Results of the COLDWATER randomized controlled trial: enhanced performance of underwater cold snare polypectomy for colorectal polyps 5-10 mm, independent of endoscopist experience

Introduction

The European Society of Gastroenterology (ESGE) suggests using conventional cold snare polypectomy (CCSP) for 5-9-mm non-pedunculated colorectal polyps [1-2]. However, data for larger polyps (10-15 mm) is limited for CCSP, despite encouraging preliminary results [3]. On the other hand, CCSP comes with drawbacks: variable R0 resection rates (32-96%) and up to 17.3% incomplete resection rates (IRR) [4-6], highlighting the need for improvement in cold snare resection techniques.

Underwater cold snare polypectomy (UCSP) was inspired by underwater endoscopic mucosal resection (UEMR) [7]. The safety and efficacy of UEMR (with use of electrocautery) for the excision of larger polyps has already been reported in recent studies [8-10], yet data regarding UCSP for polyps <10 mm are insufficient. One of the advantages of underwater techniques is that water has a higher refractive index than air, and thus causes optical zoom of the mucosa. As a result, the mucosal architecture is more easily visible and the identification of polyp margins is facilitated, reducing residual lesions and recurrence risk. As lesions are more protuberant in a water-dilated than in an air-dilated colon, the endoscopist is able to snare a larger mucosal surface, increasing the chance of size-independent R0 resection [11-14]. However, UCSP is not usually performed outside specialized centers.

Interestingly enough, limited studies have assessed UCSP in clinical practice, reporting higher R0 resection rates (R0RR) and ratio of area containing the muscularis mucosa compared to CCSP [15-16]. However, these findings stem from studies that lacked sample power evaluation and featured a high proportion of polyps <8 mm in size. Maruoka et al first reported that the ratio of area containing muscularis mucosa was significantly higher in the UCSP group (UCSP: 50%, CCSP: 35.3%) indicating a broader resection. However, these data do not result from a randomized controlled trial. We present the first randomized controlled trial comparing UCSP with CCSP in terms of comprehensive histopathological evaluation, safety and efficacy, for resecting non-pedunculated colorectal polyps ranging from 5-10 mm in size.

Patients and methods

Study interventions

Colonoscopy and instruments

Endoscopists performed all endoscopic procedures with high definition Fujinon series instruments (Fujinon Corp., Omiya, Japan), while the use of a cap and the performance of the procedure with air or water or CO₂ was left to their preference. For the excision, a 0.3-mm dedicated cold snare with 10-mm diameter was used in both groups. The polyp size was estimated by visual comparison with the opening width of biopsy forceps (Radial Jaw 4 standard capacity, Boston Scientific, Marlborough, Massachusetts, USA). In order to specify the experience level of the endoscopist who performed the polypectomy, endoscopists were categorized as non-experts if they had conducted fewer than 1000 colonoscopies and 100 CCSPs.

USCP

Five steps were followed regarding the UCSP: a) complete air suction from the intestinal tract; b) partial opening of the intestinal lumen, using sterile water at room temperature through a water pump; c) immersion of the polyp in water; d) snaring of the polyp and 1-2 mm of the surrounding healthy tissue; and e) excision (Fig. 1).

Figure 1 (Α) A 5 mm Paris Isp low grade dysplasia tubular adenoma in a gas distended colon. (Β) Lesion fully immersed in water (underwater). (C) snaring of the polyp underwater. (D) the defect at the polypectomy site after excision. (E) Part of a R0 resected tubular adenoma. The green line indicates the length of muscularis mucosa in this segment of the specimen and the black line indicates the total length of this part of the specimen

CCSP

The CCSP technique followed 4 steps: a) aspiration of water, if water assisted colonoscopy was performed; b) insufflation of the intestinal lumen with air/CO₂); c) snaring of the polyp and 1-2 mm of the surrounding healthy tissue; and d) excision. The tissue specimens were placed in Vial 1.

Resection point overview

After resection of the polyp, a thorough overview of the resection points for bleeding or perforation followed. Bleeding that persisted for >60 sec was characterized according to the ESGE guidelines [2] as intraprocedural bleeding, and treated either by water sprinkling or by placing hemostatic clips. At the end of the procedure, the resection site was reviewed endoscopically to confirm the completeness of the procedure.

Biopsies from resection site

In order to determine the IRR for polyps classified as Rx at pathological examination (according to the Residual Tumor Classification system [22]), additional biopsies were taken from the resection site. To determine the horizontal margins, 2-4 biopsies were taken from the resection area (2 diametrically biopsies in polyps 5-7 mm, 4 biopsies in polyps 8-10 mm). The retrieved tissue was placed in Vial 1A.

Marking of lesion position

To easily locate the point of the polypectomy at follow-up colonoscopy, a submucosal tattoo was made 2-3 cm distal to each lesion. For rectal or cecal polyps, a submucosal tattoo was not required, and the positioning was aided by photographic recording prior to polypectomy.

