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Objectives: To facilitate informed decision making on participating in colorectal cancer (CRC) screening, we assessed the benefit-harm balance of CRC screening for a wide range of subgroups over different time horizons., Methods: The study combined incidence proportions of benefits and harms of (not) participating in CRC screening estimated by the Adenoma and Serrated pathway to CAncer microsimulation model, a preference eliciting survey, and benefit-harm balance modeling combining all outcomes to determine the net health benefit of CRC screening over 10, 20, and 30 years. Probability of net health benefit was estimated for 210 different subgroups based on age, sex, previous participation in CRC screening, and lifestyle., Results: CRC screening was net beneficial in 183 of 210 subgroups over 30 years (median probability [MP] of 0.79, interquartile range [IQR] of 0.69-0.85) across subgroups. Net health benefit was greater for men (MP 0.82; IQR 0.69-0.89) than women (MP 0.76; IQR 0.67-0.83) and for those without history of participation in previous screenings (MP 0.84; IQR 0.80-0.89) compared with those with (MP 0.69; IQR 0.59-0.75). Net health benefit decreased with increasing age, from MP of 0.84 (IQR 0.80-0.86) at age 55 to 0.61 (IQR 0.56-0.71) at age 75. Shorter time horizons led to lower benefit, with MP of 0.70 (IQR 0.62-0.80) over 20 years and 0.54 (IQR 0.48-0.67) over 10 years., Conclusions: Our benefit-harm analysis provides information about net health benefit of screening participation, based on important characteristics and preferences of individuals, which could assist screening invitees in making informed decisions on screening participation., Competing Interests: Author Disclosures Links to the individual disclosure forms provided by the authors are available here., (Copyright © 2024. Published by Elsevier Inc.)

Background: The faecal immunochemical test (FIT) is widely employed for colorectal cancer screening. However, its sensitivity for advanced precursor lesions remains suboptimal. The multitarget FIT (mtFIT), measuring haemoglobin, calprotectin, and serpin family F member 2, has demonstrated enhanced sensitivity for advanced neoplasia, especially advanced adenomas, at equal specificity to FIT. This study aimed to prospectively validate and investigate the clinical utlitity of mtFIT versus FIT in a setting of population-based colorectal cancer screening., Methods: Individuals aged 55-75 years and who were eligible for the Dutch national FIT-based colorectal cancer screening programme were invited to submit both a FIT and mtFIT sample collected from the same bowel movement. Positive FIT (47 μg/g haemoglobin cutoff) or mtFIT (based on decision-tree algorithm) led to a colonoscopy referral. The primary outcome was the relative detection rate of mtFIT versus FIT for all advanced neoplasia. Secondary outcomes were the relative detection rates of colorectal cancer, advanced adenoma, and advanced serrated polyps individually and the long-term effect of mtFIT-based versus FIT-based programmatic screening on colorectal cancer incidence, mortality, and cost, determined with microsimulation modelling. The study has been registered in ClinicalTrials.gov, NCT05314309, and is complete., Findings: Between March 25 and Dec 7, 2022, 35 786 individuals were invited to participate in the study, of whom 15 283 (42·7%) consented, and 13 187 (86·3%) of 15 283 provided both mtFIT and FIT samples with valid results. Of the 13 187 participants, 6637 (50·3%) were male and 6550 (49·7%) were female. mtFIT showed a 9·11% (95% CI 8·62-9·61) positivity rate and 2·27% (95% CI 2·02-2·54) detection rate for advanced neoplasia, compared with a positivity rate of 4·08% (3·75-4·43) and a detection rate of 1·21% (1·03-1·41) for FIT. Detection rates of mtFIT versus FIT were 0·20% (95% CI 0·13-0·29) versus 0·17% (0·11-0·27) for colorectal cancer; 1·64% (1·43-1·87) versus 0·86% (0·72-1·04) for advanced adenoma, and 0·43% (0·33-0·56) versus 0·17% (0·11-0·26) for advanced serrated polyps. Modelling demonstrated that mtFIT-based screening could reduce colorectal cancer incidence by 21% and associated mortality by 18% compared with the current Dutch colorectal cancer screening programme, at feasible costs. Furthermore, at equal positivity rates, mtFIT outperformed FIT in terms of diagnostic yield. At an equally