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Background: Many colorectal cancer–related procedures were suspended during the COVID-19 pandemic. In this study, we predict the impact of resulting delays in screening (colonoscopy, FIT, and sigmoidoscopy) and diagnosis on colorectal cancer–related outcomes, and compare different recovery scenarios. Methods: Using the MISCAN-Colon model, we simulated the US population and evaluated different impact and recovery scenarios. Scenarios were defined by the duration and severity of the disruption (percentage of eligible adults affected), the length of delays, and the duration of the recovery. During recovery (6, 12 or 24 months), capacity was increased to catch up missed procedures. Primary outcomes were excess colorectal cancer cases and –related deaths, and additional colonoscopies required during recovery. Results: With a 24-month recovery, the model predicted that the US population would develop 7,210 (0.18%) excess colorectal cancer cases during 2020–2040, and 6,950 (0.65%) excess colorectal cancer–related deaths, and require 108,500 (8.6%) additional colonoscopies per recovery month, compared with a no-disruption scenario. Shorter recovery periods of 6 and 12 months, respectively, decreased excess colorectal cancer–related deaths to 4,190 (0.39%) and 4,580 (0.43%), at the expense of 260,200–590,100 (20.7%–47.0%) additional colonoscopies per month. Conclusions: The COVID-19 pandemic will likely cause more than 4,000 excess colorectal cancer–related deaths in the US, which could increase to more than 7,000 if recovery periods are longer. Impact: Our results highlight that catching-up colorectal cancer–related services within 12 months provides a good balance between required resources and mitigation of the impact of the disruption on colorectal cancer–related deaths.

ObjectiveHigh-quality colonoscopy (adequate bowel preparation, whole-colon visualisation and removal of all neoplastic polyps) is a prerequisite to start polyp surveillance, and is ideally achieved in one colonoscopy. In a large multinational polyp surveillance trial, we aimed to investigate clinical practice variation in number of colonoscopies needed to enrol patients with low-risk and high-risk adenomas in polyp surveillance.DesignWe retrieved data of all patients with low-risk adenomas (one or two tubular adenomas ResultsThe study comprised 15 581 patients from 38 endoscopy centres in five European countries; 6794 patients had low-risk and 8787 had high-risk adenomas. 961 patients (6.2%, 95% CI 5.8% to 6.6%) underwent two or more colonoscopies before surveillance began; 101 (1.5%, 95% CI 1.2% to 1.8%) in the low-risk group and 860 (9.8%, 95% CI 9.2% to 10.4%) in the high-risk group. Main reasons were poor bowel preparation (21.3%) or incomplete colonoscopy/polypectomy (14.4%) or planned second procedure (27.8%). Need of repeat colonoscopy varied between study centres ranging from 0% to 11.8% in low-risk adenoma patients and from 0% to 63.9% in high-risk adenoma patients. On the second colonoscopy, the two most common reasons for a repeat (third) colonoscopy were piecemeal resection (26.5%) and unspecified reason (23.9%).ConclusionThere is considerable practice variation in the number of colonoscopies performed to achieve complete polyp removal, indicating need for targeted quality improvement to reduce patient burden.Trial registration numberNCT02319928.

The incidence of colorectal cancer diagnosed before age 50, often referred to as early-onset colorectal cancer, has been increasing, whereas the overall colorectal cancer incidence has declined. Elucidating the drivers for the rising burden of early-onset colorectal cancer is a priority in cancer epidemiology and prevention. In this issue of Cancer Epidemiology, Biomarkers & Prevention, Chen and colleagues demonstrated that ecologic studies are a helpful method to reveal emerging risk factors at the population level and concluded that alcohol use might be a potential contributor to the rising incidence of early-onset colorectal cancer. Moving forward, because of the observed birth cohort effect in early-onset colorectal cancer, where younger generations have a steeper increase, hypothesis-driven investigations on emerging risk factors in recent generations, especially during early life, are warranted. Ultimately, the identified risk factors could be integrated with well-established microsimulation models of colorectal cancer, powerful tools that can simultaneously capture population-level secular changes in risk factors, relative risk estimates for each risk factor, and the natural history of colorectal cancer. This would allow us to quantitatively estimate the explained and unexplained portion of the rising incidence of early-onset colorectal cancer by calendar period and birth cohorts, and to help identify priorities in etiologic research, prevention, and early detection. See related article by Chen et al., p. 217

In the past decades the incidence of colorectal cancer (CRC) in people under the age of 50 years has increased, which is referred to as early-onset CRC or young-onset CRC (YO-CRC). YO-CRC is expected to account for 11% of colon cancers and 23% of rectal cancers by 2030. This trend is observed in different parts of the world and in both men and women. In 20% of patients with YO-CRC, a hereditary cancer syndrome is found as the underlying cause; however, in the majority of patients no genetic predisposition is present. Beginning in the 1950s, major changes in lifestyle such as antibiotic use, low physical activity and obesity have affected the gut microbiome and may be an important factor in YO-CRC development. Owing to a lack of screening, patients with YO-CRC are often diagnosed with advanced-stage disease. Long-term treatment-related complications should be taken into account in these younger patients, making the more traditional sequential approaches of drug therapy not always the most appropriate option. To better understand the underlying mechanism and define relationships between environmental factors and YO-CRC development, long-term prospective studies are needed with lifestyle data collected from childhood.

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Inflammation, as measured by the circulating inflammatory marker high-sensitivity C-reactive protein (hsCRP), has been associated with cardiovascular disease. However, data about CRP and risk of colorectal cancer have been conflicting. The Adenoma Prevention with Celecoxib (APC) trial showed that the anti-inflammatory drug celecoxib prevents recurrence of colorectal adenoma but increases risk of cardiovascular events. We examined whether serum hsCRP modified these results. We measured hsCRP from serum specimens provided at study entry by patients enrolled in the APC trial. Patients were stratified according to use of low-dose aspirin, randomized to receive 3 years of treatment with placebo, 200-mg-bid celecoxib, or 400-mg-bid celecoxib, and underwent follow-up colonoscopies at years 1 and 3. Among 1,680 patients, the estimated 3-year cumulative incidence of adenoma was 42% for patients with hsCRP 3 mg/L. The effect of celecoxib on adenoma recurrence did not vary among patients with high (>3 mg/L) compared with low (≤3 mg/L) hsCRP. However, among patients with high hsCRP, the RR of cardiovascular events compared with placebo was 2.27 (95% CI = 0.72–7.14) for those randomized to celecoxib 200-mg-bid and 3.28 (95% CI = 1.09–9.91) for 400-mg-bid. In contrast, among patients with low hsCRP, the corresponding RRs were 0.99 (95% CI = 0.53–1.83) and 1.11 (95% CI = 0.61–2.02). hsCRP may predict risk of celecoxib-associated cardiovascular toxicity but not adenoma recurrence or celecoxib treatment efficacy. Patients with low hsCRP may be a subgroup with a favorable risk-benefit profile for celecoxib chemoprevention. Cancer Prev Res; 4(8); 1172–80. ©2011 AACR.

