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High Resolution Colonoscopy With Chromoscopy Versus Standard Colonoscopy for the Detection of Colonic Neoplasia: A Randomized Study

2006; Elsevier BV; Volume: 4; Issue: 3 Linguagem: Inglês

10.1016/j.cgh.2005.12.009

1542-7714

Marc Le Rhun, Emmanuel Coron, David Parlier, Jean‐Michel Nguyen, Jean‐Marc Canard, Afchine Alamdari, Denis Sautereau, Stanislas Chaussade, Jean–Paul Galmiche,

Genetic factors in colorectal cancer

Background & Aims: High-resolution colonoscopy with chromoscopy (HRC) is a technique designed to improve the detection of colonic neoplasias. We prospectively compared standard colonoscopy (SC) and HRC in a randomized multicenter trial. Methods: Patients (n = 203; age, 58 ± 10 years; sex ratio, 1) were recruited according to the following criteria: (1) a history of either familial or personal colonic neoplasia or (2) alarm symptoms after the age of 60 years. After randomization, an SC was performed in 100 patients (resolution, ≤410,000 pixels) and a HRC in 103 patients (Fujinon EC485ZW, 850,000 pixels). In the HRC group, each colonic segment was examined before and after spraying with indigo carmine 0.4%. Results: Two hundred seventy-six polyps were detected in 198 patients. One hundred sixty of them were hyperplastic polyps, 116 were adenomas, and 2 were carcinomas. The numbers of hyperplastic polyps and purely flat adenomas were significantly higher in the HRC group than in the SC group (1.1 ± 1.6 vs 0.5 ± 1.4 and 0.22 ± 0.68 vs 0.07 ± 0.29, respectively; P = .01 and P = .04), but there was no significant difference in the total number of adenomas per patient (primary end point) detected between the HRC and the SC groups (0.6 ± 1.0 vs 0.5 ± 0.9, respectively). Conclusions: Although HRC improves detection of purely flat adenomas and hyperplastic polyps, the overall detection of colonic adenomas in a population at increased risk of neoplasia is not significantly improved. These findings do not support the routine use of HRC in clinical practice. Background & Aims: High-resolution colonoscopy with chromoscopy (HRC) is a technique designed to improve the detection of colonic neoplasias. We prospectively compared standard colonoscopy (SC) and HRC in a randomized multicenter trial. Methods: Patients (n = 203; age, 58 ± 10 years; sex ratio, 1) were recruited according to the following criteria: (1) a history of either familial or personal colonic neoplasia or (2) alarm symptoms after the age of 60 years. After randomization, an SC was performed in 100 patients (resolution, ≤410,000 pixels) and a HRC in 103 patients (Fujinon EC485ZW, 850,000 pixels). In the HRC group, each colonic segment was examined before and after spraying with indigo carmine 0.4%. Results: Two hundred seventy-six polyps were detected in 198 patients. One hundred sixty of them were hyperplastic polyps, 116 were adenomas, and 2 were carcinomas. The numbers of hyperplastic polyps and purely flat adenomas were significantly higher in the HRC group than in the SC group (1.1 ± 1.6 vs 0.5 ± 1.4 and 0.22 ± 0.68 vs 0.07 ± 0.29, respectively; P = .01 and P = .04), but there was no significant difference in the total number of adenomas per patient (primary end point) detected between the HRC and the SC groups (0.6 ± 1.0 vs 0.5 ± 0.9, respectively). Conclusions: Although HRC improves detection of purely flat adenomas and hyperplastic polyps, the overall detection of colonic adenomas in a population at increased risk of neoplasia is not significantly improved. These findings do not support the routine use of HRC in clinical practice. Colonoscopy is the only investigation that allows detection and resection of colorectal neoplastic lesions1Sonnenberg A. Delco F. Inadomi J.M. Cost-effectiveness of colonoscopy in screening for colorectal cancer.Ann Intern Med. 2000; 133: 573-584Crossref PubMed Scopus (446) Google Scholar, 2Rex D.K. Lieberman D.A. Feasibility of colonoscopy screening discussion of issues and recommendations regarding implementation.Gastrointest Endosc. 