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High definition plus colonoscopy combined with i-scan tone enhancement vs. high definition colonoscopy for colorectal neoplasia: A randomized trial
Digestive and Liver Disease 46 (2014) 991–996
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Digestive and Liver Disease journal homepage: www.elsevier.com/locate/dld
Digestive Endoscopy
High definition plus colonoscopy combined with i-scan tone enhancement vs. high definition colonoscopy for colorectal neoplasia: A randomized trial Arthur Hoffman a,b,∗ , Linn Loth a , Johannes Wilhelm Rey a,b , Fareed Rahman a , Martin Goetz b,d , Torsten Hansen c,e , Achim Tresch f , Theresa Niederberger g , Peter Robert Galle b , Ralf Kiesslich a,b a
St. Mary’s Hospital, Department of Medicine, Frankfurt, Germany 1. Medical Department, Johannes Gutenberg University Mainz, Germany c Institute of Pathology, Johannes Gutenberg University Mainz, Germany d 1. Medical Department, University of Tübingen, Germany e Clinic Lippe, Institute of Pathology, Detmold, Germany f Max Planck Institute, Cologne, Germany g Gene Zentrum Ludwig-Maximilians-Universität München, Germany b
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Article history: Received 25 February 2014 Accepted 21 July 2014 Available online 20 August 2014 Keywords: Adenoma detection rate Adenoma miss rate I-scan technique Red flag technology
a b s t r a c t Background: High definition endoscopy is the accepted standard in colonoscopy. However, an important problem is missed polyps. Aims: Our objective was to assess the additional adenoma detection rate between high definition colonoscopy with tone enhancement (digital chromoendoscopy) vs. white light high definition colonoscopy. Methods: In this prospective randomized trial patients were included to undergo a tandem colonoscopy. The first exam was a white light colonoscopy with removal of all visualized polyps. The second examination was randomly assigned in a 1:1 ratio as either again white light colonoscopy (Group A) or colonoscopy with tone enhancement (Group B). Primary endpoint was the adenoma detection rate during the second withdrawal (sample size calculation – 40 per group). Results: 67 lesions (Group A: n = 34 vs. Group B: n = 33) in 80 patients (mean age 61 years, male 64%) were identified on the first colonoscopy. The second colonoscopy detected 78 additional lesions: n = 60 with tone enhancement vs. n = 18 with white light endoscopy (p < 0.001). Tone enhancement found more additional adenomas (A n = 20 vs. B n = 6, p = 0.006) and identified significantly more missed adenomas per subject (0.5 vs. 0.15, p = 0.006). Conclusions: High definition plus colonoscopy with tone enhancement detected more adenomas missed by white light colonoscopy. © 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
1. Introduction Colorectal cancer (CRC) is one of the most common malignant tumours in the world; advanced tumours still have a disappointing 5-year survival rate [1,2]. Timely detection and removal of all premalignant lesions help to prevent the disease. Colonoscopy is the gold standard for CRC screening because it permits detection and removal of pre-cancerous polyps during the examination [3–5].
∗ Corresponding author at: St. Marienkrankenhaus Frankfurt, Richard-WagnerStr. 14, 60318 Frankfurt, Germany. Tel.: +49 15111628399; fax: +49 69 14631577. E-mail address: [email protected] (A. Hoffman).
However, not all adenomatous polyps are identified during screening and surveillance colonoscopy; some patients develop colorectal cancer even under colonoscopic surveillance [6]. This may be caused by the rapid progression of adenomas or overlooked colorectal lesions. A meta-analysis of 6 studies by Van Rijn et al., in which patients went through two colonoscopies the same day, reported a polyp miss rate of 22% [5]. Efforts to improve endoscopic detection of adenomatous polyps include changes in procedural aspects (increased withdrawal time, looking behind colonic folds) and the use of advanced optical technologies. The aims were to reduce miss rates of adenomas and optimize prevention of colorectal cancer.
http://dx.doi.org/10.1016/j.dld.2014.07.169 1590-8658/© 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
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A well established technology today is high-definition white light (HDWL) endoscopy, which can be used with or without optical filters to selectively illuminate tissue. Of the new endoscopic imaging techniques, i-scan is a digital contrast method with three modes of image enhancement [7]. I-scan 1 enhances light-dark contrast by obtaining luminance intensity data for each pixel and applying an algorithm that allows detailed observation of the structure of the mucosal surface, whereas i-scan 2/3 dissects and analyzes the individual RGB components of a normal image and recombines the components into a single, new colour image. This mode has been designed to increase mucosal and vascular contrast between suspicious and normal tissue, as in vivo chromoendoscopy does. The exact i-scan settings are recommended by the manufacturer’s protocol. Adenoma detection rates with various white light endoscopy methods have been compared in several studies, but just a few studies have addressed the usefulness of optical filters during withdrawal in a back-to-back manner. The majority of studies report controversial results concerning the usefulness of filters for the detection of colonic lesions. We conducted, for the first time, a randomized controlled trial with the primary aim of prospectively determining whether the use of i-scan 2 colonoscopy is associated with a higher adenoma detection rate in average-risk individuals undergoing colon cancer screening and surveillance compared with the widely used procedure of high-definition white light colonoscopy.