low positivity rate, mtFIT-based screening was predicted to further decrease colorectal cancer incidence by 5% and associated mortality by 4% compared with FIT-based screening., Interpretation: The higher detection rate of mtFIT for advanced adenoma compared with FIT holds the potential to translate into additional and clinically meaningful long-term colorectal cancer incidence and associated mortality reductions in programmatic colorectal cancer screening., Funding: Stand Up to Cancer, Dutch Cancer Society, Dutch Digestive Foundation, and Health~Holland., Competing Interests: Declaration of interests GAM is co-founder, stockholder, and board member (Chief Scientific Officer) of CRCbioscreen BV, he has a research collaboration with CZ Health Insurances (cash contribution to ZonMW grant) and has research collaborations with Exact Sciences, Sysmex, Sentinel Ch. SpA, Personal Genome Diagnostics (PGDX), DELFi Diagnostics, and Hartwig Medical Foundation; these companies provide materials and equipment for genomic analyses. PHAW has received honorarium for consultancy from the National Institute for Public Health and the Environment. MdW is co-founder, stockholder, and board member (Chief Operations Officer) of CRCbioscreen BV. BC, MdW, VMHC, and GM have several patents pending or issued related to the work herein. MCWS has received research support from Medtronic, Boston Scientific, Sentinel, and Sysmex. ED has endoscopic equipment on loan from FujiFilm and has received a research grant from FujiFilm. ED has also received honoraria for consultancy from FujiFilm, Olympus, InterVenn, and Ambu, and speakers' fees from Olympus, GI Supply, Norgine, IPSEN, PAION, and FujiFilm. ED is also Chair CRC Screening Committee of World Endoscopy Organisation, Chair Dutch Post-polypectomy surveillance guideline committee, and Member of Post-polypectomy surveillance guideline committee of European Gastrointestinal Endoscopy. WdK received consulting fees as member of the Dutch Post-polypectomy surveillance guideline committee of European Gastrointestinal Endoscopy. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Real-world data are necessitated to counsel patients about the risk for recurrent disease after curative treatment of colorectal cancer. This study provided a population-based overview of the epidemiology of recurrent disease in patients with surgically resected stage II/III colorectal cancer.Patients diagnosed with stage II/III primary colorectal cancer between July and December 2015 were selected from the Netherlands Cancer Registry (N = 3,762). Cumulative incidence of recurrent disease was estimated, and multivariable competing risk regression was used to identify risk factors for recurrent disease in patients with primary colon and rectal cancer. Moreover, overall survival (OS) after diagnosis of recurrent colorectal cancer was estimated.Median clinical follow-up was 58 months (Q1-Q3: 22-62). Five-year cumulative incidence of recurrent disease was 21.6% [95% confidence interval (CI): 20.0-23.2] and 30.0% (95% CI: 28.3-33.5) for patients with primary colon and rectal cancer, respectively. Stage III disease and incomplete resection margin in patients with primary colon cancer and extramural vascular invasion in patients with primary rectal cancer were strongly (HR ≥ 2) associated with recurrent disease. Median OS of patients with distant, locoregional, or the synchronous combination of distant and locoregional recurrent disease was 29, 27, and 13 months, respectively (P < 0.001). Patients with distant recurrences limited to liver or lung showed a median OS of 46 and 48 months, respectively. The incidence of recurrent disease was higher in patients with rectal cancer than in patients with colon cancer, predominantly due to higher rates of distant recurrences. OS after recurrent disease was impaired, but subgroups of patients diagnosed with recurrent disease limited to one site showed statistically significantly longer OS., Significance: Population-based data on recurrent colorectal cancer are rare, but crucial for counseling patients and their physicians. This large nationwide, population-based study provides an up-to-date overview of the epidemiology of recurrent disease in patients with stage II and III primary colon and rectal cancer treated with surgical resection., (© 2024 The Authors; Published by the American Association for Cancer Research.)

