Comparing Right Colon Adenoma and Hyperplastic Polyp Miss Rate in Colonoscopy Using Water Exchange and Carbon Dioxide Insufflation: A Prospective Randomized Controlled Trial
Phase: NA
Conditions: Right Colon Adenoma Miss Rate, Right Colon Hyperplastic Polyp Miss Rate
Sponsor: Evergreen General Hospital, Taiwan

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Title: Comparing right colon adenoma and hyperplastic polyp miss rate in 
colonoscopy using water exchange and carbon dioxide insufflation: A prospective 
randomized controlled trial 
INTRODUCTION 
  Colonoscopy is currently regarded as the gold standard to detect and prevent 
colorectal cancer (CRC) [1]. It estimated to prevent about 76%-90% of CRC [2], but 
post-colonoscopy CRCs (PCCRCs) still occur. Recent case-control studies consistently 
demonstrated that protection by colonoscopy against right-sided colon cancer, 
ranging from 40% to 60%, was lower than the 80% protection attained in the left 
colon [3-5]. Of all PCCRCs, 58% were attributed to lesions missed during examination 
[6]. In a systematic review of tandem colonoscopy studies, a 22% pooled miss-rate 
for all polyps was reported [7]. Colonoscopy maneuvers helping to reduce miss-rate 
for all polyps, particularly in the right colon, have the potential to decrease the 
incidence of PCCRCs. 
Water exchange (WE) colonoscopy is characterized by the gasless insertion to the 
cecum in clear water and maximizing cleanliness during insertion. WE colonoscopy 
has been shown to improve the overall adenoma detection rate (ADR), compared to 
air insufflation colonoscopy, in many prospective randomized controlled trials (RCTs) 
[8-13]. WE colonoscopy also has been shown to improve right colon ADR in RCTs 
[10-12] and meta-analyses [14,15]. In a pooled data from two multisite RCTs, WE also 
significantly increases right colon combined advanced and sessile serrated ADR as 
compared to air insufflation colonoscopy [16]. Decreased multitasking-related 
distraction from cleaning maneuvers has been the most recently identified 
explanation for the increase in ADR by WE [17]. The right colon is usually the worst 
prepared segment and proximal colorectal neoplasms with advanced histology 

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frequently are smaller than the ones in the left colon or have a nonpolypoid 
appearance [18,19]. Therefore, the adoption of WE in the right colon might be 
especially beneficial. 
Traditionally, all CRC are believed to arise from the adenomas through the 
adenoma-carcinoma sequence. However, recent studies showed that 35% of CRC 
were derived from serrated lesions (SLs) [20], which include hyperplastic polyp (HP), 
sessile serrated adenomas/polyps (SSA/Ps) and traditional serrated adenomas [21]. 
The presence of SLs, even small and diminutive proximal HPs, has been reported to 
be associated with higher rates of synchronous advanced neoplasia [22,23]. Proximal 
HPs might also serve as precursors of cancer through DNA methylation and deficient 
DNA mismatch repair [24-26]. However, SLs tend to be pale and flat and pose a 
challenge for the endoscopists to detect them [27]. WE might come in handy for 
uncovering the proximal SLs through the above stated mechanisms.  
The primary outcome of this study is the right colon combined adenoma miss rate 
(AMR) and hyperplastic polyp miss rate (HPMR) determined by tandem inspection of 
the right colon using WE or CO2 insufflation for screening, surveillance, or positive 
fecal immunochemical test (FIT) indications. The secondary outcomes are the overall 
ADR and other adenoma detection related metrics between the two colonoscopy 
methods. 
METHODS 
  This will be a prospective RCT comparing CO2 insufflation and WE in terms of right 
colon combined AMR and HPMR by tandem inspection. It is originally designed as a 
multicenter study conducted in three community hospitals in Taiwan. Consecutive 
patients will be enrolled from April 2019 to October 2020. A written informed 
consent will be obtained from all participating patients. The study has obtained 