the endoscope was inserted into the cecum using a white light endoscopy image. In the study group all subjects underwent a complete standard colonoscopy as the first procedure. Immediately after the standard colonoscopy, a complete procedure under i-scan 2 (TE) was performed by the same endoscopist. In the control group all subjects underwent a standard colonoscopy, and a complete standard procedure was performed again by the same endoscopist. Withdrawal times were targeted to exceed 6 min and were required to be similar in both arms [8]. The examination time included the time required for withdrawing the instrument from the cecum to the rectum, with the exception of the time taken for any polypectomy or biopsy performed during withdrawal. The goal was to recognize any circumscribed mucosal alteration (detection of any type of lesion). Missed lesions were defined as those identified only during the second withdrawal. The size and location of all lesions were recorded and further characterized using a modified version of Kudo’s classification (Kudo’s pit pattern classification) [9]. Lesions were classified in accordance with the Paris classification of early cancers [10,11]. The endoscopist rated a lesion adenomatous or non-adenomatous in the HD group, based on the above mentioned criteria. All polyps detected during withdrawal were removed, irrespective of size, colour, or subjective interpretation, and then sent for final histological confirmation. 2.2. High-definition colonoscopy
2. Patients and methods A single-centre trial was performed at the interdisciplinary endoscopic unit at Johannes Gutenberg University of Mainz. Patients were selected from those scheduled to undergo routine screening or surveillance colonoscopy at the division of gastroenterology and hepatology, University Hospital of Mainz, who provided informed consent. Patients were eligible for the study (inclusion criteria) when they had an indication for colon cancer screening, postpolypectomy surveillance, or a positive occult blood test. Patients were excluded when they were pregnant, had a previous history of colorectal cancer, previous surgery of the colon, known inflammatory bowel disease, acute gastrointestinal bleeding, a genetic risk of colon cancer, impaired coagulation parameters (INR > 1.74, PTT > 50 s), or when their bowel preparation did not permit complete inspection of the colon. The study was approved by the local ethics committee of Rheinland-Palatinate, Germany (No. 837.238.09 6744, ClinicalTrials.gov Identifier: 837.386.07), and was conducted between May 2009 and July 2010. Eighty consecutive patients fulfilled the criteria and were randomly assigned at a 1:1 ratio to undergo complete colonoscopy in the study group or in the control group. All colonoscopies were performed by four experienced colonoscopists (RK, AH, MG, FR), who were highly familiar with chromoendoscopy and HD+ endoscopy using the Pentax EPKi processor (Pentax, Japan). All procedures were performed using propofol 1% (Disoprivan® , AstraZeneca, Switzerland) or, in the presence of a contraindication, midazolam (Dormicum® , Roche Pharma AG, Switzerland) for sedation.
2.1. Examination technique All consecutive patients were randomized in a 1:1 manner to group A (the study group) or group B (controls). In all patients,
Of several image-enhancing techniques, i-scan is a digital image processor that provides high-resolution enhanced images using different software algorithms with real-time image mapping (RIM) technology embedded in the endoscopic processor (EPKi). Thus iscan combines high-resolution endoscopy with 3 adjustable modes of image enhancement (Fig. 1S): surface enhancement (SE), contrast enhancement (CE), and tone enhancement (TE) [12]. The TE mode is similar to narrow band imaging (NBI, Olympus) and Fuji intelligent chromoendoscopy (FICE, Fuji). Therefore, it is very suitable for the characterization of lesions. Although each mode can be used alone, i-scan incorporates the three software algorithms into three distinct modes for the endoscopist: i-scan 1 mode, i-scan 2 mode, and i-scan 3 mode. I-scan 1 was designed as a special mode for detection. I-scan 2 and 3 also employ SE and CE, but i-scan 2 adds tone enhancement to dissect out the dominant red and leave an elevated blue/green contrast. The result is enhanced vessel structure and better visualization of minute mucosal structures and margins of all identified lesions (Fig. 1). It appears that especially i-scan 2 has the potential to enhance the detection of colorectal lesions because the normal mucosa appears in shades of yellow and green, whereas all lesions with concomitant hypervascularization appear in shades of red (Fig. 2). As this mode provides a more clear view of mucosal changes, it has the potential of a ‘red flag’ technique. 2.3. Outcome measures The primary aim of the study was to prospectively evaluate additional adenoma detection rates achieved by HD+ definition plus colonoscopy with the feature of tone enhancement TE vs. white light HD colonoscopy, and polyp miss rates between the two groups. The adenoma detection rate was calculated by dividing the total number of patients with adenomas at insertion and during withdrawal by the total number of patients. The adenoma miss rate was calculated by dividing the total number of adenomas missed during the first withdrawal by the total number of adenomas found at the first or second withdrawal.
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Fig. 1. Small adenomas before and after tone enhancement with enhanced vessel structure and better demarcation.
Fig. 2. Non-polypoid lesions (type II according to Paris classification) before and after tone enhancement.
