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High-definition colonoscopy for improving adenoma detection: a systematic review and meta-analysis of randomized controlled studies
Journal Pre-proof High-definition colonoscopy for improving adenoma detection: a systematic review and meta-analysis of randomized controlled studies Georgios Tziatzios, Paraskevas Gkolfakis, Lazaros Dimitrios Lazaridis, Antonio Facciorusso, Giulio Antonelli, Cesare Hassan, Alessandro Repici, Prateek Sharma, Douglas K. Rex, Konstantinos Triantafyllou PII:
S0016-5107(20)30038-9
DOI:
https://doi.org/10.1016/j.gie.2019.12.052
Reference:
YMGE 11930
To appear in:
Gastrointestinal Endoscopy
Received Date: 26 September 2019 Accepted Date: 30 December 2019
Please cite this article as: Tziatzios G, Gkolfakis P, Lazaridis LD, Facciorusso A, Antonelli G, Hassan C, Repici A, Sharma P, Rex DK, Triantafyllou K, High-definition colonoscopy for improving adenoma detection: a systematic review and meta-analysis of randomized controlled studies, Gastrointestinal Endoscopy (2020), doi: https://doi.org/10.1016/j.gie.2019.12.052. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Copyright © 2020 by the American Society for Gastrointestinal Endoscopy
Manuscript title: High-definition colonoscopy for improving adenoma detection: a systematic review and meta-analysis of randomized controlled studies Authors: 1Georgios Tziatzios*, 1Paraskevas Gkolfakis*, 1Lazaros Dimitrios Lazaridis, 2Antonio Facciorusso, 3Giulio Antonelli, 4Cesare Hassan, 5Alessandro Repici, 6,7Prateek Sharma, 8Douglas K Rex, 1Konstantinos Triantafyllou *equal contribution Authors Affiliations: 1Hepatogastroenterology Unit, Second Department of Internal Medicine – Propaedeutic, Research Institute and Diabetes Center, Medical School, National and Kapodistrian University of Athens, ‘‘Attikon” University General Hospital, Athens, Greece 2Gastroenterology
Unit, Department of Medical Sciences, University of Foggia
AOU, Ospedali Riunity Viale Pinto, Foggia, Italy 3Endoscopy
Unit, Sant 'Andrea University Hospital, "Sapienza" University of
Rome, Rome, Italy 4Endoscopy Unit, Nuovo Regina Margherita Hospital, Rome, Italy 5Digestive Endoscopy Unit, Division of Gastroenterology, Humanitas Clinical and
Research Center and Humanitas University, Rozzano, Italy 6Division of Gastroenterology & Hepatology, Department of Internal Medicine,
University of Kansas Medical Center, Kansas, Missouri, USA 7Department
of Gastroenterology, Veteran Affairs Medical Center, Kansas,
Missouri, USA 8Division
of Gastroenterology/Hepatology, Indiana University Hospital,
Indianapolis, Indiana, USA
Short Title: HD colonoscopy improves adenoma detection rate Corresponding Author: Konstantinos Triantafyllou, Associate Professor of Gastroenterology, Hepatogastroenterology Unit, Second Department of Internal Medicine – Propaedeutic Research Institute and Diabetes Center, Medical School, National and Kapodistrian University of Athens, ‘‘Attikon” University General Hospital, 1, Rimini Street, 124 62 Athens, Greece, (Tel: +30 210 5832087, Fax: +30 210 5326454, Email: [email protected]) Guarantor of the article: Konstantinos Triantafyllou Author contributions: G Tziatzios and P Gkolfakis acquired the data, performed the meta-analysis, drafted and finally approved the manuscript; Lazaros Dimitrios Lazaridis acquired the data, drafted and finally approved the manuscript; Antonio Facciorusso, Giulio Antonelli, Alessandro Repici and Cesare Hassan performed the meta-analysis, revised the draft critically for important intellectual content and finally approved the manuscript; P Sharma, DK Rex and K Triantafyllou conceived the idea, revised the draft critically for important intellectual content and finally approved the manuscript. Conflict of interest: None
1
Manuscript title: High-definition colonoscopy for improving adenoma detection: a systematic review and meta-analysis of randomized controlled studies
1Georgios
Authors:
Tziatzios*,
1Paraskevas
Gkolfakis*,
1Lazaros
Dimitrios
Lazaridis, 2Antonio Facciorusso, 3Giulio Antonelli, 4Cesare Hassan, 5Alessandro Repici, 6,7Prateek Sharma, 8Douglas K Rex and 1Konstantinos Triantafyllou *equal contribution
Authors Affiliations: 1Hepatogastroenterology Unit, Second Department of Internal Medicine – Propaedeutic, Research Institute and Diabetes Center, Medical School, National and Kapodistrian University of Athens, ‘‘Attikon” University General Hospital, Athens, Greece 2Gastroenterology
Unit, Department of Medical Sciences, University of Foggia
AOU, Ospedali Riunity Viale Pinto, Foggia, Italy 3Endoscopy
Unit, Sant 'Andrea University Hospital, "Sapienza" University of
Rome, Rome, Italy 4Endoscopy 5Digestive
Unit, Nuovo Regina Margherita Hospital, Rome, Italy
Endoscopy Unit, Division of Gastroenterology, Humanitas Clinical and
Research Center and Humanitas University, Rozzano, Italy 6Division
of Gastroenterology & Hepatology, Department of Internal Medicine,
University of Kansas Medical Center, Kansas, Missouri, USA 7Department
Missouri, USA
of Gastroenterology, Veteran Affairs Medical Center, Kansas,
2
8Division
of
Gastroenterology/Hepatology,
Indiana
University
Hospital,
Indianapolis, Indiana, USA Short Title: HD colonoscopy improves adenoma detection rate Corresponding Author: Konstantinos Triantafyllou, Associate Professor of Gastroenterology, Hepatogastroenterology Unit, Second Department of Internal Medicine – Propaedeutic Research Institute and Diabetes Center, Medical School, National and Kapodistrian University of Athens, ‘‘Attikon” University General Hospital, 1, Rimini Street, 124 62 Athens, Greece, (Tel: +30 210 5832087, Fax: +30 210 5326454, Email: [email protected]) Guarantor of the article: Konstantinos Triantafyllou Author contributions: G Tziatzios and P Gkolfakis acquired the data, performed the meta-analysis, drafted and finally approved the manuscript; Lazaros Dimitrios Lazaridis acquired the data, drafted and finally approved the manuscript; Antonio Facciorusso, Giulio Antonelli, Alessandro Repici and Cesare Hassan performed the meta-analysis, revised the draft critically for important intellectual content and finally approved the manuscript; P Sharma, DK Rex and K Triantafyllou conceived the idea, revised the draft critically for important intellectual content and finally approved the manuscript. Conflict of interest: None
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Abstract Background and Aims: Previous meta-analysis showed marginal benefit of high-definition white-light endoscopy (HD-WLE) over standard-definition (SDC) colonoscopy for adenoma detection, but with residual uncertainty due to inclusion of nonrandomized studies. We aimed to further assess the effect of HDWLE on adenoma detection by including only randomized controlled trials (RCTs). Methods: A literature search was performed for RCTs evaluating HD-WLE versus SDC in terms of adenoma, advanced adenoma, and serrated sessile adenoma detection rates as well as mean number of adenomas (MAC), advanced adenomas (MAAC), and sessile serrated adenomas per colonoscopy (MSSAC). The effect size on study outcomes is presented as risk ratio (RR; 95% CI) or mean difference (MD; 95% CI). We assessed the strength of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Results: Six RCTs involving 4594 individuals (HD-WLE 2323; SDC 2271) were included. Clinical indications were screening (1 study), positive FOBT and personal/family history of colorectal cancer (1 study), and mixed indications (4 studies). Withdrawal time was similar between the 2 arms (MD, -0.06; 95% CI, 0.25 to 0.12; p=0.50). Adenoma detection rate was significantly higher in the HDWLE compared with SDC arm (40% vs 35%; RR, 1.13; 95% CI, 1.05-1.22; p=0.001; I2=0%; GRADE: low). This effect was consistent for advanced and sessile serrated adenoma detection rates (RR, 1.33; 95% CI, 1.03-1.72; p=0.03; I2=0%; GRADE: low and RR, 1.55; 95% CI, 1.05-2.28; p=0.03; I2=0%; GRADE: low,
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respectively). On the contrary, the difference was not significant for MAC, MAAC, and MSSAC. Conclusions: Meta-analysis of RCT data support the use of HD-WLE in clinical practice, although the additional benefit is limited.
Keywords: high definition; standard definition; colonoscopy; adenoma detection; meta-analysis
1. Introduction Adenoma detection rate (ADR) is the main colonoscopy quality indicator. It is inversely associated with the risk of interval colorectal cancer (CRC) and the risk of death from this neoplasia1,2. Despite its advent nearly 15 years ago, the incremental efficacy of high-definition white-light endoscopy (HD-WLE) as compared with standard-definition endoscopy (SDC) in detecting adenomas remains elusive3. Although early studies showed promising results4,5, the available meta-analysis showed only a marginal increase in adenoma detection when comparing HD-WLE with SDC6. In addition, the marked heterogeneity attributed to the inclusion of various designs of the studies generated further uncertainty when interpreting these results. Moreover, because SDC replacement with HD-WLE is associated with substantial costs, especially for those health systems with limited financial resources, the incremental efficacy of HD-WLE should be assessed not only from the clinical perspective, but also using costeffectiveness data that are currently missing. We aimed to further evaluate the
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effect of HD-WLE on adenoma detection, through a systematic review with metaanalysis incorporating data exclusively from randomized controlled trials (RCTs).
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2. Materials and Methods 2.1. Protocol registration We conducted this study according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations (Appendix 1)7. The review protocol is available at the International Prospective Register of Systematic Reviews (PROSPERO) under registration number CRD42018110105. 2.2. Eligibility criteria We defined eligibility criteria for our study according to the PICO statement; P: patients undergoing colonoscopy for colorectal cancer (CRC) screening, surveillance or symptom evaluation; I: patients undergoing colonoscopy using high-definition white-light endoscopes (HD-WLE); C: patients undergoing colonoscopy using standard-definition endoscopes (SDC); O: adenoma detection rate (ADR) and mean adenomas per colonoscopy. Only prospective, randomized controlled trials, published as full text in the English language were eligible for inclusion. 2.3. Identification and Selection of Studies Our search strategy included the free text terms “colonoscopy*,” “adenoma*,” “random*” both as medical subject headings (MeSH) and free-text terms combined with the Boolean set operator ‘AND’ with the term: “endoscop*,” as medical subject heading and the free text term. We searched PubMed and the Cochrane Central Register of Controlled Trials electronic databases starting from 01 January 2005 - year of high-definition colonoscopies introduction. The search was performed on January 19, 2019. Two investigators (G.T. and L.D.D.)