Perspective from Aberrant Crypt Foci in the Adenoma Prevention with Celecoxib Trial

Perspective on this Article from Five-Year Efficacy and Safety Analysis of the Adenoma Prevention with Celecoxib Trial

Perspective on This Article from C-reactive Protein and Risk of Colorectal Adenoma According to Celecoxib Treatment

Supplementary Information from Five-Year Efficacy and Safety Analysis of the Adenoma Prevention with Celecoxib Trial

Aspirin and celecoxib prevent colorectal adenoma recurrence. Genetic variants in the UGT1A6 enzyme are associated with delayed aspirin metabolism and greater chemopreventive efficacy. We examined the effect of combining aspirin and celecoxib in relation to UGT1A6 T181A and R184S variants among 1,647 patients in the Adenoma Prevention with Celecoxib (APC) trial who were stratified according to the use of low-dose aspirin after removal of adenomas and randomized to placebo, 200-mg twice daily, or 400-mg twice daily celecoxib for 3 years. Patients underwent follow-up colonoscopies at 1 and 3 years to assess on-treatment efficacy. At 5 years, 538 patients underwent a colonoscopy to assess risk of recurrence after treatment was discontinued for at least 1 year. During treatment, the relative risk (RR) of recurrent adenoma was 0.68 [95% confidence interval (CI), 0.59–0.79] for 200-mg twice daily celecoxib and 0.54 (95% CI, 0.46–0.64) for 400-mg twice daily celecoxib compared with placebo. Aspirin use was not independently associated with recurrent adenoma (RR, 0.98, 95% CI, 0.86–1.15). These results did not vary according to UGT1A6 genotype. However, among those with a variant UGT1A6 genotype on aspirin, the RR of adenoma was 1.60 (95% CI, 0.81–3.15) after withdrawal of 200-mg twice daily and 1.98 (95% CI, 1.06–3.70) after withdrawal of 400-mg twice daily celecoxib compared with withdrawal of placebo. In contrast, there was no increased risk associated with discontinuing celecoxib among any other groups. Concurrent use of low-dose aspirin does not influence the efficacy of celecoxib in adenoma prevention. However, discontinuing celecoxib among aspirin-using individuals who initially developed adenoma despite a UGT1A6 variant genotype resulted in rapid reemergence of disease. Cancer Prev Res; 5(1); 61–72. ©2011 AACR.

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PDF file - 149K, Appendix containing detailed model description, estimates of survival by race, age and gender over time and Formulas for Calculation of Disparities and Proportion of Disparities Explained by Screening and Survival

Purpose: Identification of single-nucleotide polymorphisms (SNP) associated with development of advanced colorectal adenomas.Experimental Design: Discovery phase: 1,406 Caucasian patients (139 advanced adenoma cases and 1,267 controls) from the Adenoma Prevention with Celecoxib (APC) trial were included in a genome-wide association study (GWAS) to identify variants associated with postpolypectomy disease recurrence. Genome-wide significance was defined as false discovery rate less than 0.05, unadjusted P = 7.4 × 10−7. Validation phase: results were further evaluated using 4,175 familial colorectal adenoma cases and 5,036 controls from patients of European ancestry [COloRectal Gene Identification consortium (CORGI), Scotland, Australia, and VQ58].Results: Our study identified eight SNPs associated with advanced-adenoma risk in the APC trial (rs2837156, rs7278863, rs2837237, rs2837241, rs2837254, rs741864 at 21q22.2, and rs1381392 and rs17651822 at 3p24.1, at P < 10−7 level with OR > 2). Five variants in strong pairwise linkage disequilibrium (rs7278863, rs2837237, rs741864, rs741864, and rs2837241; r2 = 0.8–1) are in or near the coding region for the tight junction adhesion protein, IGSF5. An additional variant associated with advanced adenomas, rs1535989 [minor allele frequency, 0.11; OR, 2.09; 95% confidence interval (CI), 1.50–2.91], also predicted colorectal cancer development in a validation analysis (P = 0.019) using a series of adenoma cases or colorectal cancer (CORGI study) and 3 sets of colorectal cancer cases and controls (Scotland, VQ58, and Australia; N = 9,211).Conclusions: Our results suggest that common polymorphisms contribute to the risk of developing advanced adenomas and might also contribute to the risk of developing colorectal cancer. The variant at rs1535989 may identify patients whose risk for neoplasia warrants increased colonoscopic surveillance. Clin Cancer Res; 19(23); 6430–7. ©2013 AACR.

Editorial for This Article from Contribution of Screening and Survival Differences to Racial Disparities in Colorectal Cancer Rates

Background: Considerable disparities exist in colorectal cancer (CRC) incidence and mortality rates between blacks and whites in the United States. We estimated how much of these disparities could be explained by differences in CRC screening and stage-specific relative CRC survival.Methods: We used the MISCAN-Colon microsimulation model to estimate CRC incidence and mortality rates in blacks, aged 50 years and older, from 1975 to 2007 assuming they had: (i) the same trends in screening rates as whites instead of observed screening rates (incidence and mortality); (ii) the same trends in stage-specific relative CRC survival rates as whites instead of observed (mortality only); and (iii) a combination of both. The racial disparities in CRC incidence and mortality rates attributable to differences in screening and/or stage-specific relative CRC survival were then calculated by comparing rates from these scenarios to the observed black rates.Results: Differences in screening accounted for 42% of disparity in CRC incidence and 19% of disparity in CRC mortality between blacks and whites. Thirty-six percent of the disparity in CRC mortality could be attributed to differences in stage-specific relative CRC survival. Together screening and survival explained a little more than 50% of the disparity in CRC mortality between blacks and whites.Conclusion: Differences in screening and relative CRC survival are responsible for a considerable proportion of the observed disparities in CRC incidence and mortality rates between blacks and whites.Impact: Enabling blacks to achieve equal access to care as whites could substantially reduce the racial disparities in CRC burden. Cancer Epidemiol Biomarkers Prev; 21(5); 728–36. ©2012 AACR.

