Exploration And Development Of Colorectal Neoplasia Based Risk-stratification Screening Model And Indicator Of Colonoscopy Withdrawal Time

Section 1 Development and validation of Fecal Immunochemical Test and Risk Factors-Based Risk Stratification Model for Colorectal Neoplasia in Chinese Population: A Nationwide Multicenter Prospective StudyBackground: Colorectal cancers(CRCs)are increasing rapidly and are projected to be the most common gastrointestinal malignancy in China,where colonoscopy is limited and no riskstratified screening strategy was established.As a result,the early-detection rate and 5-year survival rate of CRC in China is low.Therefore,this study was aimed to develop a fecal immunochemical test(FIT)and risk factors-based risk-stratification model for CRC screening and colonoscopy practice in China.Methods: In the nationwide prospective study,10,164 individuals were recruited from 175 centers between 2018 and 2020.Enrolled participants were randomly allocated at a ratio of 2:1 into the derivation cohort(n=6776)or validation cohort(n=3388).The primary outcome was colorectal neoplasia(CN,including CRC and all precancerous lesions).Based on derivation cohort,univariate and multivariate logistic analyses of risk factors for CN were conducted to develop National Colorectal Polyp Care(NCPC)score,which plus FIT formed the riskstratification model.Finally,the performance of NCPC score and risk-stratification model was validated and evaluated.The trial was registered in Clinical Trials.gov with the identifier of NCT03712059.Results: According to the regression analyses,the NCPC score was developed based on eight risk factors for CNs,which included advanced age,diabetes,male gender,first-degree relatives with CRC,body mass index ≥24,smoking(current or past),drinking(current),history of previous negative colonoscopy,with scores ranging from 0 to 28 and divided into three risk levels: low risk(LR,0-14),intermediate risk(IR,15-17)and high risk(HR,18-28);FIT successfully further stratified the risk profile of three risk levels for CNs and advanced CNs(ACNs)(all P<0.001).Therefore,participants with IR or HR in NCPC score or FIT+ were classified as increased risk in the risk-stratification model and guided to receive colonoscopy.IR/HR in the NCPC score showed significantly higher prevalence of CNs(21.8%/32.8 vs.11.0%,P<0.001)and ACNs(4.3%/9.2% vs.2.0%,P<0.001)than LR in the deviation cohort;consistent findings with similar relative risks and predicting performance indicators were also observed between derivation and validation cohort,or between nonspecific gastrointestinal symptoms(NSGS)and asymptomatic cohort.The risk-stratification model effectively identified 73.5% CNs,82.6% ACNs,and 93.6% CRCs when only guiding 52.7% participants to receive colonoscopy;and identified 55.8% early-onset ACNs and 72.7% early-onset CRCs with only 25.6% young participants recommended to receive colonoscopy.Conclusion: The risk-stratification model showed good risk-stratification ability for the Chinese population,including individuals with NSGS and young age.Therefore,this model might be beneficial to optimize the strategy of risk-stratification CRC screening and colonoscopy practice for the Chinese population.Section 2 9-minute Withdrawal Time Significantly Improved Adenoma Detection Rate of Colonoscopists: A Multicenter Randomized Controlled TrialBackground: Although current quality indicators of colonoscopy recommend 6 minutes as the minimum standard for negative withdrawal time(WT),the impact of WT longer than 6 minutes on colorectal adenoma detection is unclear,which is also the aim of the current trial.Methods: A multicenter randomized controlled trial involving 1027 patients was conducted in 12 endoscopy centers from 2018 to 2019.Participants were randomly assigned to the 9-minute(n=514)or 6-minute(n=513)WT group,and a timer was used to adjust the withdrawal speed.The time for biopsy and resection of polyp was not taken into calculation of WT and any >1 minute’s violation of WT protocol was considered as the violation of trial protocol,which was excluded for per-protocol analysis and only included in the intention-to-treat analysis.Predesigned WT timer with specific timer operators was set to record and remind colonoscopists WT for accurate recording and timely reminding.The primary outcome was the adenoma detection rate(ADR).The data analysis