Endocuff-assisted colonoscopy for surveillance of serrated polyposis syndrome: a multicenter randomized controlled trial

• Abstract
• Introduction
• Patients and methods
• Endoscopic procedures
• Identified lesions and pathology
• Adverse events
• Outcomes
• Sample size and statistical analysis
• Results
• Patient characteristics
• Procedures and adverse events
• Outcomes
• Discussion
• References

Abstract

Background and study aims Serrated polyposis syndrome (SPS) is a condition with high risk for colorectal cancer. The Endocuff device has been shown to increase adenoma detection in the general and screening population. We aimed to ascertain whether Endocuff-assisted colonoscopy increases detection of serrated lesions in comparison with standard colonoscopy during the surveillance of patients with SPS. 

Methods In a multicenter randomized controlled study, patients who met SPS criteria I and/or III under surveillance (previous resection of all serrated lesions ≥ 4 mm) were consecutively randomly allocated 1:1 to Endocuff-assisted colonoscopy or standard colonoscopy, performed by expert endoscopists. The main outcome was the mean number of serrated lesions detected per patient.

Results 122 patients (standard colonoscopy n = 60; Endocuff-assisted colonoscopy n = 62; 59 % men; mean age 60.6 (standard deviation [SD] 7.5) were included at 4 centers. Baseline variables (demographic data, SPS phenotype, colorectal cancer [CRC] history, cumulative polyps, and follow-up), cecal intubation rate, and withdrawal time were similar between groups. There was no statistically significant difference between Endocuff-assisted colonoscopy and standard colonoscopy for the mean number of serrated lesions detected per patient: 5.8 (95 % confidence interval [95 %CI] 4.4 – 7.2) and 5.0 (3.9 – 6.1), respectively (P = 0.36). There were also no differences between Endocuff-assisted and standard colonoscopy for detection of sessile serrated lesions (mean number per patient 2.5 [1.3 – 3.6] vs. 2.0 [1.1 – 3.0], P = 0.54) and adenomas (0.9 [0.5 – 1.3] vs. 0.5 [0.3 – 0.7], P = 0.12).

Conclusion Use of Endocuff-assisted colonoscopy did not significantly increase the number of serrated lesion detected per patient during surveillance of SPS.

Introduction

Serrated polyposis syndrome (SPS) is characterized by the development of large and/or multiple serrated lesions [1] with a high prevalence of colorectal cancer (CRC) that ranges between 15.8 % [2] and 29.3 % [3]. The diagnosis of SPS has a clinical basis that follows the World Health Organization (WHO) criteria: I, at least 5 serrated polyps proximal to the sigmoid colon, with at least 2 of them being 10 mm in size; II, any number of serrated polyps occurring proximal to the sigmoid colon in an individual who has a first-degree relative with SPS; and/or III, more than 20 serrated polyps spread throughout the colon [1].

Although the 5-year cumulative incidence of CRC in patients with appropriate surveillance in SPS is very low (1.4 % to 2.6 %) [2] [3], up to 42 % (95 % confidence interval [95 %CI] 32.4 % – 51.7 %) of patients will develop advanced neoplasia within 3 years [4]. Moreover, previous data have shown that CRC can arise in diminutive serrated lesions [5] suggesting that, in this specific scenario, even small serrated lesions must be taken into consideration and removed.

Sessile serrated lesions are thought to be the main precursor of CRC through the serrated pathway. The subtle appearance of sessile serrated lesions (flat, irregular shape, indistinct borders, pallid color, covered by mucus/feces) [6] make their detection challenging; they are easily overlooked during colonoscopy ([Fig. 1]). The reported prevalence of SPS ranges from < 0.1 % [7] [8] in colonoscopy-based screening to 0.9 % [9] [10] [11] in screening based on fecal occult blood testing. However, this prevalence may be an underestimate since SPS is often underdiagnosed [11] [12] because of poor detection of serrated lesions and lack of awareness of their neoplastic potential. Accordingly, ancillary techniques and add-on devices designed to heighten polyp detection can be especially advantageous in the surveillance of SPS.