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independently performed the search (Appendix B). After duplicate removal, 2 reviewers (G.T. and L.D.D.) first assessed the titles and abstracts of all results for inclusion; then, they judged eligibility of the selected articles independently, using predesigned eligibility forms. Any disagreement was resolved by discussion. We also hand-searched references of all eligible studies, to identify potentially studies missed during the first search. In case of missing or incomplete data, the corresponding author was contacted in order to provide further information. 2.4 Data extraction and Quality Assessment Two of the authors (G.T. and L.D.D.) independently extracted data from eligible studies onto a Microsoft Excel spreadsheet (XP professional edition; Microsoft, Redmond, Wash, USA) using a data extraction form. Data extraction included name of the first author, publication year, country of origin, number of centers, number of participating endoscopists, indication for colonoscopy, type of endoscope used, number of total participants, definition of adenoma (ie, conventional or sessile serrated adenoma - SSA/P), quality of bowel preparation, and withdrawal time. We also extracted the number of lesions (adenomas, advanced1 [≥10 mm, with a villous component, and/or with high-grade dysplasia] adenomas, sessile serrated adenomas, and mean number of these lesions were calculated per patient. For the purposes of our study, lesion detection rate was defined as the percentage of colonoscopies with at least one histologically proven lesion. 2.5 Assessment of Risk of Bias
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Risk of bias of individual studies was assessed using the Cochrane collaboration’s assessment tool8. Two independent researchers (G.T. and P.G.) assessed risk of bias attributed to methods used to generate the randomization schedule and conceal treatment allocation (selection bias), implementation of blinding for participants or personnel (performance bias), outcomes assessment (detection bias), proportion of subjects completed follow-up (attrition bias) and evidence of selective reporting of outcomes (reporting bias). Each study included in the meta-analysis was classified having high, low or unclear risk of bias, with reference to each of the abovementioned domains. 2.6 Outcomes assessment The primary outcomes of the meta-analysis were the measurement of ADR and mean number of adenomas per colonoscopy (MAC) in HD-WLE as compared with SDC arm. The effect of HD-WLE on, advanced adenoma detection rate (AADR), and mean number of advanced adenomas per colonoscopy (MAAC), sessile serrated adenoma detection rate (SSADR), and mean number of sessile serrated adenomas per colonoscopy (MSSAC) comprised the secondary outcomes. 2.7 Data synthesis and statistical analysis For dichotomous outcomes risk ratios (RRs) with 95% confidence intervals (95% CIs) were calculated. For continuous outcomes, we calculated mean difference (MD) with 95% CI, using inverse variance. Pooled ADR and MAC per groups were calculated using generic inverse variance analysis and they are presented with their respective 95%CI. Data were meta-analyzed using the random-effects model (DerSimonian and Laird method) to allow a more
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conservative estimate of the effect of HD-WLE. The number of patients needed to be treated (NNT) for one additional patient with an adenomatous polyp to be detected was calculated as the inverse of the difference of adenoma detection rate between the 2 arms. We assessed publication bias visually by checking the funnel plot for asymmetry, or by application of Egger’s test9. All analyses were performed at the 0.05 significance level. Review Manager 5.3 (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark) and StatsDirect 3 (StatsDirect Ltd, Sale, Cheshire, England) software packages were used to meta-analyze all data and to the construct forest and funnel plots. 2.8 Heterogeneity assessment and sensitivity analyses We assessed the presence of heterogeneity using the I2 statistic. Thresholds for the values of I2 were interpreted as follows: 0% to 40%: heterogeneity might not be important; 30% to 60%: may represent moderate heterogeneity; 50% to 90%: may represent substantial heterogeneity; 75% to 100%: considerable heterogeneity. In case of I2 value > 50%, we undertook sensitivity analysis to identify the source of heterogeneity by excluding one study at a time, as proposed by the Cochrane collaboration. We further aimed to detect those groups of patients or endoscopists who might benefit more from HD-WLE. In this respect, we undertook 2 sensitivity analyses for our primary endpoints: (1) per indication of colonoscopies (studies including ≤50% vs >50% individuals undergoing screening exams) and (2) per endoscopists ADR level (≤35% vs >35%) in the SDC arm. 2.9 Assessment of Quality of Body of Evidence
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The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess the quality of evidence. Two independent researchers (G.T. and P.G.) graded inconsistency, risk of bias, indirectness, imprecision, and publication bias. Overall quality was deemed very low, low, moderate, or high using GRADEpro (GRADE Working Group)10. 3. Results 3.1. Study selection Initial search yielded 374 citations. Of them, 363 were excluded after title and abstract review as irrelevant to study’s aim or duplicates. Thus, 11 articles were considered eligible for full-text assessment. Among these, 5 were further excluded for various reasons, leaving 6 studies11-16 to be included in the systematic review and meta-analysis. Figure 1 depicts studies’ selection flowchart. 3.2. Characteristics of studies included Overall, 6 studies enrolling 4594 individuals were included in the analysis; 2323 and 2271 underwent HD-WLE and SDC, respectively. One study was conducted in the USA13 and the rest of them in Europe11,12,14-16. In terms of design, all but one14 studies were of parallel groups design; only data from the index colonoscopies of the tandem design study were taken into account. Half of the studies13-15 were multicenter, the rest of them11,12,16 were conducted in a single center. In all 6 studies11-16 Olympus (Olympus, Tokyo, Japan - Olympus Europe, Hamburg, Germany - Olympus, America Inc, Center Valley, Pa, USA) endoscopes were used [first (180 series) and second (190 series) generation HD-WLE scopes versus the 160, 160/5 and 165 series of SDC scopes], whereas in one study16
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Fujfilm (Fujifilm Corp., Saitama, Japan) and Pentax (Pentax Medical, Tokyo, Japan) colonoscopes (590 series vs. 250 series and 3890 series vs. 3870 and 3710 series, respectively for the HD-WLE and SDC arms) were additionally used. Different populations were represented throughout included studies. Four studies11-13,16 enrolled mixed population of screening, surveillance and diagnostic examinations, one study enrolled exclusively screening individuals15, whereas in the study by Pioche et al14 only individuals at higher than average risk for CRC were considered eligible for participation. Participants’ gender (male: 45.7% vs 68%) and mean age (58.2 vs 62.5 years) were similar, and there were no significant differences in the bowel preparation quality between the 2 arms among the studies that reported on this outcome11,13-15. No difference in withdrawal times―assessed in 4 studies11-13,16 with 2517 subjects―(MD, -0.06; 95% CI, -0.25 to 0.12; p=0.50; I2=0%; P=0.44) was noted between HD-WLE and SDC groups. Histopathological samples were analyzed according to Vienna classification17,18 in 2 studies14,15, World Health Organization classification19 in one study16, whereas the other 3 studies11-13 did not provide relevant details. Two studies14,15 stated that for ADR definition, conventional, traditional serrated adenomas and SSA/P were included, one16 defined ADR as the percentage of colonoscopies with at least one adenoma, whereas 3 studies11-13 provided no detail. Table 1 shows the basic characteristics of included studies. 3.3. Methodological quality and risk of bias A summarized assessment of risk of bias per study using the Cochrane collaboration’s risk of bias assessment tool is illustrated in Figure 2. Two studies11,15 did not clarify the method used to generate randomization sequence
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and in one11 details about allocation concealment were not provided. Participating physicians were not blinded of the used equipment and the measured outcomes in any of the studies. Finally, one study16 presented data on measurements not included in the initial protocol.
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3.4. Endpoints 3.4.1 Primary endpoints Adenoma detection rate All 6 studies11-16 (n=4594) provided data regarding ADR. Overall, at least one adenoma was detected in 897 out of 2323 and 776 out of 2271 individuals in in the HD-WLE and SDC arms, respectively. ADR was higher ADR, 40; 95% CI, 33% 48% vs 35 95% CI, 30% - 41%) (Supplementary Figure 1A) in the HD-WLE compared with the SDC group (RR, 1.13; 95% CI, 1.05-1.22; p=0.001) (Figure 3). NNT to find one additional patient with an adenomatous polyp with the high definition technology was 23. We detected neither heterogeneity (I2=0%; P=0.91) nor evidence of publication bias (Egger test: bias, - 0.72; 95% CI, - 4.64 to 3.18; p = 0.63, Supplementary Figure 2A). GRADE analysis indicated that quality of the evidence supporting higher ADR with HD-WLE was low (Appendix 3, Grade Summary Table). Mean number of adenomas per colonoscopy The mean number of adenomas per colonoscopy was provided or calculated from raw data in 5 studies11,12,14-16 (n=4174). MAC did not differ between HDWLE and SDC (0.77; 95% CI, 0.55-0.99 vs 0.68, 95% CI, 0.49-0.87), (Supplementary Figure 1B) (MD, 0.06; 95% CI, -0.02 to -0.14; p=0.13; I2=0%; P=0.41) (Figure 4). There was no evidence of publication bias (Egger test: bias, 0.000283; 95% CI, -0.66 to 0.66; p = 0.99) (Supplementary Figure 2B). Quality of evidence regarding MAC was low (Appendix 3, Grade Summary Table).
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3.4.2 Secondary Endpoints Advanced adenoma detection rate Three studies12,14,16 provided data allowing advanced adenoma detection rate to be calculated. At least one advanced adenoma was detected in 113 out of 1206 and 81 out of 1210 individuals in in the HD-WLE and SDC arms, respectively (RR, 1.33; 95% CI, 1.03 - 1.72; p=0.03) (Figure 5). Neither heterogeneity (I2=0%; P=0.71) nor evidence of publication bias (Egger test: bias, - 0.90; 95% CI, - 4.34 to 2.54; p = 0.27) was found. The quality of the evidence supporting higher AADR with HD-WLE was low (Appendix 3, Grade Summary Table). Mean number of advanced adenomas per colonoscopy Mean number of advanced adenomas per colonoscopy was provided in 2 studies12,16. MAAC was not different between HD-WLE and SDC (MD, 0.05; 95% CI, -0.89 to -0.99; p=0.91; I2=0%; P=0.98) (Supplementary Figure 3). There was no evidence of publication bias visually by checking the funnel plot for asymmetry [Egger test: bias: not applicable]. Quality of evidence regarding MAAC was also low (Appendix 3, Grade Summary Table). Sessile serrated adenoma detection rate Sessile serrated adenoma detection rate was calculated from data provided by 3 studies12,14,16. At least one lesion was detected in 61 out of 1206 and 41 out of 1210 examinations in HD-WLE and SDC arms, respectively (RR, 1.55; 95% CI, 1.05-2.28; p=0.03) (Figure 6). Heterogeneity (I2=0%; P=0.43) and evidence of publication bias (Egger test: bias, - 1.26; 95% CI, - 26.8 to 24.4; p = 0.74) were absent. GRADE analysis indicated that quality of the evidence supporting higher SADR with HD-WLE was low (Appendix 3, Grade Summary Table).