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Background & Aims: Colorectal cancer (CRC) screening guidelines include screening colonoscopy and sequential high-sensitivity fecal occult blood testing (HSgFOBT), with expectation of similar effectiveness based on the assumption of similar high adherence. However, adherence to screening colonoscopy compared with sequential HSgFOBT has not been reported. In this randomized clinical trial, we assessed adherence and pathology findings for a single screening colonoscopy vs sequential and nonsequential HSgFOBTs. Methods: Participants aged 40–69 years were enrolled at 3 centers representing different clinical settings. Participants were randomized into a single screening colonoscopy arm vs sequential HSgFOBT arm composed of 4–7 rounds. Initial adherence to screening colonoscopy and sequential adherence to HSgFOBT, follow-up colonoscopy for positive HSgFOBT tests, crossover to colonoscopy, and detection of advanced neoplasia or large serrated lesions (ADN-SERs) were measured. Results: There were 3523 participants included in the trial; 1761 and 1762 participants were randomized to the screening colonoscopy and HSgFOBT arms, respectively. Adherence was 1473 (83.6%) for the screening colonoscopy arm vs 1288 (73.1%) for the HSgFOBT arm after 1 round (relative risk [RR], 1.14; 95% CI, 1.10–1.19; P ≤.001), but only 674 (38.3%) over 4 sequential HSgFOBT rounds (RR, 2.19; 95% CI, 2.05–2.33). Overall adherence to any screening increased to 1558 (88.5%) in the screening colonoscopy arm during the entire study period and 1493 (84.7%) in the HSgFOBT arm (RR, 1.04; 95% CI, 1.02–1.07). Four hundred thirty-six participants (24.7%) crossed over to screening colonoscopy during the first 4 rounds. ADN-SERs were detected in 121 of the 1473 participants (8.2%) in the colonoscopy arm who were adherent to protocol in the first 12 months of the study, whereas detection of ADN-SERs among those who were not sequentially adherent (n = 709) to HSgFOBT was subpar (0.6%) (RR, 14.72; 95% CI, 5.46–39.67) compared with those who were sequentially adherent (3.3%) (n = 647) (RR, 2.52; 95% CI, 1.61–3.98) to HSgFOBT in the first 4 rounds. When including colonoscopies from HSgFOBT patients who were never positive yet crossed over (n = 1483), 5.5% of ADN-SERs were detected (RR, 1.50; 95% CI, 1.15–1.96) in the first 4 rounds. Conclusions: Observed adherence to sequential rounds of HSgFOBT was suboptimal compared with a single screening colonoscopy. Detection of ADN-SERs was inferior when nonsequential HSgFOBT adherence was compared with sequential adherence. However, the greatest number of ADN-SERs was detected among those who crossed over to colonoscopy and opted to receive a colonoscopy. The effectiveness of an HSgFOBT screening program may be enhanced if crossover to screening colonoscopy is permitted. ClinicalTrials.gov, Number: NCT00102011.

Background & Aims: Previous studies on the cost-effectiveness of personalized colorectal cancer (CRC) screening were based on hypothetical performance of CRC risk prediction and did not consider the association with competing causes of death. In this study, we estimated the cost-effectiveness of risk-stratified screening using real-world data for CRC risk and competing causes of death. Methods: Risk predictions for CRC and competing causes of death from a large community-based cohort were used to stratify individuals into risk groups. A microsimulation model was used to optimize colonoscopy screening for each risk group by varying the start age (40–60 years), end age (70–85 years), and screening interval (5–15 years). The outcomes included personalized screening ages and intervals and cost-effectiveness compared with uniform colonoscopy screening (ages 45–75, every 10 years). Key assumptions were varied in sensitivity analyses. Results: Risk-stratified screening resulted in substantially different screening recommendations, ranging from a one-time colonoscopy at age 60 for low-risk individuals to a colonoscopy every 5 years from ages 40 to 85 for high-risk individuals. Nevertheless, on a population level, risk-stratified screening would increase net quality-adjusted life years gained (QALYG) by only 0.7% at equal costs to uniform screening or reduce average costs by 1.2% for equal QALYG. The benefit of risk-stratified screening improved when it was assumed to increase participation or costs less per genetic test. Conclusions: Personalized screening for CRC, accounting for competing causes of death risk, could result in highly tailored individual screening programs. However, average improvements across the population in QALYG and cost-effectiveness compared with uniform screening are small.

Polygenic risk scores (PRS) have great potential to guide precision colorectal cancer (CRC) prevention by identifying those at higher risk to undertake targeted screening. However, current PRS using European ancestry data have sub-optimal performance in non-European ancestry populations, limiting their utility among these populations. Towards addressing this deficiency, we expanded PRS development for CRC by incorporating Asian ancestry data (21,731 cases; 47,444 controls) into European ancestry training datasets (78,473 cases; 107,143 controls). The AUC estimates (95% CI) of PRS were 0.63(0.62-0.64), 0.59(0.57-0.61), 0.62(0.60-0.63), and 0.65(0.63-0.66) in independent datasets including 1,681-3,651 cases and 8,696-115,105 controls of Asian, Black/African American, Latinx/Hispanic, and non-Hispanic White, respectively. They were significantly better than the European-centric PRS in all four major US racial and ethnic groups (p-values