2001; 54: 662-667Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar and therefore can prevent the further development of colorectal cancer.3Winawer S.J. Zauber A.G. Colonoscopic polypectomy and the incidence of colorectal cancer.Gut. 2001; 48: 753-754Crossref PubMed Scopus (45) Google Scholar, 4Winawer S.J. Zauber A.G. Ho M.N. et al.Prevention of colorectal cancer by colonoscopic polypectomy.N Engl J Med. 1993; 329: 1977-1981Crossref PubMed Scopus (4022) Google Scholar, 5Citarda F. Tomaselli G. Capocaccia R. et al.Efficacy in standard clinical practice of colonoscopic polypectomy in reducing colorectal cancer incidence.Gut. 2001; 48: 812-815Crossref PubMed Scopus (624) Google Scholar However, recent publications have suggested that 15%–27% of small adenomas might be missed during standard colonoscopy (SC).6Hixson L.J. Fennerty M.B. Sampliner R.E. et al.Prospective study of the frequency and size distribution of polyps missed by colonoscopy.J Natl Cancer Inst. 1990; 82: 1769-1772Crossref PubMed Scopus (314) Google Scholar, 7Rex D.K. Cutler C.S. Lemmel G.T. et al.Colonoscopic miss rates of adenomas determined by back-to-back colonoscopies.Gastroenterology. 1997; 112: 24-28Abstract Full Text PDF PubMed Scopus (1410) Google Scholar Furthermore, in the National Polyp Study, 5 cancers were diagnosed in 1418 patients who had previously undergone a colonoscopy; among these cancers, 3 measured more than 15 mm and were found within 3 years of the first colonoscopy.4Winawer S.J. Zauber A.G. Ho M.N. et al.Prevention of colorectal cancer by colonoscopic polypectomy.N Engl J Med. 1993; 329: 1977-1981Crossref PubMed Scopus (4022) Google Scholar These results could be interpreted as a lack of sensitivity of SC to detect diminutive or flat adenomas because these lesions generally appear as subtle mucosal irregularities or minor changes in mucosal color or loss of vascular pattern. Moreover, recent studies in Europe and the US showed that flat lesions were found with a prevalence similar to that reported in Japan when investigated by Japanese endoscopists and/or Japanese techniques. For instance, in the United Kingdom, Rembacken et al8Rembacken B.J. Fujii T. Cairns A. et al.Flat and depressed colonic neoplasms a prospective study of 1000 colonoscopies in the UK.Lancet. 2000; 355: 1211-1214Abstract Full Text Full Text PDF PubMed Scopus (631) Google Scholar showed that flat lesions accounted for up to 36% of adenomas in a series of 1000 colonoscopies. These results have been confirmed recently by Hurlstone et al,9Hurlstone D.P. Cross S.S. Adam I. et al.Efficacy of high magnification chromoscopic colonoscopy for the diagnosis of neoplasia in flat and depressed lesions of the colorectum a prospective analysis.Gut. 2004; 53: 284-290Crossref PubMed Scopus (162) Google Scholar who reported that 45% of the 168 adenomas detected in 260 patients were flat, and also by various researchers in countries such as Sweden,10Tsuda S. Veress B. Toth E. et al.Flat and depressed colorectal tumours in a southern Swedish population a prospective chromoendoscopic and histopathological study.Gut. 2002; 51: 550-555Crossref PubMed Scopus (219) Google Scholar Germany,11Kiesslich R. von Bergh M. Hahn M. et al.Chromoendoscopy with indigocarmine improves the detection of adenomatous and nonadenomatous lesions in the colon.Endoscopy. 2001; 33: 1001-1006Crossref PubMed Scopus (256) Google Scholar and the USA.12Saitoh Y. Waxman I. West A.B. et al.Prevalence and distinctive biologic features of flat colorectal adenomas in a North American population.Gastroenterology. 2001; 120: 1657-1665Abstract Full Text Full Text PDF PubMed Scopus (361) Google Scholar Finally, malignant depressed lesions were associated with a higher risk of submucosal invasion.13Kudo S. Kashida H. Tamura T. et al.Colonoscopic diagnosis and management of nonpolypoid early colorectal cancer.World J Surg. 2000; 24: 1081-1090Crossref PubMed Scopus (381) Google Scholar Chromoscopy with various dyes has been developed for many years to enhance the detection of colorectal tumors. Recent uncontrolled studies have suggested that indigo carmine staining of the distal colon is able to increase the detection of adenomatous lesions that were otherwise overlooked by routine endoscopy.11Kiesslich R. von Bergh M. Hahn M. et al.Chromoendoscopy with indigocarmine improves the detection of adenomatous and nonadenomatous lesions in the colon.Endoscopy. 2001; 33: 1001-1006Crossref PubMed Scopus (256) Google Scholar, 14Lee J.H. Kim J.W. Cho Y.K. et al.Detection of colorectal adenomas by routine chromoendoscopy with indigocarmine.Am J Gastroenterol. 