was mainly conducted according to intention-to-treat analysis,while per-protocol analysis was used for the confirmation of primary and secondary outcomes.The trial was registered in Clinical Trials.gov with the identifier of NCT03399045.Results: The mean withdrawal time(m-WT)was significant longer with 9-minute versus 6-minute WT group(375.4 vs.533.4,P<0.001)in the intention-to-treat analysis;similar findings were also found in the right,transverse,left colon.Intention-to-treat analysis also showed a significantly higher ADR in the 9-minute versus 6-minute WT group(36.6% vs.27.1%,P=0.001).For the subgroup analysis,prolonging WT from 6 to 9 minutes significantly increased ADR of the proximal colon(21.4% vs.11.9%,P<0.001)as well as of the less experienced(or with low baseline ADR)colonoscopists(36.9% vs.23.6%,P=0.03),but the ADR of distal colon(19.6% vs.18.9%,P=0.76)or experienced(or with high baseline ADR)colonoscopists(34.0% vs.34.9%,P=0.90)did not improved.Improvements were also observed in the polyp detection rate(58.0% vs.47.8%,P<0.001),and mean number of polyps and adenomas per colonoscopy(1.1 vs.0.9,P=0.002;0.5 vs.0.4,P=0.008,respectively).The higher ADR in 9-minute WT was also confirmed by the per-protocol analysis and subgroup analysis.The multivariate logistic regression model also confirmed that 9-minute WT was independently associated with increased ADR(P=0.005)after adjusting the effect of individual colonoscopists and other confounders.Conclusion: Prolonging WT from 6 to 9 minutes significantly improved ADR,especially in the proximal colon and for less experienced(or with low baseline ADR)colonoscopists.A 9-minute WT benchmark might be considered as one of the quality indicators of colonoscopy.Section 3 Reduced Adenoma and Advanced Adenoma Miss Rates with 9-Minute vs.6-Minute Mean Withdrawal Time for Screening Colonoscopy: A Multicenter Randomized Tandem TrialBackground In the colonoscopy practice,over 1/4 adenomas and approximately 1/10 advanced adenomas may be missed by qualified colonoscopists.Although 9-minute mean withdrawal time(m-WT)is often reported to be associated with the optimal adenoma detection rate(ADR),yet no randomized controlled trials(RCTs)have demonstrated the superiority of 9-minute m-WT versus 6-minute m-WT on adenoma miss rate(AMR)or ADR in screening colonoscopy,which is the aim of the trial.Methods A multicenter RCT involving 11 centers was conducted during March 2021 and November 2021.733 screening participants were randomized to receive same-day tandem(back-to-back)colonoscopy with 9-minute withdrawal followed by 6-minute withdrawal(9-minute-first group,9MF,n=366)or vice versa(6-minute-first group,6MF,n=367).Segmental tandem colonoscopy was conducted to alleviate the difficulty and pain of colonoscopy insertion.Both intention-to-treat and per-protocol analyses were conducted,and the primary outcome was AMR(lesion level).The trial was registered in Clinical Trials.gov with the identifier of NCT04797065.Results According to the intention-to-treat analysis,when compared with the 6MF,9MF significantly reduced the lesion-level AMR(14.5% vs.36.6%,P<0.001),participant-level AMR(10.9% vs.25.9%,P<0.001),participant-level advanced adenoma miss rate(AAMR,5.3% vs.46.9%,P=0.002),and miss rate of multiple adenomas(20.7% vs.56.5%,P=0.01)and high-risk adenomas(HRAs,14.6% vs.39.5%,P=0.01)without compromising detection efficiency(0.45 vs.0.46,P=0.79);meanwhile,9MF also showed lower false-negative rates for adenoma(5.2% vs.11.7%,P=0.002)and HRA(2.2% vs.5.0%,P<0.05),and a lower shortening rate of surveillance schedule(7.7% vs.16.1%,P<0.001;0.3% vs.3.8%,P=0.001,respectively).In addition,compared with the 6-minute m-WT,higher ADRs were found in 9-minute m-WT for the first(42.3% vs.33.5%,P=0.02)and second(21.8% vs.9.8%, P<0.001)withdrawal.Finally,the results of per-protocol analysis,actual-WT subgroup analysis,sensitivity analysis,correlation analysis and multivariate regression analysis consistently demonstrated the quality improvement with 9-minute versus 6-minute WT in the term of ADR,AMR,AAMR and other colonoscopy quality indicators.Conclusion In addition to the improved ADR,9-minute WT significantly reduced the AMR and AAMR of screening colonoscopy without compromising detection efficiency.Nine-minute WT deserves to be incorporated into the current panel of indicators to monitor and improve colonoscopy quality.