Background:Polygenic risk scores (PRS) which summarize individuals’ genetic risk profile may enhance targeted colorectal cancer screening. A critical step towards clinical implementation is rigorous external validations in large community-based cohorts. This study externally validated a PRS-enhanced colorectal cancer risk model comprising 140 known colorectal cancer loci to provide a comprehensive assessment on prediction performance.Methods:The model was developed using 20,338 individuals and externally validated in a community-based cohort (n = 85,221). We validated predicted 5-year absolute colorectal cancer risk, including calibration using expected-to-observed case ratios (E/O) and calibration plots, and discriminatory accuracy using time-dependent AUC. The PRS-related improvement in AUC, sensitivity and specificity were assessed in individuals of age 45 to 74 years (screening-eligible age group) and 40 to 49 years with no endoscopy history (younger-age group).Results:In European-ancestral individuals, the predicted 5-year risk calibrated well [E/O = 1.01; 95% confidence interval (CI), 0.91–1.13] and had high discriminatory accuracy (AUC = 0.73; 95% CI, 0.71–0.76). Adding the PRS to a model with age, sex, family and endoscopy history improved the 5-year AUC by 0.06 (P < 0.001) and 0.14 (P = 0.05) in the screening-eligible age and younger-age groups, respectively. Using a risk-threshold of 5-year SEER colorectal cancer incidence rate at age 50 years, adding the PRS had a similar sensitivity but improved the specificity by 11% (P < 0.001) in the screening-eligible age group. In the younger-age group it improved the sensitivity by 27% (P = 0.04) with similar specificity.Conclusions:The proposed PRS-enhanced model provides a well-calibrated 5-year colorectal cancer risk prediction and improves discriminatory accuracy in the external cohort.Impact:The proposed model has potential utility in risk-stratified colorectal cancer prevention.

The aftermath of the initial phase of the COVID-19 pandemic may contribute to the widening of disparities in access to colorectal cancer (CRC) screening due to differential disruptions to CRC screening. This comparative microsimulation analysis uses two CISNET CRC models to simulate the impact of ongoing screening disruptions induced by the COVID-19 pandemic on long-term CRC outcomes. We evaluate three channels through which screening was disrupted: delays in screening, regimen switching, and screening discontinuation. The impact of these disruptions on long-term colorectal cancer (CRC) outcomes was measured by the number of Life-years lost due to CRC screening disruptions compared to a scenario without any disruptions. While short-term delays in screening of 3-18 months are predicted to result in minor life-years loss, discontinuing screening could result in much more significant reductions in the expected benefits of screening. These results demonstrate that unequal recovery of screening following the pandemic can widen disparities in colorectal cancer outcomes and emphasize the importance of ensuring equitable recovery to screening following the pandemic.

Background To evaluate the cost‐effectiveness of prophylactic hysterectomy (PH) in women with Lynch syndrome (LS). Methods We developed a microsimulation model incorporating the natural history for the development of hyperplasia with and without atypia into endometrial cancer (EC) based on the MISCAN‐framework. We simulated women identified as first‐degree relatives (FDR) with LS of colorectal cancer patients after universal testing for LS. We estimated costs and benefits of offering this cohort PH, accounting for reduced quality of life after PH and for having EC. Three minimum ages (30/35/40) and three maximum ages (70/75/80) were compared to no PH. Results In the absence of PH, the estimated number of EC cases was 300 per 1,000 women with LS. Total associated costs for treatment of EC were $5.9 million. Offering PH to FDRs aged 40–80 years was considered optimal. This strategy reduced the number of endometrial cancer cases to 5.4 (−98%), resulting in 516 quality‐adjusted life years (QALY) gained and increasing the costs (treatment of endometrial cancer and PH) to $15.0 million (+154%) per 1,000 women. PH from earlier ages was more costly and resulted in fewer QALYs, although this finding was sensitive to disutility for PH. Conclusions Offering PH to 40‐ to 80‐year‐old women with LS is expected to add 0.5 QALY per person at acceptable costs. Women may decide to have PH at a younger age, depending on their individual disutility for PH and premature menopause., We evaluated the cost‐effectiveness of prophylactic hysterectomy (PH) in women with Lynch syndrome (LS). Offering PH to 40–80 year old women with LS is expected to add 0.5 QALY per person at acceptable costs. Women may decide to have PH at age 35 years, depending on their individual disutility for PH and premature menopause.

Background: Although colonoscopy is widely used as a screening test to detect colorectal cancer, its effect on the risks of colorectal cancer and related death is unclear. Methods: We performed a pragmatic, randomized trial involving presumptively healthy men and women 55 to 64 years of age drawn from population registries in Poland, Norway, Sweden, and the Netherlands between 2009 and 2014. The participants were randomly assigned in a 1:2 ratio to either receive an invitation to undergo a single screening colonoscopy (the invited group) or to receive no invitation or screening (the usual-care group). The primary end points were the risks of colorectal cancer and related death, and the secondary end point was death from any cause. Results: Follow-up data were available for 84,585 participants in Poland, Norway, and Sweden - 28,220 in the invited group, 11,843 of whom (42.0%) underwent screening, and 56,365 in the usual-care group. A total of 15 participants had major bleeding after polyp removal. No perforations or screening-related deaths occurred within 30 days after colonoscopy. During a median follow-up of 10 years, 259 cases of colorectal cancer were diagnosed in the invited group as compared with 622 cases in the usual-care group. In intention-to-screen analyses, the risk of colorectal cancer at 10 years was 0.98% in the invited group and 1.20% in the usual-care group, a risk reduction of 18% (risk ratio, 0.82; 95% confidence interval [CI], 0.70 to 0.93). The risk of death from colorectal cancer was 0.28% in the invited group and 0.31% in the usual-care group (risk ratio, 0.90; 95% CI, 0.64 to 1.16). The number needed to invite to undergo screening to prevent one case of colorectal cancer was 455 (95% CI, 270 to 1429). The risk of death from any cause was 11.03% in the invited group and 11.04% in the usual-care group (risk ratio, 0.99; 95% CI, 0.96 to 1.04). Conclusions: In this randomized trial, the risk of colorectal cancer at 10 years was lower among participants who were invited to undergo screening colonoscopy than among those who were assigned to no screening. (Funded by the Research Council of Norway and others; NordICC ClinicalTrials.gov number, NCT00883792.).

