Randomized control trials may not provide a conclusive answer for complex endoscopic interventions.

Abstract

Digestive EndoscopyEarly View EditorialFree Access Randomized control trials may not provide a conclusive answer for complex endoscopic interventions Mamoru Ito, Mamoru Ito Department of Endoscopy, The Jikei University School of Medicine, Tokyo, JapanSearch for more papers by this authorKazuki Sumiyama, Corresponding Author Kazuki Sumiyama kaz_sum@jikei.ac.jp Department of Endoscopy, The Jikei University School of Medicine, Tokyo, JapanSearch for more papers by this author Mamoru Ito, Mamoru Ito Department of Endoscopy, The Jikei University School of Medicine, Tokyo, JapanSearch for more papers by this authorKazuki Sumiyama, Corresponding Author Kazuki Sumiyama kaz_sum@jikei.ac.jp Department of Endoscopy, The Jikei University School of Medicine, Tokyo, JapanSearch for more papers by this author First published: 09 November 2022 https://doi.org/10.1111/den.14457AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat A series of traction devices have been developed to provide an additional hand for endoscopists to manipulate the mucosal overlay away from the surgical plane and accelerate electrosurgical dissection by creating optimal tissue tensions to facilitate endoscopic submucosal dissection (ESD). In the 2000s and the early 2010s, both device-independent and device-dependent traction techniques were meticulously explored, mainly in Japanese institutions.1 Regardless of operator preference, optimal use of a hood attachment and device-independent techniques – such as gravitational traction, the creation of a mucosal flap, and submucosal pocket and tunnel – would be strongly recommended as standard techniques to facilitate ESD. The S–O clip (Zeoclip; Zeon Medical, Tokyo, Japan), clip-with-thread, and dental floss methods are the most widely tested device-dependent techniques in clinical settings, including randomized controlled trials (RCTs). Meanwhile, the advantages of device-dependent techniques can be limited to selective occasions or cases. Traction devices may counterintuitively hinder the surgical view, interfere with the maneuvering of surgical tools and an endoscope, and may eventually give rise to an inadvertent incision into the muscular layer. Thus, RCTs for device-dependent techniques have been conducted to compare the procedure time and safety of ESD with and without traction device assistance throughout the operation. We congratulate Ichijima et al. for their great effort completing the CONNECT-C study, the first multicenter, nonblinded RCT to test the efficacy of traction devices in patients with a superficial colorectal lesion.2 Two multicenter CONNECT studies for other locations were previously reported prior to the CONNECT-C trial. The CONNECT-G study3 for early gastric neoplasms did not find a significant difference between the traction and conventional groups (60.7 vs. 58.1 min, P = 0.45), but a subset analysis showed that lesions in the greater curvature of the upper and middle portions of the stomach resulted in shorter mean procedure time (104.1 vs. 57.2 min, P = 0.01). Conversely, the CONNECT-E study4 for esophageal cancer also showed a significantly shorter ESD procedure time for traction-assisted ESD than for conventional ESD (45.5 vs. 60.5 min, P < 0.001). The results of a series of CONNECT studies imply that the advantage of evaluated traction techniques can vary widely according to the anatomical location of the lesions. Two other RCTs on colorectal lesions have been reported, and both found favorable outcomes for traction-assisted ESD. In 2014, Ritsuno et al. reported an RCT of a total of 70 participants with a superficial colorectal tumor of ≥20 mm in diameter.5 The S–O clip-assisted ESD group had a significantly shorter mean procedure time compared to the conventional ESD group (37.4 ± 32.6 vs. 67.1 ± 44.1 min, P = 0.03). In 2018, Yamasaki et al. reported a similar RCT analyzing a total of 84 patients to evaluate whether the originally developed clip-with-thread method would facilitate colorectal ESD.6 A significantly shorter mean procedure time was observed in the traction group (40 vs. 70 min, P < 0.00001). However, these trials were single-center and lacked an external validity assessment. The CONNECT-C study was conducted at 10 facilities in Japan, assigning 123 patients to the traction ESD group and 128 to the conventional ESD group. In this study, the S–O clip-assisted, traction-assisted, or modified dental floss clip method was chosen according to the operator's discretion. The primary outcome did not show a significant difference in the median procedure time between the two groups (61 vs. 53 min, P = 0.18). Unavoidable performance bias exists in nonblinded trials, and there is a tendency to show better results for the treatment of interest. The negative results of this study could be partially explained by the hypothesis that