2.4. Calculation of sample size Our preliminary data suggested that miss rates of white light endoscopy and red flag technologies for the detection of colon adenomas were about 30.0% and 35.0%, respectively. With the alpha error set to 0.05 (two-sided) and power to 0.8, the number of required cases was estimated to be 60 patients (30 patients for each group). Twenty-five percent of the enrolled cases were expected to drop out of the study; thus the target case number was 75. Finally 80 patients were enrolled and analyzed in the study. Sample size calculations were based on the simplified assumption of statistical independence among polyps from the same patient, and use of the 2 test. A p-value <0.05 was considered to be statistically significant. To compare the distributions of confounding variables and their influence on detection rates of polyps or adenomas, the non-parametric Mann–Whitney U-test (for continuous covariates) and the 2 -test (for categorical covariates) was used. Both, the Mann–Whitney U-test and the 2 -test were also used to compare the original detection and miss rates, as well as a binarized version, between
the two groups. Furthermore, the influence of first-run results on second-run results was analyzed using logistic regression. Logistic regression was also used to analyze the influence of the second withdrawal time, which was not equally distributed in the two groups. For purposes of statistical analysis, individual lesions were assumed to constitute statistically independent observations even when more than one lesion was present in a single patient. The per-patient miss rate for i-scan 2 was defined as the number of all patients with no polyps detected by i-scan 2 in the first procedure and at least one polyp detected by subsequent white light colonoscopy. The per-patient polyp miss rate for white light colonoscopy was defined similarly, as were adenoma and hyperplastic polyp miss rates. 3. Results One hundred patients were deemed eligible for the study; 20 patients were excluded because of failure of cecal intubation (n = 5), poor or inadequate bowel preparation (n = 12), or suspected
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Fig. 3. Flow diagram of the progress through the phases of the randomized trial; (n = patients) according to the CONSORT statement [6]. HD, high definition; TE, tone enhancement.
inflammatory bowel disease (n = 3). Thus, 80 patients were included, of whom 40 were randomly assigned to the control group and 40 to the study group (Fig. 3). No other procedural complications occurred. All endoscopists performed both types of colonoscopies. No significant differences existed among the studied groups in age, sex, or bowel preparation status. The detection rate per patient during the first withdrawal did not differ significantly between groups (8 in the study group vs. 11 in controls). During the second withdrawal the number of patients with at least one adenoma increased significantly in the study group using TE (16 vs. 5, p < 0.05 Chi-square test). The total adenoma detection rate during the first withdrawal also did not differ significantly between the study group and controls (12 vs. 14), but did increase significantly in the study group during the second withdrawal (20 vs. 6, p < 0.05, Chi-square test). By analogy, the total number of lesions per group increased significantly between the first (33 in the study group vs. 34 in controls) and the second withdrawal under study conditions (60 in the study group vs. 18 in controls, p < 0.05, Chi-square test, Supplementary Tables S1–S3). The polyp detection rate was not significantly different between the control and study group during the first withdrawal (Pearson’s Chi-square test p > 0.05). In the control group the adenoma detection rate was 27.5%; 11 patients had at least one adenoma and the total number of detected adenomas was 14. In the study group the detection rate was 20.0%; 8 patients had at least one adenoma and the total number of detected adenomas was 12. During the second withdrawal the adenoma detection rate was significantly different between the two study groups (p < 0.05, Chisquare test). The control group revealed 5 patients with at least one adenoma and 6 adenomas in all, whereas the study group contained
16 patients with at least one adenoma and 20 adenomas in all (Fig. 2S). The adenoma miss rate was 30.0% in the control group and 62.5% in the study group (p < 0.05, Chi-square test). The subgroup analysis for non-polypoid lesions (type II according to Paris classification) showed that the application of tone enhancement during withdrawal in the study group significantly reduced the risk of missing a non-polypoid adenoma (Pearson’s Chi-square test p < 0.05) and more then 70% of all flat lesion were smaller than 5 mm (Supplementary Table S4). To identify risk factors for missing a polyp or adenoma during the first withdrawal, multivariate analyses were performed for the per-polyp miss rate, with adjustments for age, sex, bowel preparation, and missed polyp or adenoma characteristics, including location and histology. The distribution and influence of the parameters were tested (Mann–Whitney Utest and Chi-square test) either equally or without influence on detection rates. There were no differences between groups in regard of the location of polyps or between the first and second withdrawal. However, a significant difference was noted between the second withdrawal time in the study and control group (Fig. 3S). Since any abnormality influenced the examination time, the influence was calculated using linear regression for the first run; the second run was corrected with this coefficient. Thus, the detection rate of adenomas was not influenced by the longer second withdrawal time in the study group on linear regression (p > 0.52). The examination time did not influence detection rates (Chi-square test p = 0.946) (Fig. 4S). In the study group the histology could be predicted with high accuracy (86.3%). The sensitivity and specificity of i-scan 2 for the characterization of the detected colon polyps were 78% and 93%, respectively.