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Mean number of sessile adenomas per colonoscopy Mean number of sessile serrated adenomas per colonoscopy as derived from 2 studies12,16. MSSAC did not differ between HD-WLE and SDC (MD, 0.04; 95% CI, 0.62-0.70; p=0.9; I2=0%; P=0.98) (Supplementary Figure 4]. There was no evidence of publication bias by visually checking the funnel plot for asymmetry (Egger test: bias: not applicable). Quality of evidence regarding MSSAC was once again low (Appendix 3, Grade Summary Table). 3.4.3 Sensitivity analysis Our analysis showed that the beneficial effect of HD-WLE for ADR was evident only in studies with >50% of the participants undergoing screening colonoscopy and in studies with endoscopists SDC arm ADR >35% (RR, 1.16; 95% CI, 1.011.32 and RR, 1.18; 95% CI, 1.06-1.32, respectively). Contrariwise, we did not detect any significant effect of HD-WLE on MAC in these analyses (Table 2). 3.5 Grade Evidence Estimate Overall, our confidence in the effect estimates for efficacy was deemed low. In detail, we downgraded the quality of body of evidence by 2 levels; one due to concerns of risk of bias since in every study neither operators nor participants were blinded to technology used and one more due to the presence of indirectness in the evidence because included studies were conducted in different
settings
(different
populations,
varying
indications,
endoscopes per arm; Appendix 3, Grade Summary Table).
different
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Discussion In the present meta-analysis, based only on high-quality trials (6 RCTs with more than 4500 patients), we showed a statistically significant increase in ADR when passing from standard to HD-WLE. However, its clinical relevance is somewhat downgraded by the small ADR-difference between the 2 groups, resulting in an NNT of 23, as well as by the lack of a significant difference in MAC that is regarded as a similar important quality indicator as ADR for detection studies. Interestingly, a similar discordance between lesion detection rate and mean number of lesions per colonoscopy was also detected regarding advanced and sessile serrated adenomas. Methodological strengths of this study must be acknowledged. We undertook a comprehensive search of multiple electronic databases, based on a predefined protocol. Only RCTs were exclusively included, and we did not detect difference in withdrawal times between the 2 arms, as well as we did not detect any heterogeneity for both of our outcomes. An additional strength of our analysis as compared to the previous one by Subramanian et al6 is in the level of supporting evidence and the main outcome. In detail, Subramanian et al6 calculated the incremental diagnostic yield (IY) for polyps and adenomas of HD-WLE over standard definition by meta-analysing data from 2 RCTs, 1 prospective nonrandomized and 2 retrospective studies. Although the IY significantly increased for polyp detection rate with HD-WLE, this effect was not evident for ADR (IY, 3.5%; 95% CI, 0.9–6.1; NNT, 28). In terms of mean number of adenomas detected per colonoscopy, HD-WLE was related to higher MAC compared with SDC (MD, 0.098; 95% CI, 0.039-0.157)6. Four more RCTs13-16 as well as various
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observational and retrospective studies5,20-22 have been published later on. Thus, we analyzed only RCTs to provide robust data in the field of evidenced-based decision making. Acknowledging the fact that the current and previous meta-analyses6 are not directly comparable, we assume that any results’ discrepancy could be largely attributed to the inclusion of studies of different design (RCTs, retrospective and prospective cohort vs exclusively RCTs). We also showed that the beneficial effect of HD-WLE on ADR was maintained only for studies where >50% of the exams were performed for CRC screening, in accordance to 2 retrospectives studies that also showed higher ADR when HD-WLE was used in screening population compared to SDC20,21. Secondly, we showed that endoscopists with ADR >35% in SDC may benefit more from HD-WLE. One may speculate that the detection of smaller lesions23 - contributes to ADR increase. Among the studies we analysed, only one provided relevant data14, showing that significantly more adenomas <1 cm were detected during HD-WLE compared with SDC (120/427 [28.1%] vs 67/429 [15.6%]). As far as the favourable impact of HD-WLE on highlevel detectors is considered, the finding is consistent with the rationale that HDWLE is a highlighting technique allowing them to be "tuned in” small flat lesions detection rather larger polypoid ones, making optimal use of the technology. On the other hand, this benefit may not be uniform for low-level detectors because detection of flat lesions remains beyond their awareness. Improved image resolution is likely to be meaningless, when endoscopists fail to recognize flat lesions.
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Despite its association with long-term CRC prevention, ADR remains an imperfect colonoscopy quality indicator2,24. In this regard, adenoma miss rate (AMR),
measured in crossover design studies,
has been introduced as a
surrogate quality indicator25. It has been recently proposed that a clinically relevant correlation between adenoma miss and detection rates might provide further insights on how technology improves colonoscopy outcomes26. Unfortunately, lack of relevant studies reporting on AMR precluded its inclusion in this metaanalysis endpoints. Our analysis showed that ADR was significantly higher with HD-WLE, while no improvement in MAC was evident. Moreover, this result was evident also for advanced and sessile serrated adenomas. An interpretation of this result is challenging and rather speculative; a possible explanation could be that a small number of patients with many polyps was unevenly distributed across each study`s arms. Moreover, it could be also possible that HD-WLE indeed more often leads to first adenoma detection, therefore raising the ADR. However, it does not reveal additional lesions in those patients with one adenoma already detected; thus, its impact on mean number of lesions per colonoscopy remains minimal. Currently, HD-WLE is considered the standard of care for endoscopy and it is used together with numerous other techniques, new scopes and various novel devices to optimise performance during colonoscopy and its outcomes3,27. In this regard, one might refute the principal research question of the current study because it may refer to an outdated practice. Although HD-WLE contribution in meticulous mucosal visualization and endoscopic diagnosis, characterization, and treatment decision-making of gastrointestinal tract lesions is of paramount
19
importance by enhancing fine structural and microvascular details28,29, its exact impact on adenoma detection is still debatable. Recently, 2 studies14,15 tested the hypothesis that 2 consecutive generational improvements in colonoscopes may be needed to gain significant benefits in colonoscopy outcomes with controversial results. Thus, we underwent a posthoc subgroup analysis of enrolled studies to evaluate whether our results could be influenced by the number (111-13 vs 214,15) of intervening generational improvements of HD-WLE. Although the positive impact of the second over the first-generation HD-WLE on ADR was evident in this subgroup analysis (ADR, 1.17; 95% CI, 1.04-1.31 vs ADR, 1.13; 95% CI, 1.00-1.28), the intergroup difference failed to reach statistical significance (test for subgroup differences: chi2=0.14; p=0.70). Regarding MAC, no difference between the 2 groups (MD, 0.09; 95% CI, -0.19-0.37 and MD, 0.11; 95% CI, -0.01-0.22; test for subgroup differences: chi2=0.02; p=0.90) for 1- and 2-generational improvements, was detected. Our study is not without limitations. First, lack of available data did not allow analysis per morphology (flat adenomas), that could better precise the benefit offered by HD-WLE. Second, studies included in the meta-analysis included different populations and endoscopy settings. Third, effect sizes for the secondary outcomes were calculated using few studies data. In conclusion, our meta-analysis of randomized controlled trials indicates that high-definition colonoscopy is superior to standard definition, regarding adenoma (even advanced and sessile serrated) detection. However, the quality of evidence is low.
20
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Competing interests Authors declare no competing interests Funding None received Acknowledgements We thank Dr. R. Bisschops and Dr. G.A. Paspatis who kindly provided further information on the data of his study. Part of this study was presented as an e-poster during the ESGE Days 2019. Table Legends Table 1. Characteristics of included studies Table 2. Sensitivity analyses results Figure Legends Figure 1. Flow diagram of assessment of identified studies Figure 2. Risk of bias of included trials Figure 3. Forest plot for studies assessing the effect of high definition colonoscopy on adenoma detection rate Figure 4. Forest plot for studies assessing the effect of high definition colonoscopy on mean adenomas per colonoscopy Figure 5. Forest plot for studies assessing the effect of high definition colonoscopy on advanced adenoma detection rate Figure 6. Forest plot for studies assessing the effect of high definition colonoscopy on sessile serrated adenoma detection rate Appendices Legends
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Appendix 1. Preferred Reporting Items for Systematic Reviews and MetaAnalyses (PRISMA) checklist Appendix 2. Search strategy Appendix 3. Quality of body of evidence - Summary of Findings Table (GRADE) Supplementary Figure 1. A, Pooled ADR. B, MAC. Supplementary Figure 2. Funnel plots for studies assessing the effect of high definition colonoscopy. A, On adenoma detection rate, B, On mean number of adenomas per colonoscopy. Supplementary Figure 3. Forrest plot for studies assessing the effect of highdefinition colonoscopy on mean number of advanced adenomas per colonoscopy. Supplementary Figure 4. Forrest plot for studies assessing the effect of highdefinition colonoscopy on mean number of sessile serrated adenomas per colonoscopy.
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definition colonoscopy in the characterization of small colonic polyps: results from a randomized trial. Endoscopy 2012;44:905-10. 6.
Subramanian V, Mannath J, Hawkey CJ, Ragunath K. High definition colonoscopy vs. standard video
endoscopy for the detection of colonic polyps: a meta-analysis. Endoscopy 2011;43:499-505. 7.
Moher D, Shamseer L, Clarke M, et al. Preferred reporting items for systematic review and meta-
analysis protocols (PRISMA-P) 2015 statement. Systematic reviews 2015;4:1. 8.
Higgins JPT GS. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated
March 2011]. The Cochrane Collaboration, 2011. Available from http://handbook.cochrane.org. 2011. 9.
Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple,
graphical test. Bmj 1997;315:629-34. 10. strength
Schünemann H BJ, Guyatt G, Oxman A. GRADE handbook for grading quality of evidence and of
recommendations
(Updated
October
2013).
The
GRADE
Working
Group,
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https://gdtgradeproorg/app/handbook/handbookhtml [Accessed Jan 28, 2019] 2013. 11.
Pellise M, Fernandez-Esparrach G, Cardenas A, et al. Impact of wide-angle, high-definition
endoscopy in the diagnosis of colorectal neoplasia: a randomized controlled trial. Gastroenterology 2008;135:1062-8. 12.
Tribonias G, Theodoropoulou A, Konstantinidis K, et al. Comparison of standard vs high-definition,
wide-angle colonoscopy for polyp detection: a randomized controlled trial. Colorectal disease : the official journal of the Association of Coloproctology of Great Britain and Ireland 2010;12:e260-6.