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ethical approval from the Joint Institutional Review Board of Taiwan (19-002-T-1) and 
has been registered with ClinicalTrials.gov (NCT03845933). Due to delay in obtaining 
IRB approval in two of the participating hospitals (Dalin Tzu-Chi Hospital obtained IRB 
approval in late May 2019 and has not recruited any patient; Taipei Medical 
University Hospital has not obtained IRB approval in early June 2019) and rapid 
recruitment of Evergreen General Hospital since April 2019, which has recruited and 
completed more than 90 patients in the end of May 2019, we have amended the 
study design from multicenter study to single center study and have obtained the 
approval of this amendment on July 19, 2019 from the Joint Institutional Review 
Board of Taiwan.  
Participants 
  Consecutive patients aged 45 years or older undergoing colonoscopy for screening, 
surveillance, and positive FIT will be considered for enrollment [28]. Exclusion criteria 
will include familial adenomatous polyposis and hereditary non-polyposis CRC 
syndrome, personal history of CRC or inflammatory bowel disease, previous colonic 
resection, obstructive lesions of the colon, gastrointestinal bleeding, allergy to 
fentanyl or midazolam, American Society of Anesthesiology (ASA) classification of 
physical status grade 3 or higher (e.g. controlled congestive heart failure, stable 
angina, previous heart attack, poorly controlled hypertension, morbid obesity, 
chronic renal failure, bronchospastic diseases with intermittent symptoms), mental 
retardation, pregnancy, and refusal to provide a written informed consent.  
Randomization 
  Patients will be randomized in a 1:1 ratio to undergo either the CO2 insufflation 
colonoscopy (CO2 group) or WE colonoscopy (WE group). Randomization will be 
carried out by a computer-generated random sequence. Stratification based on 

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colonoscopists and colonoscopy indications (screening, surveillance, and positive FIT) 
will be performed. Individual random sequence will be placed in an opaque envelope 
kept by an independent research assistant not directly involved in this study, which 
will be opened immediately before the procedure. 
Bowel Preparation and Sedation 
  Patients will be instructed to eat low-residual foods for two days before 
colonoscopy. Oral and written instructions on the split-dose bowel preparation 
(Polyethylene glycol solution) will be provided to all patients. Colonoscopy will be 
performed without sedation or with moderate sedation (intravenous fentanyl plus 
midazolam). Moderate sedative agents will be administered by endoscopists. 
Colonoscopy Procedures 
  Colonoscopies will be performed by two board-certified colonoscopists (Chi-Liang 
Cheng, Yen-Lin Kuo). Standard colonoscopes (CF-Q260AL/I; Olympus Medical Systems 
Corp., Tokyo, Japan) will be used. All colonoscopists have performed more than 1000 
conventional colonoscopies. Hands-on coaching by a WE expert (Felix W. Leung) to 
standardize the WE method has been completed. Each colonoscopist has or will have 
completed 100 cases of WE learning curve. Felix W. Leung will be involved in the 
study design, data analyses, and report preparation, but not in patient enrollment. All 
the colonoscopic procedures will be recorded. 
Antispasmodic medication will not be administered during colonoscopy 
examination. CO2 insufflation will be used for CO2 group and the withdrawal phase 
of the WE group. Colonoscopy will begin with the patients in the left lateral position. 
In the WE group, the air pump will be turned off before starting the procedure. 
During the insertion phase, air and residual water or feces in the rectum will be 
aspirated, and then the colon will be irrigated with warm water (32C-35C) using 

