Contributions of early detection and cancer prevention to colorectal cancer mortality reduction by screening colonoscopy: a validated modelling study.

BACKGROUND AND AIMS: Screening colonoscopy, recommended every ten years, reduces mortality from colorectal cancer (CRC) by early detection of prevalent but undiagnosed CRC, as well as by prevention of CRC by removal of precursor lesions. The aim of this study was to assess the relative contribution of both components to total CRC mortality reduction over time. METHODS: Using a validated multistate Markov model, we simulated hypothetical cohorts of 100,000 individuals aged 55-64 with and without use of screening at baseline. Main outcomes included proportions of prevented CRC deaths arising from (asymptomatic) CRC already prevalent at baseline and from newly developed CRC during 15-years of follow-up, and mortality rate ratios of screened versus unscreened groups over time. RESULTS: Early detection of prevalent cases accounted for 52%, 30% and 18% of deaths prevented by screening colonoscopy within 5, 10 and 15 years, respectively. Relative reduction of mortality was estimated to be much larger for mortality from incident cancers than for mortality from cancers that were already present and early detected at screening endoscopy and for total CRC mortality (i.e., 88% versus 67% and 79% within 10 years from screening). CONCLUSIONS: Reduction of CRC mortality mainly arises from early detection of prevalent cancers during the early years after screening colonoscopy, but prevention of incident cases accounts for the majority of prevented deaths in the longer run. Prevention of incident cases leads to sustained strong reduction of colorectal cancer mortality, possibly warranting an extension of screening intervals.

The underestimated preventive effects of flexible sigmoidoscopy screening: re-analysis and meta-analysis of randomized trials.

Flexible sigmoidoscopy (FS), which is less invasive, resource intensive and costly than colonoscopy, is among the recommended screening options for colorectal cancer (CRC). Four large randomized trials consistently reported statistically significant, albeit modest effects of screening by FS on CRC incidence. However, their effect estimates included cancers that were already prevalent at recruitment and could not have been prevented by screening. We performed a re-analysis and meta-analysis of two of the trials (including the largest one) to estimate reduction of truly incident cases by a single FS offered between 55 and 64 years of age among the "at risk study population" without prevalent CRC at recruitment. In meta-analyses of data reported after more than 15 years of follow-up, relative risk (95% CI) in intention-to-screen and per-protocol analyses were 0.71 (0.66-0.76) and 0.59 (0.55-0.65) for any CRC, and 0.52 (0.47-0.57) and 0.34 (0.30-0.39) for distal CRC, respectively. These results indicate much stronger effects than those suggested by the original reports and imply that a single screening FS can prevent approximately two out of three distal incident CRC cases within 15 + years of follow-up.

Overall and age-specific risk advancement periods of colorectal cancer for men vs women: Implications for gender-sensitive screening offers?

Colorectal cancer (CRC) incidence and mortality are higher among men than among women. We aimed to estimate overall and age-specific risk advancement periods (RAPs) for men compared to women, which quantify how many years earlier comparable levels of risk are reached by men. RAPs were derived by Cox regression models among 331 224 participants aged 40 to 69 at baseline of the UK Biobank with no previous diagnosis of CRC and no previous CRC screening examination who were followed with respect to CRC incidence for up to 13 years. Men were at substantially higher risk of CRC than women in age groups 50 to 59 and 60 to 69, with RAPs (95% confidence intervals) as high as 8.7 (4.5-13.0) and 6.2 (4.5-7.9), respectively. These RAPs were higher than those for family history of CRC in these age groups. By contrast, no significant sex difference but a major impact of family history was seen in age group 40 to 49 (P-value for interaction between sex and age = .00079). The observed patterns suggest that consideration of gender-specific starting ages of screening might be warranted in countries in which screening offers start at ages above 50 years.

Making colonoscopy-based screening more efficient: A "gateopener" approach.