Current morphologic features defining advanced adenomas (size ≥10 mm, high-grade dysplasia or ≥25% villous component) cannot optimally distinguish individuals at high risk or low risk of metachronous colorectal cancer (me-CRC), which may result in suboptimal surveillance. Certain DNA copy-number alterations (CNAs) are associated with adenoma-to-carcinoma progression. We aimed to evaluate whether these molecular features can better predict an individual's risk of me-CRC than the morphologic advanced adenoma features.In this nested case-control study, 529 individuals with a single adenoma at first colonoscopy were selected from a Norwegian adenoma cohort. DNA copy-number profiles were determined, by low-coverage whole-genome sequencing. Prevalence of CNAs in advanced and non-advanced adenomas and its association (OR) with me-CRC was assessed. For the latter, cases (with me-CRC) were matched to controls (without me-CRC) on follow-up, age and sex.CNAs associated with adenoma-to-carcinoma progression were observed in 85/267 (32%) of advanced adenomas and in 27/262 (10%) of non-advanced adenomas. me-CRC was statistically significantly associated, also after adjustment for other variables, with age at baseline [OR, 1.14; 95% confidence interval CI), 1.03-1.26; P = 0.012], advanced adenomas (OR, 2.46; 95% CI, 1.50-4.01; P < 0.001) and with the presence of ≥3 DNA copy-number losses (OR, 1.90; 95% CI. 1.02-3.54; P = 0.043).Molecularly-defined high-risk adenomas were associated with me-CRC, but the association of advanced adenoma with me-CRC was stronger., Significance: Identifying new biomarkers may improve prediction of me-CRC for individuals with adenomas and optimize surveillance intervals to reduce risk of colorectal cancer and reduce oversurveillance of patients with low risk of colorectal cancer. Use of DNA CNAs alone does not improve prediction of me-CRC. Further research to improve risk classification is required., (© 2023 The Authors; Published by the American Association for Cancer Research.)

Objective: New screening tests for colorectal cancer (CRC) are rapidly emerging. Conducting trials with mortality reduction as the end point supporting their adoption is challenging. We re-examined the principles underlying evaluation of new non-invasive tests in view of technological developments and identification of new biomarkers., Design: A formal consensus approach involving a multidisciplinary expert panel revised eight previously established principles., Results: Twelve newly stated principles emerged. Effectiveness of a new test can be evaluated by comparison with a proven comparator non-invasive test. The faecal immunochemical test is now considered the appropriate comparator, while colonoscopy remains the diagnostic standard. For a new test to be able to meet differing screening goals and regulatory requirements, flexibility to adjust its positivity threshold is desirable. A rigorous and efficient four-phased approach is proposed, commencing with small studies assessing the test's ability to discriminate between CRC and non-cancer states ( phase I ), followed by prospective estimation of accuracy across the continuum of neoplastic lesions in neoplasia-enriched populations ( phase II ). If these show promise, a provisional test positivity threshold is set before evaluation in typical screening populations. Phase III prospective studies determine single round intention-to-screen programme outcomes and confirm the test positivity threshold. Phase IV studies involve evaluation over repeated screening rounds with monitoring for missed lesions. Phases III and IV findings will provide the real-world data required to model test impact on CRC mortality and incidence., Conclusion: New non-invasive tests can be efficiently evaluated by a rigorous phased comparative approach, generating data from unbiased populations that inform predictions of their health impact., Competing Interests: Competing interests: Board membership: TRL, RES, LG, FM, CS, RS, H-MC, ED, AK, HS, GAM, SI. Consultancy: LG, UL, GPY, FM, JM, SG, ED, AK, HS, SI. Expert testimony: FM. Grants or contract research: RSB, TRL, RES, FM, RS, FM, ED, ML, GAM, LC. Lectures/Other education events: LG, FM, H-MC, ED, AK. Patents: GPY, RSB, BC, AK, GAM. Receipt of equipment or supplies: LG, RES, ED, ML, GAM. Stock/Stock options: GPY, UL, JM, SG, ED, AK, GAM. Other professional relationships: GPY, SG., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Colorectal cancer (CRC) is among the most frequently diagnosed cancers. Approximately 20-30% of stage I-III CRC patients develop a recurrent tumour or metastases after curative surgical resection. Post-operative follow-up is indicated for the first five years after curative surgical resection. As intensified follow-up after curative surgical resection has shown no effect on survival, patient organisations and policy makers have advocated for a more patient-centred approach to follow-up. The objective of this study is to successfully implement patient-led, home-based follow-up (PHFU) in six hospitals in The Netherlands, with as ultimate aim to come to a recommendation for a patient-centred follow-up schedule for stage I-III CRC patients treated with surgical resection with curative intent., Methods: This study is designed as a stepped-wedge cluster-randomised trial (SW-CRT) in six participating centres. During the trial, three centres will implement PHFU after six months; the other three centres will implement PHFU after 12 months of inclusion in the control group. Eligible patients are those with pT2-4N0M0 or pT1-4N1-2M0 CRC, who are 18 years or older and have been free of disease for 12 months after curative surgical resection. The studied intervention is PHFU, starting 12 months after curative resection. The in-hospital, standard-of-care follow-up currently implemented in the participating centres functions as the comparator. The proportion of patients who had contact with the hospital regarding CRC follow-up between 12-24 months after curative surgical resection is the primary endpoint of this study. Quality of life, fear of cancer recurrence, patient satisfaction, cost-effectiveness and survival are the secondary endpoints., Discussion: The results of this study will provide evidence on whether nationwide implementation of PHFU for CRC in The Netherlands will be successful in reducing contact between patient and health care provider. Comparison of PROMs between in-hospital follow-up and PHFU will be provided. Moreover, the cost-effectiveness of PHFU will be assessed., Trial Registration: Dutch Trail Register (NTR): NL9266 (Registered on January 1st, 2021)., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Longitudinal adherence to colorectal cancer (CRC) screening is reported using different summarizing measures, which hampers international comparison. We provide evidence to guide recommendations on which longitudinal adherence measure to report. Using adherence data over four stool-based CRC screening rounds in three countries, we calculated six summarizing adherence measures; adherence over all rounds, adherence per round, rescreening, full programme adherence (yes/no), regularity (never/inconsistent/consistent screenees) and number of times participated. For each measure, we calculated the accuracy in capturing the observed adherence patterns. Using the ASCCA model, we predicted screening effectiveness when using summarizing measures as model input versus the observed adherence patterns. Adherence over all rounds in the Italian, Spanish and Dutch cohorts was 64.9%, 42.8% and 61.5%, respectively, and the proportion of consistent screenees was 50.9%, 26.3% and 45.7%. Number of times participated and regularity were most accurate and resulted in similar model-predicted screening effectiveness as simulating the observed adherence patterns of Italy, Spain and the Netherlands (mortality reductions: 24.4%, 16.9% and 23.5%). Adherence over all rounds and adherence per round were least accurate. Screening effectiveness was overestimated when using adherence over all rounds (mortality reductions: 26.8%, 19.4% and 25.7%) and adherence per round (mortality reductions: 26.8%, 19.5% and 25.9%). To conclude, number of times participated and regularity were most accurate and resulted in similar model-predicted screening effectiveness as using the observed adherence patterns. However they require longitudinal data. To facilitate international comparison of CRC screening programme performance, consensus on an accurate adherence measure to report should be reached., Competing Interests: Declaration of