2003; 98: 1284-1288Crossref PubMed Scopus (58) Google Scholar In addition, high-resolution colonoscopy coupled with chromoscopy (HRC) might further improve the detection of these non-polypoid or flat lesions.15Bruno M.J. Magnification endoscopy, high resolution endoscopy, and chromoscopy; towards a better optical diagnosis.Gut. 2003; 52: 7-11Crossref PubMed Scopus (129) Google Scholar To date, only 2 randomized controlled trials have compared chromoscopy with SC in terms of the detection of colorectal adenomas.16Brooker J.C. Saunders B.P. Shah S.G. et al.Total colonic dye-spray increases the detection of diminutive adenomas during routine colonoscopy a randomized controlled trial.Gastrointest Endosc. 2002; 56: 333-338Abstract Full Text Full Text PDF PubMed Google Scholar, 17Hurlstone D.P. Cross S.S. Slater R. et al.Detecting diminutive colorectal lesions at colonoscopy a randomised controlled trial of pan-colonic versus targeted chromoscopy.Gut. 2004; 53: 376-380Crossref PubMed Scopus (217) Google Scholar A significant improvement in diagnostic yield was reported in 1 of these 2 studies.16Brooker J.C. Saunders B.P. Shah S.G. et al.Total colonic dye-spray increases the detection of diminutive adenomas during routine colonoscopy a randomized controlled trial.Gastrointest Endosc. 2002; 56: 333-338Abstract Full Text Full Text PDF PubMed Google Scholar, 17Hurlstone D.P. Cross S.S. Slater R. et al.Detecting diminutive colorectal lesions at colonoscopy a randomised controlled trial of pan-colonic versus targeted chromoscopy.Gut. 2004; 53: 376-380Crossref PubMed Scopus (217) Google Scholar It is of note that these studies involved a small number of very experienced endoscopists and might therefore not reflect the true diagnostic yield of colonic chromoscopy when performed in conditions of routine practice. Therefore, the aim of our randomized controlled study was to compare high-resolution colonoscopy coupled with pancolonic indigo carmine chromoscopy (ie, HRC to SC) in a French population at increased risk of colonic neoplasia. In contrast to previous studies, the trial was conducted in a clinical setting more representative of real life. Between February 2002 and September 2004, patients referred to 4 French centers (Nantes, Paris Cochin, Paris Croix Rouge, Limoges) for colonoscopy were considered for enrollment into the study. The inclusion criteria were as follows: (1) surveillance colonoscopy of known colorectal adenomas or cancer or screening colonoscopy in patients with a first-degree relative with colon cancer or adenomatous polyps diagnosed at age 5 mm were resected by mucosectomy. In both groups of polyps (< or ≥5 mm in diameter) we defined purely flat polyps as mucosal elevations with a flat or slightly rounded surface and a height of less than half the diameter of the lesion.17Hurlstone D.P. Cross S.S. Slater R. et al.Detecting diminutive colorectal lesions at colonoscopy a randomised controlled trial of pan-colonic versus targeted chromoscopy.Gut. 2004; 53: 376-380Crossref PubMed Scopus (217) Google Scholar The immediate outcome after colonoscopy was assessed by a questionnaire completed by the patient between the 7th and the 15th day after endoscopy. This questionnaire was based on a visual analog scale graded from 0 (poor tolerance or side effects) to 10 (excellent tolerance). All resected tissues were examined by the pathologists of each center after fixation in buffered formalin solution and hematoxylin-eosin staining. The Vienna criteria were used to classify dysplasia as either low grade or high grade. Early cancer was defined as intramucosal or submucosal carcinoma without vertical extension into the muscularis propria. Invasive cancer was defined as neoplastic proliferation beyond the muscularis propria. To set power calculations, we made a preliminary analysis of a cohort of similar patients recruited in the Nantes center. In this cohort, the mean number of adenomas detected was 0.6 ± 1 per SC. The controlled study was powered to establish a 30% significant increase in the rate of adenoma detection with HRC. With these parameters, we calculated that a total of 310 patients in each group were required to achieve significance (α = 0.05, β = 0.2). Because of uncertainty concerning the exact diagnostic yield of HRC and variability concerning the number of polyps detected, an interim analysis was planned after inclusion of 200 patients (100 in each group) according to a procedure by O'Brien and Fleming.18O'Brien P.C. Fleming T.R. A multiple testing procedure for clinical trials.Biometrics. 