The Endocuff-Vision device (Arc Medical Design, Leeds, UK) consists of a soft plastic cuff that is placed on the tip of the colonoscope. The cuff has one row of eight finger-like projections that fold along the axis of the endoscope during insertion and open during withdrawal. The Endocuff-Vision helps to flatten mucosal folds in order to detect small lesions located behind haustral folds that could be overlooked during routine colonoscopy ([Fig. 1]). Recent systematic reviews and meta-analyses in mixed populations (i. e., CRC screening, post-polypectomy surveillance, and symptomatic patients [13] [14] [15] [16]) have shown that use of the Endocuff-Vision, and the first-generation Endocuff significantly increases the adenoma detection rate (ADR) in comparison to standard colonoscopy, but the evidence is of low quality [16]. Although a few studies have reported a potential advantage of Endocuff in detecting serrated lesions as a secondary endpoint [17] [18] [19] [20], to our knowledge, no study has specifically addressed the usefulness of Endocuff-assisted colonoscopy for detecting serrated lesions. We hypothesized that Endocuff-assisted colonoscopy would be helpful for increasing the detection of serrated lesions.

Patients and methods

This study follows the ethical principles of nonmaleficence, beneficence, autonomy, and justice contained in the Declaration of Helsinki, in addition to the Spanish Basic Laws 41/2002 on patient autonomy and 14/2007 on biomedical research. Patients asked to participate in the study were given prior oral information and signed a written consent if they agreed. The institutional review board of each participating center approved the protocol. This protocol was registered in ClinicalTrials.gov under the number NCT02592603.

This was a prospective multicenter randomized parallel trial conducted from September 2015 until July 2017 at 4 Spanish centers (3 academic, 1 community). All colonoscopies were performed by 6 clinicians who were expert endoscopists in screening and conditions with high risk of CRC. They had each performed 400 – 1000 colonoscopies and had a proven high ADR (range 50 % – 67 %) in a fecal immunochemical testing (FIT)-based CRC screening program.

Eligible participants were adults (aged ≥ 18) who met the WHO SPS criteria I and/or III [21] and were undergoing annual endoscopic surveillance after the complete removal of all serrated lesions ≥ 4 mm and adenomas in previous procedures. Exclusion criteria were presence of hereditary CRC syndromes (i. e., germline mutations of APC, MUTYH, and mismatch repair genes), known colonic strictures, total colectomy, acute diverticulitis, inflammatory bowel disease, suspected or proven lower gastrointestinal bleeding, noncorrectable coagulopathy or anticoagulant/clopidogrel therapy during the procedure, inadequate bowel cleansing, or incomplete colonoscopy.

Patients were assigned in a 1:1 ratio to undergo Endocuff-assisted colonoscopy or standard colonoscopy. A block design computerized program (4 patients per block) was used for randomization. The allocation procedure corresponding to random numbers was sent to each center within a closed envelope by the study coordinator. The randomization to Endocuff-assisted colonoscopy or standard colonoscopy was blinded until the patient signed their informed consent before starting the colonoscopy.

Endoscopic procedures

As general rule, all patients were encouraged to undertake a diet low in fibre and fat for the 3 days before the procedure. Anterograde cleansing was done with 4 L of polyethylene glycol electrolyte lavage solution (Bohm; Laboratorios Bohm, Madrid, Spain), or 2 L polyethylene glycol and ascorbate solution (Moviprep; Norgine, Harefield, United Kingdom), or sodium picosulfate, magnesium oxide, and citric acid (CitraFleet; Casen-Fleet, Zaragoza, Spain) in split doses.

Procedures were scheduled in 40 – 60-minute time slots, with patients under deep sedation (propofol perfusion alone or plus remifentanil) administered by anesthesiologists, gastroenterologists, or supervised trained nurses, depending on center policy. Bowel cleansing was considered adequate if the Boston score was ≥ 6 points (≥ 2 by colonic segment).

