procedural time and reduce the risk of perforation. (Table1) The conventional steps of colorectal ESD include submucosal injection, mucosal incision, submucosal dissection, and hemostasis. These steps are switched back and forth with the use of an injection needle, cutting and dissecting knife, and coagulation forceps. To shorten the step of device exchange, the cutting knife with an injectable channel was developed, ie. Dual knife (Olympus, Tokyo, Japan), Flush knife (Fujifilm, Tokyo, Japan), Hybrid knife (ERBE, Tubingen, Germany). (Table 1) These knives are monopolar electrosurgical devices that require higher voltages with associated risk of complications.

Recently, a newly designed electrosurgical knife incorporating an injection needle and cutting knife with hemostasis, namely Speedboat (Creo Medical Ltd, UK), has been created. The Speedboat blade delivers bipolar radio frequency (RF-400KHz) cutting and microwave coagulation (5.8GHz) for hemostasis and contains a retractable needle for submucosal injection/tissue irrigation. It also has an insulated hull to prevent thermal injury to the underlying muscle layer. Figure 1 Preliminary data suggest the safety and utility of this device in performing a variety of endoscopic dissection and resection procedures, including endoscopic submucosal dissection, peroral endoscopic myotomy, and resection of subepithelial tumors.

For colorectal ESD, the initial report has been announced by the group from St Mark's Hospital.(6) The treatment outcome in terms of en bloc resection, muscularis propria injury, and recurrence rate was comparable to those reported from the use of conventional knives. However, it has been shown that monopolar coagulation forceps for hemostasis were required in only 12.5% of cases. This might help to reduce the overall cost of accessory use. The exchange of accessories was also minimized with the use of the Speedboat device in many procedures(7), which might reduce the total procedural time. There is also growing published data regarding the feasibility and safety of using Speedboat devices in colorectal ESD. Figure 2 Although this all-in-one device proposed several advantages, there are some limitations that might mitigate the generalizability. It requires a dedicated electrosurgical generator along with a Speedboat device, which incurs additional costs. Moreover, close coordination between the endoscopist and the assistant maneuvering the device for optimum orientation of the dissection plane is required. Thus, it is worth comparing the effectiveness and safety of colorectal ESD using a Speedboat device with the conventional techniques using separate devices in a prospective, randomized, controlled trial.

Objectives Primary objective - To investigate the resection speed of colorectal endoscopic submucosal dissection using the Speedboat device compared with the standard needle knife.

Secondary objectives

• To investigate the en bloc resection rate and curative resection(R0) rate between using a Speedboat and needle knife in colorectal ESD.
• To investigate the safety of using a Speedboat and needle knife in colorectal ESD.

Sample size calculation This study aims to investigate the resection speed of colorectal endoscopic submucosal dissection using Speedboat device compared with the standard needle knife. According to Imai's study, the median resection speed of colorectal endoscopic submucosal dissection when using needle knife is 19.9 mm2/min (Range: 3.2 to 64.3, n= 44).(8) We predict that using Speedboat device in colorectal ESD might increase resection speed up to 50% of median resection speed of needle knife. Then, the median resection speed of using Speedboat device in colorectal ESD is 29.85 mm3/min. In asymmetry distribution data, we calculate of subject number by using Mann-Whitney U test. We define the standard normal is 1.96, 5% of significant level and 80% power (1- ). Then, the calculation of subject number using nQuery as following.

The median and range of resection speed for colorectal ESD using a needle knife is 19.9 mm2/min (range: 3.2 to 64.3, n= 44). Then, a standard deviation of resection speed for colorectal ESD using needle knife is 13.578 From the above calculation, the number of subjects was 34 patients. We increase the subject number for preventing missing data for 15% of calculated subject number, which is equal to 6. Then, the number of subjects was 40 patients per group. Thus, study's total number of subjects was 80 patients.

Inclusion criteria 1) Age 18 or above with large non-pedunculated colorectal polyp size > 20 mm. in which 1st endoscopist decided that lesion cannot be resected with endoscopic mucosal resection to achieve en bloc resection Exclusion criteria

1. Patients who have coagulopathy which is contraindicated for colonoscopy and polypectomy (Prothrombin time > 3-second ULN, INR > 1.5, Platelet \< 50,000)
2. The non-pedunculated lesion that was recurrence from the previous polypectomy or ESD
3. Suspected deep submucosal invasion using image-enhanced endoscopy by expert endoscopist
4. Patients who were diagnosed with inflammatory bowel disease
5. Pregnancy or breastfeeding
6. A patient who is unable to provide consent Withdrawal or termination criteria

1. Patients who cannot undergo colonoscopy or endoscopic resection due to non-tumor-related conditions eg. Cardiopulmonary compromise, poor bowel preparation, fail to withhold the antithrombotics 2. Severe intraprocedural bleeding that cannot stop with coagulation forceps 3. Large perforation defect that cannot be closed or secured with endoscopic clipping and preclude further dissection.