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Rastogi A, Early DS, Gupta N, et al. Randomized, controlled trial of standard-definition white-light,
high-definition white-light, and narrow-band imaging colonoscopy for the detection of colon polyps and prediction of polyp histology. Gastrointestinal endoscopy 2011;74:593-602. 14.
Pioche M, Denis A, Allescher HD, et al. Impact of 2 generational improvements in colonoscopes on
adenoma miss rates: results of a prospective randomized multicenter tandem study. Gastrointestinal endoscopy 2018;88:107-16. 15.
Zimmermann-Fraedrich K, Groth S, Sehner S, et al. Effects of two instrument-generation changes
on adenoma detection rate during screening colonoscopy: results from a prospective randomized comparative study. Endoscopy 2018;50:878-85. 16.
Roelandt P, Demedts I, Willekens H, et al. Impact of endoscopy system, high definition, and virtual
chromoendoscopy in daily routine colonoscopy: a randomized trial. Endoscopy 2019;51:237-43. 17.
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neoplasia. Gut 2000;47:251-5. 18.
Dixon MF. Gastrointestinal epithelial neoplasia: Vienna revisited. Gut 2002;51:130-1.
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26
Table 1. Characteristics of included studies Author (Year)
Country
Study period
Centr es, n
Endosco pists, n
Endoscope Types
Patien ts, n
Adenoma definition
ADR definition
Pellise – 200811
Spain
09/200607/2007
1
7
Olympus Q160 vs. Olympus H180
620
NA
NA
SDC/ HD-WLE, n/n 310 /310
Indicati on
Male SDC/ HDWLE n (%)
Mixed
147 (47)/ 151 (49)
Withdrawal Time SDC/ HD-WLE Mean ± SE (min) 6.3 ± 0.114 / 6.2 ± 0.108
Age SD/HD, Mean ± SD 58.6±16 / 58.5±17.1
Preparation quality SDC/ HD-WLE N (%) *Excellent 247 (80)/ 248 (80)
Tribonias – 200912 Rastogi – 201113
Greece US
05/200810/2008 08/200811/2009
1
1
2
6
Pioche – 2018 (Tandem design)14
France, Italy, Germany, Netherla nds
07/201204/2014
6
ZimmermannFraedrich – 201815
Germany
11/20139/2016
7
Roelandt 201816
Belgium
12/2010 – 06/2014
1
NA
Olympus CF -Q165 vs. Olympus CFH180 Olympus PCF 160 vs. Olympus PCF H180 AL
Olympus 160 –16 5C vs. Olympus190-C
390
NA
NA
197/ 193
Mixed
420
Polyps were removed and sent in separate jars for histopathol ogical examinatio n
NA
210/ 210
Mixed
856 According to Vienna classificati on§
14
Olympus 160/5 vs. Olympus 190
24
1221 According to Vienna classificati on§
1087 Fujinon (EC-250WM5, EC-590WI, EC-590WM, and EC- 590ZW/M); Olympus (CF-Q160AI, CF-Q180AI, and CFH180AI); and Pentax (EC-3870FK2, EC3870LK, EC- 3810F, EC-3890F12, and EC-
According to World Health Organizati on classificati on§§
Tubular, villous, tubulovillo us, traditional serrated adenomas, and SSA/P were included. Tubular, villous, tubulovillo us, and SSA/Ps were included, but not invasive carcinomas Percentage of colonoscop ies with at least one adenoma identified
427/ 429
101 (51)/ 108(56) 143 (68) / 133 (63)
8.85 ± 0.096 / 8.94 ± 0.116 6.9 ± 0.124 / 6.6 ± 0.152
Increase d risk for colorecta l neoplasia
418 (48.8)
NA
622/ 599
Screenin g
289 (46.5) /274 (45,7)
7.0 (6.0 – 8.0) / 6.8 (6.0 – 8.3)ϯ
505/ 582
Mixed
253 (50) / 280 (48.1)
10.1 ± 0.3 / 10.2 ± 0.31
60.6± 11 / 62.4± 9.9 59.7± 8.4/ 62±9.3
58.3±12.7/ 58.2 ± 13.3
61.9± 6.3 / 62.5 ± 7
Good
Screening SDC/ HD-WLE, n (%) Fair
53 (17)/ 56 (18)
10 (3)/ 6(2)
NAϯϯ
38 (19)/ 35 (18)
**Excellent
Good
Fair
22 (10)/ 21 (10)
141 (67)/ 142 (68)
47 (22)/ 47 (22)
¶Adequate
Inadequate
315 (73.8) / 112 (26.2)
341 (79.5) / 88 (20.5)
¶¶Excellent 594 (95.5)/ 579 (96.7)
At least Fair 290 (46.6)/ 314 (52.4)
¶ NAϯϯ
82 (26) / 70 (23)
143 (68) / 132 (63)
NA
100%
191 (37.8) /239 (41)
27
3890Fi) colonoscopes
HD-WLE: high-definition white-light endoscopy; SDC: standard definition; SSA/P: sessile serrated adenoma/polyp; SD: standard deviation; NA: Not available; ϯ study not reporting on this outcome Ϯ: Median (IQR) examination time, minutes Ϯϯ: only adequately prepared patients were included in the analysis *: The quality of preparation was graded by the endoscopist as follows: (1) excellent, no solid or liquid residue; (2) good, complete mucosal examination after aspiration; (3) fair, persistence of residue despite aspiration, thus preventing correct examination of 5%–20% of the mucosa; and (4) poor, persistence of residue despite aspiration, thus preventing correct examination of >20% of the mucosa. Patients with poor preparation were excluded from the study **: Bowel preparation was evaluated as proposed by Rex et al.30. This bowel preparation classification was discussed and agreed on by all the endoscopists before the start of enrollment. Subjects with inadequate bowel preparation (<90% mucosa seen, mixture of semisolid and solid colonic contents that could not be suctioned or washed) were excluded ¶: Bowel cleansing quality was assessed using the Boston Bowel Preparation Scale (BBPS)31. Adequate quality was defined as BBPS≥6 ¶¶: Bowel cleansing quality was assessed using a modified combined “Boston Bowel Preparation Scale”
32.
Colon was assessed and scored (instead of segmental
scoring) as follows: 0 = largely unprepared colon, large areas not visible due to residual stool and/or dark fluid; 1 = only parts of the colonic mucosa visible because of stool and dark fluid; 2 = small amounts of residual stool, small stool fragments and/or dark fluid, but colonic mucosa adequately visible in the majority of the colon; 3 = entire colonic mucosa clearly visible, no residual stool (fragments) or dark fluid §: Vienna classification17,18 §§: World Health Organization classification19
28
Table 2. Sensitivity analysis
ADR
MAC
I2% (P value) / RR(95%CI)
I2% (P value) / MD(95%CI)
Screening ≤50%11,12,16
0 (0.80) / 1.08 (0.97-1.21)
53 (0.12) / 0.00 (-0.21-0.22)
Screening >50%13,15
0 (0.79) / 1.16 (1.01-1.32)
NA / 0.10 (-0.04-0.24)
≤35%11,15,16
0 (0.78) / 1.09 (0.99-1.22)
43 (0.17) / 0.00 (-0.14-0.14)
>35%12-14
0 (0.93) / 1.18 (1.06-1.32)
0 (0.46) / 0.17 (-0.01-0.35)
By indication of examinations
By ADR in the SDC arm
ADR: Adenoma detection rate; MAC: mean adenomas per colonoscopy; NA: not applicable; SDC: standard-definition colonoscopy
Section/topic
#
Appendix 1. Prisma guidelines
Checklist item
Reported on page #
TITLE Title
1
Identify the report as a systematic review, meta-analysis, or both.
1
2
Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number.
3
Rationale
3
Describe the rationale for the review in the context of what is already known.
5
Objectives
4
Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS).
5
Protocol and registration
5
Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number.
6, PROSPERO database CRD42018110105
Eligibility criteria
6
Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale.
6
Information sources
7
Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.
6
Search
8
Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.
6-7, Appendix B
Study selection
9
State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis).
7
Data collection process
10
Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.
7
Data items
11
List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made.
7
ABSTRACT Structured summary
INTRODUCTION
METHODS
Risk of bias in individual studies
12
Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis.
Summary measures
13
State the principal summary measures (e.g., risk ratio, difference in means).
Synthesis of results
14
Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I2) for each meta-analysis.
7-8 8 8-9
Risk of bias across studies
15
Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies).
9
Additional analyses
16
Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating which were pre-specified.
9
Study selection
17
Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram.
10
Study characteristics
18
For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations.
10, Table 1
Risk of bias within studies
19
Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12).
11 Figure 3
Results of individual studies
20
For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot.
10-13
Synthesis of results
21
Present results of each meta-analysis done, including confidence intervals and measures of consistency.
10 - 13
Risk of bias across studies
22
Present results of any assessment of risk of bias across studies (see Item 15).
11 Fig 3
Additional analysis
23
Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]).
12-13
Summary of evidence
24
Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers).
14 - 17
Limitations
25
Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias).
17
Conclusions
26
Provide a general interpretation of the results in the context of other evidence, and implications for future research.
17
RESULTS
DISCUSSION
FUNDING
Funding
27
Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review.