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flushing pumps (Olympus AFU-100; Olympus Corp.). There will be no restriction 
placed on the overall volume of water infused to achieve adequate cleansing. Suction 
and infusion of water will be performed sequentially because the endoscope has only 
one channel. Air pockets, when encountered, will be aspirated. When the cecum is 
reached and after most of the water is suctioned to collapse the cecal lumen, CO2 
will be opened. In the CO2 group, colonoscopy is performed in the usual fashion, 
with minimal insufflation required to aid insertion. Cleaning in the CO2 group will be 
performed entirely during withdrawal. In the CO2 group, suction marks will be 
deliberately produced in the hepatic flexure and cecum to mimic the same marks 
frequently produced by the WE technique. Cecal intubation will be defined as the 
passage of the scope tip beyond the ileocecal valve with visualization of the medial 
wall between the ileocecal valve and the appendix orifice.  
Upon arriving at the cecum, CO2 insufflation will be used in both groups and the 
scope will be withdrawn from the cecum to the hepatic flexure, with inspection of 
the mucosa at the same time. All polyps identified will be resected and sent for 
pathology evaluation. The most distal part of the hepatic flexure will be marked by a 
forceps biopsy and then the scope will be reinserted into the cecum by the first 
endoscopist using CO2 insufflation. A tandem inspection of the right colon will then 
be performed by a second endoscopist blinded to the insertion method in both study 
groups. All polyps found herein will be counted as the missed polyps. After the 
second withdrawal to the mark of distal hepatic flexure, the remainder of the colon 
will be examined in a standard manner by the first endoscopist. To assess the 
adequacy of blinding, the second endoscopist will be asked at the end of tandem 
right colon examination to guess which insertion method has been used. If less than 
66% of these answers are correct, then adequate blinding will be considered to have 

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been achieved.  
Polyp search and resection will be performed during the withdrawal phase in both 
groups. Insertion polypectomy will not be performed. All proximal colon polyps will 
be removed irrespective of their size and appearance. All diminutive polyps with 
hyperplastic appearance (based on narrow band imaging) in the rectosigmoid colon 
will be documented by photography and left alone. Polyp size will be determined by 
comparison with an opened biopsy forceps or a snare.  
In both groups, the following information will be recorded: bowel preparation 
quality using the Boston Bowel Preparation Scale (BBPS) score [29]; the total amount 
of sedative medications (in procedures with sedation); the length of colonoscopy 
reaching cecum; the amount of water infused and suctioned during insertion and 
withdrawal phases; the procedure time taken for insertion and withdrawal for the 
first examiner; the procedure time taken for tandem right colon inspection; the need 
of abdominal compression and/or positon change to assist colonoscopy insertion; 
the overall polyp number, size, histology and location; the missed right colon polyp 
number, size, histology and location.  
Definition 
Screening colonoscopy will be defined as either asymptomatic patients undergoing 
their first colonoscopic examination or patients with a history of negative screening 
colonoscopy undergoing their 5-year or 10-year follow-up examinations. Surveillance 
colonoscopy will be defined as patients with a history of colon polyps undergoing 
their follow-up examinations. Complete colonoscopy will be defined as successful 
cecal intubation. Insertion time will be defined as the time between the scope 
insertion and cecal intubation. Three stopwatches will be used to record the time 
taken for mucosal cleaning (water infusion and suction), mucosal inspection, and 

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polyp treatment respectively. Withdrawal time will be defined as the time from cecal 
intubation to the time when the colonoscope is withdrawn from the anus, including 
the time taken for mucosal cleaning, mucosal inspection, polyp biopsy and 
polypectomy. Total procedure time will be the sum of insertion time and withdrawal 
time. Three stopwatches will be used to record the time taken for mucosal cleaning, 
mucosal inspection, and polyp treatment, respectively, during the tandem right colon 
examination. Total duration of tandem right colon examination will be defined as the 
time of repeated examination from cecum to hepatic flexure by the blinded examiner, 
including the time taken for mucosal clearing, inspection and polyp treatment. 
Near-complete removal of infused water during insertion of WE is defined as ≥90% 
removal of infused water. Inspection times by the first and second endoscopists will 
be recorded. Comparable inspection times in the study and control groups will 
support the use of equivalent withdrawal inspection methods. 
All colonic polyps removed during procedures will be sent for histological 
examination with clear labeling of location and sequences of colonoscopy. The 
location of colonic polyps will be defined according to the anatomical distribution. 
Right colon will be defined as cecum, ascending colon, and hepatic flexure. Proximal 
colon will be defined as right and transverse colon. Diminutive polyps will be defined 
as polyps with size ≤5 mm. Small polyps will be defined as polyps with size 6-9 mm. 
Large polyps will be defined as polyps with size ≥10 mm. Adenomas will include all 
adenomas and sessile serrated adenoma. Advanced adenomas will be defined as 
those lesions with one of the following criteria: 1) lesions larger than 10 mm in 
diameter; 2) lesions with a villous component; 3) lesions with high-grade dysplasia; 
and 4) lesions with invasive features.  
ADR will be defined as the proportion of colonoscopies with at least one adenoma. 