1979; 35: 549-556Crossref PubMed Scopus (2482) Google Scholar All calculations were made using the S-PLUS 6.2 software (Insightful Corporation, Seattle, WA). The interim analysis was performed after inclusion of 203 consecutive patients recruited from February 2002–September 2004; 103 were randomized to the HRC group (49 men; median age, 59 years; range, 31–80 years) and 100 to the SC group (53 men; median age, 57 years; range, 30–78 years). The mean number of colonoscopies per endoscopist was 17 (range, 2–38). Among the 100 patients randomized to the SC group, a subgroup of 36 patients decided to undergo a HRC immediately after the SC. There were no differences between groups with respect to sex, age, quality of bowel preparation (Table 1), or indications for colonoscopy (Table 2). Five cases were excluded because of poor bowel preparation (4 in the HRC group and 1 in the SC group). The extubation time was significantly longer in the HRC group when compared with the SC group (26 ± 11 vs 8 ± 4 minutes; P < .0001). The median volume of indigo carmine solution used was 62.5 mL (range, 37.5–87.5 mL). Tolerance of the colonoscopy was good in both the HRC and the SC groups (visual analog scale, 7.0 ± 2.5 and 7.5 ± 2.5 in the HRC and SC groups, respectively; P = .24). There were no immediate ( 24 hours) complications.Table 1Patient DemographicsStandard colonoscopyHigh-resolution + chromoscopyP valueNumber of patients100103Male sex53 (53%)49 (48%).48Age (y) (median, range)59 (30–78)59 (31–80).15Preparation.24 Excellent48 (48%)49 (48%) Good45 (45%)38 (37%) Fair6 (6%)12 (11%) Poor1 (1%)4 (4%) Open table in a new tab Table 2Indications for ColonoscopyStandard colonoscopyHigh-resolution + chromoscopyP valueNumber of patients100103Screening or surveillance88 (88%)86 (83%)NSSymptoms after 60 y of age12 (12%)18 (17%)NS Iron deficiency anemia2 (2%)4 (4%) Change in bowel habit5 (5%)8 (7%) Abdominal pain5 (5%)6 (5%) Open table in a new tab The overall findings are summarized in Table 3. A total of 276 polyps were seen in 198 patients. One hundred seventy two (62%) polyps were found in the HRC group and 104 (38%) in the SC group (P = .01). One hundred sixteen polyps were found to be adenomas, and 2 were carcinomas (1 in the rectum in the HRC group and 1 in the left colon in the SC group).Table 3Summary of Lesions and Patient Numbers in the Standard Colonoscopy and High-Resolution Chromoscopy GroupsStandard colonoscopy (n = 99)High-resolution + chromoscopy (n = 99)P valueNumber of polyps per patient1.1 ± 1.81.7 ± 2.0.01Number of adenomas per patient0.5 ± 0.90.6 ± 1.0NSNumber of adenomas <5 mm per patient0.3 ± 0.80.4 ± 0.8NSNumber of purely flat adenomas per patient0.07 ± 0.290.22 ± 0.68.04Number of hyperplastic polyps per patient0.5 ± 1.41.1 ± 1.6.01Patients with at least 1 polyp (%)45 (45)65 (66).01Patients with at least 1 adenoma (%)31 (31)40 (39)NSPatients with at least 3 adenomas (%)6 (6)7 (7)NSPatients with at least 1 hyperplastic polyp (%)26 (26)48 (48)<.0001 Open table in a new tab Discounting histology, HRC found more polyps than SC (1.7 ± 2.0 vs 1.1 ± 1.8 polyps per patient, respectively; P = .01). However, before chromoscopy, the mean number of polyps detected per patient by HR alone and by SC was nonsignificantly different (0.9 ± 1.3 vs 1.1 ± 1.8; P = .75). The mean size of polyps was also nonsignificantly different between both groups (3.3 ± 1.5 vs 3.8 ± 2.2 mm for HRC and SC, respectively; P= .07). Histopathologic analysis revealed that HRC detected significantly more hyperplastic polyps per patient than SC (1.1 ± 1.6 vs 0.5 ± 1.4, respectively; P = .01). In contrast, there was no difference between the number of adenomas per patient found with HRC and SC (0.6 ± 1.0 vs 0.5 ± 0.9, respectively; P = .38). However, the number of purely flat adenomas was significantly higher in the HRC group than in the SC group (0.22 ± 0.68 vs 0.07 ± 0.29, respectively; P = .04). HRC revealed more flat adenomas <5 mm in diameter than SC (0.12 ± 05 vs 0.03 ± 0.17; P = .09), whereas there was no significant difference