Meta-analysis of dye-based chromoendoscopy compared with standard- and high-definition white-light endoscopy in patients with inflammatory bowel disease at increased risk of colon cancer

Published:April 19, 2019DOI:https://doi.org/10.1016/j.gie.2019.04.219

      Background

      Patients with ulcerative colitis have an increased risk of colorectal cancer. We sought to assess the comparative efficacy of standard white-light endoscopy (SDWLE) or high-definition white-light endoscopy (HDWLE) versus dye-based chromoendoscopy through a meta-analysis and rate the quality of evidence using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) system.

      Methods

      A systematic review of the literature in PubMed, EMBASE, and Web of Science was performed in April 2018. The primary outcome was the number of patients in whom dysplasia was identified using a per patient analysis in randomized controlled trials (RCT) and analyzed separately for non-RCTs. Analysis was performed using RevMan 5.3 reporting random-effects risk ratios.

      Results

      Of the 27,904 studies identified, 10 studies were included 6 of which were RCTs (3 SDWLE and 3 HDWLE). Seventeen percent (84/494) of patients were noted to have dysplasia using chromoendoscopy compared with 11% (55/496) with white-light endoscopy (relative risk [RR] 1.50; 95% confidence interval [CI], 1.08-2.10). When analyzed separately, chromoendoscopy (n = 249) was more effective at identifying dysplasia than SDWLE (n = 248) (RR, 2.12; 95% CI, 1.15-3.91), but chromoendoscopy (n = 245) was not more effective compared with HDWLE (n = 248) (RR, 1.36; 95% CI, 0.84-2.18). The quality of evidence was moderate. In non-RCTs, dysplasia was identified in 16% (114/698) of patients with chromoendoscopy compared with 6% (62/1069) with white-light endoscopy (RR, 3.41; 95% CI, 2.13-5.47). Chromoendoscopy (n = 58) was more effective than SDWLE (n = 141) for identification of dysplasia (RR, 3.52; 95% CI, 1.38-8.99), and chromoendoscopy (n = 113) was also more effective than HDWLE (n = 257) (RR, 3.15; 95% CI, 1.62-6.13). The quality of the evidence was very low.

      Conclusion

      Based on this meta-analysis, non-RCTs demonstrate a benefit of chromoendoscopy over SDWLE and HDWLE, whereas RCTs only show a small benefit of chromoendoscopy over SDWLE, but not over HDWLE.

      Graphical abstract

      Abbreviations:

      CI (confidence interval), CRC (colorectal cancer), GRADE (Grading of Recommendations Assessment, Development, and Evaluation), HDWLE (high-definition white-light endoscopy), IBD (inflammatory bowel disease), RCT (randomized controlled trial), RR (risk ratio), SCENIC (Surveillance for Colorectal Endoscopic Neoplasia Detection and Management in Inflammatory Bowel Disease Patients: International Consensus Recommendations), SDWLE (standard-definition white-light endoscopy)