Screening colonoscopy for early detection and prevention of colorectal cancer (CRC) is mostly used inefficiently. Here, we assessed the potential of an innovative approach to colonoscopy-based screening, by use of a single, low threshold fecal immunochemical test (FIT) as a "gateopener" for screening colonoscopy. Using COSIMO, a validated simulation model, we modeled scenarios including either direct invitation to screening colonoscopy or an alternative approach involving mailing a single ("gateopener") FIT along with an invitation to colonoscopy contingent on a FIT value above a low threshold yielding a 50% positivity rate (ie, every other pretest will be positive). Under plausible assumptions on screening offer adherence, we found that such "gateopener screening" (use of screening colonoscopy contingent on a positive, low threshold gateopener FIT) approximately doubled cancer detection rates vs conventional screening. In those spared from screening colonoscopy due to a negative gateopener FIT pretest, numbers needed to screen were 10-times higher vs those for individuals with a positive FIT, peaking in >2000 and >3800 (hypothetically) needed colonoscopies to detect one case of cancer in men and women, respectively. Gateopener screening resulted in 42%-51% and 59%-65% more prevented CRC cases and deaths, respectively. In summary, by directing colonoscopy capacities to those most likely to benefit, offering screening colonoscopy contingent on a "gateopener" low-threshold FIT would substantially enhance efficiency of colonoscopy screening.

When gold standards are not so golden: prevalence bias in randomized trials on endoscopic colorectal cancer screening.

Randomized trials on the effectiveness of screening endoscopy in reducing colorectal cancer (CRC) risk have reported statistically significant, but rather modest reduction of CRC risk by the screening offer. However, risk estimates in these trials included substantial proportions of prevalent CRC cases which were early detected, but could not possibly have been prevented by screening. Thereby, a key principle of randomized prevention trials is violated that only "at risk" persons who do not yet have the disease one aims to prevent should be included in measures of preventive effects. Using recently published data from the Nordic-European Initiative on Colorectal Cancer (NordICC) trial as an example, we illustrate that approaches aimed to account for "prevalence bias" lead to effect estimates that are substantially larger than those reported in the trial and more in line with results from observational studies and real life settings. More rigorous methodological work is needed to develop effective and user-friendly tools to prevent or adjust for prevalence bias in future screening studies.

Model based evaluation of long-term efficacy of existing and alternative colorectal cancer screening offers: A case study for Germany.

For individuals willing to minimize their lifetime risk of colorectal cancer (CRC), the most effective screening approach remains unclear. Here, we sought to compare the long-term performance of existing and alternative CRC screening offers in a case study for Germany. Applying the perspective of a perfectly adhering man or woman at average risk, we used COSIMO, a validated Markov-based multistate model, to simulate the effects of current CRC screening offers in Germany. These include age- and sex-dependent offers for fecal immunochemical testing (FIT) or screening colonoscopy, which may be used twice starting at age 50 in men and age 55 in women. For comparison, we modeled screening colonoscopies at ages 50, 60 and 70, screening colonoscopies at ages 50 and 60, followed by biennial FITs and conventional FIT-based strategies at varying intervals. We found that the highest reductions in lifetime risks of developing (76%-84%) and dying from CRC (82%-90%) were achieved by three colonoscopies, followed by annual FIT screening and strategies combining both modalities. In men, additional screening from age 70 onwards reduced the risk of dying from CRC by another 9% units and resulted in 32 to 39 additional life-years-gained per 1000 individuals. Among women, three colonoscopies outperformed current screening offers in all outcomes, at little risk of screening-related complications. In summary, several FIT- and colonoscopy-based offers yield comparably high CRC risk reductions, including approaches combining both modalities. German screening offers may be optimized by lowering the eligibility age for screening colonoscopy for women, along with additional offers for the elderly.

Colorectal cancer incidence, mortality, and stage distribution in European countries in the colorectal cancer screening era: an international population-based study.