between the numbers of flat adenomas ≥5 mm detected by HRC and SC (0.10 ± 0.39 vs 0.04 ± 0.20, respectively; P = .17). There were 2 adenomas with high-grade dysplasia in the SC group versus 0 in the HRC group (not significant). The number of patients with at least 1 adenoma and the number of individuals with multiple (≥3) adenomas were nonsignificantly different between the HRC and the SC groups. Similarly, a significant difference was not noted between the HRC and the SC groups according to the anatomic location of adenomas (ie, proximal versus distal colon; data not shown). The total number of adenomas detected was not significantly affected by the experience of endoscopists (data not shown). In the subgroup of 36 patients who had HRC immediately after SC, the number of adenomas per patient found with SC and HRC were 0.3 ± 0.5 and 0.4 ± 0.7, respectively. In the 5 patients (14%) with negative SC, HRC found 5 adenomas. In our study, HRC did not detect significantly more adenomas than SC. In addition to the lack of a statistical difference in the overall detection of colorectal adenomas, no statistically significant difference was detected in patients with multiple (≥3) adenomas, who represent a subgroup of patients at a higher risk of developing colorectal neoplasia,4Winawer S.J. Zauber A.G. Ho M.N. et al.Prevention of colorectal cancer by colonoscopic polypectomy.N Engl J Med. 1993; 329: 1977-1981Crossref PubMed Scopus (4022) Google Scholar, 19Togashi K. Konishi F. Ishizuka T. et al.Efficacy of magnifying endoscopy in the differential diagnosis of neoplastic and non-neoplastic polyps of the large bowel.Dis Colon Rectum. 1999; 42: 1602-1608Crossref PubMed Scopus (162) Google Scholar or in the detection of diminutive (<5 mm) adenomas between HRC and SC. In contrast, the number of purely flat adenomas was significantly increased. These results provide a contrast to 2 other recently published trials.16Brooker J.C. Saunders B.P. Shah S.G. et al.Total colonic dye-spray increases the detection of diminutive adenomas during routine colonoscopy a randomized controlled trial.Gastrointest Endosc. 2002; 56: 333-338Abstract Full Text Full Text PDF PubMed Google Scholar, 17Hurlstone D.P. Cross S.S. Slater R. et al.Detecting diminutive colorectal lesions at colonoscopy a randomised controlled trial of pan-colonic versus targeted chromoscopy.Gut. 2004; 53: 376-380Crossref PubMed Scopus (217) Google Scholar Brooker et al16Brooker J.C. Saunders B.P. Shah S.G. et al.Total colonic dye-spray increases the detection of diminutive adenomas during routine colonoscopy a randomized controlled trial.Gastrointest Endosc. 2002; 56: 333-338Abstract Full Text Full Text PDF PubMed Google Scholar showed that chromoscopy significantly increased the proportion of patients found to have multiple adenomas and also the detection of diminutive adenomas in the "proximal to the sigmoid-descending junction." However, the overall detection rate of adenomas did not differ significantly between the 2 techniques. Hurlstone et al17Hurlstone D.P. Cross S.S. Slater R. et al.Detecting diminutive colorectal lesions at colonoscopy a randomised controlled trial of pan-colonic versus targeted chromoscopy.Gut. 2004; 53: 376-380Crossref PubMed Scopus (217) Google Scholar showed a significant increase in the detection of colonic adenomas including diminutive polyps. In comparison, we detected fewer adenomas per patient in our chromoscopy group than Brooker et al and Hurlstone et al. Technical shortcomings are unlikely to explain these differences. In fact, the quality of the bowel preparation was excellent or good in 85% of cases. Both the volume and the concentration of the dye were consistent with other studies; indigo carmine was generally noted to have been used at a concentration of 0.2%–0.5% with volumes up to 150 mL.8Rembacken B.J. Fujii T. Cairns A. et al.Flat and depressed colonic neoplasms a prospective study of 1000 colonoscopies in the UK.Lancet. 2000; 355: 1211-1214Abstract Full Text Full Text PDF PubMed Scopus (631) Google Scholar, 9Hurlstone D.P. Cross S.S. Adam I. et al.Efficacy of high magnification chromoscopic colonoscopy for the diagnosis of neoplasia in flat and depressed lesions of the colorectum a prospective analysis.Gut. 2004; 53: 284-290Crossref PubMed Scopus (162) Google Scholar, 14Lee J.H. Kim J.W. Cho Y.K. et al.Detection of colorectal adenomas by routine chromoendoscopy with indigocarmine.Am J Gastroenterol. 