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4. Discussion Colorectal cancer (CRC) is the second leading cause of cancer in the Western world [13–15]. More than 90% of CRC incidents develop over several years from polyps that grow in the colon [15–18]. Effective detection and subsequent removal of the polyps prevent the disease. Although colonoscopy with adenoma removal can prevent colorectal cancer in as many as 76–90% of cases, we know that some patients undergoing colonoscopy with adenoma removal still develop colorectal cancer before the surveillance interval, particularly in the right side of the colon [17–19]. The development of de novo cancer before this interval may be explained by the rapid progression of adenomas, their incomplete removal, or the fact that colonoscopy is not infallible as regards the detection of all adenomas. Studies that use adenoma detection rates as a marker of the quality of colonoscopy have clearly shown that low adenoma detection rates (and presumably high miss rates) are a very good marker of the risk of interval colon cancers. However, we also know that lesions can be missed during routine colonoscopy [20]. In a prospective randomized back-to-back trial, we registered a significant improvement in adenoma detection rates and reduced miss rate by using TE during the entire withdrawal step. Polyp miss rates during the first withdrawal were similar in both groups (27.5% in controls vs. 20.0% in the study group), in accordance with other published studies. A meta-analysis of 5 studies by Van Rijn et al., in which 465 patients underwent two colonoscopies in the same day, reported an overall polyp miss rate of 22% [5]. A clinical study by Rex et al., in which back-to-back colonoscopy was performed the same day in 183 patients, reported an overall adenoma miss rate of 24% [6]. A back-to-back same-day colonoscopy study in 286 patients by Heresbach et al. reported miss rates of 28% for polyps and 20% for adenomas during the first colonoscopy [21]. Deenadayalu et al. randomized 50 patients to undergo tandem SDWL colonoscopies with a standard angle (140-degree field of view) and a wide angle (170-degree) colonoscope. The miss rate for adenomas with both methods was estimated to be 30% [22]. In all of these studies, adenoma miss rates were stratified by size: the rate was 2% for adenomas greater than 10 mm, 13% for those measuring 6–10 mm, and 26% for those measuring 1–5 mm. The authors concluded that adenoma miss rates were higher for smaller polyps. The development of cancer before this interval may be explained by the rapid progression of adenomas or their incomplete removal, as well as the fact that colonoscopy is not always infallible in the detection of small adenomas. Thus, many efforts have been made to maximize the sensitivity of colonoscopy. Although small adenomas as such may not be clinically important, they are good surrogate markers of the quality of colonoscopy and the effectiveness of colon cancer prevention. In the recent past, chromoendoscopy has enhanced the detection of neoplasia in the colon, but the technique is inconvenient, time consuming, and often impractical in clinical routine [23]. To overcome this inconvenience, several alternative approaches have been introduced to enhance the contrast of the mucosal surface without the use of dye, including applications such as narrow band imaging (NBI: Olympus Tokyo, Japan), Fujinon imaging colour enhancement (FICE: Fujinon, Tokyo, Japan) or i-scan (PENTAX, Tokyo, Japan) [24–26]. The effectiveness of such image-enhanced endoscopy has been well documented in a plethora of studies. NBI has been the most extensively studied in regard of adenoma detection [27–33,7,34]. While older studies found no significant difference in overall adenoma detection rates during the withdrawal phase, recent investigations have been very promising in regard of improving the detection rate of colorectal adenoma [31,35]. Their
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results suggest that NBI is superior when utilized for adenoma detection, and the studies have demonstrated adenoma miss rates of 40–46% for white light endoscopy when a second examination was performed with NBI. In a recent study by Gross, the estimated polyp miss rates were as high as 27% and 58% for standard white light and HD-NBI [36]. The results of our second withdrawal were not only similar, but also showed a higher miss rate for adenomas on comparison of white light imaging and the use of i-scan 2 as virtual chromoendoscopy (30.0% vs. 62.5%). The number of polyps missed in our control group were small. The importance of such lesions is still debated. The current recommendation is to remove all adenomatous polyps. In our last published study we could prove the advantage of i-scan 1 (surface enhancement) for detection while i-scan 2/3 was used for characterization [37]. Using TE (i-scan 2) for this purpose, we observed that all minute mucosal lesions were enhanced in terms of subtle colour changes: these appeared reddish whereas normal mucosa appeared yellowish-green. However, the practical usefulness of TE for screening colonoscopy has not been investigated yet. All these facts seem to make this filter useful for better detection, in the manner of a red flag technique. So far (auto-) fluorescence imaging (AFI) has been a red flag technique [38]. The adenoma miss rates of AFI and HD endoscopy were 20% and 29%, respectively. The most important drawback of AFI was its high false positive rates. Among all of these image-enhancing techniques, i-scan technology is classified as a digital contrast method with three modes of image enhancement. Several studies reported real-time histologic prediction of colorectal lesions by using i-scan 2/3 [39,40]. In our study we registered a sensitivity of 82% and a specificity of 96% for the prediction of adenomatous polyps when the i-scan modes were used [37]. Lee et al. reported a sensitivity of 94.6%, a specificity of 86.4%, and an overall accuracy of 90.7% for the prediction of adenomas using i-scan for discrimination [39]. However, the histologic examination for colorectal lesions remains the standard criterion for differentiating non-neoplastic lesions from neoplastic ones. I scan 2 has the potential to minimize costs and complications associated with endoscopic biopsy and polypectomy. Moreover, we should be more prudent in incorporating the routine use of pancolonic tone enhancement (i-scan 2) in colorectal screening. In summary, our tandem colonoscopy trial suggests that the use of i-scan enhanced colonoscopy may increase detection rates for colorectal polyps and, importantly, reduce miss rates for adenomas compared with older and widely used versions of standard white light colonoscopy. The study was conducted at a