a multicenter study involving operators with varied backgrounds and expertise might reduce performance bias. Many operators might not appreciate the assistance of traction devices as well as operators in the preceding single-center RCTs, who should be more familiar with a specific traction device. The authors also inferred that the lower risk of intraoperative bleeding and the higher effectiveness of device-independent traction techniques in colorectal areas could lead to the negligible effect of traction assistance on the procedure time of this study, contrary to the results of other CONNECT studies. Subgroup analyses, however, reflected a shorter procedure time tendency in patients with a lesion diameter of ≥30 mm in traction ESD (69 vs. 89 min, P = 0.05) and nonexpert operators (64 vs. 81 min, P = 0.07). Notably, nine conventional cases (7%) were converted to the traction method during the procedure, which could have underestimated the result in the intention-to-treat analysis. It is surmised that the use of traction devices would be more effective for challenging larger lesions and nonexperts. These controversial results among RCTs raise an important question of whether an RCT is the best study design to measure the effectiveness of traction devices in the current inaugural phase when novel devices still appear continuously. While performing ESD, endoscopists face complex multiple procedural tasks, such as identifying and defining the optimal tissue plane, precisely dissecting target tissues to minimize bystander tissue damage, promptly managing bleeding, and gently retrieving an excised specimen. Moreover, the procedural challenges of ESD are greatly affected by unstable surrounding conditions, such as anatomical location, tissue vascularity, respiratory changes, submucosal fibrosis, and even peristalsis, which changes case-by-case and sometimes moment-by-moment. In the CONNECT-E study, the simple hollow anatomy of the esophagus might enable traction-assisted ESD to be more easily accepted by operators, regardless of their skill and experience. Meanwhile, the broad range of variable conditions observed in the stomach and colorectum with larger and more intricate spaces may explain the reasons for the negative outcomes of CONNECT-G and CONNECT-C. We anticipate that traction devices could be occasionally useful during ESD, even in the stomach and colorectum, but such effectiveness would be difficult to find in RCTs assigning cases to ESD, with or without the use of a traction device throughout the procedure. The results of this study imply that the tested traction techniques could be more effective for nonexperts, but troublesome for experts who can accommodate various challenges using conventional tool sets. Lastly, traction devices cannot be easily readjusted once they are fixed to tissues. Therefore, the negative results of this RCT clarified that the application of these devices at the beginning of the procedure would not resolve every challenge encountered during ESD. The development of traction devices is still incomplete. We believe that continuous refinements of these devices would provide a more intuitive additional hand for endoscopists, and the next RCT would find a different conclusion. CONFLICT OF INTEREST Authors declare no conflict of interest for this article. FUNDING INFORMATION None. REFERENCES 1Nagata M. Advances in traction methods for endoscopic submucosal dissection: What is the best traction method and traction direction? World J Gastroenterol 2022; 28: 1– 22. CrossrefPubMedWeb of Science®Google Scholar 2Ichijima R, Ikehara H, Sumida Y et al. Randomized controlled trial comparing conventional and traction endoscopic submucosal dissection for early colon tumor (CONNECT-C trial). Dig Endosc Published online: 23 Aug 2022; DOI: 10.1111/den.14426. Wiley Online LibraryWeb of Science®Google Scholar 3Yoshida M, Takizawa K, Suzuki S et al. Conventional versus traction-assisted endoscopic submucosal dissection for gastric neoplasms: A multicenter, randomized controlled trial (with video). Gastrointest Endosc 2018; 87: 1231– 40. CrossrefPubMedWeb of Science®Google Scholar 4Yoshida M, Takizawa K, Nonaka S et al. Conventional versus traction-assisted endoscopic submucosal dissection for large esophageal cancers: A multicenter, randomized controlled trial (with video). Gastrointest Endosc 2020; 91: 55– 65.e2. CrossrefPubMedWeb of Science®Google Scholar 5Ritsuno H, Sakamoto N, Osada T et al. Prospective clinical trial of traction device-assisted endoscopic submucosal dissection of large superficial colorectal tumors using the S–O clip. Surg Endosc 2014; 28: 3143– 9. CrossrefPubMedWeb of Science®Google Scholar 6Yamasaki Y, Takeuchi Y, Uedo N et al. Efficacy of traction-assisted colorectal endoscopic submucosal dissection using a clip-and-thread technique: A prospective randomized study. Dig Endosc 2018; 30: 467– 76. 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