Water Exchange Improves Detection of Advanced Colorectal Neoplasia: Pooled Analysis of Four Randomized Trials.

1
Introduction
The primary goal of colonoscopy is to detect and, if possible, remove precancerous and cancerous lesions of the colon. Advanced adenoma—defined as an adenoma measuring ≥ 10 mm, containing high‐grade dysplasia, or exhibiting a prominent villous component—is a validated surrogate marker of colorectal cancer (CRC) risk. The estimated risk of progression from an advanced adenoma to CRC exceeds 25% over 10 years [1]. Patients with advanced adenomas also have an elevated risk of CRC among their first‐degree relatives [2]. Consequently, advanced colorectal neoplasia, which includes advanced adenomas and CRC, is the main target of CRC screening programs and is used to assess new screening technologies [3].
The adenoma detection rate (ADR), defined as the proportion of patients in whom at least one adenoma is detected, is a key quality indicator of colonoscopy. A low ADR has been associated with an increased risk of post‐colonoscopy interval cancer and CRC‐related mortality [4]. Recent advances—including artificial intelligence, mucosa‐exposing devices, high‐definition endoscopes, prolonged withdrawal time, improved bowel preparation, and endoscopist training—have led to rising ADRs during screening colonoscopy [5]. However, this increase is largely attributed to the detection of small, non‐advanced adenomas [6]. Whether a higher ADR is also linked to a higher advanced neoplasia detection rate (ANDR, the proportion of patients with at least one advanced adenoma or CRC) remains uncertain [7].
Water exchange (WE) is an innovative colonoscopy insertion technique with established benefits. Randomized controlled trials (RCTs) and meta‐analyses have demonstrated that WE significantly increases ADR compared to conventional air or carbon dioxide insufflation colonoscopy [8, 9, 10]. However, its effect on ANDR remains unclear. One RCT with blinded endoscopists found that while the overall advanced adenoma detection rate (AADR) was similar between WE and air insufflation, detection was higher in the right colon with WE [9]. A pooled analysis of six published RCTs also reported increased overall ADR and AADR with WE, but regional data were not specified—likely due to heterogeneity in study location, population, and design [11]. The specific impact of WE on ANDR, particularly in the proximal colon where interval cancers more frequently arise [12], remains to be clarified.
To address this gap, we conducted a pooled analysis of data from four RCTs (NCT01894191, NCT02737514, NCT01535326, and NCT01699399) comparing WE and air insufflation. Although these trials had different primary endpoints, they shared similar designs, patient populations, and endoscopists, allowing for integration of data to enhance statistical power. We tested the hypothesis that WE increases ANDR.

2
Materials and Methods
2.1
Aggregated Studies
Four RCTs comparing WE with air insufflation were conducted by our group between February 2012 and February 2020 in Chiayi and Hualien, Taiwan. The primary endpoints of these trials were: the proportion of patients reporting no insertion pain [13], overall ADR [8], right colon ADR [14], and the proportion of patients completing unsedated colonoscopy with the option of on‐demand sedation [15]. Patients underwent colonoscopy under varying sedation levels (unsedated, minimally sedated with 25 mg intramuscular meperidine, or fully sedated). Indications for colonoscopy included screening, surveillance, and diagnostic evaluation. All studies were registered on ClinicalTrials.gov and approved by the respective institutional review boards. Written informed consent was obtained from all participants. The study protocols conformed to the ethical guidelines of the 1975 Declaration of Helsinki and were approved by the Ethics Committee of Dalin Tzu Chi Hospital (approval number: B11004011).

2.2
Trial Registration
The included randomized controlled trials were registered at ClinicalTrials.gov (NCT01894191, NCT02737514, NCT01535326, and NCT01699399).

2.3
Bowel Preparation and Colonoscopy Procedure
All patients received a standard split‐dose bowel preparation consisting of 2 L of polyethylene glycol plus 10 mg of bisacodyl. The decision to use full sedation with propofol (Diprivan; AstraZeneca, Stockholm, Sweden) was made by the patient.
Colonoscopy was performed using standard colonoscopes (EC‐590WM, Fujinon, Tokyo, Japan; CF‐H260 or CF‐HQ290, Olympus, Tokyo, Japan). Cecal intubation was defined as insertion of the colonoscope tip to the cecal base, confirmed by visualization of the appendiceal orifice and/or ileocecal valve. If the assigned method failed, the endoscopist was permitted to switch to an alternative insertion technique.
In the WE group, residual fecal material and air were suctioned, followed by infusion of clean water to facilitate advancement. The infused water was almost completely aspirated to maintain a collapsed lumen. Warm tap water was infused using a foot‐switch‐controlled pump (JW2, Fujinon, or OFP‐2, Olympus). Upon reaching the cecum, air insufflation was initiated to enable inspection during withdrawal. In the air insufflation group, minimal air was used for luminal distension during insertion. Polyp detection and removal occurred primarily during withdrawal. Histopathological evaluations were conducted by a pathologist blinded to the insertion method.