BACKGROUND: Colorectal cancer screening programmes and uptake vary substantially across Europe. We aimed to compare changes over time in colorectal cancer incidence, mortality, and stage distribution in relation to colorectal cancer screening implementation in European countries. METHODS: Data from nearly 3·1 million patients with colorectal cancer diagnosed from 2000 onwards (up to 2016 for most countries) were obtained from 21 European countries, and were used to analyse changes over time in age-standardised colorectal cancer incidence and stage distribution. The WHO mortality database was used to analyse changes over time in age-standardised colorectal cancer mortality over the same period for the 16 countries with nationwide data. Incidence rates were calculated for all sites of the colon and rectum combined, as well as the subsites proximal colon, distal colon, and rectum. Average annual percentage changes (AAPCs) in incidence and mortality were estimated and relevant patterns were descriptively analysed. FINDINGS: In countries with long-standing programmes of screening colonoscopy and faecal tests (ie, Austria, the Czech Republic, and Germany), colorectal cancer incidence decreased substantially over time, with AAPCs ranging from -2·5% (95% CI -2·8 to -2·2) to -1·6% (-2·0 to -1·2) in men and from -2·4% (-2·7 to -2·1) to -1·3% (-1·7 to -0·9) in women. In countries where screening programmes were implemented during the study period, age-standardised colorectal cancer incidence either remained stable or increased up to the year screening was implemented. AAPCs for these countries ranged from -0·2% (95% CI -1·4 to 1·0) to 1·5% (1·1 to 1·8) in men and from -0·5% (-1·7 to 0·6) to 1·2% (0·8 to 1·5) in women. Where high screening coverage and uptake were rapidly achieved (ie, Denmark, the Netherlands, and Slovenia), age-standardised incidence rates initially increased but then subsequently decreased. Conversely, colorectal cancer incidence increased in most countries where no large-scale screening programmes were available (eg, Bulgaria, Estonia, Norway, and Ukraine), with AAPCs ranging from 0·3% (95% CI 0·1 to 0·5) to 1·9% (1·2 to 2·6) in men and from 0·6% (0·4 to 0·8) to 1·1% (0·8 to 1·4) in women. The largest decreases in colorectal cancer mortality were seen in countries with long-standing screening programmes. INTERPRETATION: We observed divergent trends in colorectal cancer incidence, mortality, and stage distribution across European countries, which appear to be largely explained by different levels of colorectal cancer screening implementation. FUNDING: German Cancer Aid (Deutsche Krebshilfe) and the German Federal Ministry of Education and Research.

Effects of screening for colorectal cancer: Development, documentation and validation of a multistate Markov model.

Simulation models are a powerful tool to overcome gaps of evidence needed to inform medical decision-making. Here, we present development and application of COSIMO, a Markov-based Colorectal Cancer (CRC) Multi-state Simulation Model to simulate effects of CRC screening, along with a thorough assessment of the model's ability to reproduce real-life outcomes. Firstly, we provide a comprehensive documentation of COSIMO's development, structure and assumptions. Secondly, to assess the model's external validity, we compared model-derived cumulative incidence and prevalences of colorectal neoplasms to (a) results from KolosSal, a study in German screening colonoscopy participants, (b) registry-based estimates of CRC incidence in Germany, and (c) outcome patterns of randomized sigmoidoscopy screening studies. We found that (a) more than 90% of observed prevalences in the KolosSal study were within the 95% confidence intervals of the model-predicted neoplasm prevalences; (b) the 15-year cumulative CRC incidences estimated by simulations for the German population deviated by 0.0% to 0.2% units in men and 0.0% to 0.3% units in women when compared to corresponding registry-derived estimates; and (c) the time course of cumulative CRC incidence and mortality in the modeled intervention group and control group closely resembles the time course reported from sigmoidoscopy screening trials. Overall, COSIMO adequately predicted colorectal neoplasm prevalences and incidences in a German population for up to 25 years, with estimated patterns of the effect of screening colonoscopy resembling those seen in registry data and real-world studies. This suggests that the model may represent a valid tool to assess the comparative effectiveness of CRC screening strategies.

To what extent is male excess risk of advanced colorectal neoplasms explained by known risk factors? Results from a large German screening population.