      Introduction

      The risk of colorectal cancer (CRC) is increased in patients with ulcerative colitis and Crohn colitis that involves at least one-third of the colon and has been reported to be as high as 18% at 30 years.
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      • Beaugerie L.
      • Egan L.
      • et al.
      European evidence-based consensus: inflammatory bowel disease and malignancies.
      To minimize this risk, practice guidelines in the United States recommend that patients start CRC screening 8 years after disease diagnosis and continue with surveillance every 1 to 3 years thereafter.
      • Lichtenstein G.R.
      • Loftus E.V.
      • Isaacs K.L.
      • et al.
      ACG clinical guideline: management of Crohn’s disease in adults.
      • Farraye F.A.
      • Melmed G.Y.
      • Lichtenstein G.R.
      • et al.
      ACG clinical guideline: preventive care in inflammatory bowel disease.
      • Kornbluth A.
      • Sachar D.B.
      Ulcerative colitis practice guidelines in adults: American College of Gastroenterology, Practice Parameters Committee.
      Historically, CRC screening in patients with inflammatory bowel disease (IBD) was performed using white-light colonoscopy with biopsies performed in 4 quadrants every 10 cm for a total of at least 32 samples.
      • Farraye F.A.
      • Odze R.D.
      • Eaden J.
      • et al.
      AGA medical position statement on the diagnosis and management of colorectal neoplasia in inflammatory bowel disease.
      Although this technique may identify dysplasia, it has several limitations. Very little of the colon is assessed with random biopsies because this samples less than 0.1% of the surface area of the colon.
      • Xie J.
      • Itzkowitz S.H.
      Cancer in inflammatory bowel disease.
      • Hlavaty T.
      • Huorka M.
      • Koller T.
      • et al.
      Colorectal cancer screening in patients with ulcerative and Crohn's colitis with use of colonoscopy, chromoendoscopy and confocal endomicroscopy.
      In addition, when dysplastic lesions are present, they are most often visible, and the usefulness of the random biopsies is unclear.
      • Krugliak Cleveland N.
      • Colman R.J.
      • Rodriquez D.
      • et al.
      Surveillance of IBD using high definition colonoscopes does not miss adenocarcinoma in patients with low-grade dysplasia.
      • Shah S.C.
      • Torres J.
      • Itzkowitz S.H.
      Management of dysplasia in IBD.
      • Rubin D.T.
      • Rothe J.A.
      • Hetzel J.T.
      • et al.
      Are dysplasia and colorectal cancer endoscopically visible in patients with ulcerative colitis?.
      As a result, the Surveillance for Colorectal Endoscopic Neoplasia Detection and Management in Inflammatory Bowel Disease Patients: International Consensus Recommendations (SCENIC) consensus statement was developed to better standardize and improve methods for identifying dysplasia.
      • Laine L.
      • Kaltenbach T.
      • Barkun A.
      • et al.
      SCENIC international consensus statement on surveillance and management of dysplasia in inflammatory bowel disease.
      The SCENIC consensus statement evaluated different screening modalities, including standard-definition white-light endoscopy (SDWLE), high-definition white-light endoscopy (HDWLE), narrow-band imaging, and virtual chromoendoscopy but considered them all inferior to dye-based chromoendoscopy for the identification of dysplasia.
      • Laine L.
      • Kaltenbach T.
      • Barkun A.
      • et al.
      SCENIC international consensus statement on surveillance and management of dysplasia in inflammatory bowel disease.
      In addition, the use of dye-based chromoendoscopy has been shown to be cost effective and to increase colectomy-free survival.
      • Konijeti G.G.
      • Shrime M.G.
      • Ananthakrishnan A.N.
      • et al.
      Cost-effectiveness analysis of chromoendoscopy for colorectal cancer surveillance in patients with ulcerative colitis.
      However, the overall benefits of chromoendoscopy are still not completely clear.
      • Higgins P.D.
      Miles to go on the SCENIC route: should chromoendoscopy become the standard of care in IBD surveillance?.
      Current guidelines are equivocal in their recommendations for chromoendoscopy in IBD.
      • Lichtenstein G.R.
      • Loftus E.V.
      • Isaacs K.L.
      • et al.
      ACG clinical guideline: management of Crohn’s disease in adults.
      • Farraye F.A.
      • Odze R.D.
      • Eaden J.
      • et al.
      AGA medical position statement on the diagnosis and management of colorectal neoplasia in inflammatory bowel disease.
      • Laine L.
      • Kaltenbach T.
      • Barkun A.
      • et al.
      SCENIC international consensus statement on surveillance and management of dysplasia in inflammatory bowel disease.
      • Abdalla M.
      • Herfarth H.
      Rethinking colorectal cancer screening in IBD, is it time to revisit the guidelines?.
      • Mowat C.
      • Cole A.
      • Windsor A.
      • et al.
      Guidelines for the management of inflammatory bowel disease in adults.
      There are a number of randomized and nonrandomized trials evaluating chromoendoscopy, but these studies have significant heterogeneity with variable comparator arms (SDWLE or others use HDWLE).
      • Marion J.F.
      • Waye J.D.
      • Present D.H.
      • et al.
      Chromoendoscopy-targeted biopsies are superior to standard colonoscopic surveillance for detecting dysplasia in inflammatory bowel disease patients: a prospective endoscopic trial.
      • Mooiweer E.
      • Van der Meulen-de Jong A.
      • Ponsioen C.
      • et al.
      Chromoendoscopy for surveillance in inflammatory bowel disease does not increase neoplasia detection compared with conventional colonoscopy with random biopsies: results from a large retrospective study.
      • Kiesslich R.
      • Goetz M.
      • Lammersdorf K.
      • et al.
      Chromoscopy-guided endomicroscopy increases the diagnostic yield of intraepithelial neoplasia in ulcerative colitis.
      • Marion J.F.
      • Waye J.D.
      • Israel Y.
      • et al.
      Chromoendoscopy is more effective than standard colonoscopy in detecting dysplasia during long-term surveillance of patients with colitis.
      • Rutter M.D.
      • Saunders B.P.
      • Schofield G.
      • et al.
      Pancolonic indigo carmine dye spraying for the detection of dysplasia in ulcerative colitis.
      Furthermore, practical concerns have been raised that chromoendoscopy is difficult to master and is more time consuming than standard colonoscopy with random biopsies, and most insurance companies do not provide reimbursement for the additional time or the contrast dye used for chromoendoscopy.
      • Higgins P.D.
      Miles to go on the SCENIC route: should chromoendoscopy become the standard of care in IBD surveillance?.
      A recent network meta-analysis by Restellini et al
      • Restellini S.
      • Bessissow T.
      • Dulai P.S.
      • et al.
      Comparison of endoscopic dysplasia detection techniques in patients with ulcerative colitis: a systematic review and network meta-analysis.
      showed that chromoendoscopy is likely more effective than SDWLE for identification of dysplasia but there is low confidence supporting its use over HDWLE. This study, however, did not evaluate the difference in available data from randomized controlled trials (RCTs) and non-RCTs to determine whether there is a difference in the identification of dysplasia associated with the underlying study design.
      Given the variability of the study designs associated with chromoendoscopy and the fact that many of these studies were not performed with HDWLE, we performed a meta-analysis of RCTs of dye-based chromoendoscopy compared with SDWLE and HDWLE; we also compared these findings in non-RCTs.

      Methods

      Data source and literature search

      A comprehensive literature search was performed with the assistance of a medical librarian at Harvard Medical School with expertise in meta-analysis searches. The literature was searched for RCTs and non-RCTs of chromoendoscopy in patients with ulcerative colitis or Crohn disease in PubMed, EMBASE, and Web of Science. Reference lists from extracted studies and societal practice guidelines were also reviewed for additional studies. The search strategy was based on the SCENIC guidelines search criteria.
      • Laine L.
      • Kaltenbach T.
      • Barkun A.
      • et al.
      SCENIC international consensus statement on surveillance and management of dysplasia in inflammatory bowel disease.
      The initial search was performed on September 1, 2017, and repeated on April 1, 2018, to identify any newly published studies.

      Study selection

      Inclusion criteria

      Studies were included if they involved the use of chromoendoscopy to evaluate for dysplasia in patients with ulcerative colitis or Crohn disease in comparison with another modality of screening. Both randomized and nonrandomized studies were included. Only studies that reported dysplasia per patient were included. Studies that used a cross-over design with patients undergoing 2 colonoscopies separated by several weeks were included, but only the data from first procedure were assessed.

      Exclusion criteria

      Non-human studies and studies that assessed the use of chromoendoscopy in patients who did not have IBD were excluded. Virtual chromoendoscopy (ie, narrow-band imaging, Iscan, and confocal microscopy) was excluded. Studies that only reported dysplasia per colonoscopy in which patients underwent multiple colonoscopies were also excluded. Similarly, studies with no comparator arm were also not included in the analysis.

