The were the only multi-centre studies including two

The electronicsearches of PubMed and EMBASE yielded a total of 79 studies. Two additionalstudies were identified after screening of references, generating a total of 81studies.

After correcting for duplicates, 73 studies remained. Of these, 53were excluded because after reading their titles and abstracts they clearly failedto meet the eligibility criteria or did not answer the research question. The full-textof the remaining 20 studies was assessed in more detail.

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Fourteen of thesestudies did not meet the pre-defined inclusion criteria due to various reasons(wrong population (n = 3), addition of technique to conventional control (n =10), not clear randomization process (n = 1)). Six studies met the eligibilitycriteria and were included in this systematic review 17-20, 25, 26. Anoverview of the study selection is provided in the flow diagram of Figure 1. 3.2Study characteristicsAn overview of the study characteristicscan be found in Tables 1 and 2. Amore detailed summary of the characteristics is given this chapter and has beenattached in Appendix III.

3.2.1 Setting and Methods All six includedstudies were RCTs assessing the effect of chromoendoscopy on the detection ofcolorectal neoplasms compared to conventional colonoscopy. Two trials, Pohl et al.18 and Kiesslich et al.26, werefrom Germany and carried out by one of five or one of two experiencedendoscopists respectively. Hashimoto etal.17 and Park et al.

25 werethe only trials from Asia (Japan and Korea) and a total of ten experiencedendoscopists divided over the two trials performed the procedures. One trialwas from five centres in Canada, USA and Israel and colonoscopies were carriedout by one of the eight trained endoscopists (Stoffel et al.19).Another trial was from the UK and one of two experienced endoscopists performedthe procedures (Hurlstone et al.20). Pohl et al.

18 and Stoffel et al.19 werethe only multi-centre studies including two and five centres respectively (Table 1). Three out of sixtrials had a different study design (Hashimotoet al.17; Park et al.25; Stoffel et al.19). Inthese three trials two consecutive colonoscopies were performed on eachparticipant. During the first intubation the colon was examined withconventional WLC in both study arms.

The second intubation was eitherchromocolonoscopy in the intervention arm or repeated conventional WLC in thecontrol arm. As these trials essentially measured the additional number ofneoplasms detected, subgroup analysis differentiating between single and doubleintubation was carried out. The remaining three trials intubated participantsonce (Pohl et al.18; Hurlstone et al.

20; Kiesslich et al.26).3.

2.2 ParticipantsA total of 1913participants (mean age: 56.3 ± 8.3) dividedover six studies were included in this review (Table 1). These participants varied from consecutive patientsundergoing routine colonoscopies in three trials (Pohl et al.

18; Park et al.25; Hurlstone et al.20), topatients undergoing follow-up screening for alarming abdominal symptoms orsuspicion of malignancies (Hashimoto etal.17), patients with longstanding ulcerativecolitis (Kiesslich et al.26) and patients with a previous personalor familial history of CRC (Stoffel etal.19).

The population of the three last-mentioned studies wasconsidered as high-risk and as a consequence subgroup analysis was performed.3.2.3 InterventionAll studies investigated the effect of chromocolonoscopy onneoplasm detection. Four studies performed pancolonic dye-spraying using anendoscopic catheter (Pohl et al.18; Stoffel et al.19; Hurlstone et al.

20; Kiesslich et al.26),whereas the two other studies only applied dye to the ascending colon (Park et al.25)and descending colon (Hashimoto et al.17). Indigo carmine was used in all studies except for Kiesslich et al.

26,where methylene blue was used as the dye. Conventional WLC was used as thecomparator in all studies (Table 2). 3.2.4 OutcomesAll studiesassessed the primary outcome measure of interest: the number of detected colorectalneoplasms per patient. Data regarding secondary outcome measures was availablein most of the studies. All studies reported extubation times, three out of sixstudies reported the number of adenocarcinomas and four out of six studiesreported the number of hyperplastic lesions. The occurrence of adverse eventswas only reported in two studies (Table2).

3.3Risk of bias within studiesMethodological quality of the included studies was assessed for sixdifferent criteria. Judgement of bias was scored as low risk, high risk orunclear risk and results are presented in Figure2 and Figure 3. Support for these judgements has been attached in AppendixIII.

Overall risk of biaswas graded as low/unclear.   3.3.1 AllocationHashimoto et al.17wasthe only study that did not provide details on the randomization process and concealmentof allocation. The other studies, who provided these details, randomized participants usingstandard randomization lists (Pohl et al.18) stratified randomization (Stoffel et al.

19) andcomputer-generated randomization lists (Parket al.25; Hurlstone et al.20; Kiesslich et al.26). Inthese studies allocation remained concealed until the intervention started. 3.3.2 BlindingDue to thenature of this intervention it was impossible to blind the colonoscopists.