BACKGROUND Computer-aided detection (CADe) of colorectal polyps has been shown to increase adenoma detection rates, which would potentially shorten subsequent surveillance intervals. OBJECTIVE The purpose of this study is to simulate the potential changes in subsequent colonoscopy surveillance intervals after the application of CADe in a large cohort of patients. METHODS We simulated the projected increase in polyp and adenoma detection by universal CADe application in our patients who had undergone colonoscopy with complete endoscopic and histological findings between 2016 and 2020. The simulation was based on bootstrapping the published performance of CADe. The corresponding changes in surveillance intervals for each patient, as recommended by the US Multi-Society Task Force on Colorectal Cancer (USMSTF) or the European Society of Gastrointestinal Endoscopy (ESGE), were determined after the CADe was determined. RESULTS A total of 3735 patients who had undergone colonoscopy were included. Based on the simulated CADe effect, the application of CADe would result in 19.1% (n=714) and 1.9% (n=71) of patients having shorter surveillance intervals, according to the USMSTF and ESGE guidelines, respectively. In particular, all (or 2.7% (n=101) of the total) patients who were originally scheduled to have 3-5 years of surveillance would have their surveillance intervals shortened to 3 years, following the USMSTF guidelines. The changes in this group of patients were largely attributed to an increase in the number of adenomas (n=75, 74%) rather than serrated lesions being detected. CONCLUSIONS Widespread adoption of CADe would inevitably increase the demand for surveillance colonoscopies with the shortening of original surveillance intervals, particularly following the current USMSTF guideline.

Background: Worldwide, many countries have adopted colorectal cancer (CRC) screening programmes, often based on faecal occult blood tests (FOBTs). CRC screening aims to detect advanced neoplasia (AN), which is defined as CRC or advanced adenomas. FOBTs fall into two categories based on detection technique and the detected blood component: qualitative guaiac-based FOBTs (gFOBTs) and faecal immunochemical tests (FITs), which can be qualitative and quantitative. Screening with gFOBTs reduces CRC-related mortality. Objectives: To compare the diagnostic test accuracy of gFOBT and FIT screening for detecting advanced colorectal neoplasia in average-risk individuals. Search methods: We searched CENTRAL, MEDLINE, Embase, BIOSIS Citation Index, Science Citation Index Expanded, and Google Scholar. We searched the reference lists and PubMed-related articles of included studies to identify additional studies. Selection criteria: We included prospective and retrospective studies that provided the number of true positives, false positives, false negatives, and true negatives for gFOBTs, FITs, or both, with colonoscopy as reference standard. We excluded case-control studies. We included studies in which all participants underwent both index test and reference standard ("reference standard: all"), and studies in which only participants with a positive index test underwent the reference standard while participants with a negative test were followed for at least one year for development of interval carcinomas ("reference standard: positive"). The target population consisted of asymptomatic, average-risk individuals undergoing CRC screening. The target conditions were CRC and advanced neoplasia (advanced adenomas and CRC combined). Data collection and analysis: Two review authors independently screened and selected studies for inclusion. In case of disagreement, a third review author made the final decision. We used the Rutter and Gatsonis hierarchical summary receiver operating characteristic model to explore differences between tests and identify potential sources of heterogeneity, and the bivariate hierarchical model to estimate sensitivity and specificity at common thresholds: 10 µg haemoglobin (Hb)/g faeces and 20 µg Hb/g faeces. We performed indirect comparisons of the accuracy of the two tests and direct comparisons when both index tests were evaluated in the same population. Main results: We ran the initial search on 25 June 2019, which yielded 63 studies for inclusion. We ran a top-up search on 14 September 2021, which yielded one potentially eligible study, currently awaiting classification. We included a total of 33 "reference standard: all" published articles involving 104,640 participants. Six studies evaluated only gFOBTs, 23 studies evaluated only FITs, and four studies included both gFOBTs and FITs. The cut-off for positivity of FITs varied between 2.4 μg and 50 µg Hb/g faeces. For each Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2 domain, we assessed risk of bias as high in less than 20% of studies. The summary curve showed that FITs had a higher discriminative ability than gFOBTs for AN (P < 0.001) and CRC (P = 0.004). For the detection of AN, the summary sensitivity of gFOBTs was 15% (95% confidence interval (CI) 12% to 20%), which was significantly lower than FITs at both 10 μg and 20 μg Hb/g cut-offs with summary sensitivities of 33% (95% CI 27% to 40%; P < 0.001) and 26% (95% CI 21% to 31%, P = 0.002), respectively. Results were simulated in a hypothetical cohort of 10,000 screening participants with 1% CRC prevalence and 10% AN prevalence. Out of 1000 participants with AN, gFOBTs missed 850, while FITs missed 670 (10 μg Hb/g cut-off) and 740 (20 μg Hb/g cut-off). No significant differences in summary specificity for AN detection were found between gFOBTs (94%; 95% CI 92% to 96%), and FITs at 10 μg Hb/g cut-off (93%; 95% CI 90% to 95%) and at 20 μg Hb/g cut-off (97%; 95% CI 95% to 98%). So, among 9000 participants without AN, 540 were offered (unnecessary) colonoscopy with gFOBTs compared to 630 (10 μg Hb/g) and 270 (20 μg Hb/g) with FITs. Similarly, for the detection of CRC, the summary sensitivity of gFOBTs, 39% (95% CI 25% to 55%), was significantly lower than FITs at 10 μg and 20 μg Hb/g cut-offs: 76% (95% CI 57% to 88%: P = 0.001) and 65% (95% CI 46% to 80%; P = 0.035), respectively. So, out of 100 participants with CRC, gFOBTs missed 61, and FITs missed 24 (10 μg Hb/g) and 35 (20 μg Hb/g). No significant differences in summary specificity for CRC were found between gFOBTs (94%; 95% CI 91% to 96%), and FITs at the 10 μg Hb/g cut-off (94%; 95% CI 87% to 97%) and 20 μg Hb/g cut-off (96%; 95% CI 91% to 98%). So, out of 9900 participants without CRC, 594 were offered (unnecessary) colonoscopy with gFOBTs versus 594 (10 μg Hb/g) and 396 (20 μg Hb/g) with FITs. In five studies that compared FITs and gFOBTs in the same population, FITs showed a higher discriminative ability for AN than gFOBTs (P = 0.003). We included a total of 30 "reference standard: positive" studies involving 3,664,934 participants. Of these, eight were gFOBT-only studies, 18 were FIT-only studies, and four studies combined both gFOBTs and FITs. The cut-off for positivity of FITs varied between 5 µg to 250 µg Hb/g faeces. For each QUADAS-2 domain, we assessed risk of bias as high in less than 20% of studies. The summary curve showed that FITs had a higher discriminative ability for detecting CRC than gFOBTs (P < 0.001). The summary sensitivity for CRC of gFOBTs, 59% (95% CI 55% to 64%), was significantly lower than FITs at the 10 μg Hb/g cut-off, 89% (95% CI 80% to 95%; P < 0.001) and the 20 μg Hb/g cut-off, 89% (95% CI 85% to 92%; P < 0.001). So, in the hypothetical cohort with 100 participants with CRC, gFOBTs missed 41, while FITs missed 11 (10 μg Hb/g) and 11 (20 μg Hb/g). The summary specificity of gFOBTs was 98% (95% CI 98% to 99%), which was higher than FITs at both 10 μg and 20 μg Hb/g cut-offs: 94% (95% CI 92% to 95%; P < 0.001) and 95% (95% CI 94% to 96%; P < 0.001), respectively. So, out of 9900 participants without CRC, 198 were offered (unnecessary) colonoscopy with gFOBTs compared to 594 (10 μg Hb/g) and 495 (20 μg Hb/g) with FITs. At a specificity of 90% and 95%, FITs had a higher sensitivity than gFOBTs. Authors' conclusions: FITs are superior to gFOBTs in detecting AN and CRC in average-risk individuals. Specificity of both tests was similar in "reference standard: all" studies, whereas specificity was significantly higher for gFOBTs than FITs in "reference standard: positive" studies. However, at pre-specified specificities, the sensitivity of FITs was significantly higher than gFOBTs.