      Data extraction

      Two reviewers (J.F. and A.Y.) independently reviewed all search results. The initial results were reviewed by title to determine whether a trial was potentially eligible for inclusion. If a screened title was deemed eligible or potentially eligible, then the abstract was reviewed in detail. Any disagreement was resolved by the evaluation of a third reviewer (J.D.F.).

      Outcome measures

      The primary outcome of this study was to assess the number of patients with dysplastic lesions identified with dye-based chromoendoscopy compared with non–dye-based modalities. The comparator arms included SDWLE or HDWLE. Studies were grouped into randomized controlled studies or nonrandomized controlled studies. Procedure times were also compared. Intention-to-treat analysis was used when extracting the data.

      Risk of bias assessment and quality of evidence assessment

      Risk of bias and quality of evidence were assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach.
      • Harbour R.
      • Miller J.
      A new system for grading recommendations in evidence based guidelines.
      The overall certainty in the evidence was assessed using the GRADE domains, including risk of bias, inconsistency, indirectness, impression, and other publication bias considerations. Evidence was then graded as high, moderate, low, or very low. In the GRADE approach, RCTs start at high-quality evidence but can be rated down based on any of the above-mentioned domains. In contrast, observational studies start at low-quality evidence but can be graded up or down based on the above-mentioned domains.

      Statistical analysis

      Comparative studies were analyzed using pooled relative risk (RR), and 95% confidence intervals (CI) were calculated based on the DerSimonian-Liard random-effects model. Heterogeneity was assessed using the I2 statistic with values >50% suggesting significant heterogeneity. Statistical analysis was performed using RevMan, version 5.3 (Cochrane Collaboration, Copenhagen, Denmark) and GradePro/GDT software (McMaster University, 2015).
      The review was performed using the standards set forth by the Preferred Reporting Items for Systematic Reviews and Meta-analysis statement.