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Advanced ADR will be defined as the proportion of colonoscopies with at least one 
advanced adenoma. Mean adenoma per procedure (MAP) will be defined as the total 
number of adenomas detected divided by the number of colonoscopies. Mean 
adenoma per positive procedure (MAP+) will be defined as the total number of 
adenoma detected divided by the number of colonoscopies in which at least one 
adenoma is found. Mean additional adenomas detected beyond the first adenoma 
per positive procedure (ADR-Plus) will be defined as the mean number of adenomas 
detected after the first adenoma in procedures in which at least one adenoma is 
found.  
Lesions detected on the tandem right colon examination will be used for the 
calculation of adenoma or polyp miss rate. Right colon AMR and hyperplastic polyp 
miss rate (HPMR) will be calculated as the number of adenomas and hyperplastic 
polyps missed in the first right colon examination divided by the total number of 
adenoma and hyperplastic polyps detected during both the first and tandem right 
colon examinations.  
Study Outcomes 
The primary outcome is the right colon combined AMR and HPMR. Secondary 
outcomes include right colon AMR, right colon HPMR, overall ADR, right colon ADR 
and HPDR after the first examination, combined right colon ADR and HPDR after the 
first and tandem examinations, overall advanced ADR, right colon advanced ADR, 
overall MAP, right colon MAP, overall MAP+, right colon MAP+, overall ADR-Plus, and 
right colon ADR-Plus. Procedure related parameters, including bowel cleansing, 
insertion and withdrawal times, duration of tandem right colon examination, volume 
of water infused and aspirated during insertion and withdrawal, and number of 
abdominal compressions and/or position change, are also evaluated. 

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Sample size estimation 
The sample size estimation is based on the assumption that WE colonoscopy 
reduces right colon combined AMR and HPMR compared to conventional CO2 
insufflation colonoscopy. We estimate the overall right colon combined AMR and 
HPMR in the CO2 group to be 30% [30,31]. According to our previous study, the 
average detected number of right colon adenoma and hyperplastic polyp is 0.8 per 
subject after first right colon examination [32]. To show a clinically important 
improvement of AMR reduction by the WE colonoscopy, we assume that WE 
colonoscopy should reduce the AMR by 15%. With a statistical power of 80% and a 
two-side significance level of 0.05, 131 patients will be needed in each study arm. To 
account for dropouts, incomplete procedures, and inadequate preparation, an 
additional 10% will be enrolled. Therefore, a total of 292 patients (146 patients in 
each group) will be enrolled. 
Statistical analysis 
Summary statistics will be presented as frequencies and percentages in the case of 
categorical variables and as the means with standard deviations (SD) in the case of 
continuous variables. Analysis will be performed by using an Intention-to-treat (ITT) 
approach. Interim analysis will be performed after enrollment of 131 patients. 
Student’s t-test for continuous factors, Wilcoxon rank sum test for ordinal variables 
(such as polyp size), and Chi-square test for categorical variables will be used to 
assess differences in demographic and clinical characteristics of patients in each 
group. Factors associated with adenoma detection by the first examiner will be 
identified by univariate analysis. Factors with a P value <0.1 on univariate analysis 
will be further entered into forward stepwise logistic regression analysis. The 
adjusted odds ratio with 95% confidence interval (CI) will be used to describe the 

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influence of various factors on adenoma detection. All statistical analyses will be 
performed by using SAS version 9.3 or later (SAS Institute Inc., Cary, NC, USA). The 
criterion for statistical significance will be P value <0.05. 
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