Subject allocation All participants were randomized using a computerized block of four randomizations into two groups.

1. Patients who undergo colorectal ESD using a conventional needle knife 2. Patients who undergo colorectal ESD using a Speedboat device

After enrollment, the patients undergo the standard colonoscopy following the steps below.

1. All participants would be admitted to the hospital for 1 night before the procedure and bowel-prepared before colonoscopy using 3-4 liters of polyethylene glycol. Then, they will avoid anything oral for at least 4 hours before the colonoscopy.
2. A colonoscopy will be performed under general or intravenous sedation anesthesia provided by the anesthesiologist or the attending physician.
3. All participating endoscopists have experience in colorectal ESD for at least 50 cases.
4. The pediatric colonoscope or therapeutic gastroscope will be inserted via the anus and traverse to the lesion.
5. After reaching the lesion, the endoscopist will carefully characterize it using the NICE classification (Table 2). If the endoscopist suspects a deep submucosal invasion, those lesions must be excluded from the study.
6. In both groups, the ESD procedure was performed using conventional, pocket-creation, or tunnel methods, depending on the endoscopist's decision.
7. In the Speedboat group, any of the 2.8, 3.2, or 3.7 mm Speedboat devices is used in all procedure steps, including submucosal injection, mucosal incision, submucosal dissection, and vessel coagulation. A 25G injection needle can be used to initiate the submucosal injection in the case of using a 2.8 mm Speedboat device. If any devices other than Speedboat were used in the procedure, those should be recorded. (ขั้นตอนการวิจัย)
8. In the control group (needle knife group), a 25G injection needle is used in the initial submucosal injection step. A 1.5 mm needle knife is used for mucosal incision, submucosal dissection, and additional submucosal injection. Coagrasper is used for coagulating submucosal vessels. All used devices were recorded.
9. During the procedure, we recorded the procedure time using a timer, which will be started from the point of the 1st mucosal incision using any knife to the point of the last cutting dissection to get complete resection. The administrative nurse who does not involve in the procedure will record the procedure time.
10. Hemoclips or over-the-scope clips can be applied in case of muscularis propria injury.
11. Photo documentation and video are recorded during the procedure.
12. The specimen size and tumor size will be measured and recorded. The specimen will be prepared on the board and sent for pathological evaluation.
13. We will record the polyp's characteristics, the total procedure time, the intraprocedural complications, including muscularis propria injury and perforation, and the postprocedural complications, including bleeding, post-coagulation syndrome, and perforation. A single blood draw for CBC and CRP will be taken the day after the procedure.
14. According to the endoscopist's decision, the patient will be observed for complications as an in-patient or out-patient after the procedure. If there is a suspicion of peritoneal contamination, antibiotics will be prescribed.
15. Total procedure time is defined as the duration from 1st mucosal incision to the last incision to get complete resection. En bloc resection is defined as the resection of the total lesion in one piece. Curative resection(R0) is defined as all margins of the resected lesion that are not involved by adenoma, the tumor does not invade beyond superficial submucosa, no lympho-vascular invasion, no high-grade tumor budding, and no evidence of poorly differentiated carcinoma.

16. Resection speed was calculated using the following formulation. Resection speed = ((specimen diameter in the long axis, mm) x (specimen diameter in the short axis, mm) x 3.14 x 0.25) /procedure time (min).

    In case of patients with multiple lesions, the biggest lesion will be included in the study

17. All patients will be followed two weeks to observe any late complications. The pathological diagnosis and plan of further treatment will be informed. Typically, the surveillance colonoscopy will be performed in the next 6-12 months depends on the pathological diagnosis.

Primary Outcome: The resection speed of colorectal endoscopic submucosal dissection using a Speedboat device compared with the standard needle knife.

Secondary Outcomes:

• The en bloc resection rate and curative resection(R0) rate between using Speedboat and needle knife in colorectal ESD
• The intraprocedural and postprocedural complications of using Speedboat and needle knife in colorectal ESD. Complications include delayed bleeding, intraprocedural and delayed perforation, and post-ESD coagulation syndrome.

We will do the interim analysis after 50% of the subjects' enrollment.

Statistical Analysis

1. Descriptive statistic Descriptive statistics will be used to summarize the basic demographic and clinical characteristics of the study population. Quantitative variables will be expressed as the mean+/- standard deviation. Categorical variables will be analyzed using the chi-square test or Fisher's exact test. Continuous variables will be analyzed using the Student's t-test or Mann-Whitney U test.
2. Inferential statistic The Chi-square or Fisher's exact test will determine the statistical difference between the Speedboat and the needle knife outcome.