      Results

      The search of the databases and references resulted in 27,904 articles (Fig. 1). After removing duplicates, non-human studies, and non-IBD–related chromoendoscopy, 767 studies were reviewed in depth. Of these, 10 were included in the final qualitative and quantitative analysis.
      • Hlavaty T.
      • Huorka M.
      • Koller T.
      • et al.
      Colorectal cancer screening in patients with ulcerative and Crohn's colitis with use of colonoscopy, chromoendoscopy and confocal endomicroscopy.
      • Kiesslich R.
      • Goetz M.
      • Lammersdorf K.
      • et al.
      Chromoscopy-guided endomicroscopy increases the diagnostic yield of intraepithelial neoplasia in ulcerative colitis.
      • Kiesslich R.
      • Fritsch J.
      • Holtmann M.
      • et al.
      Methylene blue-aided chromoendoscopy for the detection of intraepithelial neoplasia and colon cancer in ulcerative colitis.
      • Freire P.
      • Figueiredo P.
      • Cardoso R.
      • et al.
      Surveillance in ulcerative colitis: is chromoendoscopy-guided endomicroscopy always better than conventional colonoscopy? A randomized trial.
      • Mohammed N.
      • Kant P.
      • Abid F.
      • et al.
      High definition white light endoscopy (HDWLE) versus high definition with chromoendoscopy (HDCE) in the detection of dysplasia in long standing ulcerative colitis: a randomized controlled trial [abstract].
      • Park S.J.
      • Kim H.-S.
      • Yang D.-H.
      • et al.
      Tu2086 high definition chromoendoscopy with water-jet versus high definition white light endoscopy in the detection of dysplasia in long standing ulcerative colitis: a multicenter prospective randomized controlled study.
      • Iacucci M.
      • Kaplan G.G.
      • Panaccione R.
      • et al.
      A randomized trial comparing high definition colonoscopy alone with high definition dye spraying and electronic virtual chromoendoscopy for detection of colonic neoplastic lesions during IBD surveillance colonoscopy.
      • Gasia M.F.
      • Ghosh S.
      • Panaccione R.
      • et al.
      Targeted biopsies identify larger proportions of patients with colonic neoplasia undergoing high-definition colonoscopy, dye chromoendoscopy, or electronic virtual chromoendoscopy.
      • Günther U.
      • Kusch D.
      • Heller F.
      • et al.
      Surveillance colonoscopy in patients with inflammatory bowel disease: comparison of random biopsy vs. targeted biopsy protocols.
      • Iacucci M.
      • Hassan C.
      • Gasia M.F.
      • et al.
      Serrated adenoma prevalence in inflammatory bowel disease surveillance colonoscopy, and characteristics revealed by chromoendoscopy and virtual chromoendoscopy.
      See Table 1 for a summary of the trials included. In total, 731 patients underwent a colonoscopy evaluation with dye-based chromoendoscopy compared with 831 patients in the non-chromoendoscopy arm. The dye-based chromoendoscopy studies used indigo carmine or methylene blue with variable dilutions. Most of the studies were performed in Europe or Asia. Six of the studies were RCTs,
      • Kiesslich R.
      • Goetz M.
      • Lammersdorf K.
      • et al.
      Chromoscopy-guided endomicroscopy increases the diagnostic yield of intraepithelial neoplasia in ulcerative colitis.
      • Kiesslich R.
      • Fritsch J.
      • Holtmann M.
      • et al.
      Methylene blue-aided chromoendoscopy for the detection of intraepithelial neoplasia and colon cancer in ulcerative colitis.
      • Freire P.
      • Figueiredo P.
      • Cardoso R.
      • et al.
      Surveillance in ulcerative colitis: is chromoendoscopy-guided endomicroscopy always better than conventional colonoscopy? A randomized trial.
      • Mohammed N.
      • Kant P.
      • Abid F.
      • et al.
      High definition white light endoscopy (HDWLE) versus high definition with chromoendoscopy (HDCE) in the detection of dysplasia in long standing ulcerative colitis: a randomized controlled trial [abstract].
      • Park S.J.
      • Kim H.-S.
      • Yang D.-H.
      • et al.
      Tu2086 high definition chromoendoscopy with water-jet versus high definition white light endoscopy in the detection of dysplasia in long standing ulcerative colitis: a multicenter prospective randomized controlled study.
      • Iacucci M.
      • Kaplan G.G.
      • Panaccione R.
      • et al.
      A randomized trial comparing high definition colonoscopy alone with high definition dye spraying and electronic virtual chromoendoscopy for detection of colonic neoplastic lesions during IBD surveillance colonoscopy.
      and 2 of the studies were only published in abstract form.
      • Mohammed N.
      • Kant P.
      • Abid F.
      • et al.
      High definition white light endoscopy (HDWLE) versus high definition with chromoendoscopy (HDCE) in the detection of dysplasia in long standing ulcerative colitis: a randomized controlled trial [abstract].
      • Park S.J.
      • Kim H.-S.
      • Yang D.-H.
      • et al.
      Tu2086 high definition chromoendoscopy with water-jet versus high definition white light endoscopy in the detection of dysplasia in long standing ulcerative colitis: a multicenter prospective randomized controlled study.
      Chromoendoscopy was compared with SDWLE in 3 RCTs and in 2 non-RCTs.
      • Hlavaty T.
      • Huorka M.
      • Koller T.
      • et al.
      Colorectal cancer screening in patients with ulcerative and Crohn's colitis with use of colonoscopy, chromoendoscopy and confocal endomicroscopy.
      • Kiesslich R.
      • Goetz M.
      • Lammersdorf K.
      • et al.
      Chromoscopy-guided endomicroscopy increases the diagnostic yield of intraepithelial neoplasia in ulcerative colitis.
      • Kiesslich R.
      • Fritsch J.
      • Holtmann M.
      • et al.
      Methylene blue-aided chromoendoscopy for the detection of intraepithelial neoplasia and colon cancer in ulcerative colitis.
      • Freire P.
      • Figueiredo P.
      • Cardoso R.
      • et al.
      Surveillance in ulcerative colitis: is chromoendoscopy-guided endomicroscopy always better than conventional colonoscopy? A randomized trial.
      • Gasia M.F.
      • Ghosh S.
      • Panaccione R.
      • et al.
      Targeted biopsies identify larger proportions of patients with colonic neoplasia undergoing high-definition colonoscopy, dye chromoendoscopy, or electronic virtual chromoendoscopy.
      Chromoendoscopy was compared with HDWLE in 3 RCTs and in 3 non-RCTs.
      • Mohammed N.
      • Kant P.
      • Abid F.
      • et al.
      High definition white light endoscopy (HDWLE) versus high definition with chromoendoscopy (HDCE) in the detection of dysplasia in long standing ulcerative colitis: a randomized controlled trial [abstract].
      • Park S.J.
      • Kim H.-S.
      • Yang D.-H.
      • et al.
      Tu2086 high definition chromoendoscopy with water-jet versus high definition white light endoscopy in the detection of dysplasia in long standing ulcerative colitis: a multicenter prospective randomized controlled study.
      • Iacucci M.
      • Kaplan G.G.
      • Panaccione R.
      • et al.
      A randomized trial comparing high definition colonoscopy alone with high definition dye spraying and electronic virtual chromoendoscopy for detection of colonic neoplastic lesions during IBD surveillance colonoscopy.
      • Gasia M.F.
      • Ghosh S.
      • Panaccione R.
      • et al.
      Targeted biopsies identify larger proportions of patients with colonic neoplasia undergoing high-definition colonoscopy, dye chromoendoscopy, or electronic virtual chromoendoscopy.
      • Günther U.
      • Kusch D.
      • Heller F.
      • et al.
      Surveillance colonoscopy in patients with inflammatory bowel disease: comparison of random biopsy vs. targeted biopsy protocols.
      • Iacucci M.
      • Hassan C.
      • Gasia M.F.
      • et al.
      Serrated adenoma prevalence in inflammatory bowel disease surveillance colonoscopy, and characteristics revealed by chromoendoscopy and virtual chromoendoscopy.
      Figure thumbnail gr1
      Figure 1The studies included in the meta-analysis.
      Table 1Study demographics
      StudyYearCountryAbstractEndoscopy techniqueStudy designIBDTotal numberChromoendoscopy, nNon-chromoendoscopy, nAge of the patients (years)Duration of diseaseType of chromoendoscopyPSC
      With chromoendoscopyWithout chromoendoscopyWith chromoendoscopyWithout chromoendoscopyAdenoma detectionHigh-grade dysplasiaWithdrawal timeTotal procedure time
      Kiesslich
      • Kiesslich R.
      • Fritsch J.
      • Holtmann M.
      • et al.
      Methylene blue-aided chromoendoscopy for the detection of intraepithelial neoplasia and colon cancer in ulcerative colitis.
      2003GermanyNoSDRCTUC1748787848111.2 ± 7.39.7 ± 6.2Methylene blue 0.1%1913/68/244/35
      Kiesslich
      • Kiesslich R.
      • Goetz M.
      • Lammersdorf K.
      • et al.
      Chromoscopy-guided endomicroscopy increases the diagnostic yield of intraepithelial neoplasia in ulcerative colitis.
      2007GermanyNoSDRCTUC1618180807312.3 ± 9.214.5 ± 7.9Methylene blue 0.1%1511/47/142/31
      Freire
      • Freire P.
      • Figueiredo P.
      • Cardoso R.
      • et al.
      Surveillance in ulcerative colitis: is chromoendoscopy-guided endomicroscopy always better than conventional colonoscopy? A randomized trial.
      2015PortugalNoSDRCTUC162818149.2 ± 13.551.7 ± 15.616.2 ± 9.818.4 ± 8.0Methylene blue 0.1%06/40/061.5/40.7
      Mohammed
      • Mohammed N.
      • Kant P.
      • Abid F.
      • et al.
      High definition white light endoscopy (HDWLE) versus high definition with chromoendoscopy (HDCE) in the detection of dysplasia in long standing ulcerative colitis: a randomized controlled trial [abstract].
      2015UKYesHDRCTUC1035053nanananaIndigo carmine 0.2%na11/51/017.8/18.9
      Park
      • Park S.J.
      • Kim H.-S.
      • Yang D.-H.
      • et al.
      Tu2086 high definition chromoendoscopy with water-jet versus high definition white light endoscopy in the detection of dysplasia in long standing ulcerative colitis: a multicenter prospective randomized controlled study.
      2016South KoreaYesHDRCTUC210102108nanananaIndigo carminena21/13na
      Iacucci
      • Iacucci M.
      • Kaplan G.G.
      • Panaccione R.
      • et al.
      A randomized trial comparing high definition colonoscopy alone with high definition dye spraying and electronic virtual chromoendoscopy for detection of colonic neoplastic lesions during IBD surveillance colonoscopy.
      2018CanadaNoHDRCTUC/CD225909049.92 ± 11.9648.14 ± 13.7317.92 ± 9.0716.51 ± 9.66Indigo carmine 0.03% or methylene blue 0.04%822/231/016.2/15.4
      Hlavaty
      • Hlavaty T.
      • Huorka M.
      • Koller T.
      • et al.
      Colorectal cancer screening in patients with ulcerative and Crohn's colitis with use of colonoscopy, chromoendoscopy and confocal endomicroscopy.
      2011SlovakiaNoSDObsUC/CD453015nanananaIndigo carmine 0.4%17/00/166.1/28
      Günther
      • Günther U.
      • Kusch D.
      • Heller F.
      • et al.
      Surveillance colonoscopy in patients with inflammatory bowel disease: comparison of random biopsy vs. targeted biopsy protocols.
      2011GermanyNoHDObsUC/CD150505049 ± 1745.58 ± 141412Indigo carmine 0.1%na2/0na49/45
      Iacucci
      • Iacucci M.
      • Hassan C.
      • Gasia M.F.
      • et al.
      Serrated adenoma prevalence in inflammatory bowel disease surveillance colonoscopy, and characteristics revealed by chromoendoscopy and virtual chromoendoscopy.
      2014CanadaNoHDObsUC/CD87362451.94 ± 11.0747.62 ± 14.4618.31 ± 8.9415.58 ± 7.88Methylene blue 0.2%85/20/0
      Gasia
      Study had 2 arms for chromoendoscopy and non-chromoendoscopy patients, so data are listed for both arms separately.
      • Gasia M.F.
      • Ghosh S.
      • Panaccione R.
      • et al.
      Targeted biopsies identify larger proportions of patients with colonic neoplasia undergoing high-definition colonoscopy, dye chromoendoscopy, or electronic virtual chromoendoscopy.
      2016CanadaNoSD/HDObsUC/CD4542825057.2 ± 14.2/52.1 ± 13.947.4 ± 12.7/47.4 ± 13.425.5 ± 13.28/11.79 ± 5.8215.99 ± 7.08/16.57 ± 7.98Indigo carmine 0.03% or methylene blue 0.04%279/220/1
      IBD, Inflammatory bowel disease; SD, standard definition; RCT, randomized controlled trial; UC, ulcerative colitis; HD, high definition; na, not available; CD, Crohn’s disease; Obs, observational.
      Study had 2 arms for chromoendoscopy and non-chromoendoscopy patients, so data are listed for both arms separately.