Competing Interest Beatriz Carvalho is inventor on several biomarker patents pending. GA Meijer is co-founder and board member (CSO) of CRCbioscreen BV, he has a research collaboration with CZ Health Insurances (cash matching to ZonMW grant) and he has research collaborations with Exact Sciences, Sysmex, Sentinel Ch. SpA, Personal Genome Diagnostics (PGDX), DELFI and Hartwig Medical Foundation; these companies provide materials, equipment and/or sample/genomic analyses. Evelien Dekker has endoscopic equipment on loan of FujiFilm and Olympus, received a research grant from FujiFilm, and received honorarium for consultancy from FujiFilm, Olympus, GI Supply, CPP-FAP, PAION and Ambu, and speakers' fees from Olympus, GI Supply, Norgine, IPSEN, PAION and FujiFilm., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: To optimize colorectal cancer (CRC) screening and surveillance, information regarding the time-dependent risk of advanced adenomas (AA) to develop into CRC is crucial. However, since AA are removed after diagnosis, the time from AA to CRC cannot be observed in an ethically acceptable manner. We propose a statistical method to indirectly infer this time in a progressive three-state disease model using surveillance data., Methods: Sixteen models were specified, with and without covariates. Parameters of the parametric time-to-event distributions from the adenoma-free state (AF) to AA and from AA to CRC were estimated simultaneously, by maximizing the likelihood function. Model performance was assessed via simulation. The methodology was applied to a random sample of 878 individuals from a Norwegian adenoma cohort., Results: Estimates of the parameters of the time distributions are consistent and the 95% confidence intervals (CIs) have good coverage. For the Norwegian sample (AF: 78%, AA: 20%, CRC: 2%), a Weibull model for both transition times was selected as the final model based on information criteria. The mean time among those who have made the transition to CRC since AA onset within 50 years was estimated to be 4.80 years (95% CI: 0; 7.61). The 5-year and 10-year cumulative incidence of CRC from AA was 13.8% (95% CI: 7.8%;23.8%) and 15.4% (95% CI: 8.2%;34.0%), respectively., Conclusions: The time-dependent risk from AA to CRC is crucial to explain differences in the outcomes of microsimulation models used for the optimization of CRC prevention. Our method allows for improving models by the inclusion of data-driven time distributions., (© 2022. The Author(s).)

Objectives: Colorectal cancer (CRC) screening with a faecal immunochemical test (FIT) has been disrupted in many countries during the COVID-19 pandemic. Performing catch-up of missed screens while maintaining regular screening services requires additional colonoscopy capacity that may not be available. This study aimed to compare strategies that clear the screening backlog using limited colonoscopy resources., Methods: A range of strategies were simulated using four country-specific CRC natural-history models: Adenoma and Serrated pathway to Colorectal CAncer (ASCCA) and MIcrosimulation SCreening ANalysis for CRC (MISCAN-Colon) (both in the Netherlands), Policy1-Bowel (Australia) and OncoSim (Canada). Strategies assumed a 3-month screening disruption with varying recovery period lengths (6, 12, and 24 months) and varying FIT thresholds for diagnostic colonoscopy. Increasing the FIT threshold reduces the number of referrals to diagnostic colonoscopy. Outcomes for each strategy were colonoscopy demand and excess CRC-related deaths due to the disruption., Results: Performing catch-up using the regular FIT threshold in 6, 12 and 24 months could prevent most excess CRC-related deaths, but required 50%, 25% and 12.5% additional colonoscopy demand, respectively. Without exceeding usual colonoscopy demand, up to 60% of excess CRC-related deaths can be prevented by increasing the FIT threshold for 12 or 24 months. Large increases in FIT threshold could lead to additional deaths rather than preventing them., Conclusions: Clearing the screening backlog in 24 months could avert most excess CRC-related deaths due to a 3-month disruption but would require a small increase in colonoscopy demand. Increasing the FIT threshold slightly over 24 months could ease the pressure on colonoscopy resources.