All colonoscopies were performed with high definition technology (CF-H180AL, CF-H185 L, CF-H190 L, or CF-HQ190L; EVIS EXERA III processor; Olympus Medical, Tokyo, Japan). For Endocuff-assisted colonoscopy, the Endocuff Vision device (ARV 120; Arc Medical Design, Leeds, England) was fitted to the tip of the endoscope before colonoscopy was started. For all procedures the endoscopists were advised to not perform polypectomy during colonoscopy insertion before reaching the cecum. Cecal intubation was verified by identification of the usual landmarks (ileocecal valve, triradiate cecal folds, and the appendix orifice). During extubation, each segment was carefully examined with white light. A stopwatch was used to measure both total procedure time and withdrawal time. Explanation of the study to patients, obtaining informed consent signature, and consecutive collection of data during the procedure were performed by a research nurse specifically dedicated to those tasks.

Identified lesions and pathology

Identified lesions were characterized using white-light and narrow-band imaging (NBI). Only if considered necessary, targeted indigo carmine was used for delineation of lesion borders prior to polypectomy. Lesion morphology was described according to the Paris Classification [22]. The cecum and the ascending, transverse, and descending colon were considered to be proximal colon. Lesion size was estimated by comparison with an open-jaw biopsy forceps or polypectomy snare located next to the lesion before resection. For each lesion a histological prediction was made based on the pit and vascular pattern, using the Kudo [23] and NBI International Colorectal Endoscopic (NICE) [24] classifications. Resection techniques were employed at the discretion of the endoscopist.

Resected lesions were retrieved in separated flasks and evaluated by expert pathologists dedicated to gastrointestinal oncology and following the European guidelines for quality assurance in CRC screening and diagnosis [25]. The Vienna criteria [25] were used for histopathology evaluation. Lesions were classified as adenomas (tubular, villous, or tubulovillous), serrated lesions (hyperplastic, sessile serrated, or traditional serrated adenomas), and carcinomas. Advanced adenomas were defined as those ≥ 10 mm in size, or with a villous component, or with high grade dysplasia. Advanced serrated lesions were defined as serrated lesions with dysplasia or ≥ 10 mm in size.

Adverse events

Major adverse events were defined as colonic perforation or bleeding occurring during or after the procedure that required emergency room presentation, endoscopic re-intervention, hemostatic techniques other than endoscopy (angiography or surgery), transfusion and/or unexpected hospitalization. Minor adverse events were defined as self-limited bleeding or abdominal pain managed on an outpatient basis. Superficial mucosal abrasions whether or not attributable to the Endocuff were recorded. The Gloucester comfort score [27] was used to register the patient feedback related to the colonoscopy, ranging from 1 (no discomfort) to 5 (extreme discomfort). Early complications and comfort were prospectively recorded during the procedure or afterward (at the recovery area). Late adverse events were recorded 2 weeks after the colonoscopy during an outpatient visit.

Outcomes

The primary outcome was to compare the mean number of serrated lesions detected per patient, defined as all serrated lesions detected in each group (Endocuff-assisted or standard colonoscopy) divided by the total number of patients in each group. 

Secondary outcomes were to compare Endocuff-assisted colonoscopy with standard colonoscopy regarding the total number of polyps and adenomas per patient, and also the detection rate for polyps, serrated lesions, and adenomas (proportion of patients with at least 1 lesion of interest in each group) overall and also subcategorized by location and size of lesion. Other secondary outcomes were procedural, such as: the procedure time (from insertion until removal of endoscope through the anus), the withdrawal time (time for mucosal inspection, from the cecum until removal of the endoscope through the anus, excluding the time spent for washing or polypectomy), colonoscopy-related comfort, and the rate of adverse events.

Sample size and statistical analysis

According to data from our group [2], in patients with SPS in whom all serrated lesions ≥ 4 mm had been removed in previous procedures, a mean of 5.86 (standard deviation [SD] 6.47) serrated lesions are found in each subsequent surveillance colonoscopy. A sample size of 124 patients (62 in each group) was estimated to give a power of 80 % at a two-sided alpha of 0.05 for a 25 % increase in the mean number of serrated lesions detected per patient in the Endocuff-assisted colonoscopy group, assuming a dropout rate of 10 % (https://www.dssresearch.com/KnowledgeCenter/ToolkitCalculators/SampleSizeCalculators).