      Chromoendoscopy compared with standard-definition colonoscopy and high-definition colonoscopy in the detection of dysplasia in RCTs

      Three RCTs compared chromoendoscopy with SDWLE,
      • Kiesslich R.
      • Goetz M.
      • Lammersdorf K.
      • et al.
      Chromoscopy-guided endomicroscopy increases the diagnostic yield of intraepithelial neoplasia in ulcerative colitis.
      • Kiesslich R.
      • Fritsch J.
      • Holtmann M.
      • et al.
      Methylene blue-aided chromoendoscopy for the detection of intraepithelial neoplasia and colon cancer in ulcerative colitis.
      • Freire P.
      • Figueiredo P.
      • Cardoso R.
      • et al.
      Surveillance in ulcerative colitis: is chromoendoscopy-guided endomicroscopy always better than conventional colonoscopy? A randomized trial.
      and 3 RCTs compared chromoendoscopy with HDWLE.
      • Mohammed N.
      • Kant P.
      • Abid F.
      • et al.
      High definition white light endoscopy (HDWLE) versus high definition with chromoendoscopy (HDCE) in the detection of dysplasia in long standing ulcerative colitis: a randomized controlled trial [abstract].
      • Park S.J.
      • Kim H.-S.
      • Yang D.-H.
      • et al.
      Tu2086 high definition chromoendoscopy with water-jet versus high definition white light endoscopy in the detection of dysplasia in long standing ulcerative colitis: a multicenter prospective randomized controlled study.
      • Iacucci M.
      • Kaplan G.G.
      • Panaccione R.
      • et al.
      A randomized trial comparing high definition colonoscopy alone with high definition dye spraying and electronic virtual chromoendoscopy for detection of colonic neoplastic lesions during IBD surveillance colonoscopy.
      In total, 494 patients underwent chromoendoscopy compared with 496 patients who underwent non-chromoendoscopy surveillance. When combining SDWLE and HDWLE, there was a small benefit favoring chromoendoscopy for detection of dysplasia (RR, 1.50; 95% CI, 1.08-2.10). However, when evaluating SDWLE and HDWLE individually, chromoendoscopy only showed a benefit when compared with SDWLE (SDWLE: RR, 2.2; 95% CI, 1.15-3.91 vs HDWLE: RR, 1.36; 95% CI, 0.84-2.18) (Fig. 2).
      Figure thumbnail gr2
      Figure 2Forest plot for chromoendoscopy versus standard-definition and high-definition colonoscopy randomized controlled trials.

