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.

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.

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.

Personalized Initial Screening Age for Colorectal Cancer in Individuals at Average Risk.

Importance: Colorectal cancer (CRC) risk varies widely in the population at average risk without a family history, but there are no established routines for translating this variation into personalized starting ages of screening. Objective: To illustrate derivation of risk-adapted starting ages of CRC screening based on the concept of risk advancement period (RAP) using sex and a polygenic risk score (PRS) as an example. Design, Setting, and Participants: This cohort study included participants in the UK Biobank study recruited in England, Wales, and Scotland between March 13, 2006, and October 1, 2010. Participants were aged 40 to 69 years, with no previous bowel cancer screening and no family history of CRC. Follow-up of cancer data was completed February 29, 2020, for England and Wales and January 31, 2021, for Scotland. The censoring date for death data was September 30, 2021, for England and Wales and October 31, 2021, for Scotland. Exposures: Data on age, sex, and family history were collected at the baseline interview. A PRS was calculated based on 139 CRC-related risk loci. Main Outcomes and Measures: Hazard ratios (HRs) of sex and PRS with CRC risk and mortality were estimated using Cox proportional hazards regression models and were translated to RAPs to quantify how many years of age earlier or later men and individuals in higher or lower PRS deciles would reach risks comparable with those of the reference group (ie, women or those in the 5th and 6th PRS deciles). Results: Among 242 779 participants (median age, 55 [IQR, 48-61] years; 55.7% women), 2714 incident CRC cases were identified during a median follow-up of 11.2 (IQR, 10.5-11.8) years and 758 deaths during a median follow-up of 12.8 (IQR, 12.0-13.4) years. The HRs of CRC risk were 1.57 (95% CI, 1.46-1.70) for men vs women and ranged from 0.51 (95% CI, 0.41-0.62) to 2.29 (95% CI, 2.01-2.62) across PRS deciles compared with the reference. The RAPs were 5.6 (95% CI, 4.6-6.6) years for men vs women and ranged from -8.4 (95% CI, -11.0 to -5.9) to 10.3 (95% CI, 8.5-12.1) years across PRS deciles compared with the reference deciles. Risk-adapted starting ages of screening would vary by 24 years between men in the highest PRS decile and women in the lowest PRS decile. Similar results were obtained regarding CRC mortality. Conclusions and Relevance: In this large cohort study including women and men at average risk of CRC, risk-adapted starting ages of screening strongly varied by sex and a PRS. The RAP concept could easily accommodate additional factors for defining personalized starting ages of 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.

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.

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.

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.

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.

Treatment Costs of Colorectal Cancer by Sex and Age: Population-Based Study on Health Insurance Data from Germany.

Objective: Evidence on the cost-effectiveness of screening for colorectal cancer (CRC) in the German general population remains scarce as key input parameters, the costs to treat CRC, are largely unknown. Here, we provide detailed estimates on CRC treatment costs over time. Methods: Using insurance claims data from the Vilua healthcare research database, we included subjects with newly diagnosed CRC and subjects who died of CRC between 2012 and 2016. We assessed annualized CRC-related inpatient, outpatient and medication costs for up to five years after first diagnosis and prior to death, stratified by sex and age. Findings: We identified 1748 and 1117 subjects with follow-up data for at least 1 year after diagnosis and prior to death, respectively. In those newly diagnosed, average costs were highest in the first year after diagnosis (men, EUR 16,375−16,450; women, EUR 10,071−13,250) and dropped steeply in the following years, with no consistent pattern of differences with respect to age. Costs prior to death were substantially higher as compared to the initial phase of care and consistently on a high level even several years before death, peaking in the final year of life, with strong differences by sex and age (men vs. women, <70 years, EUR 34,351 vs. EUR 31,417; ≥70 years, EUR 14,463 vs. EUR 9930). Conclusion: Once clinically manifest, CRC causes substantial treatment costs over time, particularly in the palliative care setting. Strong differences in treatment costs by sex and age warrant further investigation.

Impact of demographic changes and screening colonoscopy on long-term projection of incident colorectal cancer cases in Germany: A modelling study.

Background: Demographic aging is expected to increase the number of colorectal cancer (CRC) cases in many countries. Screening for CRC can substantially reduce the disease burden but its use has remained rather limited in Germany. We aimed to quantify the expected impact of demographic aging on the future CRC burden and the potential to reduce that burden by increased use of screening colonoscopy offers in Germany. Methods: We obtained sex- and age-specific data on colonoscopy use from AOK, the biggest health insurance provider in Germany, and combined these with the projected demographic development and current CRC incidence rates. We estimated the number of new CRC cases until 2060, assuming screening colonoscopy use to be constant or to increase to between 1·5 and 3 times the current levels. Findings: Ten-year screening colonoscopy utilization rates were low (<20% in both sexes in all age groups). Assuming no change in screening colonoscopy use, the overall annual caseload was predicted to increase from approximately 62,000 cases in 2020 to more than 70,000 cases by the year 2040 and more than 75,000 cases by 2050. To avoid increasing case numbers, an increase of screening colonoscopy use to more than 3 times current levels would be needed. Interpretation: At current levels of screening use, the strong effects of the demographic aging imply that the CRC caseload will significantly increase in the decades to come. CRC screening efforts will need to be substantially increased to even maintain the current level of incident cases. Funding: German Federal Ministry of Education and Research (grant 01GL1712).