Colorectal cancer (CRC) incidence and prevalence of its precursors are substantially higher among males than among females in most countries but the reasons for the male excess risk are incompletely understood. We aimed to assess to what extent it is explained by known risk factors. Prevalence of advanced neoplasia (AN, ie, CRC or advanced adenoma) and CRC risk and preventive factors were ascertained among 15 985 participants of screening colonoscopy aged 55-79 years in Germany. Logistic regression was used to calculate odds ratios (ORs) for the association between male sex and AN with and without adjustment for known risk and preventive factors. In age-adjusted comparisons, men had 2-fold increased risk for AN compared to women (OR = 1.98, 95% confidence interval [CI] 1.79-2.19). After comprehensive adjustment for medical, lifestyle and dietary factors, the OR was reduced to 1.52 (95% CI 1.30-1.77), suggesting that these factors accounted for 47% of male excess risk. Male excess risk increased from proximal colon to distal colon and rectum, with age-adjusted ORs (95% CI) of 1.63 (1.38-1.91), 2.13 (1.85-2.45) and 2.36 (1.95-2.85), respectively, and with the proportion of excess risk explained by covariates being lower for AN in the rectum (26%) than for AN in the proximal (52%) or distal colon (46%). Male excess risk was somewhat lower (age-adjusted OR 1.87) and explained excess risk was smaller (36%) when men were compared to women who never used hormone replacement therapy. In conclusion, most of the male excess risk and the potential to overcome it remain to be explored by further research.

Age-specific sequence of colorectal cancer screening options in Germany: A model-based critical evaluation.

BACKGROUND: The current organized screening program for colorectal cancer in Germany offers both sexes 5 annual fecal immunochemical tests (FITs) between ages 50 and 54 years, followed by a first screening colonoscopy at age 55 years if all of these FITs were negative. We sought to assess the implications of this approach for key parameters of diagnostic performance. METHODS AND FINDINGS: Using a multistate Markov model, we estimated the expected detection rates of advanced neoplasms (advanced adenomas and cancers) and number needed to scope (NNS) to detect 1 advanced neoplasm at a first screening colonoscopy conducted at age 55 after 5 preceding negative FITs and compared them with the corresponding estimates for a first screening colonoscopy at age 55 with no preceding FIT testing. In individuals with 5 consecutive negative FITs undergoing screening colonoscopy at age 55, expected colonoscopy detection rate (NNS) was 3.7% (27) and 0.10% (1,021) for any advanced neoplasm and cancer, respectively, in men, and 2.1% (47) and 0.05% (1,880) for any advanced neoplasm and cancer, respectively, in women. These NNS values for detecting 1 advanced neoplasm are approximately 3-fold higher, and the NNS values for detecting 1 cancer are approximately 8-fold higher, than those for a first screening colonoscopy at age 55 without prior FITs. This study is limited by model simplifying assumptions and uncertainties related to input parameters. CONCLUSIONS: Screening colonoscopy at age 55 after 5 consecutive negative FITs at ages 50-54, as currently offered in the German cancer early detection program, is expected to have very low positive predictive value. Our results may inform efforts to enhance the design of screening programs.

Use of Polygenic Risk Scores to Select Screening Intervals After Negative Findings From Colonoscopy.

BACKGROUND & AIMS: Polygenic risk scores (PRSs) could help to define starting ages for colorectal cancer (CRC) screening. However, the role of PRS in determining the length of screening interval after negative findings from colonoscopies is unclear. We aimed to evaluate CRC risk according to PRS and time since last negative colonoscopy. METHODS: We collected data from 3827 cases and 2641 CRC-free controls in a population-based case-control study in Germany. We constructed a polygenic risk scoring system, based on 90 single-nucleotide polymorphisms, associated with risk of CRC in people of European descent. Participants were classified as having low, medium, or high genetic risk according to tertiles of PRSs among controls. Multiple logistic regression models were used to assess CRC risk according to PRS and time since last negative colonoscopy. RESULTS: Compared to individuals without colonoscopy in the low PRS category, a 42%-85% lower risk of CRC was observed for individuals who had a negative finding from colonoscopy within 10 years. Beyond 10 years after a negative finding from colonoscopy, significantly lower risk only persisted for the low and medium PRS groups, but not for the high PRS group. Adjusted odds ratios were 0.44 (95% CI, 0.29-0.68), 0.51 (95% CI, 0.34-0.77), and 0.85 (95% CI, 0.58-1.23) in the low, medium, and high PRS group, respectively. Within any time interval, risks were lower for distal than for proximal CRCs. CONCLUSIONS: Based on findings from a population-based case-control study, the recommended 10-year screening interval for colonoscopy may not need to be shortened among people with high PRSs, but could potentially be prolonged for people with low and medium PRSs. Studies are needed to address personalized time intervals for repeat colonoscopies in average-risk screening cohorts.