      Quality of evidence in RCT comparison

      The overall quality of evidence in the RCTs was moderate. Evidence was rated down for imprecision given the wide 95% CIs. The quality of the evidence was high when SDWLE was compared with chromoendoscopy but moderate quality for HDWLE compared with chromoendoscopy as the 95% CI crossed the line of unity in the HDWLE subgroup, indicating no clear benefit of chromoendoscopy compared with HDWLE (Table 2).
      Table 2GRADE quality of evidence for RCTs comparing chromoendoscopy with standard-definition and high-definition white-light colonoscopy
      Certainty assessmentSummary of findings
      No. of participants (studies)Risk of biasInconsistencyIndirectnessImprecisionPublication biasOverall certainty of evidenceStudy event rates (%)Relative risk (95% CI)Anticipated absolute effects
      With routine colonoscopyWith chromoendoscopyRisk with routine colonoscopyRisk difference with chromoendoscopy
      Identification of dysplasia
      990 (6 RCTs)Not seriousNot seriousNot seriousSerious
      CI cross line is unity.
      None⊕⊕◯ Moderate55/496 (11.1)84/494 (17.0)1.50 (1.08-2.10)111 per 100055 more per 1000 (9 more to 122 more)
      Identification of dysplasia compared with standard definition
      497 (3 RCTs)Not seriousNot seriousNot seriousSerious
      CI cross line is unity.
      None⊕⊕⊕◯ Moderate14/248 (5.6)30/249 (12.0)2.12 (1.15-3.91)56 per 100063 more per 1000 (8 more to 164 more)
      Identification of dysplasia compared with high definition
      493 (3 RCTs)Not seriousNot seriousNot seriousSerious
      CI cross line is unity.
      None⊕⊕⊕◯ Moderate41/248 (16.5)54/245 (22.0)1.36 (0.84-2.18)165 per 100060 more per 1000 (26 fewer to 195 more)
      GRADE, Grading of Recommendations Assessment, Development, and Evaluation; RCT, randomized controlled trial; CI, confidence interval.
      CI cross line is unity.

      Chromoendoscopy compared with standard-definition colonoscopy and high-definition colonoscopy in the detection of dysplasia in non-RCTs

      Two non-RCTs compared chromoendoscopy with SDWLE,
      • Hlavaty T.
      • Huorka M.
      • Koller T.
      • et al.
      Colorectal cancer screening in patients with ulcerative and Crohn's colitis with use of colonoscopy, chromoendoscopy and confocal endomicroscopy.
      • Gasia M.F.
      • Ghosh S.
      • Panaccione R.
      • et al.
      Targeted biopsies identify larger proportions of patients with colonic neoplasia undergoing high-definition colonoscopy, dye chromoendoscopy, or electronic virtual chromoendoscopy.
      and 3 non-RCTs compared chromoendoscopy with HDWLE.
      • Gasia M.F.
      • Ghosh S.
      • Panaccione R.
      • et al.
      Targeted biopsies identify larger proportions of patients with colonic neoplasia undergoing high-definition colonoscopy, dye chromoendoscopy, or electronic virtual chromoendoscopy.
      • Günther U.
      • Kusch D.
      • Heller F.
      • et al.
      Surveillance colonoscopy in patients with inflammatory bowel disease: comparison of random biopsy vs. targeted biopsy protocols.
      • Iacucci M.
      • Hassan C.
      • Gasia M.F.
      • et al.
      Serrated adenoma prevalence in inflammatory bowel disease surveillance colonoscopy, and characteristics revealed by chromoendoscopy and virtual chromoendoscopy.
      In total, 171 patients underwent chromoendoscopy, and 398 underwent non-chromoendoscopy colonoscopy screening. In aggregate, as well as when analyzed separately by SDWLE or HDWLE, the studies indicated a benefit of chromoendoscopy (RR, 3.48; 95% CI, 2.11-5.73; SDWLE: RR, 6.85; 95% CI, 2.79-16.81; HDWLE: RR, 2.57; 95% CI, 1.41-4.68) (Fig. 3).
      Figure thumbnail gr3
      Figure 3Forest plot for chromoendoscopy versus standard-definition and high-definition colonoscopy in nonrandomized controlled trials.

      Quality of evidence in non-RCT comparison

      The quality of evidence was rated as very low. The studies were rated down for very serious risk of bias given the lack of allocation concealment and lack of blinding. The studies were also rated down for imprecision given the wide confidence intervals in the studies that crossed the line of unity and the optimal information size was not achieved (Table 3).
      Table 3GRADE quality of evidence for non-RCTs comparing chromoendoscopy with standard-definition and high-definition white-light colonoscopy
      Certainty assessmentSummary of findings
      No. of participants (studies)Risk of biasInconsistencyIndirectnessImprecisionPublication biasOverall certainty of evidenceStudy event rates (%)Relative risk (95% CI)Anticipated absolute effects
      With routine colonoscopyWith chromoendoscopyRisk with routine colonoscopyRisk difference with chromoendoscopy
      Identification of dysplasia
      569 (4 observational studies)Serious
      Lack of allocation concealment. Lack of blinding.
      Not seriousNot seriousVery serious
      CI cross line of unity and poor overlap. Optimal information size not met.
      NoneVery low24/398 (6.0)16/171 (9.4)2.66 (1.46-4.84)60 per 1000100 more per 1000 (28 more to 232 more)
      Identification of dysplasia compared with standard definition
      199 (2 observational studies)Serious
      Lack of allocation concealment. Lack of blinding.
      Not seriousNot seriousVery serious
      CI cross line of unity and poor overlap. Optimal information size not met.
      NoneVery low6/141 (4.3)16/58 (27.6)6.98 (2.59-18.79)43 per 1000254 more per 1000 (68 more to 757 more)
      Identification of dysplasia compared with high definition
      370 (3 observational studies)Serious
      Lack of allocation concealment. Lack of blinding.
      Not seriousNot seriousVery serious
      CI cross line of unity and poor overlap. Optimal information size not met.
      NoneVery low25/257 (9.7)16/113 (14.2)2.57 (1.41-4.68)97 per 1000153 more per 1000 (40 more to 358 more)
      GRADE, Grading of Recommendations Assessment, Development, and Evaluation; RCT, randomized controlled trial; CI, confidence interval.
      Lack of allocation concealment. Lack of blinding.
      CI cross line of unity and poor overlap. Optimal information size not met.