Importance: The US Preventive Services Task Force (USPSTF) is updating its 2016 colorectal cancer screening recommendations. Objective: To provide updated model-based estimates of the benefits, burden, and harms of colorectal cancer screening strategies and to identify strategies that may provide an efficient balance of life-years gained (LYG) from screening and colonoscopy burden to inform the USPSTF. Design, Setting, and Participants: Comparative modeling study using 3 microsimulation models of colorectal cancer screening in a hypothetical cohort of 40-year-old US individuals at average risk of colorectal cancer. Exposures: Screening from ages 45, 50, or 55 years to ages 70, 75, 80, or 85 years with fecal immunochemical testing (FIT), multitarget stool DNA testing, flexible sigmoidoscopy alone or with FIT, computed tomography colonography, or colonoscopy. All persons with an abnormal noncolonoscopy screening test result were assumed to undergo follow-up colonoscopy. Screening intervals varied by test. Full adherence with all procedures was assumed. Main Outcome and Measures: Estimated LYG relative to no screening (benefit), lifetime number of colonoscopies (burden), number of complications from screening (harms), and balance of incremental burden and benefit (efficiency ratios). Efficient strategies were those estimated to require fewer additional colonoscopies per additional LYG relative to other strategies. Results: Estimated LYG from screening strategies ranged from 171 to 381 per 1000 40-year-olds. Lifetime colonoscopy burden ranged from 624 to 6817 per 1000 individuals, and screening complications ranged from 5 to 22 per 1000 individuals. Among the 49 strategies that were efficient options with all 3 models, 41 specified screening beginning at age 45. No single age to end screening was predominant among the efficient strategies, although the additional LYG from continuing screening after age 75 were generally small. With the exception of a 5-year interval for computed tomography colonography, no screening interval predominated among the efficient strategies for each modality. Among the strategies highlighted in the 2016 USPSTF recommendation, lowering the age to begin screening from 50 to 45 years was estimated to result in 22 to 27 additional LYG, 161 to 784 additional colonoscopies, and 0.1 to 2 additional complications per 1000 persons (ranges are across screening strategies, based on mean estimates across models). Assuming full adherence, screening outcomes and efficient strategies were similar by sex and race and across 3 scenarios for population risk of colorectal cancer. Conclusions and Relevance: This microsimulation modeling analysis suggests that screening for colorectal cancer with stool tests, endoscopic tests, or computed tomography colonography starting at age 45 years provides an efficient balance of colonoscopy burden and life-years gained.

Microsimulation models are often used to predict long-term outcomes and guide policy decisions regarding cancer screening. The United Kingdom Flexible Sigmoidoscopy Screening (UKFSS) Trial examines a one-time intervention of flexible sigmoidoscopy that was implemented before a colorectal cancer (CRC) screening program was established. Long-term study outcomes, now a full 17 years following randomization, have been published. We use the outcomes from this trial to validate three microsimulation models for CRC to long-term study outcomes. We find that two of three models accurately predict the relative effect of screening (the hazard ratios) on CRC-specific incidence 17 years after screening. We find that all three models yield predictions of the relative effect of screening on CRC incidence and mortality (i.e., the hazard ratios) that are reasonably close to the UKFSS results. Two of the three models accurately predict the relative reduction in CRC incidence 17-years after screening. One model accurately predicted absolute incidence and mortality rates in the screened group. The models differ in their estimates related to adenoma detection at screening. While high-quality screening results help to inform models, trials are expensive, last many years, and can be complicated by ethical issues and technological changes across the duration of the trial. Thus, well-calibrated and validated models are necessary to predict outcomes for which data are not available. The results from this validation demonstrate the utility of models in predicting long-term outcomes, and in collaborative modeling to account for uncertainty.