2.4
Outcome Measures and Data Collection
The primary outcome was the ANDR, defined as the proportion of patients with advanced adenomas (≥ 10 mm, high‐grade dysplasia, or a significant villous component) or colorectal cancer. Lesion location was recorded.
Demographic data (age, sex, height, weight), clinical history (e.g., abdominal or pelvic surgery, constipation, chronic laxative use), and procedural data (e.g., sedation, cecal intubation time, withdrawal time, total procedure time, insertion length) were collected. Withdrawal time included time spent on polypectomy, inspection, and cleaning. The volume of water infused and aspirated during insertion was recorded at cecal arrival. Body mass index (BMI) was calculated as weight (kg) divided by height squared (m2).
Bowel preparation quality was graded using the Boston Bowel Preparation Scale (BBPS), which assigns segmental scores from 0 to 3 to each colonic region (right, transverse, and left), yielding a total score from 0 to 9 [16].
For minimally sedated or unsedated patients, a study nurse asked each patient to rate the severity of insertion pain using a 0–10 numeric scale (0 = no pain, 10 = most severe) every 2 min or whenever discomfort was reported. Patient satisfaction was assessed using a similar scale (0 = not satisfied at all, 10 = most satisfied). After the procedure, patients were asked about their willingness to undergo the same method for future colonoscopies.

2.5
Statistical Analysis
Patient characteristics were summarized using descriptive statistics. Pooled data were reported as sample size–weighted means and standard deviations (SD) for continuous variables, or as frequencies and percentages for categorical variables. The normality of continuous variables was assessed using the Shapiro–Wilk test. Normally distributed data were analyzed with the independent‐samples Student's t‐test, whereas non‐normally distributed data were compared using the Mann–Whitney U test. Categorical variables were compared between groups using the Chi‐square test, and when the expected cell counts were less than five, Fisher's exact test was applied. Statistical analyses were conducted using IBM SPSS Statistics for Windows, version 24.0 (IBM Corp., Armonk, NY, USA). A two‐sided p < 0.05 was considered statistically significant for all analyses.

3
Results
A total of 1048 patients were included in the analysis (522 in the air insufflation group and 526 in the WE group). Baseline demographic characteristics, including age, sex, colonoscopy indications, and sedation status, were comparable between the two groups (Table 1).
3.1
Procedural Outcomes
Table 2 summarizes the procedure‐related outcomes. The final cecal intubation rates were similar between groups. However, the intention‐to‐treat cecal intubation rate with the assigned method was significantly higher in the WE group than in the air insufflation group (96.4% vs. 90.4%; p < 0.001). Although the cecal intubation time was longer in the WE group (mean ± SD: 15.0 ± 5.9 min vs. 8.4 ± 5.9 min; p < 0.001), the withdrawal time was shorter (12.3 ± 8.5 min vs. 12.7 ± 6.9 min; p = 0.023), as was the inspection time (6.4 ± 2.5 min vs. 7.1 ± 2.7 min; p < 0.001).
The WE group had significantly greater water infusion volumes (1160.9 ± 492.0 mL vs. 83.1 ± 267.5 mL; p < 0.001). The aspirated‐to‐infused water volume ratio in the WE group was 106% (1236 mL/1161 mL), indicating adequate technique implementation. Total and segmental Boston Bowel Preparation Scale (BBPS) scores were significantly higher in the WE group, suggesting enhanced cleansing.
Fewer patients in the WE group required manual abdominal compression (59.5% vs. 72.0%; p = 0.001) or position changes (9.1% vs. 24.5%; p < 0.001). The scope length at the cecum was shorter in the WE group (77.8 ± 13.7 cm vs. 80.6 ± 16.4 cm; p = 0.003), and the maximum insertion pain score was lower (1.7 ± 2.5 vs. 3.6 ± 3.0; p < 0.001). Patient satisfaction and willingness to repeat the procedure did not differ significantly between groups.

3.2
Detection Outcomes
As shown in (Table 3), the overall adenoma detection rate (ADR) was significantly higher in the WE group compared to the air insufflation group (54.0% vs. 45.7%; p = 0.007). When stratified by colonic segment, right colon ADR was significantly higher in the WE group (29.7% vs. 22.1%; p = 0.005).
The overall ANDR was significantly greater in the WE group (17.9% vs. 13.4%; p = 0.047). When stratified by colonic segment, the transverse colon ANDR was higher in the WE group (3.4% vs. 1.5%; p = 0.049). ANDR in the proximal colon (cecum to splenic flexure) was also significantly higher in the WE group (8.7% vs. 4.6%; p = 0.007). Similarly, the proximal colon AADR was higher with WE (8.0% vs. 4.4%; p = 0.017).
The WE group demonstrated significantly higher serrated lesion detection rates compared with the air group in the right colon (13.5% vs. 8.4%, p = 0.009), descending colon (4.6% vs. 2.3%, p = 0.044), and proximal colon (18.6% vs. 14.0%, p = 0.042).