2003; 98: 1284-1288Crossref PubMed Scopus (58) Google Scholar Furthermore, the significant increase in the number of purely flat adenomas and hyperplastic polyps detected in the colon with HRC was consistent with other reports,11Kiesslich R. von Bergh M. Hahn M. et al.Chromoendoscopy with indigocarmine improves the detection of adenomatous and nonadenomatous lesions in the colon.Endoscopy. 2001; 33: 1001-1006Crossref PubMed Scopus (256) Google Scholar and our number of hyperplastic polyps was even higher than that reported by Brooker et al and Hurlstone et al. In addition, the issue of endoscopists' expertise and their experience with chromoendoscopy in particular deserve further consideration. Indeed, a learning curve effect has been reported to occur in colonoscopic training especially for chromoscopic recognition of the pit pattern of intestinal lesions.9Hurlstone D.P. Cross S.S. Adam I. et al.Efficacy of high magnification chromoscopic colonoscopy for the diagnosis of neoplasia in flat and depressed lesions of the colorectum a prospective analysis.Gut. 2004; 53: 284-290Crossref PubMed Scopus (162) Google Scholar, 19Togashi K. Konishi F. Ishizuka T. et al.Efficacy of magnifying endoscopy in the differential diagnosis of neoplastic and non-neoplastic polyps of the large bowel.Dis Colon Rectum. 1999; 42: 1602-1608Crossref PubMed Scopus (162) Google Scholar However in a recent study, no statistical difference was found in the mean number of polyps (including flat lesions) detected by using chromoscopy by a Western endoscopist with no previous experience of chromoscopy and an expert Japanese endoscopist (2.4 ± 0.3 vs 2.7 ± 0.19; P = NS).20Togashi K. Radford-Smith G. Hewett D. et al.The use of indigo carmine increases the colonoscopic detection rate of flat adenomas and large sessile hyperplastic polyps.Gastrointest Endosc. 2004; 59: AB96Google Scholar In our series, the number of procedures previously performed by endoscopists did not seem to influence the diagnostic performance. However, the learning curve influence should be addressed more specifically in further studies of chromoscopy. Another hypothesis that might account for the absence of a statistical difference between HRC and SC in the detection of colorectal adenomas could be, at least in part, related to the excellent diagnostic performance of SC in our study. In fact, the numbers of adenomas detected per patient were higher than those reported by Brooker et al16Brooker J.C. Saunders B.P. Shah S.G. et al.Total colonic dye-spray increases the detection of diminutive adenomas during routine colonoscopy a randomized controlled trial.Gastrointest Endosc. 2002; 56: 333-338Abstract Full Text Full Text PDF PubMed Google Scholar and Hurlstone et al17Hurlstone D.P. Cross S.S. Slater R. et al.Detecting diminutive colorectal lesions at colonoscopy a randomised controlled trial of pan-colonic versus targeted chromoscopy.Gut. 2004; 53: 376-380Crossref PubMed Scopus (217) Google Scholar in their control groups, in addition to Rembacken et al,8Rembacken B.J. Fujii T. Cairns A. et al.Flat and depressed colonic neoplasms a prospective study of 1000 colonoscopies in the UK.Lancet. 2000; 355: 1211-1214Abstract Full Text Full Text PDF PubMed Scopus (631) Google Scholar who found 321 adenomas in 1000 colonoscopies performed by a single experienced endoscopist. Moreover, the mean size of adenomas detected in SC and HRC groups did not differ (about 4 mm). This size was generally smaller than that reported by Kiesslich et al,11Kiesslich R. von Bergh M. Hahn M. et al.Chromoendoscopy with indigocarmine improves the detection of adenomatous and nonadenomatous lesions in the colon.Endoscopy. 