18
Appendix B. Search Strategy
Cochrane Central Register of Clinical Trials (Date Run: 19/01/19) ID
Search strategy
Found
#1
MeSH descriptor: [Colonoscopy] Explode all trees
1837
#2
MeSH descriptor: [adenoma] Explode all trees
1227
#3
MeSH descriptor: [Endoscopy] Explode all trees
15916
#4
MeSH descriptor: [Randomized Controlled Trial] Explode all trees
138
#5
#1 AND #2 AND #3 OR #4
5
PubMed Search (Date Run: 19/01/19): colonoscop* AND adenoma* AND endoscop* AND random* AND ( ("2005/01/01"[PDat] : "3000/12/31"[PDat] ) AND English[lang]) Results: 369
Appendix 2. Quality of body of evidence - Summary of Findings Table (GRADE) High definition-white light endoscopy (HD-WLE) compared to standard definition (SDC) for Colonoscopy outcomes Certainty assessment № of participants (studies) Follow-up
Summary of findings Study event rates (%) Overall Publication bias certainty of evidence
Risk of bias
Inconsistency
Indirectness
Imprecision
serious a
not serious
serious b
not serious
none
serious a
not serious
serious b
not serious
serious a
not serious
serious b
serious a
not serious
not serious
Anticipated absolute effects Relative effect (95% CI)
Risk with SDC Colonoscopy
Risk difference with HDWLE Colonoscopy
With SDC Colonoscopy
With HDWLE Colonoscopy
⨁⨁◯◯ LOW
776/2271 (34.2%)
897/2323 (38.6%)
RR 1.13 (1.05 to 1.22)
342 per 1,000
44 more per 1,000 (from 17 more to 75 more)
none
⨁⨁◯◯ LOW
2063
2111
-
The mean MAC was 0
MD 0.06 higher (0.02 lower to 0.14 higher)
not serious
none
⨁⨁◯◯ LOW
81/1210 (6.7%)
113/1206 (9.4%)
RR 1.33 (1.03 to 1.72)
67 per 1,000
22 more per 1,000 (from 2 more to 48 more)
serious b
not serious
none
⨁⨁◯◯ LOW
702
775
-
The mean MAAC was 0
MD 0.05 higher (0.89 lower to 0.99 higher)
serious b
not serious
none
⨁⨁◯◯ LOW
RR 1.55 (1.05 to 2.28)
34 per 1,000
19 more per 1,000 (from 2 more to 43 more)
ADR 4594 (6 RCTs)
MAC 4174 (5 RCTs)
Advanced ADR 2416 (3 RCTs)
MAAC 1477 (2 RCTs)
Sessile serrated ADR 2416 (3 RCTs)
serious a
41/1210 (3.4%) 61/1206 (5.1%)
High definition-white light endoscopy (HD-WLE) compared to standard definition (SDC) for Colonoscopy outcomes Certainty assessment
Summary of findings
MSSAC 1477 (2 RCTs)
serious a
not serious
serious b
not serious
none
⨁⨁◯◯ LOW
702
775
-
The mean MSAC was 0
CI: Confidence interval; RR: Risk ratio; MD: Mean difference
Explanations a. This domain was downgraded by 1 point, because there were evidence of performance and detection bias in all studies included this review b. This domain was downgraded by 1 point, because of differences in population (applicability), interventions and outcomes measures (surrogate outcomes) among the studies
MD 0.04 higher (0.62 lower to 0.7 higher)
S0016-5107(20)30038-9
DOI:
https://doi.org/10.1016/j.gie.2019.12.052
Reference:
YMGE 11930
To appear in:
Gastrointestinal Endoscopy
Received Date: 26 September 2019 Accepted Date: 30 December 2019
Please cite this article as: Tziatzios G, Gkolfakis P, Lazaridis LD, Facciorusso A, Antonelli G, Hassan C, Repici A, Sharma P, Rex DK, Triantafyllou K, High-definition colonoscopy for improving adenoma detection: a systematic review and meta-analysis of randomized controlled studies, Gastrointestinal Endoscopy (2020), doi: https://doi.org/10.1016/j.gie.2019.12.052. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Copyright © 2020 by the American Society for Gastrointestinal Endoscopy
Manuscript title: High-definition colonoscopy for improving adenoma detection: a systematic review and meta-analysis of randomized controlled studies Authors: 1Georgios Tziatzios*, 1Paraskevas Gkolfakis*, 1Lazaros Dimitrios Lazaridis, 2Antonio Facciorusso, 3Giulio Antonelli, 4Cesare Hassan, 5Alessandro Repici, 6,7Prateek Sharma, 8Douglas K Rex, 1Konstantinos Triantafyllou *equal contribution Authors Affiliations: 1Hepatogastroenterology Unit, Second Department of Internal Medicine – Propaedeutic, Research Institute and Diabetes Center, Medical School, National and Kapodistrian University of Athens, ‘‘Attikon” University General Hospital, Athens, Greece 2Gastroenterology
Unit, Department of Medical Sciences, University of Foggia
AOU, Ospedali Riunity Viale Pinto, Foggia, Italy 3Endoscopy
Unit, Sant 'Andrea University Hospital, "Sapienza" University of
Rome, Rome, Italy 4Endoscopy Unit, Nuovo Regina Margherita Hospital, Rome, Italy 5Digestive Endoscopy Unit, Division of Gastroenterology, Humanitas Clinical and
Research Center and Humanitas University, Rozzano, Italy 6Division of Gastroenterology & Hepatology, Department of Internal Medicine,
University of Kansas Medical Center, Kansas, Missouri, USA 7Department
of Gastroenterology, Veteran Affairs Medical Center, Kansas,
Missouri, USA 8Division
of Gastroenterology/Hepatology, Indiana University Hospital,
Indianapolis, Indiana, USA
Short Title: HD colonoscopy improves adenoma detection rate Corresponding Author: Konstantinos Triantafyllou, Associate Professor of Gastroenterology, Hepatogastroenterology Unit, Second Department of Internal Medicine – Propaedeutic Research Institute and Diabetes Center, Medical School, National and Kapodistrian University of Athens, ‘‘Attikon” University General Hospital, 1, Rimini Street, 124 62 Athens, Greece, (Tel: +30 210 5832087, Fax: +30 210 5326454, Email: [email protected]) Guarantor of the article: Konstantinos Triantafyllou Author contributions: G Tziatzios and P Gkolfakis acquired the data, performed the meta-analysis, drafted and finally approved the manuscript; Lazaros Dimitrios Lazaridis acquired the data, drafted and finally approved the manuscript; Antonio Facciorusso, Giulio Antonelli, Alessandro Repici and Cesare Hassan performed the meta-analysis, revised the draft critically for important intellectual content and finally approved the manuscript; P Sharma, DK Rex and K Triantafyllou conceived the idea, revised the draft critically for important intellectual content and finally approved the manuscript. Conflict of interest: None
1
Manuscript title: High-definition colonoscopy for improving adenoma detection: a systematic review and meta-analysis of randomized controlled studies
1Georgios
Authors:
Tziatzios*,
1Paraskevas
Gkolfakis*,
1Lazaros
Dimitrios
Lazaridis, 2Antonio Facciorusso, 3Giulio Antonelli, 4Cesare Hassan, 5Alessandro Repici, 6,7Prateek Sharma, 8Douglas K Rex and 1Konstantinos Triantafyllou *equal contribution
Authors Affiliations: 1Hepatogastroenterology Unit, Second Department of Internal Medicine – Propaedeutic, Research Institute and Diabetes Center, Medical School, National and Kapodistrian University of Athens, ‘‘Attikon” University General Hospital, Athens, Greece 2Gastroenterology
Unit, Department of Medical Sciences, University of Foggia
AOU, Ospedali Riunity Viale Pinto, Foggia, Italy 3Endoscopy
Unit, Sant 'Andrea University Hospital, "Sapienza" University of
Rome, Rome, Italy 4Endoscopy 5Digestive
Unit, Nuovo Regina Margherita Hospital, Rome, Italy
Endoscopy Unit, Division of Gastroenterology, Humanitas Clinical and
Research Center and Humanitas University, Rozzano, Italy 6Division
of Gastroenterology & Hepatology, Department of Internal Medicine,
University of Kansas Medical Center, Kansas, Missouri, USA 7Department
Missouri, USA
of Gastroenterology, Veteran Affairs Medical Center, Kansas,
2
8Division
of
Gastroenterology/Hepatology,
Indiana
University
Hospital,
Indianapolis, Indiana, USA Short Title: HD colonoscopy improves adenoma detection rate Corresponding Author: Konstantinos Triantafyllou, Associate Professor of Gastroenterology, Hepatogastroenterology Unit, Second Department of Internal Medicine – Propaedeutic Research Institute and Diabetes Center, Medical School, National and Kapodistrian University of Athens, ‘‘Attikon” University General Hospital, 1, Rimini Street, 124 62 Athens, Greece, (Tel: +30 210 5832087, Fax: +30 210 5326454, Email: [email protected]) Guarantor of the article: Konstantinos Triantafyllou Author contributions: G Tziatzios and P Gkolfakis acquired the data, performed the meta-analysis, drafted and finally approved the manuscript; Lazaros Dimitrios Lazaridis acquired the data, drafted and finally approved the manuscript; Antonio Facciorusso, Giulio Antonelli, Alessandro Repici and Cesare Hassan performed the meta-analysis, revised the draft critically for important intellectual content and finally approved the manuscript; P Sharma, DK Rex and K Triantafyllou conceived the idea, revised the draft critically for important intellectual content and finally approved the manuscript. Conflict of interest: None
3
Abstract Background and Aims: Previous meta-analysis showed marginal benefit of high-definition white-light endoscopy (HD-WLE) over standard-definition (SDC) colonoscopy for adenoma detection, but with residual uncertainty due to inclusion of nonrandomized studies. We aimed to further assess the effect of HDWLE on adenoma detection by including only randomized controlled trials (RCTs). Methods: A literature search was performed for RCTs evaluating HD-WLE versus SDC in terms of adenoma, advanced adenoma, and serrated sessile adenoma detection rates as well as mean number of adenomas (MAC), advanced adenomas (MAAC), and sessile serrated adenomas per colonoscopy (MSSAC). The effect size on study outcomes is presented as risk ratio (RR; 95% CI) or mean difference (MD; 95% CI). We assessed the strength of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Results: Six RCTs involving 4594 individuals (HD-WLE 2323; SDC 2271) were included. Clinical indications were screening (1 study), positive FOBT and personal/family history of colorectal cancer (1 study), and mixed indications (4 studies). Withdrawal time was similar between the 2 arms (MD, -0.06; 95% CI, 0.25 to 0.12; p=0.50). Adenoma detection rate was significantly higher in the HDWLE compared with SDC arm (40% vs 35%; RR, 1.13; 95% CI, 1.05-1.22; p=0.001; I2=0%; GRADE: low). This effect was consistent for advanced and sessile serrated adenoma detection rates (RR, 1.33; 95% CI, 1.03-1.72; p=0.03; I2=0%; GRADE: low and RR, 1.55; 95% CI, 1.05-2.28; p=0.03; I2=0%; GRADE: low,
4
respectively). On the contrary, the difference was not significant for MAC, MAAC, and MSSAC. Conclusions: Meta-analysis of RCT data support the use of HD-WLE in clinical practice, although the additional benefit is limited.
Keywords: high definition; standard definition; colonoscopy; adenoma detection; meta-analysis
1. Introduction Adenoma detection rate (ADR) is the main colonoscopy quality indicator. It is inversely associated with the risk of interval colorectal cancer (CRC) and the risk of death from this neoplasia1,2. Despite its advent nearly 15 years ago, the incremental efficacy of high-definition white-light endoscopy (HD-WLE) as compared with standard-definition endoscopy (SDC) in detecting adenomas remains elusive3. Although early studies showed promising results4,5, the available meta-analysis showed only a marginal increase in adenoma detection when comparing HD-WLE with SDC6. In addition, the marked heterogeneity attributed to the inclusion of various designs of the studies generated further uncertainty when interpreting these results. Moreover, because SDC replacement with HD-WLE is associated with substantial costs, especially for those health systems with limited financial resources, the incremental efficacy of HD-WLE should be assessed not only from the clinical perspective, but also using costeffectiveness data that are currently missing. We aimed to further evaluate the
5
effect of HD-WLE on adenoma detection, through a systematic review with metaanalysis incorporating data exclusively from randomized controlled trials (RCTs).