Quantitative variables were summarized using means with 95 %CI or SD. Comparison of continuous distributions of unpaired samples was done using Student’s t test with bootstrapping (1000 replications), while the Mann – Whitney U test was used for skewed data. Categorical variables were shown as frequencies (%) and Pearson’s chi-squared test was used to test for association between them. SPSS statistics software version 20.0 (SPSS Inc., Chicago, Illinois, USA) was used to analyze the data

Results

Patient characteristics

From September 2015 to July 2017, 128 eligible patients (63 in the standard colonoscopy group and 65 in the Endocuff-assisted colonoscopy group) were consecutively enrolled. After inclusion, 6 patients were excluded: 5 because of inadequate bowel preparation and 1 because the polyp collector broke down during colonoscopy and it was not possible to recover all resected lesions for histopathological analysis. Finally, data from 122 patients (40 % women; mean age 60.6 [SD 7.4] years) were analyzed: 60 in the standard colonoscopy group and 62 in the Endocuff-assisted colonoscopy group. The proportions of patients included from each center were 62 % (Hospital Clinic de Barcelona [HCB]), 20 % (Hospital Universitario de Móstoles [HUM]), 10 % (Hospital Santos Reyes [HSR]) and 8 % (Althaia, Xarxa Assistencial Universitària de Manresa [AXAUM]).

At SPS diagnosis, 55 patients (45.1 %) met WHO criterion I, 48 (39.3 %) met criterion III, and 19 (15.6 %) met both criteria I and III. A total of 13 patients (10.7 %) had a history of CRC and segmental colectomy. Patients had previously undergone 4.4 (SD 2.6) clearance/surveillance colonoscopies. The last colonoscopy had been performed 15.4 (SD 6.1) months before the current procedure. The last colonoscopy had been performed with high definition technology in 82 % of patients (100/122) and indigo carmine or electronic chromoendoscopy had been used in 44.3 % (54/122) of them. As shown in [Table 1], demographic and baseline data were similar for the Endocuff-assisted and standard colonoscopy groups with a higher proportion of men in the Endocuff-assisted group. 

Procedures and adverse events

The cecum was reached in all procedures. [Table 2] shows the data regarding colonoscopies and adverse events. Procedure times for the two groups were similar, as were withdrawal times. The vast majority of colonoscopies were performed with carbon dioxide insufflation, with an identical proportion (97 %) in each group. 

There were 2 major adverse events in the 122 procedures (1.6 %) ([Table 2]). In the Endocuff-assisted colonoscopy group, 1 patient presented a self-limited rectal bleeding requiring emergency room consultation. The bleeding was attributed to external hemorrhoids, complementary tests were not required, and the patient was discharged on the same day. In the standard colonoscopy group, 1 patient had a muscularis propria injury (target sign) during a polypectomy. The post-resection defect was successfully closed with clips in the same procedure. The patient remained in the recovery area for 4 hours without discomfort (1 on the Gloucester comfort scale) and was discharged on the same day without further consequences.

Regarding mild adverse events, 1 patient in the Endocuff-assisted group had post-polypectomy syndrome; this was managed on an outpatient basis as the patient was asymptomatic (Gloucester comfort scale 1) at 2 weeks after the procedure. Superficial mucosal abrasions were described in 7/62 colonoscopies (11 %) in the Endocuff group, and none in the standard colonoscopy group (P = 0.01). There were no significant differences in global Gloucester comfort scores between the Endocuff and the standard colonoscopy groups in the first 24 hours and at 2 weeks after the procedure.

Outcomes

A total of 893 polyps were resected (409 standard colonoscopy, 484 Endocuff-assisted) among the 122 included patients, and 149 polyps were excluded from the analysis because they were not retrieved (86 polyps) or not representative of normal mucosa (63 polyps). Finally, 744 polyps (standard group n = 329, Endocuff-assisted n = 415) were analyzed corresponding to 660 (88.7 %) serrated lesions (standard colonoscopy n = 299 vs. Endocuff-assisted colonoscopy n = 361) and 84 (11.2 %) adenomas (standard colonoscopy n = 30 vs. Endocuff-assisted colonoscopy n = 54).