Blinding of participants was irrelevant because they underwent the procedureand could not have affected the outcome measures. In an attempt to reduce, orat least minimize, bias two studies (Pohlet al.18; Hurlstone et al.20) triedto correct for longer extubation times in the chromocolonoscopy arm by using asaline solution to spray the colon in the control arm. 3.3 Incomplete outcome dataAll studiesexcept Stoffel et al.19 and Hurlstone et al.20documented reasons for secondary dropouts (withdrawals after randomization).

Dropout rates were comparable across study arms (Table 1). 3.3.4 Selective reportingAll studiesreported pre-specified outcomes, but differentiation between type of lesionswas not clearly documented in Hashimotoet al.17.Furthermore, no study reported the occurrence of adverse events.3.

3.5 Other biasPohl et al.18 and Hashimoto et al.

17reported statistically significant increases in extubation times in thechromocolonoscopy arm, whereas the other studies either controlled for possibleincreases in extubation times or showed no statistical differences. 3.4 Results of individualstudiesResults ofindividual studies have been extracted based on predefined outcome measures ofinterest and are presented in Table 2.The primary outcome measure, mean number of detected colorectal neoplasms perpatient, was reported in all studies and ranged from 0.

19-0.95 (SD: 2.00) inthe chromocolonoscopy group to 0.06-0.66 (SD: 2.

00) in the WLC group. Withregard to secondary outcome measures, data on number of adenocarcinomas wasunavailable in three studies (Hashimoto et al.17; Park et al.

25; Stoffel et al.19) andnumber of hyperplastic lesions in two studies (Hashimoto et al.17; Kiesslich et al.26). Studiesthat did measure these secondary outcomes, reported similar results acrossstudy arms for adenocarcinoma detection (Pohlet al.

18; Hurlstone et al.20)except for Kiesslich et al.26 whofound three adenocarcinomas in 84 patients in the chromocolonoscopy and onlyone adenocarcinoma in 81 patients in the WLC arm. Extubation timesand adverse events have not been included in the meta analyses due to thenature of these outcome measures (extubation) and availability of data (adverseevents) . Only two studies (Park et al.

25; Stoffel et al.19) reportedon occurrences of adverse events (n= 0 in both studies) and the remaining four studiesdid not disclose any information on procedure-related adverse events. Extubationtimes differed significantly across studies, but in all studieschromocolonoscopy took longer to complete than conventional WLC. Hashimoto et al.17 and Park et al.25, whoonly inspected segments of the colon, revealed shorter extubation times as alogical consequence (10.9 vs. 6.

8 and1.9 vs. 1.8 minutes, respectively). Overalldifferences in mean extubation time varied from 0.1 minutes to 9.6 minutesbetween the two study arms.3.

5 Syntheses of resultsA significantdifference in favour of chromocolonoscopy was observed for almost all measuredoutcomes. The mean number of detected colorectal neoplasms per patient (primaryoutcome) was greater for all studies in the chromocolonoscopy arm except for Hashimoto et al.17, inwhich more neoplasms were detected in the conventional arm (Table 2). Combining the studies resulted in a great statistical significance(Mean difference (MD) 0.29; 95%CI 0.12-0.46; P=0.

0007; 6 studies; 1913 participants) with no significantheterogeneity (I2 = 0%, P=0.52)(Figure 4, Analysis 1.1). Subgroupanalysis differentiating between study designs using single or doubleintubation had effect on effect estimates. The increased detection ofcolorectal neoplasms in the double intubation group was not statisticallysignificant (MD 0.24; 95%CI -0.

04-0.53; P=0.09)(Figure 4, Analysis 1.1.

1),but remained significant in the single intubation group (MD 0.31; 95%CI 0.11-0.52; P=0.003)(Figure 4, Analysis 1.1.

2). A subgroupanalysis considering the effects of high or low-risk patients on the primaryoutcome ruled out differences as increase in yield was comparable betweengroups (Figure 7, Analysis 4.1).

Increases inadenocarcinoma detection with chromocolonoscopy could be of great clinical use.Unfortunately, chromocolonoscopy did not affect the detection rate ofadenocarcinomas (MD 0.00; 95%CI -0.10-0.11; P=0.

95;3 studies; 1433 participants)(Figure 5, Analysis 2.1). Furthermore,hyperplastic lesions were clearly detected more in the chromocolonoscopy arm (MD0.49; 95%CI 0.30-0.67; P<0.

00001; 4studies; 1618 participants)(Figure 6, Analysis 3.1). However,substantial heterogeneity was detected (I2 = 60%) anddifferentiation between intubation strategy revealed that this statisticalsignificant yield was only maintained in the single intubation group (Figure 6, Analysis 3.1.

1). Finally, astatistically significant increase in the number of patients with at least onecolorectal neoplasm was found in the chromocolonoscopy arm (Oddsratio (OR) 1.89; 95%CI 1.

53-2.32; P<0.00001;5 studies; 1783 participants)(Figure 8, Analysis 5.1)and this increase was maintained following a subgroup analysis of both studydesigns (Figure 8,Analysis 5.1.1 and 5.



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