Several U.S. organizations now recommend starting average-risk colorectal cancer screening at age 45 years, but the prevalence of colonic neoplasia in individuals younger than 50 years has not been well characterized. We used a national endoscopic registry to calculate age-stratified prevalence and predictors of colorectal neoplasia.Outpatient screening colonoscopies performed during 2010-2020 in the GI Quality Improvement Consortium registry were analyzed. We measured the prevalence of advanced neoplasia and adenomas by age, sex, and race/ethnicity, as well as the prevalence ratio of neoplasia compared with the reference group of 50- to 54-year-olds. Multivariable logistic regression models were used to identify predictors of neoplasia.We identified 3,928,727 screening colonoscopies, of which 129,736 (3.3%) were performed on average-risk individuals younger than 50 years. The prevalence of advanced neoplasia was 6.2% for 50- to 54-year-olds and 5.0% (prevalence ratio, 0.81; 95% confidence interval, 0.78-0.83) for average-risk 45- to 49-year-olds. Men had higher prevalence of neoplasia than women for all age groups. White individuals had higher prevalence of advanced neoplasia than persons of other racial/ethnic groups in most age groups, which was partially driven by serrated lesions. On multivariable regression, White individuals had higher odds of advanced neoplasia than Black, Hispanic, and Asian individuals in both younger and older age groups.In a large U.S. endoscopy registry, the prevalence of advanced neoplasia in 45- to 49-year-olds was substantial and supports beginning screening at age 45 years. White individuals had higher risk of advanced neoplasia than Black, Hispanic, and Asian individuals across the age spectrum. These findings may inform adenoma detection benchmarks and risk-based screening strategies.

Introduction. Colorectal cancer (CRC) prevention programs using fecal immunochemical testing (FIT) in screening rely on colonoscopy for secondary and surveillance testing. Colonoscopy capacity is an important constraint. Some European programs lack sufficient capacity to provide optimal screening intensity regarding age ranges, intervals, and FIT cutoffs. It is currently unclear how to optimize programs within colonoscopy capacity constraints. Design. Microsimulation modeling, using the MISCAN-Colon model, was used to determine if more effective CRC screening programs can be identified within constrained colonoscopy capacity. A total of 525 strategies were modeled and compared, varying 3 key screening parameters: screening intervals, age ranges, and FIT cutoffs, including previously unevaluated 4- and 5-year screening intervals (using a lifetime horizon and 100% adherence). Results were compared with the policy decisions taken in Ireland to provide CRC screening within available colonoscopy capacity. Outcomes estimated net costs, quality-adjusted life-years (QALYs), and required colonoscopies. The optimal strategies within finite colonoscopy capacity constraints were identified. Results. Combining a reduced FIT cutoff of 10 µg Hb/g, an extended screening interval of 4 y and an age range of 60–72 y requires 6% fewer colonoscopies, reduces net costs by 23% while preventing 15% more CRC deaths and saving 16% more QALYs relative to a strategy (FIT 40 µg Hb/g, 2-yearly, 60–70 year) approximating current policy. Conclusion. Previously overlooked longer screening intervals may optimize cancer prevention with finite colonoscopy capacity constraints. Changes could save lives, reduce costs, and relieve colonoscopy capacity pressures. These findings are relevant to CRC screening programs across Europe that employ FIT-based testing, which face colonoscopy capacity constraints.

Background Although colorectal cancer screening has contributed to decreased incidence and mortality, disparities are present by race/ethnicity. The Citywide Colon Cancer Control Coalition (C5) and NYC Department of Health and Mental Hygiene (DOHMH) promoted screening colonoscopy from 2003 on, and hypothesized future reductions in CRC incidence, mortality and racial/ethnic disparities. Methods We assessed annual percent change (APC) in NYC CRC incidence, stage and mortality rates through 2016 in a longitudinal cross-sectional study of NY State Cancer Registry, NYC Vital Statistics, and NYC Community Health Survey (CHS) data. Linear regression tested associations between CRC mortality rates and risk factors. Results Overall CRC incidence rates from 2000 decreased 2.8% yearly from 54.1 to 37.3/100,000 population in 2016, and mortality rates from 2003 decreased 2.9% yearly from 21.0 to 13.9 in 2016 at similar rates for all racial/ethnic groups. Local stage disease decreased overall with a transient increase from 2002 to 2007. In 2016, CRC incidence was higher among Blacks (42.5 per 100,000) than Whites (38.0), Latinos (31.7) and Asians (30.0). In 2016, Blacks had higher mortality rates (17.9), than Whites (15.2), Latinos (10.4) and Asians (8.8). In 2016, colonoscopy rates among Blacks were 72.2%, Latinos 71.1%, Whites 67.2%, and Asians, 60.9%. CRC mortality rates varied by neighborhood and were independently associated with Black race, CRC risk factors and access to care. Conclusions In a diverse urban population, a citywide campaign to increase screening colonoscopy was associated with decreased incidence and mortality among all ethnic/racial groups. Higher CRC burden among the Black population demonstrate more interventions are needed to improve equity.

Objective To examine whether receiving a fecal occult blood test after a negative sigmoidoscopy reduced mortality from colorectal cancer. Methods We used a nested case–control design with incidence-density matching in historical cohorts of 1,877,740 50–90-year-old persons during 2006–2012, in an integrated health-system setting. We selected 1758 average risk patients who died from colorectal cancer and 3503 matched colorectal cancer-free persons. Colorectal cancer-specific death was ascertained from cancer and mortality registries. Screening histories were determined from electronic and chart–audit clinical data in the 5- to 10-year period prior to the reference date. We evaluated receipt of subsequent fecal occult blood test within five years of the reference date among patients with negative sigmoidoscopy two to six years before the reference date. Results Of the 5261 patients, 831 patients (204 colorectal cancer deaths/627 controls) had either negative sigmoidoscopy only ( n = 592) or negative sigmoidoscopy with subsequent screening fecal occult blood test ( n = 239). Fifty-six (27.5%) of the 204 patients dying of colorectal cancer and 183 (29.2%) of the 627 colorectal cancer-free patients received fecal occult blood test following a negative sigmoidoscopy. Conditional regressions found no significant association between fecal occult blood test receipt and colorectal cancer death risk, overall (adjusted odds ratio = 0.93, confidence interval: 0.65–1.33), or for right (odds ratio = 1.02, confidence interval: 0.65–1.60) or left-colon/rectum (odds ratio = 0.77, confidence interval: 0.39–1.52) cancers. Similar results were obtained in sensitivity analyses with alternative exposure ascertainment windows or timing of fecal occult blood test. Conclusions Our results suggest that receipt of at least one fecal occult blood test during the several years after a negative sigmoidoscopy did not substantially reduce mortality from colorectal cancer.