6
2. Materials and Methods 2.1. Protocol registration We conducted this study according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations (Appendix 1)7. The review protocol is available at the International Prospective Register of Systematic Reviews (PROSPERO) under registration number CRD42018110105. 2.2. Eligibility criteria We defined eligibility criteria for our study according to the PICO statement; P: patients undergoing colonoscopy for colorectal cancer (CRC) screening, surveillance or symptom evaluation; I: patients undergoing colonoscopy using high-definition white-light endoscopes (HD-WLE); C: patients undergoing colonoscopy using standard-definition endoscopes (SDC); O: adenoma detection rate (ADR) and mean adenomas per colonoscopy. Only prospective, randomized controlled trials, published as full text in the English language were eligible for inclusion. 2.3. Identification and Selection of Studies Our search strategy included the free text terms “colonoscopy*,” “adenoma*,” “random*” both as medical subject headings (MeSH) and free-text terms combined with the Boolean set operator ‘AND’ with the term: “endoscop*,” as medical subject heading and the free text term. We searched PubMed and the Cochrane Central Register of Controlled Trials electronic databases starting from 01 January 2005 - year of high-definition colonoscopies introduction. The search was performed on January 19, 2019. Two investigators (G.T. and L.D.D.)
7
independently performed the search (Appendix B). After duplicate removal, 2 reviewers (G.T. and L.D.D.) first assessed the titles and abstracts of all results for inclusion; then, they judged eligibility of the selected articles independently, using predesigned eligibility forms. Any disagreement was resolved by discussion. We also hand-searched references of all eligible studies, to identify potentially studies missed during the first search. In case of missing or incomplete data, the corresponding author was contacted in order to provide further information. 2.4 Data extraction and Quality Assessment Two of the authors (G.T. and L.D.D.) independently extracted data from eligible studies onto a Microsoft Excel spreadsheet (XP professional edition; Microsoft, Redmond, Wash, USA) using a data extraction form. Data extraction included name of the first author, publication year, country of origin, number of centers, number of participating endoscopists, indication for colonoscopy, type of endoscope used, number of total participants, definition of adenoma (ie, conventional or sessile serrated adenoma - SSA/P), quality of bowel preparation, and withdrawal time. We also extracted the number of lesions (adenomas, advanced1 [≥10 mm, with a villous component, and/or with high-grade dysplasia] adenomas, sessile serrated adenomas, and mean number of these lesions were calculated per patient. For the purposes of our study, lesion detection rate was defined as the percentage of colonoscopies with at least one histologically proven lesion. 2.5 Assessment of Risk of Bias
8
Risk of bias of individual studies was assessed using the Cochrane collaboration’s assessment tool8. Two independent researchers (G.T. and P.G.) assessed risk of bias attributed to methods used to generate the randomization schedule and conceal treatment allocation (selection bias), implementation of blinding for participants or personnel (performance bias), outcomes assessment (detection bias), proportion of subjects completed follow-up (attrition bias) and evidence of selective reporting of outcomes (reporting bias). Each study included in the meta-analysis was classified having high, low or unclear risk of bias, with reference to each of the abovementioned domains. 2.6 Outcomes assessment The primary outcomes of the meta-analysis were the measurement of ADR and mean number of adenomas per colonoscopy (MAC) in HD-WLE as compared with SDC arm. The effect of HD-WLE on, advanced adenoma detection rate (AADR), and mean number of advanced adenomas per colonoscopy (MAAC), sessile serrated adenoma detection rate (SSADR), and mean number of sessile serrated adenomas per colonoscopy (MSSAC) comprised the secondary outcomes. 2.7 Data synthesis and statistical analysis For dichotomous outcomes risk ratios (RRs) with 95% confidence intervals (95% CIs) were calculated. For continuous outcomes, we calculated mean difference (MD) with 95% CI, using inverse variance. Pooled ADR and MAC per groups were calculated using generic inverse variance analysis and they are presented with their respective 95%CI. Data were meta-analyzed using the random-effects model (DerSimonian and Laird method) to allow a more
9
conservative estimate of the effect of HD-WLE. The number of patients needed to be treated (NNT) for one additional patient with an adenomatous polyp to be detected was calculated as the inverse of the difference of adenoma detection rate between the 2 arms. We assessed publication bias visually by checking the funnel plot for asymmetry, or by application of Egger’s test9. All analyses were performed at the 0.05 significance level. Review Manager 5.3 (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark) and StatsDirect 3 (StatsDirect Ltd, Sale, Cheshire, England) software packages were used to meta-analyze all data and to the construct forest and funnel plots. 2.8 Heterogeneity assessment and sensitivity analyses We assessed the presence of heterogeneity using the I2 statistic. Thresholds for the values of I2 were interpreted as follows: 0% to 40%: heterogeneity might not be important; 30% to 60%: may represent moderate heterogeneity; 50% to 90%: may represent substantial heterogeneity; 75% to 100%: considerable heterogeneity. In case of I2 value > 50%, we undertook sensitivity analysis to identify the source of heterogeneity by excluding one study at a time, as proposed by the Cochrane collaboration. We further aimed to detect those groups of patients or endoscopists who might benefit more from HD-WLE. In this respect, we undertook 2 sensitivity analyses for our primary endpoints: (1) per indication of colonoscopies (studies including ≤50% vs >50% individuals undergoing screening exams) and (2) per endoscopists ADR level (≤35% vs >35%) in the SDC arm. 2.9 Assessment of Quality of Body of Evidence
10
The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess the quality of evidence. Two independent researchers (G.T. and P.G.) graded inconsistency, risk of bias, indirectness, imprecision, and publication bias. Overall quality was deemed very low, low, moderate, or high using GRADEpro (GRADE Working Group)10. 3. Results 3.1. Study selection Initial search yielded 374 citations. Of them, 363 were excluded after title and abstract review as irrelevant to study’s aim or duplicates. Thus, 11 articles were considered eligible for full-text assessment. Among these, 5 were further excluded for various reasons, leaving 6 studies11-16 to be included in the systematic review and meta-analysis. Figure 1 depicts studies’ selection flowchart. 3.2. Characteristics of studies included Overall, 6 studies enrolling 4594 individuals were included in the analysis; 2323 and 2271 underwent HD-WLE and SDC, respectively. One study was conducted in the USA13 and the rest of them in Europe11,12,14-16. In terms of design, all but one14 studies were of parallel groups design; only data from the index colonoscopies of the tandem design study were taken into account. Half of the studies13-15 were multicenter, the rest of them11,12,16 were conducted in a single center. In all 6 studies11-16 Olympus (Olympus, Tokyo, Japan - Olympus Europe, Hamburg, Germany - Olympus, America Inc, Center Valley, Pa, USA) endoscopes were used [first (180 series) and second (190 series) generation HD-WLE scopes versus the 160, 160/5 and 165 series of SDC scopes], whereas in one study16
11
Fujfilm (Fujifilm Corp., Saitama, Japan) and Pentax (Pentax Medical, Tokyo, Japan) colonoscopes (590 series vs. 250 series and 3890 series vs. 3870 and 3710 series, respectively for the HD-WLE and SDC arms) were additionally used. Different populations were represented throughout included studies. Four studies11-13,16 enrolled mixed population of screening, surveillance and diagnostic examinations, one study enrolled exclusively screening individuals15, whereas in the study by Pioche et al14 only individuals at higher than average risk for CRC were considered eligible for participation. Participants’ gender (male: 45.7% vs 68%) and mean age (58.2 vs 62.5 years) were similar, and there were no significant differences in the bowel preparation quality between the 2 arms among the studies that reported on this outcome11,13-15. No difference in withdrawal times―assessed in 4 studies11-13,16 with 2517 subjects―(MD, -0.06; 95% CI, -0.25 to 0.12; p=0.50; I2=0%; P=0.44) was noted between HD-WLE and SDC groups. Histopathological samples were analyzed according to Vienna classification17,18 in 2 studies14,15, World Health Organization classification19 in one study16, whereas the other 3 studies11-13 did not provide relevant details. Two studies14,15 stated that for ADR definition, conventional, traditional serrated adenomas and SSA/P were included, one16 defined ADR as the percentage of colonoscopies with at least one adenoma, whereas 3 studies11-13 provided no detail. Table 1 shows the basic characteristics of included studies. 3.3. Methodological quality and risk of bias A summarized assessment of risk of bias per study using the Cochrane collaboration’s risk of bias assessment tool is illustrated in Figure 2. Two studies11,15 did not clarify the method used to generate randomization sequence
12
and in one11 details about allocation concealment were not provided. Participating physicians were not blinded of the used equipment and the measured outcomes in any of the studies. Finally, one study16 presented data on measurements not included in the initial protocol.
13
3.4. Endpoints 3.4.1 Primary endpoints Adenoma detection rate All 6 studies11-16 (n=4594) provided data regarding ADR. Overall, at least one adenoma was detected in 897 out of 2323 and 776 out of 2271 individuals in in the HD-WLE and SDC arms, respectively. ADR was higher ADR, 40; 95% CI, 33% 48% vs 35 95% CI, 30% - 41%) (Supplementary Figure 1A) in the HD-WLE compared with the SDC group (RR, 1.13; 95% CI, 1.05-1.22; p=0.001) (Figure 3). NNT to find one additional patient with an adenomatous polyp with the high definition technology was 23. We detected neither heterogeneity (I2=0%; P=0.91) nor evidence of publication bias (Egger test: bias, - 0.72; 95% CI, - 4.64 to 3.18; p = 0.63, Supplementary Figure 2A). GRADE analysis indicated that quality of the evidence supporting higher ADR with HD-WLE was low (Appendix 3, Grade Summary Table). Mean number of adenomas per colonoscopy The mean number of adenomas per colonoscopy was provided or calculated from raw data in 5 studies11,12,14-16 (n=4174). MAC did not differ between HDWLE and SDC (0.77; 95% CI, 0.55-0.99 vs 0.68, 95% CI, 0.49-0.87), (Supplementary Figure 1B) (MD, 0.06; 95% CI, -0.02 to -0.14; p=0.13; I2=0%; P=0.41) (Figure 4). There was no evidence of publication bias (Egger test: bias, 0.000283; 95% CI, -0.66 to 0.66; p = 0.99) (Supplementary Figure 2B). Quality of evidence regarding MAC was low (Appendix 3, Grade Summary Table).