4
Discussion
In this pooled analysis of four RCTs, we found that WE significantly increased both the overall and proximal colon ANDR compared to air insufflation. Specifically, overall, ANDR was 17.9% in the WE group versus 13.4% in the air insufflation group (p = 0.047), with the difference primarily observed in the proximal colon (8.7% vs. 4.6%; p = 0.007). In addition, WE significantly improved the overall ADR (54.0% vs. 45.7%; p = 0.007).
The ADR is a well‐established quality indicator for colonoscopy and is independently associated with the risk of interval colorectal cancer [17]. However, ADR alone does not fully reflect variability in endoscopic performance. For example, Wang et al. demonstrated that, despite similar ADRs, endoscopists at teaching institutions achieved significantly higher AADR, mean adenomas per colonoscopy (MAP), and ADR‐Plus—defined as the mean number of adenomas detected after the first adenoma in procedures where at least one was found—compared to those at non‐teaching hospitals [18]. These findings underscore the importance of incorporating additional detection metrics, such as AADR and ANDR, when evaluating both procedural techniques and endoscopist performance.
Several technological advancements—such as computer‐aided detection (CAD), mucosal exposure devices (e.g., Endocuff), and enhanced imaging modalities—have been developed to improve ADR. However, their impact on AADR or ANDR has been inconsistent. In some trials, only the combination of CAD and mucosal exposure devices yielded a significantly higher AADR [19, 20], while other studies showed no difference with CAD alone [21, 22]. A large multicenter trial demonstrated an increase in AADR with Endocuff‐assisted colonoscopy [23], and cap‐assisted colonoscopy was also associated with higher AADR in one study [24]. These mixed results contrast with the more consistent findings seen with WE.
One European RCT showed that WE significantly increased right‐sided AADR compared to air insufflation (6.1% vs. 2.5%; p = 0.03) [9]. A pooled analysis of six RCTs involving over 5400 patients confirmed that WE significantly increased both ADR and AADR [11]. Similarly, a network meta‐analysis including 21 RCTs found that WE was more effective than Endocuff or cap in improving AADR [25]. Our current study, which includes detailed segmental analysis, supports these findings and suggests a particular benefit of WE in the proximal colon—an area where interval cancers are more likely to arise [12].
Detection of advanced neoplasia has critical implications for CRC prevention, surveillance intervals, and familial risk stratification. Studies have shown that patients with advanced adenomas at baseline are at higher risk of developing advanced neoplasia during follow‐up [26]. Moreover, first‐degree relatives of patients with CRC or advanced adenomas are at elevated risk themselves, justifying earlier or more frequent screening [27].
Despite the effectiveness of colonoscopy, its protective effect against proximal colon cancer remains suboptimal [28]. Interval cancers are more likely to occur in the proximal colon, often due to missed lesions during baseline colonoscopy [29, 30]. By enhancing proximal colon ANDR, WE may help reduce the incidence of interval cancers.
One plausible mechanism for improved detection with WE is enhanced bowel cleanliness. In this study, the WE group had significantly higher BBPS scores, consistent with previous literature [31]. RCTs have shown that better bowel preparation is associated with increased AADR [32]. Furthermore, reduced multitasking and improved mucosal visualization during WE may contribute to higher detection rates [33, 34].
WE is associated with a longer insertion time due to the need for water infusion and suction. However, both withdrawal and inspection times were shorter in the WE group. Additionally, WE provided greater patient comfort during unsedated or minimally sedated procedures, as evidenced by lower insertion pain scores, shorter scope length at the cecum, and reduced need for manual abdominal compression or position changes.
This study has several strengths. It is based on pooled data from four RCTs conducted by the same research group, ensuring consistency in methodology. All patients received a standardized bowel preparation regimen, reducing variability in cleanliness. Detailed data on lesion location and histology allowed for comprehensive analysis.
However, some limitations should be noted. While this is a pooled analysis of RCTs, ANDR was not the primary endpoint in the original trials. Moreover, blinding of endoscopists to insertion method occurred in only one of the four studies, which could introduce detection bias. Nevertheless, two of the included trials focused on patient comfort rather than detection outcomes, which may mitigate this concern. Sedation practices varied among patients, ranging from unsedated or minimally sedated procedures to full sedation. Although randomization resulted in comparable baseline sedation rates between the water exchange and air insufflation groups, differences in sedation level could theoretically influence patient cooperation and endoscopist performance and should be considered when interpreting detection outcomes. The four RCTs informing the manuscript compared WE to air, not CO2 insufflation. This may have influenced the analysis of patient discomfort, as CO2 is associated with lower levels of post‐procedural discomfort and is typically used in modern endoscopy units. We did not analyze outcomes according to endoscopist expertise, which is a known confounding factor influencing polyp detection rates and patient comfort. This limitation should be addressed in future studies.
In conclusion, this pooled analysis of four randomized controlled trials demonstrated that WE colonoscopy significantly increases the detection of advanced colorectal neoplasia, particularly in the proximal colon, compared to air insufflation. These findings suggest that WE may enhance the preventive effectiveness of colonoscopy and could play a critical role in reducing the incidence of interval colorectal cancers. Further prospective studies are warranted to confirm these results and evaluate long‐term clinical outcomes.

Funding
Supported by research fund from the Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation. Dr. Leung's research and publication effort is supported by VA Clinical Merit and ASGE Clinical Research Funds.

Conflicts of Interest
The authors declare no conflicts of interest.