Pathological examination

Specimens were placed in 2 vials with 10% formalin and were sent to the pathology laboratory. The slides were stained in the DAKO Cover Stainer using the DAKO Hematoxylin & Eosin Staining Kit, and were then evaluated by 2 independent experienced pathologists, under a Nikon Eclipse 50i and a Nikon Eclipse E400 optical microscope (4X). A Nikon 10X microscope lens was used for microscopic measurement. Dysplastic changes were classified using the Vienna classification system [22]. In the case of multiple tissue fragments, the parameters were calculated cumulatively.

Pathologists examining samples from Vial 1 performed: a) determination of the polypectomy margin according to Residual Tumor Classification [23], in order to report R0RR and IRR; b) calculation of the percentage of muscularis mucosa included in the specimen, according to the formula [length of muscularis mucosa of the lesion in mm/length of specimen in mm × 100%], after measuring the length and maximum depth of the muscularis mucosa underlying a neoplastic lesion, along with the specimen’s maximum diameter, using an ocular and stage micrometer; c) determination of presence or absence of submucosa; and d) measurement of submucosa depth in μm when present. Pathologists examining samples from Vial 1A determined the horizontal margins in order to detect the presence or not of residual damage.

Follow up for adverse events

The study physician from the gastroenterology department evaluated any potential adverse events 30 days post-polypectomy through phone consultation.

Followup endoscopy

After 12 months, a follow-up endoscopy was performed to check for any recurrence of the resected lesion.

Results

Participants

From March 2021 to December 2022, we enrolled 229 patients with 408 colorectal lesions (intention-to-treat population) and randomly assigned them to the UCSP group (n=115 patients, n=203 polyps) or to the CCSP group (n=114 patients, n=205 polyps). In the UCSP group 2 polyps (0.96%) were not removed by UCSP, as it was not possible to immerse them in water, and thus were excluded. In addition, in the UCSP and CCSP groups 3 and 6 polyps, respectively, were not amenable to excision using a 10-mm diameter cold snare, necessitating a switch to a 15-mm diameter cold snare. These particular polyps were all 10 mm and Paris IIa and they were all excluded from the per-protocol analysis. A total of 220 patients with 397 colorectal lesions (115 patients and 198 polyps in the UCSP group; 114 patients and 199 polyps in the CCSP group) were finally included in the per-protocol analysis for the primary outcome (Fig. 2). Regarding the follow-up endoscopy 12 months after polypectomy, 63 patients in the UCSP and 74 patients in the CCSP group refused to participate because of anxiety about the hospital transmission of COVID 2019.

Figure 2 CONSORT 2010 flow diagram of the COLDWATER study

UCSP, underwater cold snare polypectomy group; CCSP, conventional cold snare polypectomy group

Baseline data

Baseline characteristics of the patients, lesions and procedures are shown in Table 1. Altogether, 19 patients in the UCSP group and 20 patients in the CCSP group were on antithrombotic treatment. Both treatment groups were identical and homogeneous regarding the use of antithrombotic medication, polyp characteristics (location, size, histology and Paris classification) as well as the endoscopist’s experience. Operator experience (non-expert vs. expert) was similar in the UCSP and CCSP groups (P=0.334).

Table 1 Baseline characteristics of the patients (A), lesions and procedures (B)

Primary outcome

Primary and secondary outcomes are presented in Table 2. Regarding the primary outcome, muscularis mucosa resection ratio, UCSP was found to have better results compared to CCSP (P=0.003). Multiple linear regression analysis showed a statistically significant relationship between the ratio of area containing muscularis mucosa and the technique applied (P=0.044), whereas no such relationship was found for polyp location, en bloc resection, Paris classification, size category or endoscopist’s experience (Supplementary Table 2). Subgroup analysis showed no differences for either group in the muscularis mucosa resection ratio in relation to the endoscopist’s experience (Table 3).

Table 2 Procedure-related outcomes. Primary and secondary outcomes of the COLDWATER study

Table 3 Subgroup analysis according to endoscopist’s experience

Discussion

To our knowledge, this is the first randomized controlled trial comparing UCSP and CCSP for small colorectal polyps, focusing particularly on the histologic characteristics of resection. In the COLDWATER study, UCSP was associated with a significantly higher ratio of muscularis mucosa resection, thus enabling a broader resection. Although there were no differences between the 2 treatment groups in terms of R0RR and submucosa excision, the UCSP group exhibited a higher en bloc resection rate and a lower IRR compared to the CCSP group.