BACKGROUND : The European Society of Gastrointestinal Endoscopy (ESGE) has developed a core curriculum for high quality optical diagnosis training for practice across Europe. The development of easy-to-measure competence standards for optical diagnosis can optimize clinical decision-making in endoscopy. This manuscript represents an official Position Statement of the ESGE aiming to define simple, safe, and easy-to-measure competence standards for endoscopists and artificial intelligence systems performing optical diagnosis of diminutive colorectal polyps (1 - 5 mm). METHODS : A panel of European experts in optical diagnosis participated in a modified Delphi process to reach consensus on Simple Optical Diagnosis Accuracy (SODA) competence standards for implementation of the optical diagnosis strategy for diminutive colorectal polyps. In order to assess the clinical benefits and harms of implementing optical diagnosis with different competence standards, a systematic literature search was performed. This was complemented with the results from a recently performed simulation study that provides guidance for setting alternative competence standards for optical diagnosis. Proposed competence standards were based on literature search and simulation study results. Competence standards were accepted if at least 80 % agreement was reached after a maximum of three voting rounds. RECOMMENDATION 1:  In order to implement the leave-in-situ strategy for diminutive colorectal lesions (1-5 mm), it is clinically acceptable if, during real-time colonoscopy, at least 90 % sensitivity and 80 % specificity is achieved for high confidence endoscopic characterization of colorectal neoplasia of 1-5 mm in the rectosigmoid. Histopathology is used as the gold standard.Level of agreement 95 %. RECOMMENDATION 2:  In order to implement the resect-and-discard strategy for diminutive colorectal lesions (1-5 mm), it is clinically acceptable if, during real-time colonoscopy, at least 80 % sensitivity and 80 % specificity is achieved for high confidence endoscopic characterization of colorectal neoplasia of 1-5 mm. Histopathology is used as the gold standard.Level of agreement 100 %. CONCLUSION : The developed SODA competence standards define diagnostic performance thresholds in relation to clinical consequences, for training and for use when auditing the optical diagnosis of diminutive colorectal polyps., Competing Interests: R. Bisschops has received research support from Cook and Medtronic, and financial support for symposium organization from Cook, Boston Scientific, Olympus, and Erbe (2009–2109), and speakers’ fees from Boston Scientific and Medtronic (2009–2019). E. Coron has received speakerʼs fees from Fujifilm (2018–2020). E. Dekker has received speaker’s fees from Roche (2018), Norgine (2019), Olympus and GI Supply (both 2019 to 2020), and Fujifilm (2020), and has provided consultancy to Fujifilm (2018), CPP-FAP (2019), GI Supply (2019 to 2020), Olympus (2020 to present), PAION and Ambu (both 2021); she received a research grant from Fujifilm (2017 to 2020) and her department has equipment on loan from Fujifilm (2017 to present) and Olympus (2021). M. Dinis-Ribeiro receives an educational grant from Olympus (2020 to present) and a research grant from Fujifilm (2020 to present); he is co-editor in-chief of Endoscopy. J.E. East has provided consultancy to, and holds share options in, Satisfai Health (2020 to present). C. Hassan has received research support from Fujifilm (2017 to present); his department has received support from Sonoscape. M. Iacucci receives research support from Pentax (2011 to present), Olympus (2017 to present) and Fujifilm (2018 to present). Y. Mori receives consultancy and speaker’s fees from Olympus (2018 to present) and has an ownership interest in Cybernet System Corp. (2020 to present). H. Neumann has provided consultancy to Fujifilm, Sonoscope, and Boston Scientific (all 2019 to 2020). M. Pellisé has received consultancy and speaker’s fees from Norgine Iberia (2015 to 2020), a consultancy fee from GI Supply (2019), speaker’s fees from Casen Recordati (2016 to 2019), Olympus (2018), and Jansen (2018), and research funding from Fujifilm Spain (2019), Fujifilm Europe (2020), and Casen Recordati (2020); her department has received loan material from Fujifilm Spain (2017 to present), a research grant from Olympus Europe (2005 to 2019), and loan material and a research grant from Fujifilm Europe (2020 to 2021); she is a Board member of ESGE and SEED, and is a co-editor of Endoscopy (2015 to 2021). I. Puig has provided advisory services to Fujifilm (2020 to present) and has equipment on loan from Olympus and Fujifilm (both 2019 to present). B. Saunders receives research funding from Olympus (2019 to present). D.J. Tate received an educational grant from Olympus (2018 to 2019). G. Antonelli, M. Bustamante-Balén, G. Cortas, V.M.H. Coupé, D.E. Dobru, M.J.E. Greuter, Y. Hazewinkel, B.B.S.L. Houwen, R. Jover, R. Kuvaev, G. Longcroft-Wheaton, M.D. Rutter, and J.L.A. Vleugels declare that they have no conflict of interest., (European Society of Gastrointestinal Endoscopy. All rights reserved.)