2001; 33: 1001-1006Crossref PubMed Scopus (256) Google Scholar who found a mean size of adenomas of 14 mm before indigo carmine spraying of the 30 cm of the distal colon. The quality of bowel preparation as well as the careful examination during extubation in conditions of both insufflation and exsufflation with a mean examination time of 8 minutes might have increased the quality of the SC procedure and consequently the overall detection of adenomas in our control group. Extubation time in the HRC group was almost 3 times as long as in the SC group, correlating with the data of Brooker et al. Some authors have tried to control for extubation time by spraying a saline solution during SC, thus prolonging the duration of SC. In our study our choice was rather to reproduce the conditions of routine use of SC and chromoscopy, therefore allowing for a true head-to-head comparison. Moreover, the failure to detect a higher rate of adenomas with chromoscopy, even though there were longer extubation times, argues in favor that we are not missing a lack of effect of chromoscopy. Regarding the description of polyp morphology, flat adenomas were defined according to previous literature, and we did not take photographs of all lesions, allowing independent interpretation. Therefore, we cannot completely exclude potential bias in interpreting the morphology of adenomas. However, it is not really surprising that the number of non-flat adenomas was similar in both groups, because indigo carmine is a contrast dye that accumulates between pits and valleys and enhances mucosal architecture. Therefore, chromoscopy is not expected to improve the detection of protrusive or large lesions (which can be easily identified without indigo carmine) but rather the diagnosis of small tiny lesions. This assumption is further supported by the fact that HRC revealed more flat adenomas <5 mm in diameter than SC, whereas there was no significant difference between the numbers of flat adenomas ≥5 mm detected by HRC and SC. We were unable to apply the Paris Endoscopic Classification of Superficial Neoplastic Lesions21The Paris endoscopic classification of superficial neoplastic lesions esophagus, stomach and colon.Gastrointest Endosc. 2003; 58Google Scholar because this system was published after our study had commenced. Therefore, differentiation between small protruded sessile polyps and flat sessile lesions was a particular difficulty. However, our proportion of purely flat adenomas was similar to that of other recent Western studies, ranging from 36%–45%.8Rembacken B.J. Fujii T. Cairns A. et al.Flat and depressed colonic neoplasms a prospective study of 1000 colonoscopies in the UK.Lancet. 2000; 355: 1211-1214Abstract Full Text Full Text PDF PubMed Scopus (631) Google Scholar, 10Tsuda S. Veress B. Toth E. et al.Flat and depressed colorectal tumours in a southern Swedish population a prospective chromoendoscopic and histopathological study.Gut. 2002; 51: 550-555Crossref PubMed Scopus (219) Google Scholar, 12Saitoh Y. Waxman I. West A.B. et al.Prevalence and distinctive biologic features of flat colorectal adenomas in a North American population.Gastroenterology. 2001; 120: 1657-1665Abstract Full Text Full Text PDF PubMed Scopus (361) Google Scholar It is important to note that almost 50% of the lesions diagnosed in our HRC group were not detected by high-resolution alone and only after chromoscopy. This aspect was not evaluated in the trials of Brooker et al16Brooker J.C. Saunders B.P. Shah S.G. et al.Total colonic dye-spray increases the detection of diminutive adenomas during routine colonoscopy a randomized controlled trial.Gastrointest Endosc. 2002; 56: 333-338Abstract Full Text Full Text PDF PubMed Google Scholar and Hurlstone et al17Hurlstone D.P. Cross S.S. Slater R. et al.Detecting diminutive colorectal lesions at colonoscopy a randomised controlled trial of pan-colonic versus targeted chromoscopy.Gut. 2004; 53: 376-380Crossref PubMed Scopus (217) Google Scholar; however, our data are consistent with other studies.11Kiesslich R. von Bergh M. Hahn M. et al.Chromoendoscopy with indigocarmine improves the detection of adenomatous and nonadenomatous lesions in the colon.Endoscopy. 2001; 33: 1001-1006Crossref PubMed Scopus (256) Google Scholar, 14Lee J.H. Kim J.W. Cho Y.K. et al.Detection of colorectal adenomas by routine chromoendoscopy with indigocarmine.Am J Gastroenterol. 2003; 98: 1284-1288Crossref PubMed Scopus (58) Google Scholar Indeed, Kiesslich et al11Kiesslich R. von Bergh M. Hahn M. et al.Chromoendoscopy with indigocarmine improves the detection of adenomatous and nonadenomatous lesions in the colon.Endoscopy. 2001; 33: 1001-1006Crossref PubMed Scopus (256) Google Scholar noted that 165 of 210 hyperplastic polyps were seen after staining of the distal 30 cm. In addition, Lee et al14Lee J.H. Kim J.W. Cho Y.K. et al.Detection of colorectal adenomas by routine chromoendoscopy with indigocarmine.Am J Gastroenterol. 