single academic institution by a few endoscopists. Although randomized tandem design is considered to be the most reliable method for evaluating different modalities, a study performed at a single academic institution by a few endoscopists is prone to limitations. Although diagnostic criteria were adopted on the basis of previous validated classifications, the endoscopist factor may have influenced the detection rate. Another potential bias of the study is the fact that both endoscopic examinations were performed by the same endoscopist and the second endoscopic diagnosis was therefore influenced by the findings of the first one. Another noteworthy drawback of the current study is that the efficacy of i-scan 2 in detecting colorectal adenoma is limited, even for experienced endoscopists. The latter appeared to empirically identify many adenomas, including flat and depressed ones. For better objectivity, pancolonic i-scan 2 should be used by less experienced endoscopists to ease the detection of colorectal adenomas, especially flat and depressed ones. Finally, large-scale multicenter trials will be needed to establish the usefulness of i-scan in practice
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Digestive and Liver Disease journal homepage: www.elsevier.com/locate/dld
Digestive Endoscopy
High definition plus colonoscopy combined with i-scan tone enhancement vs. high definition colonoscopy for colorectal neoplasia: A randomized trial Arthur Hoffman a,b,∗ , Linn Loth a , Johannes Wilhelm Rey a,b , Fareed Rahman a , Martin Goetz b,d , Torsten Hansen c,e , Achim Tresch f , Theresa Niederberger g , Peter Robert Galle b , Ralf Kiesslich a,b a
St. Mary’s Hospital, Department of Medicine, Frankfurt, Germany 1. Medical Department, Johannes Gutenberg University Mainz, Germany c Institute of Pathology, Johannes Gutenberg University Mainz, Germany d 1. Medical Department, University of Tübingen, Germany e Clinic Lippe, Institute of Pathology, Detmold, Germany f Max Planck Institute, Cologne, Germany g Gene Zentrum Ludwig-Maximilians-Universität München, Germany b
a r t i c l e
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Article history: Received 25 February 2014 Accepted 21 July 2014 Available online 20 August 2014 Keywords: Adenoma detection rate Adenoma miss rate I-scan technique Red flag technology
a b s t r a c t Background: High definition endoscopy is the accepted standard in colonoscopy. However, an important problem is missed polyps. Aims: Our objective was to assess the additional adenoma detection rate between high definition colonoscopy with tone enhancement (digital chromoendoscopy) vs. white light high definition colonoscopy. Methods: In this prospective randomized trial patients were included to undergo a tandem colonoscopy. The first exam was a white light colonoscopy with removal of all visualized polyps. The second examination was randomly assigned in a 1:1 ratio as either again white light colonoscopy (Group A) or colonoscopy with tone enhancement (Group B). Primary endpoint was the adenoma detection rate during the second withdrawal (sample size calculation – 40 per group). Results: 67 lesions (Group A: n = 34 vs. Group B: n = 33) in 80 patients (mean age 61 years, male 64%) were identified on the first colonoscopy. The second colonoscopy detected 78 additional lesions: n = 60 with tone enhancement vs. n = 18 with white light endoscopy (p < 0.001). Tone enhancement found more additional adenomas (A n = 20 vs. B n = 6, p = 0.006) and identified significantly more missed adenomas per subject (0.5 vs. 0.15, p = 0.006). Conclusions: High definition plus colonoscopy with tone enhancement detected more adenomas missed by white light colonoscopy. © 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
1. Introduction Colorectal cancer (CRC) is one of the most common malignant tumours in the world; advanced tumours still have a disappointing 5-year survival rate [1,2]. Timely detection and removal of all premalignant lesions help to prevent the disease. Colonoscopy is the gold standard for CRC screening because it permits detection and removal of pre-cancerous polyps during the examination [3–5].
∗ Corresponding author at: St. Marienkrankenhaus Frankfurt, Richard-WagnerStr. 14, 60318 Frankfurt, Germany. Tel.: +49 15111628399; fax: +49 69 14631577. E-mail address: [email protected] (A. Hoffman).
However, not all adenomatous polyps are identified during screening and surveillance colonoscopy; some patients develop colorectal cancer even under colonoscopic surveillance [6]. This may be caused by the rapid progression of adenomas or overlooked colorectal lesions. A meta-analysis of 6 studies by Van Rijn et al., in which patients went through two colonoscopies the same day, reported a polyp miss rate of 22% [5]. Efforts to improve endoscopic detection of adenomatous polyps include changes in procedural aspects (increased withdrawal time, looking behind colonic folds) and the use of advanced optical technologies. The aims were to reduce miss rates of adenomas and optimize prevention of colorectal cancer.
http://dx.doi.org/10.1016/j.dld.2014.07.169 1590-8658/© 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
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A well established technology today is high-definition white light (HDWL) endoscopy, which can be used with or without optical filters to selectively illuminate tissue. Of the new endoscopic imaging techniques, i-scan is a digital contrast method with three modes of image enhancement [7]. I-scan 1 enhances light-dark contrast by obtaining luminance intensity data for each pixel and applying an algorithm that allows detailed observation of the structure of the mucosal surface, whereas i-scan 2/3 dissects and analyzes the individual RGB components of a normal image and recombines the components into a single, new colour image. This mode has been designed to increase mucosal and vascular contrast between suspicious and normal tissue, as in vivo chromoendoscopy does. The exact i-scan settings are recommended by the manufacturer’s protocol. Adenoma detection rates with various white light endoscopy methods have been compared in several studies, but just a few studies have addressed the usefulness of optical filters during withdrawal in a back-to-back manner. The majority of studies report controversial results concerning the usefulness of filters for the detection of colonic lesions. We conducted, for the first time, a randomized controlled trial with the primary aim of prospectively determining whether the use of i-scan 2 colonoscopy is associated with a higher adenoma detection rate in average-risk individuals undergoing colon cancer screening and surveillance compared with the widely used procedure of high-definition white light colonoscopy.