Background and Aims: One reason the optical diagnosis strategy for diminutive colorectal polyps has not yet been implemented is that the current competence criteria (Preservation and Incorporation of Valuable Endoscopic Innovation [PIVI] initiative) are difficult to use in daily practice. To provide guidance for setting alternative easy-to-adopt competence criteria, we determined the lowest proportion of diminutive polyps that should have a correct optical diagnosis to meet the PIVI., Methods: For this simulation study, we used datasets from 2 prospectively collected cohorts of patients who underwent colonoscopy in either a primary colonoscopy or fecal immunochemical test (FIT) screening setting. In the simulation approach, virtual endoscopists or computer-aided diagnosis systems performed optical diagnosis of diminutive polyps with a fixed diagnostic performance level (strategy) on all individuals in the cohort who had ≥1 diminutive polyp. Strategies were defined by systematically varying the proportion of correct optical diagnoses for each polyp subtype (ie, adenomas, hyperplastic polyps, sessile serrated lesions). For each strategy, we determined whether PIVI-1 (≥90% agreement with U.S. or European Society for Gastrointestinal Endoscopy [ESGE] surveillance guidelines) and PIVI-2 (≥90% negative predictive value [NPV] for neoplastic lesions in the rectosigmoid) were met using Monte Carlo sampling with 1000 repetitions, with histology as reference., Results: The level of overall diagnostic accuracy to achieve the PIVI differed significantly depending on the clinical setting and guidelines used. In the colonoscopy screening setting, all diagnostic strategies in which 92% of all diminutive polyps (regardless of histology) were diagnosed correctly led to 90% or more agreement with U.S. surveillance intervals (ie, PIVI-1). For all diagnostic strategies in which ≥89% of all diminutive polyps were correctly diagnosed, at least 90% NPV was achieved (ie, PIVI-2). For the FIT screening setting, values were respectively ≥77% and ≥94%. When using ESGE guidelines, PIVI-1 was in both settings already met when 40% of all diminutive polyps were diagnosed correctly., Conclusions: In contrast to the fixed PIVI criteria, our simulation study shows that different thresholds for the proportion of correctly diagnosed diminutive polyps lead to different clinical consequences depending on guidelines and clinical setting. However, this target proportion of diminutive colorectal polyps correctly diagnosed with optical diagnosis represents easier-to-adopt competence criteria., (Copyright © 2021 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Background: The fecal immunochemical test (FIT) is used in colorectal cancer (CRC) screening, yet it leaves room for improvement., Objective: To develop a multitarget FIT (mtFIT) with better diagnostic performance than FIT., Design: Diagnostic test accuracy study., Setting: Colonoscopy-controlled series., Participants: Persons ( n = 1284) from a screening ( n = 1038) and referral ( n = 246) population were classified by their most advanced lesion (CRC [ n = 47], advanced adenoma [ n = 135], advanced serrated polyp [ n = 30], nonadvanced adenoma [ n = 250], and nonadvanced serrated polyp [ n = 53]), along with control participants ( n = 769)., Measurements: Antibody-based assays were developed and applied to leftover FIT material. Classification and regression tree (CART) analysis was applied to biomarker concentrations to identify the optimal combination for detecting advanced neoplasia. Performance of this combination, the mtFIT, was cross-validated using a leave-one-out approach and compared with FIT at equal specificity., Results: The CART analysis showed a combination of hemoglobin, calprotectin, and serpin family F member 2-the mtFIT-to have a cross-validated sensitivity for advanced neoplasia of 42.9% (95% CI, 36.2% to 49.9%) versus 37.3% (CI, 30.7% to 44.2%) for FIT ( P = 0.025), with equal specificity of 96.6%. In particular, cross-validated sensitivity for advanced adenomas increased from 28.1% (CI, 20.8% to 36.5%) to 37.8% (CI, 29.6% to 46.5%) ( P = 0.006). On the basis of these results, early health technology assessment indicated that mtFIT-based screening could be cost-effective compared with FIT., Limitation: Study population is enriched with persons from a referral population., Conclusion: Compared with FIT, the mtFIT showed better diagnostic accuracy in detecting advanced neoplasia because of an increased detection of advanced adenomas. Moreover, early health technology assessment indicated that these results provide a sound basis to pursue further development of mtFIT as a future test for population-based CRC screening. A prospective screening trial is in preparation., Primary Funding Source: Stand Up to Cancer/Dutch Cancer Society, Dutch Digestive Foundation, and HealthHolland.