2003; 98: 1284-1288Crossref PubMed Scopus (58) Google Scholar reported that 158 of 174 hyperplastic or inflammatory lesions were seen only after chromoscopy. Finally, statistical considerations regarding previous studies should also be discussed. Brooker et al16Brooker J.C. Saunders B.P. Shah S.G. et al.Total colonic dye-spray increases the detection of diminutive adenomas during routine colonoscopy a randomized controlled trial.Gastrointest Endosc. 2002; 56: 333-338Abstract Full Text Full Text PDF PubMed Google Scholar assumed from historical data that the mean number of adenomas per patient was 0.36 with a standard deviation of 0.3. Therefore, they calculated that 117 patients were required in each group for a 30% increase in adenoma detection with dye spray. It is somewhat surprising that they did not reach the statistical difference (P = .06) because they finally reported 49 adenomas in 135 patients in the control group, compared with 125 adenomas in 124 patients in the chromoscopy group, corresponding to 0.36 and 1 adenoma per patient, respectively. These data resulted in a 56% increase instead of the presumed 30%. We calculated that these results should have shown a statistical difference (P < .0001) if the initial hypothesis of a standard deviation equal to 0.3 was verified. These negative results could only be explained by a higher than expected standard deviation; however, this information was not available in the publication. Hurlstone et al17Hurlstone D.P. Cross S.S. Slater R. et al.Detecting diminutive colorectal lesions at colonoscopy a randomised controlled trial of pan-colonic versus targeted chromoscopy.Gut. 2004; 53: 376-380Crossref PubMed Scopus (217) Google Scholar based their sample calculation on the data of Brooker et al. They detected 57 adenomas in 132 patients in the control group and 111 adenomas in 128 patients in the chromoscopy group, corresponding to 0.43 and 0.87 adenoma per patient, respectively. However, their results differed from those of Brooker et al in that they noted a statistically significant increase in detection with chromoscopy; the standard deviation and therefore the variability were not mentioned in the article. At the time of our trial design, neither of these 2 studies had been published. Therefore, we assumed from a pilot study that the mean number of adenomas would be 0.6 ± 1 per patient in the SC group. This number was in fact slightly greater than the one actually observed in our study. Moreover, the interim analysis showed that the increase in adenoma detection in the HRC group was 20%, slightly lower than the expected 30% but with considerable intersubject variability. Although our study might not have been sufficiently powered to ascertain a statistical significance regarding the primary end point (ie, the number of adenomas detected), to establish a 20% advantage with the results of the interim analysis would require a recalculation of the sample with considerably higher recruitment (ie, 1127 patients per group). These data led us to discontinue the study for a number of reasons, namely (1) the recruitment of 2254 patients seemed difficult to achieve within a reasonable time period, (2) a better classification of lesions is now available (Paris classification), and (3) a period of chromoscopic training should be included in the protocol to assess more accurately the influence of the learning curve. Consideration of these different issues would result in a new trial rather than continuation of the present study design. In conclusion, HRC is a time-consuming procedure that did not significantly increase the overall detection of colorectal adenomas in a moderately high-risk population. Although the number of purely flat adenomas detected was increased by HRC, we do not believe that this finding, in isolation, justifies the recommendation of HRC in routine practice, but rather it highlights the importance of performing SC of excellent technical quality. The authors thank the anesthesiologists and nurses from the various GI and endoscopy departments for their valuable help during all the trials, and their pathologist colleagues for characterization of neoplastic polyps.