14
3.4.2 Secondary Endpoints Advanced adenoma detection rate Three studies12,14,16 provided data allowing advanced adenoma detection rate to be calculated. At least one advanced adenoma was detected in 113 out of 1206 and 81 out of 1210 individuals in in the HD-WLE and SDC arms, respectively (RR, 1.33; 95% CI, 1.03 - 1.72; p=0.03) (Figure 5). Neither heterogeneity (I2=0%; P=0.71) nor evidence of publication bias (Egger test: bias, - 0.90; 95% CI, - 4.34 to 2.54; p = 0.27) was found. The quality of the evidence supporting higher AADR with HD-WLE was low (Appendix 3, Grade Summary Table). Mean number of advanced adenomas per colonoscopy Mean number of advanced adenomas per colonoscopy was provided in 2 studies12,16. MAAC was not different between HD-WLE and SDC (MD, 0.05; 95% CI, -0.89 to -0.99; p=0.91; I2=0%; P=0.98) (Supplementary Figure 3). There was no evidence of publication bias visually by checking the funnel plot for asymmetry [Egger test: bias: not applicable]. Quality of evidence regarding MAAC was also low (Appendix 3, Grade Summary Table). Sessile serrated adenoma detection rate Sessile serrated adenoma detection rate was calculated from data provided by 3 studies12,14,16. At least one lesion was detected in 61 out of 1206 and 41 out of 1210 examinations in HD-WLE and SDC arms, respectively (RR, 1.55; 95% CI, 1.05-2.28; p=0.03) (Figure 6). Heterogeneity (I2=0%; P=0.43) and evidence of publication bias (Egger test: bias, - 1.26; 95% CI, - 26.8 to 24.4; p = 0.74) were absent. GRADE analysis indicated that quality of the evidence supporting higher SADR with HD-WLE was low (Appendix 3, Grade Summary Table).
15
Mean number of sessile adenomas per colonoscopy Mean number of sessile serrated adenomas per colonoscopy as derived from 2 studies12,16. MSSAC did not differ between HD-WLE and SDC (MD, 0.04; 95% CI, 0.62-0.70; p=0.9; I2=0%; P=0.98) (Supplementary Figure 4]. There was no evidence of publication bias by visually checking the funnel plot for asymmetry (Egger test: bias: not applicable). Quality of evidence regarding MSSAC was once again low (Appendix 3, Grade Summary Table). 3.4.3 Sensitivity analysis Our analysis showed that the beneficial effect of HD-WLE for ADR was evident only in studies with >50% of the participants undergoing screening colonoscopy and in studies with endoscopists SDC arm ADR >35% (RR, 1.16; 95% CI, 1.011.32 and RR, 1.18; 95% CI, 1.06-1.32, respectively). Contrariwise, we did not detect any significant effect of HD-WLE on MAC in these analyses (Table 2). 3.5 Grade Evidence Estimate Overall, our confidence in the effect estimates for efficacy was deemed low. In detail, we downgraded the quality of body of evidence by 2 levels; one due to concerns of risk of bias since in every study neither operators nor participants were blinded to technology used and one more due to the presence of indirectness in the evidence because included studies were conducted in different
settings
(different
populations,
varying
indications,
endoscopes per arm; Appendix 3, Grade Summary Table).
different
16
Discussion In the present meta-analysis, based only on high-quality trials (6 RCTs with more than 4500 patients), we showed a statistically significant increase in ADR when passing from standard to HD-WLE. However, its clinical relevance is somewhat downgraded by the small ADR-difference between the 2 groups, resulting in an NNT of 23, as well as by the lack of a significant difference in MAC that is regarded as a similar important quality indicator as ADR for detection studies. Interestingly, a similar discordance between lesion detection rate and mean number of lesions per colonoscopy was also detected regarding advanced and sessile serrated adenomas. Methodological strengths of this study must be acknowledged. We undertook a comprehensive search of multiple electronic databases, based on a predefined protocol. Only RCTs were exclusively included, and we did not detect difference in withdrawal times between the 2 arms, as well as we did not detect any heterogeneity for both of our outcomes. An additional strength of our analysis as compared to the previous one by Subramanian et al6 is in the level of supporting evidence and the main outcome. In detail, Subramanian et al6 calculated the incremental diagnostic yield (IY) for polyps and adenomas of HD-WLE over standard definition by meta-analysing data from 2 RCTs, 1 prospective nonrandomized and 2 retrospective studies. Although the IY significantly increased for polyp detection rate with HD-WLE, this effect was not evident for ADR (IY, 3.5%; 95% CI, 0.9–6.1; NNT, 28). In terms of mean number of adenomas detected per colonoscopy, HD-WLE was related to higher MAC compared with SDC (MD, 0.098; 95% CI, 0.039-0.157)6. Four more RCTs13-16 as well as various
17
observational and retrospective studies5,20-22 have been published later on. Thus, we analyzed only RCTs to provide robust data in the field of evidenced-based decision making. Acknowledging the fact that the current and previous meta-analyses6 are not directly comparable, we assume that any results’ discrepancy could be largely attributed to the inclusion of studies of different design (RCTs, retrospective and prospective cohort vs exclusively RCTs). We also showed that the beneficial effect of HD-WLE on ADR was maintained only for studies where >50% of the exams were performed for CRC screening, in accordance to 2 retrospectives studies that also showed higher ADR when HD-WLE was used in screening population compared to SDC20,21. Secondly, we showed that endoscopists with ADR >35% in SDC may benefit more from HD-WLE. One may speculate that the detection of smaller lesions23 - contributes to ADR increase. Among the studies we analysed, only one provided relevant data14, showing that significantly more adenomas <1 cm were detected during HD-WLE compared with SDC (120/427 [28.1%] vs 67/429 [15.6%]). As far as the favourable impact of HD-WLE on highlevel detectors is considered, the finding is consistent with the rationale that HDWLE is a highlighting technique allowing them to be "tuned in” small flat lesions detection rather larger polypoid ones, making optimal use of the technology. On the other hand, this benefit may not be uniform for low-level detectors because detection of flat lesions remains beyond their awareness. Improved image resolution is likely to be meaningless, when endoscopists fail to recognize flat lesions.
18
Despite its association with long-term CRC prevention, ADR remains an imperfect colonoscopy quality indicator2,24. In this regard, adenoma miss rate (AMR),
measured in crossover design studies,
has been introduced as a
surrogate quality indicator25. It has been recently proposed that a clinically relevant correlation between adenoma miss and detection rates might provide further insights on how technology improves colonoscopy outcomes26. Unfortunately, lack of relevant studies reporting on AMR precluded its inclusion in this metaanalysis endpoints. Our analysis showed that ADR was significantly higher with HD-WLE, while no improvement in MAC was evident. Moreover, this result was evident also for advanced and sessile serrated adenomas. An interpretation of this result is challenging and rather speculative; a possible explanation could be that a small number of patients with many polyps was unevenly distributed across each study`s arms. Moreover, it could be also possible that HD-WLE indeed more often leads to first adenoma detection, therefore raising the ADR. However, it does not reveal additional lesions in those patients with one adenoma already detected; thus, its impact on mean number of lesions per colonoscopy remains minimal. Currently, HD-WLE is considered the standard of care for endoscopy and it is used together with numerous other techniques, new scopes and various novel devices to optimise performance during colonoscopy and its outcomes3,27. In this regard, one might refute the principal research question of the current study because it may refer to an outdated practice. Although HD-WLE contribution in meticulous mucosal visualization and endoscopic diagnosis, characterization, and treatment decision-making of gastrointestinal tract lesions is of paramount
19
importance by enhancing fine structural and microvascular details28,29, its exact impact on adenoma detection is still debatable. Recently, 2 studies14,15 tested the hypothesis that 2 consecutive generational improvements in colonoscopes may be needed to gain significant benefits in colonoscopy outcomes with controversial results. Thus, we underwent a posthoc subgroup analysis of enrolled studies to evaluate whether our results could be influenced by the number (111-13 vs 214,15) of intervening generational improvements of HD-WLE. Although the positive impact of the second over the first-generation HD-WLE on ADR was evident in this subgroup analysis (ADR, 1.17; 95% CI, 1.04-1.31 vs ADR, 1.13; 95% CI, 1.00-1.28), the intergroup difference failed to reach statistical significance (test for subgroup differences: chi2=0.14; p=0.70). Regarding MAC, no difference between the 2 groups (MD, 0.09; 95% CI, -0.19-0.37 and MD, 0.11; 95% CI, -0.01-0.22; test for subgroup differences: chi2=0.02; p=0.90) for 1- and 2-generational improvements, was detected. Our study is not without limitations. First, lack of available data did not allow analysis per morphology (flat adenomas), that could better precise the benefit offered by HD-WLE. Second, studies included in the meta-analysis included different populations and endoscopy settings. Third, effect sizes for the secondary outcomes were calculated using few studies data. In conclusion, our meta-analysis of randomized controlled trials indicates that high-definition colonoscopy is superior to standard definition, regarding adenoma (even advanced and sessile serrated) detection. However, the quality of evidence is low.
20
21
Competing interests Authors declare no competing interests Funding None received Acknowledgements We thank Dr. R. Bisschops and Dr. G.A. Paspatis who kindly provided further information on the data of his study. Part of this study was presented as an e-poster during the ESGE Days 2019. Table Legends Table 1. Characteristics of included studies Table 2. Sensitivity analyses results Figure Legends Figure 1. Flow diagram of assessment of identified studies Figure 2. Risk of bias of included trials Figure 3. Forest plot for studies assessing the effect of high definition colonoscopy on adenoma detection rate Figure 4. Forest plot for studies assessing the effect of high definition colonoscopy on mean adenomas per colonoscopy Figure 5. Forest plot for studies assessing the effect of high definition colonoscopy on advanced adenoma detection rate Figure 6. Forest plot for studies assessing the effect of high definition colonoscopy on sessile serrated adenoma detection rate Appendices Legends
22
Appendix 1. Preferred Reporting Items for Systematic Reviews and MetaAnalyses (PRISMA) checklist Appendix 2. Search strategy Appendix 3. Quality of body of evidence - Summary of Findings Table (GRADE) Supplementary Figure 1. A, Pooled ADR. B, MAC. Supplementary Figure 2. Funnel plots for studies assessing the effect of high definition colonoscopy. A, On adenoma detection rate, B, On mean number of adenomas per colonoscopy. Supplementary Figure 3. Forrest plot for studies assessing the effect of highdefinition colonoscopy on mean number of advanced adenomas per colonoscopy. Supplementary Figure 4. Forrest plot for studies assessing the effect of highdefinition colonoscopy on mean number of sessile serrated adenomas per colonoscopy.