BACKGROUND: Screening colonoscopy (SC) for colorectal cancer (CRC) is underused by Latinos. This randomized-clinical trial examined the impact of three interventions: 1) patient navigation, 2) patient navigation plus standard CDC print materials, and 3) patient navigation plus culturally-targeted print materials for Latinos referred for SC. Demographic, personal/health history, and psychometric factors associated with SC were also explored. METHODS: Urban Latinos (N=344) ages 50 to 85 with no personal/immediate family history of CRC before age 60, no personal history of gastrointestinal disorder, no colonoscopy in the past five years, with insurance coverage, and a referral for SC were consented. Participants were randomized to patient navigation (20%), patient navigation plus standard CDC print materials (40%), and patient navigation plus culturally-targeted print materials (40%). Completion of SC was assessed at 12 months. RESULTS: The interventions had an overall SC rate of 82%. Counterintuitively, patients with an average income less than $10,000 had higher SC rates (87%) than those with greater income (75%). CONCLUSION: The addition of standard or culturally-targeted print materials did not increase SC rates above that of patient navigation. Indeed, after controlling for other variables, culturally-targeted print materials were associated with lower SC rates for Puerto Ricans. CONDENSED ABSTRACT: This randomized-clinical trial found that patient navigation led to high SC rates among Latinos. Adding print materials did not increase SC rates above that of patient navigation alone.

Background Cancer screening is a complex process encompassing risk assessment, the initial screening examination, diagnostic evaluation, and treatment of cancer precursors or early cancers. Metrics that enable comparisons across different screening targets are needed. We present population-based screening metrics for breast, cervical, and colorectal cancers for nine sites participating in the Population-based Research Optimizing Screening through Personalized Regimens consortium. Methods We describe how selected metrics map to a trans-organ conceptual model of the screening process. For each cancer type, we calculated calendar year 2013 metrics for the screen-eligible target population (breast: ages 40–74 years; cervical: ages 21–64 years; colorectal: ages 50–75 years). Metrics for screening participation, timely diagnostic evaluation, and diagnosed cancers in the screened and total populations are presented for the total eligible population and stratified by age group and cancer type. Results The overall screening-eligible populations in 2013 were 305 568 participants for breast, 3 160 128 for cervical, and 2 363 922 for colorectal cancer screening. Being up-to-date for testing was common for all three cancer types: breast (63.5%), cervical (84.6%), and colorectal (77.5%). The percentage of abnormal screens ranged from 10.7% for breast, 4.4% for cervical, and 4.5% for colorectal cancer screening. Abnormal breast screens were followed up diagnostically in almost all (96.8%) cases, and cervical and colorectal were similar (76.2% and 76.3%, respectively). Cancer rates per 1000 screens were 5.66, 0.17, and 1.46 for breast, cervical, and colorectal cancer, respectively. Conclusions Comprehensive assessment of metrics by the Population-based Research Optimizing Screening through Personalized Regimens consortium enabled systematic identification of screening process steps in need of improvement. We encourage widespread use of common metrics to allow interventions to be tested across cancer types and health-care settings.

Background Colorectal cancer (CRC) screening with colonoscopy and the fecal immunochemical test (FIT) is underused. Innovative tests could increase screening acceptance. This study determined which of the available alternatives is most promising from a cost-effectiveness perspective. Methods The previously validated Microsimulation Screening Analysis-Colon model was used to evaluate the cost-effectiveness of screening with capsule endoscopy every 5 or 10 years, computed tomographic colonography every 5 years, the multi-target stool DNA test every 1 or 3 years, and the methylated SEPT9 DNA plasma assay (mSEPT9) every 1 or 2 years. We also compared these strategies with annual FIT screening and colonoscopy screening every 10 years. Quality-adjusted life-years gained (QALYG), number of colonoscopies, and incremental cost-effectiveness ratios were projected. We assumed a willingness-to-pay threshold of $100 000 per QALYG. Results Among the alternative tests, computed tomographic colonography every 5 years, annual mSEPT9, and annual multi-target stool DNA screening had incremental cost-effectiveness ratios of $1092, $63 253, and $214 974 per QALYG, respectively. Other screening strategies were more costly and less effective than (a combination of) these 3. Under the assumption of perfect adherence, annual mSEPT9 screening resulted in more QALYG, CRC cases averted, and CRC deaths averted than annual FIT screening but led to a high rate of colonoscopy referral (51% after 3 years, 69% after 5 years). The alternative tests were not cost-effective compared with FIT and colonoscopy. Conclusions This study suggests that for individuals not willing to participate in FIT or colonoscopy screening, mSEPT9 is the test of choice if the high colonoscopy referral rate is acceptable to them.

IntroductionColorectal cancer (CRC) prevention programmes using faecal immunochemical testing (FIT) as the primary screen typically rely on colonoscopy for secondary and surveillance testing. Colonoscopy capacity is an important constraint, limiting the number of primary tests offered. Many European programmes lack sufficient colonoscopy capacity to provide optimal screening intensity regarding screening age ranges, intervals and FIT cut-offs. It is currently unclear how to optimise programmes within colonoscopy capacity constraints.DesignThe MISCAN-Colon microsimulation model was used to determine if more effective CRC screening programmes can be identified within existing colonoscopy capacity. The model assessed 525 strategies of varying screening intervals, age ranges and FIT cut-offs, including previously unevaluated 4 and 5 year screening intervals. These strategies were compared with policy decisions taken in Ireland to provide CRC screening within available colonoscopy capacity. Outcomes estimated net costs, quality-adjusted-life-years and required colonoscopy numbers. The optimal strategies within finite colonoscopy capacity constraints were identified.ResultsCombining a reduced FIT cut-off of 10 µg Hb/g, an extended screening interval of 4 years and an age range of 60-72 years requires 6% fewer colonoscopies, reduces net costs by 23% while preventing 15% more CRC deaths and saving 16% more QALYs relative to current policy.ConclusionPreviously overlooked longer screening intervals may balance optimal cancer prevention with finite colonoscopy capacity constraints. Simple changes to screening configurations could save lives, reduce costs, and relieve colonoscopy capacity pressures. These findings are directly relevant to CRC screening programmes across Europe that employ FIT-based testing and face colonoscopy capacity constraints.