the endoscope was inserted into the cecum using a white light endoscopy image. In the study group all subjects underwent a complete standard colonoscopy as the first procedure. Immediately after the standard colonoscopy, a complete procedure under i-scan 2 (TE) was performed by the same endoscopist. In the control group all subjects underwent a standard colonoscopy, and a complete standard procedure was performed again by the same endoscopist. Withdrawal times were targeted to exceed 6 min and were required to be similar in both arms [8]. The examination time included the time required for withdrawing the instrument from the cecum to the rectum, with the exception of the time taken for any polypectomy or biopsy performed during withdrawal. The goal was to recognize any circumscribed mucosal alteration (detection of any type of lesion). Missed lesions were defined as those identified only during the second withdrawal. The size and location of all lesions were recorded and further characterized using a modified version of Kudo’s classification (Kudo’s pit pattern classification) [9]. Lesions were classified in accordance with the Paris classification of early cancers [10,11]. The endoscopist rated a lesion adenomatous or non-adenomatous in the HD group, based on the above mentioned criteria. All polyps detected during withdrawal were removed, irrespective of size, colour, or subjective interpretation, and then sent for final histological confirmation. 2.2. High-definition colonoscopy
2. Patients and methods A single-centre trial was performed at the interdisciplinary endoscopic unit at Johannes Gutenberg University of Mainz. Patients were selected from those scheduled to undergo routine screening or surveillance colonoscopy at the division of gastroenterology and hepatology, University Hospital of Mainz, who provided informed consent. Patients were eligible for the study (inclusion criteria) when they had an indication for colon cancer screening, postpolypectomy surveillance, or a positive occult blood test. Patients were excluded when they were pregnant, had a previous history of colorectal cancer, previous surgery of the colon, known inflammatory bowel disease, acute gastrointestinal bleeding, a genetic risk of colon cancer, impaired coagulation parameters (INR > 1.74, PTT > 50 s), or when their bowel preparation did not permit complete inspection of the colon. The study was approved by the local ethics committee of Rheinland-Palatinate, Germany (No. 837.238.09 6744, ClinicalTrials.gov Identifier: 837.386.07), and was conducted between May 2009 and July 2010. Eighty consecutive patients fulfilled the criteria and were randomly assigned at a 1:1 ratio to undergo complete colonoscopy in the study group or in the control group. All colonoscopies were performed by four experienced colonoscopists (RK, AH, MG, FR), who were highly familiar with chromoendoscopy and HD+ endoscopy using the Pentax EPKi processor (Pentax, Japan). All procedures were performed using propofol 1% (Disoprivan® , AstraZeneca, Switzerland) or, in the presence of a contraindication, midazolam (Dormicum® , Roche Pharma AG, Switzerland) for sedation.
2.1. Examination technique All consecutive patients were randomized in a 1:1 manner to group A (the study group) or group B (controls). In all patients,
Of several image-enhancing techniques, i-scan is a digital image processor that provides high-resolution enhanced images using different software algorithms with real-time image mapping (RIM) technology embedded in the endoscopic processor (EPKi). Thus iscan combines high-resolution endoscopy with 3 adjustable modes of image enhancement (Fig. 1S): surface enhancement (SE), contrast enhancement (CE), and tone enhancement (TE) [12]. The TE mode is similar to narrow band imaging (NBI, Olympus) and Fuji intelligent chromoendoscopy (FICE, Fuji). Therefore, it is very suitable for the characterization of lesions. Although each mode can be used alone, i-scan incorporates the three software algorithms into three distinct modes for the endoscopist: i-scan 1 mode, i-scan 2 mode, and i-scan 3 mode. I-scan 1 was designed as a special mode for detection. I-scan 2 and 3 also employ SE and CE, but i-scan 2 adds tone enhancement to dissect out the dominant red and leave an elevated blue/green contrast. The result is enhanced vessel structure and better visualization of minute mucosal structures and margins of all identified lesions (Fig. 1). It appears that especially i-scan 2 has the potential to enhance the detection of colorectal lesions because the normal mucosa appears in shades of yellow and green, whereas all lesions with concomitant hypervascularization appear in shades of red (Fig. 2). As this mode provides a more clear view of mucosal changes, it has the potential of a ‘red flag’ technique. 2.3. Outcome measures The primary aim of the study was to prospectively evaluate additional adenoma detection rates achieved by HD+ definition plus colonoscopy with the feature of tone enhancement TE vs. white light HD colonoscopy, and polyp miss rates between the two groups. The adenoma detection rate was calculated by dividing the total number of patients with adenomas at insertion and during withdrawal by the total number of patients. The adenoma miss rate was calculated by dividing the total number of adenomas missed during the first withdrawal by the total number of adenomas found at the first or second withdrawal.
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Fig. 1. Small adenomas before and after tone enhancement with enhanced vessel structure and better demarcation.
Fig. 2. Non-polypoid lesions (type II according to Paris classification) before and after tone enhancement.