      Procedure time

      Total procedure time was reported in 3 studies,
      • Hlavaty T.
      • Huorka M.
      • Koller T.
      • et al.
      Colorectal cancer screening in patients with ulcerative and Crohn's colitis with use of colonoscopy, chromoendoscopy and confocal endomicroscopy.
      • Kiesslich R.
      • Fritsch J.
      • Holtmann M.
      • et al.
      Methylene blue-aided chromoendoscopy for the detection of intraepithelial neoplasia and colon cancer in ulcerative colitis.
      • Freire P.
      • Figueiredo P.
      • Cardoso R.
      • et al.
      Surveillance in ulcerative colitis: is chromoendoscopy-guided endomicroscopy always better than conventional colonoscopy? A randomized trial.
      and 2 studies reported withdrawal time only.
      • Mohammed N.
      • Kant P.
      • Abid F.
      • et al.
      High definition white light endoscopy (HDWLE) versus high definition with chromoendoscopy (HDCE) in the detection of dysplasia in long standing ulcerative colitis: a randomized controlled trial [abstract].
      • Park S.J.
      • Kim H.-S.
      • Yang D.-H.
      • et al.
      Tu2086 high definition chromoendoscopy with water-jet versus high definition white light endoscopy in the detection of dysplasia in long standing ulcerative colitis: a multicenter prospective randomized controlled study.
      Total procedure time included 186 patients for chromoendoscopy and 169 patients for non-chromoendoscopy. The mean difference in procedure time was 21.69 minutes (95% CI, 9.01-34.38) (Supplementary Fig. 1, available online at www.giejournal.org). When limited to withdrawal time, 2 studies included 152 patients for chromoendoscopy and 161 patients for non-chromoendoscopy with a mean difference of 3.51 minutes (95% CI, 2.17-4.85) (Supplementary Fig. 2, available online at www.giejournal.org).