Reduction in colorectal cancer incidence by screening endoscopy.

Colorectal cancer (CRC) incidence rates decreased by up to 50% in older age groups in the USA in the era of the widespread uptake of screening colonoscopy, despite adverse trends in CRC risk factors and increasing CRC incidence at younger ages. However, reported first results from a randomized trial, the NordICC study, suggested rather modest effects of screening colonoscopy. As outlined in this Perspective, the apparent discrepancy between real-world and trial evidence could be explained by strong attenuation of effect estimates from screening endoscopy trials by several factors, including limited screening adherence, widespread uptake of colonoscopy outside the screening offers and the inclusion of prevalent, non-preventable CRC cases in reported numbers of incident cases. Alternative interpretations of screening endoscopy trial results accounting for prevalence bias are in line with trends in CRC incidence reduction in countries offering CRC screening, and should encourage more widespread implementation and uptake of effective CRC screening.

Colorectal cancer: A health and economic problem.

Colorectal Cancer (CRC) is the third most commonly diagnosed form of cancer and accounts for approximately 1.9 million cancer cases each year (10% of all new cancer cases globally). Incidence strongly increases with age and has been traditionally highest in Western, affluent countries, but it is rapidly increasing in many less developed countries and in younger generations in both developed and developing countries. With demographic aging, CRC will pose a rapidly increasing challenge for many societies, which underlines the need for major efforts on primary and secondary prevention. A number of effective screening options are available, and implementation of well-organized screening programs could have a major impact on lowering the future burden of the disease.

Prevalence of Colorectal Neoplasia 10 or More Years After a Negative Screening Colonoscopy in 120 000 Repeated Screening Colonoscopies.

Importance: Screening colonoscopy to prevent and early detect colorectal cancer is recommended to be repeated in 10-year intervals, which goes along with high demands of capacities and costs. Evidence of findings at screening colonoscopies conducted 10 or more years after a negative colonoscopy result is sparse, and it remains unclear whether screening colonoscopy intervals could possibly be prolonged. Objective: To assess the prevalence of advanced colorectal neoplasms (ADNs) at least 10 years after a negative screening colonoscopy in a very large cohort of repeated screening colonoscopy participants in Germany. Design, Setting, and Participants: This registry-based cross-sectional study on screening colonoscopy findings reported to the German screening colonoscopy registry during January 2013 to December 2019 included data on screening colonoscopies that were offered to the German general population 55 years or older since 2002; virtually all screening colonoscopies among individuals covered by Statutory Health Insurance (approximately 90% of eligible adults) are reported to the national registry. A total of 120 298 repeat screening colonoscopy participants 65 years or older were identified who had a previous negative screening colonoscopy at least 10 years prior. The findings were compared with all screening colonoscopies conducted at 65 years or older during the same period (1.25 million). The data were analyzed from March to July 2022. Main Outcomes and Measures: Prevalence of colorectal cancers and ADNs (advanced adenomas and cancers). Results: Of 120 298 participants, 72 349 (60.1%) were women. Prevalence of ADN was 3.6% and 5.2% among women and men 10 years after a negative screening colonoscopy and gradually increased to 4.9% and 6.6%, respectively, among those who had a negative colonoscopy 14 years or longer prior compared with 7.1% and 11.6% among all screening colonoscopies. Sex-specific and age-specific prevalence of ADNs at repeated colonoscopies conducted 10 or more years after a negative colonoscopy were consistently at least 40% lower among women than among men, lower at younger vs older ages, and much lower than among all screening colonoscopies (standardized prevalence ratios for cancers: 0.22-0.38 among women, 0.15-0.24 among men; standardized prevalence ratios for ADNs: 0.49-0.62 among women, 0.50-0.56 among men). Conclusions and Relevance: The results of this cross-sectional study suggest that ADN prevalence at screening colonoscopies conducted 10 or more years after a negative screening colonoscopy is low. Extension of the currently recommended 10-year screening intervals may be warranted, especially for female and younger participants without gastrointestinal symptoms.