As shown in [Table 3] and [Fig. 2], there were no differences between Endocuff-assisted colonoscopy and standard colonoscopy in the mean number per patient of total polyps (7.8 [95 %CI 6.3 – 9.3] vs. 6.8 [5.6 – 8.1]; P = 0.31), of serrated lesions (5.8 [4.4 – 7.2] vs. 5.0 [3.9 – 6.1]; P = 0.36), sessile serrated lesions (2.5 [1.3 – 3.6] vs. 2.0 [1.1 – 3.0]; P = 0.54), or adenomas (0.9 [0.5 – 1.3] vs. 0.5 [0.3 – 0.7]; P = 0.12).

Similar results were found when lesions were analyzed according to size. However, when lesions were analyzed according to location, in the right colon Endocuff-assisted colonoscopy was superior to standard colonoscopy for the detection of polyps (1.4 [1.0 – 1.9] vs. 0.8 [0.5 – 1.0], respectively; P = 0.01), and principally for serrated lesions (1.0 [0.6 – 1.4] vs. 0.5 [0.3 – 0.7], respectively; P = 0.02).

Similar results were obtained when analyzing only those patients with 5 polyps or less (Table 1 s, available online-only in Supplementary material).

Standard colonoscopy was associated with a higher detection rate for serrated lesions compared with Endocuff-assisted colonoscopy but this difference was not statistically significant (98.3 % [91.1 – 0.99] vs. 90.3 % [79.4 – 96.0]; P = 0.06). There were no differences between the two groups in detection rates for adenomas, advanced adenomas, sessile serrated lesions, and serrated lesions with dysplasia or ≥ 10 mm in size ([Table 3]).

Discussion

This is the first study specifically designed to assess the usefulness of Endocuff-assisted colonoscopy for detecting serrated lesions. In this multicenter, randomized, controlled, and parallel trial, Endocuff-assisted colonoscopy did not significantly improve the detection of serrated lesions in SPS patients under endoscopic surveillance.

We could argue that Endocuff-assisted colonoscopy was not superior to standard colonoscopy in terms of overall detection of serrated lesions because the endoscopists who participated in our study were known to have high lesion detection rates (“high detectors”) and were considerably involved in the management of SPS patients. Consequently, the potential benefits of the add-on device might have been obscured by the endoscopists’ outstanding baseline polyp detection rate. Support for this hypothesis comes from a recent systematic review and network meta-analysis (published as an abstract so far) that compared colonoscopies assisted by fold-flattening devices (n = 1661) with standard colonoscopies (n = 1649) [28]. A subanalysis showed that in those studies with high ADRs (> 30 % in the standard colonoscopy arm), no improvement was observed when fold-flattening devices were used (logarithmic odds ratio [log OR] – 0.09 % [95 %CI – 5.8 % to 3.9 %]; P = 0.71) in contrast to to those studies with low ADRs (log OR + 11.9 % [95 %CI 5.9 % to 17.9 %; P = 0.00) [28]. Furthermore, a recent multicenter randomized study, in a mixed population aged > 50 years, that compared Endocuff, EndoRings, and the full spectrum endoscopy (FUSE) system with conventional colonoscopy and involved only high-detector endoscopists, did not show any consistent differences among all modalities [18] for rates of detection of sessile serrated lesions and sessile serrated lesions per colonoscopy, despite showing that Endocuff-assisted colonoscopy was superior to the other modalities with regard to ADR and adenomas per colonoscopy. Conversely, another recent meta-analysis that included several add-on devices, found opposite results pointing, with a low quality of evidence, that Endocuff-assisted colonoscopy provides more advantage over standard colonoscopy for adenoma detection by high-performing detectors rather than by low-performing detectors [16].