CCSP stands as the established technique for removing small colorectal polyps [2]. Nevertheless, there is an ongoing debate regarding the predictability of muscularis mucosa resection. Previously published studies observed that muscularis mucosa was absent in 27.8% of excision specimens, while its presence ranged from 57-92%, even in cases involving cold snare polypectomy with submucosal injection [24-27]. The COLDWATER study revealed a significantly higher muscularis mucosa resection rate for UCSP (UCSP: 81.72±62.81%, CCSP: 72.33± 22.33%, P=0.003), suggesting a more favorable efficacy profile. This aligns with findings from a study by Maruoka et al, who initially assessed the efficacy of UCSP [16]. Furthermore, the UCSP technique emerged as an independent factor favoring extended muscularis mucosa excision, potentially contributing to achieving R0 resection, as demonstrated previously [25,28]. Interestingly, Maruoka et al [15] and Myung et al [16] reported a significantly higher R0RR in the UCSP group, which contrasts with the findings of the COLDWATER study, where no difference was observed between UCSP and CCSP. Our study revealed superiority of UCSP over CCSP concerning IRR, diverging from the results presented by Yen et al [29].

The presence of submucosa has been observed in 9-24% of resected specimens following CCSP [24,26,30]. However, our study revealed a superficial depth of excision, with only 16.6% and 12.5% of specimens including submucosa in UCSP and CCSP (P=0.25), respectively. The limited depth of resection and the inability to access and remove a portion of the submucosa are well-documented drawbacks of the cold snare technique [31,32], which, as per our findings, were not mitigated by the underwater technique. This suggests that, in adenomas with high-grade dysplasia, potentially concealing in situ or invasive cancer, both UCSP and CCSP are inferior to techniques involving electrocautery. Moreover, it appears that deeper resections are facilitated by the use of electrocautery and are not influenced by submucosal injection or water immersion in EMR or UCSP/UEMR, respectively.

Our results regarding the safety of UCSP align with the literature. Previous studies reported no clinically significant adverse event in either group [15,16,29]. As per the COLDWATER study findings, UCSP emerges as an exceptionally safe technique, with the sole adverse event being intra-procedural bleeding (UCSP: 0.5%, CCSP: 2%, P=0.37), effectively managed through mechanical hemostasis. The UCSP safety profile hinges primarily on employing a cold snare instead of electrocautery, and secondarily on using a water-distended colon rather than gas distention.

Perhaps the most noteworthy finding of the COLDWATER study is the favorable R0RR of UCSP, irrespective of the endoscopist’s experience. While both UCSP and CCSP exhibit a high R0RR, only in UCSP does this appear to be unrelated to the endoscopist’s experience, enabling both experts and non-experts to achieve adequate outcomes. This pivotal discovery from our study not only holds promise for young endoscopists striving for complete excision, but also for introducing polypectomy training in gastroenterology residents. UCSP ensures patient safety by minimizing the risk of incomplete resection. Considering that the removal of small polyps is a fundamental skill for every endoscopist, and that small polyps are the most prevalent during screening colonoscopes, perhaps local and international educational organizations should contemplate recommending the underwater technique for less experienced endoscopists

During the COLDWATER study, we observed certain issues associated with cold snare excision that fell beyond the scope of this research, yet remained noteworthy. Approximately 2.2% of enrolled polyps did not undergo the allocated intervention because of the cold snare’s inability to excise the lesion. In these cases, we attempted to maneuver the snared polyp toward the endoscope tip and persisted with the snare closed, yet we were unable to successfully excise the polyp. Ultimately, we needed to switch to a 15-mm diameter snare to resect the polyp. These cases were deemed inappropriate for inclusion in the per-protocol analysis. Our conclusion, drawn from clinical experience, highlighted a potential correlation between polyp size, morphology, and snare diameter. All polyps measured 10 mm, exhibited Paris IIa morphology, and were initially subjected to a 10-mm snare. Further prospective randomized studies are necessary to comprehensively address this issue.

The COLDWATER study, despite yielding valuable insights, has certain limitations. Primarily, it was a single-center study involving multiple participating endoscopists. To mitigate potential bias, we opted to present comprehensive data concerning the endoscopists’ experience and conducted a subgroup analysis, categorizing the endoscopists into experts and non-experts. This division was made according to the opinion of the research team and heterogeneous literature data [6,8,9,33]. Additionally, only 3 experts and 2 non-experts participated, and thus it is difficult to generalize the results. Secondly, blinding the endoscopists was not feasible; however, both pathologists and patients were blinded to ensure an objective assessment. Thirdly, the resection specimens were not pinned to a cork and thus the direction of sectioning did not ensure appropriate evaluation of the muscularis mucosa in a proportion of specimens. Lastly, an omission in our documentation includes the timing of procedures. Our experience suggested that UCSP generally required more time compared to CCSP, particularly in cases located in the sigmoid colon. However, we did not record specific time-related data. Contrarily, existing data from another randomized controlled trial support the inverse claim, indicating that resection time was longer in CCSP compared to UCSP for small polyps [16]. Future studies may be expected to provide detailed insights in this regard.Αρχή φόρμας

In summary, UCSP achieves a broader excision compared to CCSP concerning the muscularis mucosa resection ratio, despite not achieving a deeper excision. Moreover, UCSP demonstrates a higher rate of en bloc resections, a lower IRR, while it appears to be a promising technique for polypectomy training among inexperienced endoscopists, given its experience-independent R0RR.