23
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26
Table 1. Characteristics of included studies Author (Year)
Country
Study period
Centr es, n
Endosco pists, n
Endoscope Types
Patien ts, n
Adenoma definition
ADR definition
Pellise – 200811
Spain
09/200607/2007
1
7
Olympus Q160 vs. Olympus H180
620
NA
NA
SDC/ HD-WLE, n/n 310 /310
Indicati on
Male SDC/ HDWLE n (%)
Mixed
147 (47)/ 151 (49)
Withdrawal Time SDC/ HD-WLE Mean ± SE (min) 6.3 ± 0.114 / 6.2 ± 0.108
Age SD/HD, Mean ± SD 58.6±16 / 58.5±17.1
Preparation quality SDC/ HD-WLE N (%) *Excellent 247 (80)/ 248 (80)
Tribonias – 200912 Rastogi – 201113
Greece US
05/200810/2008 08/200811/2009
1
1
2
6
Pioche – 2018 (Tandem design)14
France, Italy, Germany, Netherla nds
07/201204/2014
6
ZimmermannFraedrich – 201815
Germany
11/20139/2016
7
Roelandt 201816
Belgium
12/2010 – 06/2014
1
NA
Olympus CF -Q165 vs. Olympus CFH180 Olympus PCF 160 vs. Olympus PCF H180 AL
Olympus 160 –16 5C vs. Olympus190-C
390
NA
NA
197/ 193
Mixed
420
Polyps were removed and sent in separate jars for histopathol ogical examinatio n
NA
210/ 210
Mixed
856 According to Vienna classificati on§
14
Olympus 160/5 vs. Olympus 190
24
1221 According to Vienna classificati on§
1087 Fujinon (EC-250WM5, EC-590WI, EC-590WM, and EC- 590ZW/M); Olympus (CF-Q160AI, CF-Q180AI, and CFH180AI); and Pentax (EC-3870FK2, EC3870LK, EC- 3810F, EC-3890F12, and EC-
According to World Health Organizati on classificati on§§
Tubular, villous, tubulovillo us, traditional serrated adenomas, and SSA/P were included. Tubular, villous, tubulovillo us, and SSA/Ps were included, but not invasive carcinomas Percentage of colonoscop ies with at least one adenoma identified
427/ 429
101 (51)/ 108(56) 143 (68) / 133 (63)
8.85 ± 0.096 / 8.94 ± 0.116 6.9 ± 0.124 / 6.6 ± 0.152
Increase d risk for colorecta l neoplasia
418 (48.8)
NA
622/ 599
Screenin g
289 (46.5) /274 (45,7)
7.0 (6.0 – 8.0) / 6.8 (6.0 – 8.3)ϯ
505/ 582
Mixed
253 (50) / 280 (48.1)
10.1 ± 0.3 / 10.2 ± 0.31
60.6± 11 / 62.4± 9.9 59.7± 8.4/ 62±9.3
58.3±12.7/ 58.2 ± 13.3
61.9± 6.3 / 62.5 ± 7
Good
Screening SDC/ HD-WLE, n (%) Fair
53 (17)/ 56 (18)
10 (3)/ 6(2)
NAϯϯ
38 (19)/ 35 (18)
**Excellent
Good
Fair
22 (10)/ 21 (10)
141 (67)/ 142 (68)
47 (22)/ 47 (22)
¶Adequate
Inadequate
315 (73.8) / 112 (26.2)
341 (79.5) / 88 (20.5)
¶¶Excellent 594 (95.5)/ 579 (96.7)
At least Fair 290 (46.6)/ 314 (52.4)
¶ NAϯϯ
82 (26) / 70 (23)
143 (68) / 132 (63)
NA
100%
191 (37.8) /239 (41)
27
3890Fi) colonoscopes
HD-WLE: high-definition white-light endoscopy; SDC: standard definition; SSA/P: sessile serrated adenoma/polyp; SD: standard deviation; NA: Not available; ϯ study not reporting on this outcome Ϯ: Median (IQR) examination time, minutes Ϯϯ: only adequately prepared patients were included in the analysis *: The quality of preparation was graded by the endoscopist as follows: (1) excellent, no solid or liquid residue; (2) good, complete mucosal examination after aspiration; (3) fair, persistence of residue despite aspiration, thus preventing correct examination of 5%–20% of the mucosa; and (4) poor, persistence of residue despite aspiration, thus preventing correct examination of >20% of the mucosa. Patients with poor preparation were excluded from the study **: Bowel preparation was evaluated as proposed by Rex et al.30. This bowel preparation classification was discussed and agreed on by all the endoscopists before the start of enrollment. Subjects with inadequate bowel preparation (<90% mucosa seen, mixture of semisolid and solid colonic contents that could not be suctioned or washed) were excluded ¶: Bowel cleansing quality was assessed using the Boston Bowel Preparation Scale (BBPS)31. Adequate quality was defined as BBPS≥6 ¶¶: Bowel cleansing quality was assessed using a modified combined “Boston Bowel Preparation Scale”
32.
Colon was assessed and scored (instead of segmental
scoring) as follows: 0 = largely unprepared colon, large areas not visible due to residual stool and/or dark fluid; 1 = only parts of the colonic mucosa visible because of stool and dark fluid; 2 = small amounts of residual stool, small stool fragments and/or dark fluid, but colonic mucosa adequately visible in the majority of the colon; 3 = entire colonic mucosa clearly visible, no residual stool (fragments) or dark fluid §: Vienna classification17,18 §§: World Health Organization classification19
28
Table 2. Sensitivity analysis
ADR
MAC
I2% (P value) / RR(95%CI)
I2% (P value) / MD(95%CI)
Screening ≤50%11,12,16
0 (0.80) / 1.08 (0.97-1.21)
53 (0.12) / 0.00 (-0.21-0.22)
Screening >50%13,15
0 (0.79) / 1.16 (1.01-1.32)
NA / 0.10 (-0.04-0.24)
≤35%11,15,16
0 (0.78) / 1.09 (0.99-1.22)
43 (0.17) / 0.00 (-0.14-0.14)
>35%12-14
0 (0.93) / 1.18 (1.06-1.32)
0 (0.46) / 0.17 (-0.01-0.35)
By indication of examinations
By ADR in the SDC arm
ADR: Adenoma detection rate; MAC: mean adenomas per colonoscopy; NA: not applicable; SDC: standard-definition colonoscopy
Section/topic
#
Appendix 1. Prisma guidelines
Checklist item
Reported on page #
TITLE Title
1
Identify the report as a systematic review, meta-analysis, or both.
1
2
Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number.
3
Rationale
3
Describe the rationale for the review in the context of what is already known.
5
Objectives
4
Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS).
5
Protocol and registration
5
Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number.
6, PROSPERO database CRD42018110105
Eligibility criteria
6
Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale.
6
Information sources
7
Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.
6
Search
8
Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.
6-7, Appendix B
Study selection
9
State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis).
7
Data collection process
10
Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.
7
Data items
11
List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made.
7
ABSTRACT Structured summary
INTRODUCTION
METHODS
Risk of bias in individual studies
12
Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis.
Summary measures
13
State the principal summary measures (e.g., risk ratio, difference in means).
Synthesis of results
14
Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I2) for each meta-analysis.
7-8 8 8-9
Risk of bias across studies
15
Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies).
9
Additional analyses
16
Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating which were pre-specified.
9
Study selection
17
Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram.
10
Study characteristics
18
For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations.
10, Table 1
Risk of bias within studies
19
Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12).
11 Figure 3
Results of individual studies
20
For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot.
10-13
Synthesis of results
21
Present results of each meta-analysis done, including confidence intervals and measures of consistency.
10 - 13
Risk of bias across studies
22
Present results of any assessment of risk of bias across studies (see Item 15).
11 Fig 3
Additional analysis
23
Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]).
12-13
Summary of evidence
24
Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers).
14 - 17
Limitations
25
Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias).
17
Conclusions
26
Provide a general interpretation of the results in the context of other evidence, and implications for future research.
17
RESULTS
DISCUSSION
FUNDING
Funding
27
Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review.
18
Appendix B. Search Strategy
Cochrane Central Register of Clinical Trials (Date Run: 19/01/19) ID
Search strategy
Found
#1
MeSH descriptor: [Colonoscopy] Explode all trees
1837
#2
MeSH descriptor: [adenoma] Explode all trees
1227
#3
MeSH descriptor: [Endoscopy] Explode all trees
15916
#4
MeSH descriptor: [Randomized Controlled Trial] Explode all trees
138
#5
#1 AND #2 AND #3 OR #4
5
PubMed Search (Date Run: 19/01/19): colonoscop* AND adenoma* AND endoscop* AND random* AND ( ("2005/01/01"[PDat] : "3000/12/31"[PDat] ) AND English[lang]) Results: 369
Appendix 2. Quality of body of evidence - Summary of Findings Table (GRADE) High definition-white light endoscopy (HD-WLE) compared to standard definition (SDC) for Colonoscopy outcomes Certainty assessment № of participants (studies) Follow-up
Summary of findings Study event rates (%) Overall Publication bias certainty of evidence
Risk of bias
Inconsistency
Indirectness
Imprecision
serious a
not serious
serious b
not serious
none
serious a
not serious
serious b
not serious
serious a
not serious
serious b
serious a
not serious
not serious
Anticipated absolute effects Relative effect (95% CI)
Risk with SDC Colonoscopy
Risk difference with HDWLE Colonoscopy
With SDC Colonoscopy
With HDWLE Colonoscopy
⨁⨁◯◯ LOW
776/2271 (34.2%)
897/2323 (38.6%)
RR 1.13 (1.05 to 1.22)
342 per 1,000
44 more per 1,000 (from 17 more to 75 more)
none
⨁⨁◯◯ LOW
2063
2111
-
The mean MAC was 0
MD 0.06 higher (0.02 lower to 0.14 higher)
not serious
none
⨁⨁◯◯ LOW
81/1210 (6.7%)
113/1206 (9.4%)
RR 1.33 (1.03 to 1.72)
67 per 1,000
22 more per 1,000 (from 2 more to 48 more)
serious b
not serious
none
⨁⨁◯◯ LOW
702
775
-
The mean MAAC was 0
MD 0.05 higher (0.89 lower to 0.99 higher)
serious b
not serious
none
⨁⨁◯◯ LOW
RR 1.55 (1.05 to 2.28)
34 per 1,000
19 more per 1,000 (from 2 more to 43 more)
ADR 4594 (6 RCTs)
MAC 4174 (5 RCTs)
Advanced ADR 2416 (3 RCTs)
MAAC 1477 (2 RCTs)
Sessile serrated ADR 2416 (3 RCTs)
serious a
41/1210 (3.4%) 61/1206 (5.1%)
High definition-white light endoscopy (HD-WLE) compared to standard definition (SDC) for Colonoscopy outcomes Certainty assessment
Summary of findings
MSSAC 1477 (2 RCTs)
serious a
not serious
serious b
not serious
none
⨁⨁◯◯ LOW
702
775
-
The mean MSAC was 0
CI: Confidence interval; RR: Risk ratio; MD: Mean difference
Explanations a. This domain was downgraded by 1 point, because there were evidence of performance and detection bias in all studies included this review b. This domain was downgraded by 1 point, because of differences in population (applicability), interventions and outcomes measures (surrogate outcomes) among the studies
MD 0.04 higher (0.62 lower to 0.7 higher)