On the other hand, while Endocuff-assisted colonoscopy is useful for revealing lesions that are concealed behind folds, it appears that clinical awareness, high competency, a trained eye, and dye-chromoendoscopy are the key factors that help to improve detection of serrated lesions. In fact, the detection rate for serrated lesions and sessile serrated lesions is highly variable among centers and endoscopists, ranging from 0 up to 18 % in the general/screening population [29] [30] and correlating strongly with ADR [29]. In a previous study in an organized CRC-screening population, we demonstrated that a reassessment colonoscopy within a year, specially directed to detect serrated lesions and performed by aware and dedicated endoscopists, tripled the prevalence of SPS in this cohort [11]. We also recently reported in a multicenter randomized crossover study that dye-based panchromoendoscopy detected twofold more serrated lesions than conventional endoscopy during surveillance colonoscopy of previously cleared SPS patients [31]. Chromoendoscopy was found to be especially useful in detecting flat and subtle polyps, such as small serrated lesions, and added little value for the detection of adenomas (usually darker than surrounding mucosa) and large polyps [30]. This finding reinforces the idea that detection of serrated lesions is probably mostly related to endoscopists’ awareness and optimal recognition of their subtle endoscopic features [6] ( [Fig.1]) rather than to major exposure of the hidden mucosa.

This is the first study to assesses the usefulness of the Endocuff-assisted colonoscopy device in patients with a condition associated with a high risk of CRC. The average number of serrated lesions found in the study is in line with the estimate for the sample size calculation that was based on previous data [2] [3] [31]. However, SPS is a very heterogeneous condition and our study might be underpowered, especially when secondary outcomes are analyzed. In order to homogenize the study population, we included only those patients under surveillance in whom all adenomatous and serrated lesions ≥ 4 mm had been removed in previous procedures. Moreover, around 90 % of our patients presented at least one of the recently described risk factors for advanced neoplasia in SPS cohorts (personal history of cytological dysplasia on a serrated lesion, sessile serrated lesion histology, proximal location [2], advanced adenomas, and SPS phenotype I + III [3]) which ensures a polyp-enriched population. Finally, the subanalysis that excluded those patients with a higher burden of polyps (> 5) did not provided any different result (Table 1 s).

We acknowledge that we based our sample size calculation on a considerable proportional increase (25 %) in detection of serrated lesions by the new modality. However, this same proportion has been used in recent studies with a similar design [18] and can easily be justified in terms of clinical relevance. For instance, in this cohort of patients who present a mean of 5.86 (SD 6.47) serrated lesions at each surveillance colonoscopy and undergo surveillance every 1 – 2 years, from a clinical point of view the beneficial effect of a new device would be difficult to justify for less than one extra serrated lesion found per patient. In any case, a randomized controlled trial with a larger cohort would be desirable to confirm our results.

Another limitation is that the endoscopists were not blinded to the use of the device, which can favor an observer bias. However, procedure time and withdrawal time were similarly long in both arms of the study, which ensures that the inspection was equally exhaustive in both groups. Finally, the pathological analysis was not centralized. It is well known that there is high interobserver variability among pathologists for distinguishing sessile serrated lesions from hyperplastic polyps [32]. Likewise, pathologists could misleadingly classify a sessile serrated lesion with dysplasia as a conventional tubular adenoma if they overlooked the serrated histology or if they received only the dysplastic nodule in an incompletely resected specimen. However, the histological analysis was performed by dedicated gastrointestinal pathologists at each center, and we took into account all serrated lesions regardless of subtype in order to minimize this bias.

In conclusion, in the context of SPS patients who have previously undergone clearing colonoscopy and in dedicated endoscopist hands, Endocuff-assisted colonoscopy failed to demonstrate any clear advantage compared with high definition standard colonoscopy. The detection of serrated lesions seems to be influenced more by endoscopist awareness, optical training, and the meticulousness with which colonoscopy is performed than by the use of add-on devices.

Competing interests

M. Pellisé is a consultant for Norgine Iberia; has received fees for conferences from Norgine, Olympus, and Casen Recordati; and receives an editorial fee from Thieme. Other authors do not have any conflict of interest.

Acknowledgments

To the EndoCAR group of the Spanish Gastroenterology Association and Spanish Society of Digestive Endoscopy. This study was supported by a grant from the Agència de Gestió d’Ajuts Universitaris i de Recerca (2017 SGR 653), and the Asociación Española contra el Cáncer (Fundación Científica GCB13131592CAST). CIBERehd is funded by the Instituto de Salud Carlos III. This study received a grant from the Grupo de Apoyo a la Investigación of the Spanish Gastroenterology Association in 2016.

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Corresponding author

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• Supplementary Material