2.4. Calculation of sample size Our preliminary data suggested that miss rates of white light endoscopy and red flag technologies for the detection of colon adenomas were about 30.0% and 35.0%, respectively. With the alpha error set to 0.05 (two-sided) and power to 0.8, the number of required cases was estimated to be 60 patients (30 patients for each group). Twenty-five percent of the enrolled cases were expected to drop out of the study; thus the target case number was 75. Finally 80 patients were enrolled and analyzed in the study. Sample size calculations were based on the simplified assumption of statistical independence among polyps from the same patient, and use of the 2 test. A p-value <0.05 was considered to be statistically significant. To compare the distributions of confounding variables and their influence on detection rates of polyps or adenomas, the non-parametric Mann–Whitney U-test (for continuous covariates) and the 2 -test (for categorical covariates) was used. Both, the Mann–Whitney U-test and the 2 -test were also used to compare the original detection and miss rates, as well as a binarized version, between
the two groups. Furthermore, the influence of first-run results on second-run results was analyzed using logistic regression. Logistic regression was also used to analyze the influence of the second withdrawal time, which was not equally distributed in the two groups. For purposes of statistical analysis, individual lesions were assumed to constitute statistically independent observations even when more than one lesion was present in a single patient. The per-patient miss rate for i-scan 2 was defined as the number of all patients with no polyps detected by i-scan 2 in the first procedure and at least one polyp detected by subsequent white light colonoscopy. The per-patient polyp miss rate for white light colonoscopy was defined similarly, as were adenoma and hyperplastic polyp miss rates. 3. Results One hundred patients were deemed eligible for the study; 20 patients were excluded because of failure of cecal intubation (n = 5), poor or inadequate bowel preparation (n = 12), or suspected
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Fig. 3. Flow diagram of the progress through the phases of the randomized trial; (n = patients) according to the CONSORT statement [6]. HD, high definition; TE, tone enhancement.
inflammatory bowel disease (n = 3). Thus, 80 patients were included, of whom 40 were randomly assigned to the control group and 40 to the study group (Fig. 3). No other procedural complications occurred. All endoscopists performed both types of colonoscopies. No significant differences existed among the studied groups in age, sex, or bowel preparation status. The detection rate per patient during the first withdrawal did not differ significantly between groups (8 in the study group vs. 11 in controls). During the second withdrawal the number of patients with at least one adenoma increased significantly in the study group using TE (16 vs. 5, p < 0.05 Chi-square test). The total adenoma detection rate during the first withdrawal also did not differ significantly between the study group and controls (12 vs. 14), but did increase significantly in the study group during the second withdrawal (20 vs. 6, p < 0.05, Chi-square test). By analogy, the total number of lesions per group increased significantly between the first (33 in the study group vs. 34 in controls) and the second withdrawal under study conditions (60 in the study group vs. 18 in controls, p < 0.05, Chi-square test, Supplementary Tables S1–S3). The polyp detection rate was not significantly different between the control and study group during the first withdrawal (Pearson’s Chi-square test p > 0.05). In the control group the adenoma detection rate was 27.5%; 11 patients had at least one adenoma and the total number of detected adenomas was 14. In the study group the detection rate was 20.0%; 8 patients had at least one adenoma and the total number of detected adenomas was 12. During the second withdrawal the adenoma detection rate was significantly different between the two study groups (p < 0.05, Chisquare test). The control group revealed 5 patients with at least one adenoma and 6 adenomas in all, whereas the study group contained
16 patients with at least one adenoma and 20 adenomas in all (Fig. 2S). The adenoma miss rate was 30.0% in the control group and 62.5% in the study group (p < 0.05, Chi-square test). The subgroup analysis for non-polypoid lesions (type II according to Paris classification) showed that the application of tone enhancement during withdrawal in the study group significantly reduced the risk of missing a non-polypoid adenoma (Pearson’s Chi-square test p < 0.05) and more then 70% of all flat lesion were smaller than 5 mm (Supplementary Table S4). To identify risk factors for missing a polyp or adenoma during the first withdrawal, multivariate analyses were performed for the per-polyp miss rate, with adjustments for age, sex, bowel preparation, and missed polyp or adenoma characteristics, including location and histology. The distribution and influence of the parameters were tested (Mann–Whitney Utest and Chi-square test) either equally or without influence on detection rates. There were no differences between groups in regard of the location of polyps or between the first and second withdrawal. However, a significant difference was noted between the second withdrawal time in the study and control group (Fig. 3S). Since any abnormality influenced the examination time, the influence was calculated using linear regression for the first run; the second run was corrected with this coefficient. Thus, the detection rate of adenomas was not influenced by the longer second withdrawal time in the study group on linear regression (p > 0.52). The examination time did not influence detection rates (Chi-square test p = 0.946) (Fig. 4S). In the study group the histology could be predicted with high accuracy (86.3%). The sensitivity and specificity of i-scan 2 for the characterization of the detected colon polyps were 78% and 93%, respectively.