      Discussion

      Based on this meta-analysis, when the studies are assessed in aggregate, chromoendoscopy appears to be more effective than non-chromoendoscopy for detection of dysplasia. However, the RCT comparison only showed a benefit of chromoendoscopy when compared with SDWLE and not HDWLE. Importantly, in this subgroup analysis, the number of patients included was of adequate optimal information size to conclude that chromoendoscopy is not superior to HDWLE. In contrast to the RCT comparison, non-RCT showed a benefit to chromoendoscopy when compared with both SDWLE and HDWLE. The quality of this evidence, however, was very low given concerns within multiple GRADE domains. However, now that HDWLE is the standard of care, based on the RCTs, it is unclear how much additional benefit chromoendoscopy provides in detecting dysplasia.
      Over the past decade, endoscope technology has advanced from standard-definition endoscopes to high-definition endoscopes.
      • Trindade A.J.
      • Lichtenstein D.R.
      • Aslanian H.R.
      • et al.
      Devices and methods to improve colonoscopy completion (with videos).
      • Subramanian V.
      • Ragunath K.
      advanced endoscopic imaging: a review of commercially available technologies.
      The high-definition endoscopes provide higher-quality detail and have been shown to identify more polyps and sessile polyps, which may have been missed previously with standard-definition technology. As endoscope technology has advanced, the ability to identify subtle abnormalities within the mucosa has also improved.
      • Bhat Y.M.
      • Abu Dayyeh B.K.
      • Chauhan S.S.
      • et al.
      High-definition and high-magnification endoscopes.
      The ability to discern subtle irregularities is important in IBD when most cancers and dysplasia are visible. However, invisible dysplasia progressing to cancer remains an ongoing concern.
      • Feagins L.A.
      • Souza R.F.
      • Spechler S.J.
      Carcinogenesis in IBD: potential targets for the prevention of colorectal cancer.
      Different modalities have been used to improve the detection of dysplasia, including the following: biopsies every 10 cm, dye-based chromoendoscopy, and virtual chromoendoscopy.
      • Kaltenbach T.
      • Sandborn W.J.
      Endoscopy in inflammatory bowel disease: advances in dysplasia detection and management.
      • Cohen-Mekelburg S.
      • Schneider Y.
      • Gold S.
      • et al.
      Advances in the diagnosis and management of colonic dysplasia in patients with inflammatory bowel disease.
      However, the ability to detect dysplasia with advances in endoscope technology in combination with these techniques is unclear. Our subgroup analysis further supports this in the RCT arm. SDWLE, which is an older technology, provides inferior mucosal assessment compared with HDWLE, and therefore, it is not surprising that chromoendoscopy is superior to SDWLE; but when compared, HDWLE chromoendoscopy does not show a benefit. This finding is similar to the network meta-analysis findings by Restellini et al,
      • Restellini S.
      • Bessissow T.
      • Dulai P.S.
      • et al.
      Comparison of endoscopic dysplasia detection techniques in patients with ulcerative colitis: a systematic review and network meta-analysis.
      which showed a benefit of chromoendoscopy over SDWLE but unclear benefits when compared with HDWLE or narrow-band imaging. Interestingly, in the non-RCT studies, both SDWLE and HDWLE were inferior to chromoendoscopy. The reason for this discrepancy is unclear, but the study design and unintended biases of a non-RCT may be the reason for the discrepant findings. What has not yet been elucidated, however, is whether HDWLE provides adequate visualization of the margins of subtle dysplasia or if chromoendoscopy is necessary to identify margins to allow for complete endoscopic resection.
      Even though chromoendoscopy provides a theoretical benefit of enhanced identification of dysplasia, the ideal contrast and dilution method is unclear. The studies included in this analysis used different concentrations of methylene blue and indigo carmine. The importance of the concentration and the depth of the color hue is unclear. However, given the lack of standardization in the studies, it is possible that this variable could be a factor in the amount of dysplasia identified with chromoendoscopy. In addition, the lack of reimbursement associated with the use of either methylene blue or indigo carmine increases the overall cost of colonoscopy and may further limit the use of chromoendoscopy in practice. The availability of these agents is also limited by recent drug shortages, limiting the ability to choose which dye is used.
      • Steers W.D.
      Falling short: causes and implications of drug shortages in the United States.
      Previous studies have suggested that methylene blue might be intercalated into the DNA, resulting in an increased risk of cancer. However, this risk has not been substantiated in follow-up studies.
      • Boland B.S.
      • Shergill A.
      • Kaltenbach T.
      Endoscopic surveillance in long-standing colitis.
      Overall, chromoendoscopy is safe, but it does increase procedural time.
      • Shukla R.
      • Salem M.
      • Hou J.K.
      Use and barriers to chromoendoscopy for dysplasia surveillance in inflammatory bowel disease.
      The additional procedural time likely results in increased sedation time, which may increase the risk of adverse events from prolonged sedation. If HDWLE is equal to chromoendoscopy, it is unclear if this additional sedation time is worthwhile if the technique is not providing a clear additive benefit in the overall ability to detect dysplasia. In addition, the increased procedure time is likely to provide a secondary benefit of increased detection of dysplasia, which may be the reason why higher rates of dysplasia were identified in the non-randomized studies. Previous studies have suggested that longer procedure times in general are associated with higher rates of adenoma detection and perhaps that may explain some of the differences in dysplasia yield.
      • Barclay R.L.
      • Vicari J.J.
      • Doughty A.S.
      • et al.
      Colonoscopic withdrawal times and adenoma detection during screening colonoscopy.
      • Barclay R.L.
      • Vicari J.J.
      • Greenlaw R.L.
      Effect of a time-dependent colonoscopic withdrawal protocol on adenoma detection during screening colonoscopy.
      Nonetheless, our meta-analysis suggests that chromoendoscopy in addition to HDWLE may not have an additional benefit for dysplasia detection.
      Our study has a number of strengths and limitations. By performing a systematic review and meta-analysis, we were able to include multiple studies to achieve an optimal information size allowing for adequate sampling to assess our outcomes of interest. We were also able to highlight the differences in study design (RCT vs non-RCT) and differences in endoscope technology (ie, SDWLE vs HDWLE) to detect dysplasia and alter outcomes when comparing chromoendoscopy with non-chromoendoscopy colonoscopy. However, our study has a number of limitations. We did exclude several studies, but all of these were done a priori based on our meta-analysis design. Studies were excluded when they did not report dysplasia per patient per colonoscopy because the goal of our analysis was to determine whether chromoendoscopy enhances dysplasia detection in a patient with IBD and not to assess overall dysplasia detection in colonoscopies that include the same patient undergoing multiple colonoscopies. This latter analysis would introduce a different potential bias. An individual without a history of dysplasia is at lower risk of subsequent dysplasia than an individual with previous dysplasia. Depending on which arm of the study the patient falls into, this could bias the results in either direction. Therefore, we believed that excluding these studies actually provided a more realistic assessment of the yield of chromoendoscopy in any given patient with IBD. Abstracts were included in this study, and this could have introduced some bias because these studies are not always analyzed as rigorously as complete manuscripts. However, we did believe that it was important to include the added data. Demographic data are included in Table 1, but studies did not always include similar background data, limiting some subgroup analysis. In addition, certain outcomes such as colectomy or mortality were not reported consistently, limiting the ability to analyze these outcomes, which may be more ideal outcomes to determine the efficacy of CRC screening. Finally, the variability of contrast agents and dilutions used for chromoendoscopy may make some of the results difficult to generalize if a different agent or dilution is used in an individual practice.

      Conclusion

      Although overall, chromoendoscopy appears superior to non-chromoendoscopy, these findings are limited to SDWLE and to non-RCT studies. When using HDWLE in RCTs as a comparator, there does not appear to be a difference between chromoendoscopy and HDWLE in detecting dysplasia. Further studies are needed to evaluate chromoendoscopy, HDWLE with biopsies every 10 cm, and HDWLE with targeted biopsies.

      Appendix

      Figure thumbnail fx2
      Supplementary Figure 1Total procedure time.
      Figure thumbnail fx3
      Supplementary Figure 2Total withdrawal time.

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      Linked Article

      • Chromoendoscopy meta-analysis: correcting subgroup analysis interpretation
        Gastrointestinal EndoscopyVol. 91Issue 3
        • Preview
          Feuerstein et al1 conclude that chromoendoscopy is superior to standard-definition white-light endoscopy (SDWLE) but not superior to high-definition white-light endoscopy (HDWLE) in patients with inflammatory bowel disease. They base this conclusion on an analysis of 2 subgroups (chromoendoscopy vs SDWLE and chromoendoscopy vs HDWLE) within their meta-analysis of randomized trials of chromoendoscopy versus white-light endoscopy. However, their interpretation of this subgroup analysis is incorrect.
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