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4. Discussion Colorectal cancer (CRC) is the second leading cause of cancer in the Western world [13–15]. More than 90% of CRC incidents develop over several years from polyps that grow in the colon [15–18]. Effective detection and subsequent removal of the polyps prevent the disease. Although colonoscopy with adenoma removal can prevent colorectal cancer in as many as 76–90% of cases, we know that some patients undergoing colonoscopy with adenoma removal still develop colorectal cancer before the surveillance interval, particularly in the right side of the colon [17–19]. The development of de novo cancer before this interval may be explained by the rapid progression of adenomas, their incomplete removal, or the fact that colonoscopy is not infallible as regards the detection of all adenomas. Studies that use adenoma detection rates as a marker of the quality of colonoscopy have clearly shown that low adenoma detection rates (and presumably high miss rates) are a very good marker of the risk of interval colon cancers. However, we also know that lesions can be missed during routine colonoscopy [20]. In a prospective randomized back-to-back trial, we registered a significant improvement in adenoma detection rates and reduced miss rate by using TE during the entire withdrawal step. Polyp miss rates during the first withdrawal were similar in both groups (27.5% in controls vs. 20.0% in the study group), in accordance with other published studies. A meta-analysis of 5 studies by Van Rijn et al., in which 465 patients underwent two colonoscopies in the same day, reported an overall polyp miss rate of 22% [5]. A clinical study by Rex et al., in which back-to-back colonoscopy was performed the same day in 183 patients, reported an overall adenoma miss rate of 24% [6]. A back-to-back same-day colonoscopy study in 286 patients by Heresbach et al. reported miss rates of 28% for polyps and 20% for adenomas during the first colonoscopy [21]. Deenadayalu et al. randomized 50 patients to undergo tandem SDWL colonoscopies with a standard angle (140-degree field of view) and a wide angle (170-degree) colonoscope. The miss rate for adenomas with both methods was estimated to be 30% [22]. In all of these studies, adenoma miss rates were stratified by size: the rate was 2% for adenomas greater than 10 mm, 13% for those measuring 6–10 mm, and 26% for those measuring 1–5 mm. The authors concluded that adenoma miss rates were higher for smaller polyps. The development of cancer before this interval may be explained by the rapid progression of adenomas or their incomplete removal, as well as the fact that colonoscopy is not always infallible in the detection of small adenomas. Thus, many efforts have been made to maximize the sensitivity of colonoscopy. Although small adenomas as such may not be clinically important, they are good surrogate markers of the quality of colonoscopy and the effectiveness of colon cancer prevention. In the recent past, chromoendoscopy has enhanced the detection of neoplasia in the colon, but the technique is inconvenient, time consuming, and often impractical in clinical routine [23]. To overcome this inconvenience, several alternative approaches have been introduced to enhance the contrast of the mucosal surface without the use of dye, including applications such as narrow band imaging (NBI: Olympus Tokyo, Japan), Fujinon imaging colour enhancement (FICE: Fujinon, Tokyo, Japan) or i-scan (PENTAX, Tokyo, Japan) [24–26]. The effectiveness of such image-enhanced endoscopy has been well documented in a plethora of studies. NBI has been the most extensively studied in regard of adenoma detection [27–33,7,34]. While older studies found no significant difference in overall adenoma detection rates during the withdrawal phase, recent investigations have been very promising in regard of improving the detection rate of colorectal adenoma [31,35]. Their
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results suggest that NBI is superior when utilized for adenoma detection, and the studies have demonstrated adenoma miss rates of 40–46% for white light endoscopy when a second examination was performed with NBI. In a recent study by Gross, the estimated polyp miss rates were as high as 27% and 58% for standard white light and HD-NBI [36]. The results of our second withdrawal were not only similar, but also showed a higher miss rate for adenomas on comparison of white light imaging and the use of i-scan 2 as virtual chromoendoscopy (30.0% vs. 62.5%). The number of polyps missed in our control group were small. The importance of such lesions is still debated. The current recommendation is to remove all adenomatous polyps. In our last published study we could prove the advantage of i-scan 1 (surface enhancement) for detection while i-scan 2/3 was used for characterization [37]. Using TE (i-scan 2) for this purpose, we observed that all minute mucosal lesions were enhanced in terms of subtle colour changes: these appeared reddish whereas normal mucosa appeared yellowish-green. However, the practical usefulness of TE for screening colonoscopy has not been investigated yet. All these facts seem to make this filter useful for better detection, in the manner of a red flag technique. So far (auto-) fluorescence imaging (AFI) has been a red flag technique [38]. The adenoma miss rates of AFI and HD endoscopy were 20% and 29%, respectively. The most important drawback of AFI was its high false positive rates. Among all of these image-enhancing techniques, i-scan technology is classified as a digital contrast method with three modes of image enhancement. Several studies reported real-time histologic prediction of colorectal lesions by using i-scan 2/3 [39,40]. In our study we registered a sensitivity of 82% and a specificity of 96% for the prediction of adenomatous polyps when the i-scan modes were used [37]. Lee et al. reported a sensitivity of 94.6%, a specificity of 86.4%, and an overall accuracy of 90.7% for the prediction of adenomas using i-scan for discrimination [39]. However, the histologic examination for colorectal lesions remains the standard criterion for differentiating non-neoplastic lesions from neoplastic ones. I scan 2 has the potential to minimize costs and complications associated with endoscopic biopsy and polypectomy. Moreover, we should be more prudent in incorporating the routine use of pancolonic tone enhancement (i-scan 2) in colorectal screening. In summary, our tandem colonoscopy trial suggests that the use of i-scan enhanced colonoscopy may increase detection rates for colorectal polyps and, importantly, reduce miss rates for adenomas compared with older and widely used versions of standard white light colonoscopy. The study was conducted at a single academic institution by a few endoscopists. Although randomized tandem design is considered to be the most reliable method for evaluating different modalities, a study performed at a single academic institution by a few endoscopists is prone to limitations. Although diagnostic criteria were adopted on the basis of previous validated classifications, the endoscopist factor may have influenced the detection rate. Another potential bias of the study is the fact that both endoscopic examinations were performed by the same endoscopist and the second endoscopic diagnosis was therefore influenced by the findings of the first one. Another noteworthy drawback of the current study is that the efficacy of i-scan 2 in detecting colorectal adenoma is limited, even for experienced endoscopists. The latter appeared to empirically identify many adenomas, including flat and depressed ones. For better objectivity, pancolonic i-scan 2 should be used by less experienced endoscopists to ease the detection of colorectal adenomas, especially flat and depressed ones. Finally, large-scale multicenter trials will be needed to establish the usefulness of i-scan in practice
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