Patient's quality of life should be included in clinical decision making regarding the administration of adjuvant chemotherapy (ACT) in stage II/III colon cancer. Therefore, quality of life, summarized as health utility (HU), was evaluated for patients treated with and without ACT. Furthermore, the role of chemotherapy-induced peripheral neuropathy (CIPN) on HU was evaluated. Patients diagnosed with stage II/III colon cancer between 2011 and 2019 and participating in the Prospective Dutch ColoRectal Cancer cohort were included (n = 914). HU scores were assessed with the EQ-5D-5L at baseline, 3, 6, 12, 18, and 24 months. Patients treated with ACT received mainly capecitabine and oxaliplatin (57%) or capecitabine monotherapy (40%) (average duration: 3.5 months). HU 3 to 18 months after diagnosis (potential ACT period + 12 months follow-up) was compared between patients treated with and without ACT using a mixed model adjusted for age, sex and education level. Subsequently, the CIPN sensory, motor and autonomy scales, measured using the EORTC QLQ-CIPN20, were independently included in the model to evaluate the impact of neuropathy. Using a mixed model, a significant difference of -0.039 (95% confidence interval: -0.062; -0.015) in HU was found between patients treated with and without ACT. Including the CIPN sensory, motor and autonomy scales decreased the difference with 0.019, 0.015 and 0.02, respectively. HU 3 to 18 months after diagnosis is significantly lower in patients treated with ACT vs without ACT. This difference is on the boundary of clinical relevance and appears to be partly related to the sensory and motor neuropathy-related side effects of ACT., (© 2021 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: Colorectal cancer screening programmes worldwide have been disrupted during the COVID-19 pandemic. We aimed to estimate the impact of hypothetical disruptions to organised faecal immunochemical test-based colorectal cancer screening programmes on short-term and long-term colorectal cancer incidence and mortality in three countries using microsimulation modelling., Methods: In this modelling study, we used four country-specific colorectal cancer microsimulation models-Policy1-Bowel (Australia), OncoSim (Canada), and ASCCA and MISCAN-Colon (the Netherlands)-to estimate the potential impact of COVID-19-related disruptions to screening on colorectal cancer incidence and mortality in Australia, Canada, and the Netherlands annually for the period 2020-24 and cumulatively for the period 2020-50. Modelled scenarios varied by duration of disruption (3, 6, and 12 months), decreases in screening participation after the period of disruption (0%, 25%, or 50% reduction), and catch-up screening strategies (within 6 months after the disruption period or all screening delayed by 6 months)., Findings: Without catch-up screening, our analysis predicted that colorectal cancer deaths among individuals aged 50 years and older, a 3-month disruption would result in 414-902 additional new colorectal cancer diagnoses (relative increase 0·1-0·2%) and 324-440 additional deaths (relative increase 0·2-0·3%) in the Netherlands, 1672 additional diagnoses (relative increase 0·3%) and 979 additional deaths (relative increase 0·5%) in Australia, and 1671 additional diagnoses (relative increase 0·2%) and 799 additional deaths (relative increase 0·3%) in Canada between 2020 and 2050, compared with undisrupted screening. A 6-month disruption would result in 803-1803 additional diagnoses (relative increase 0·2-0·4%) and 678-881 additional deaths (relative increase 0·4-0·6%) in the Netherlands, 3552 additional diagnoses (relative increase 0·6%) and 1961 additional deaths (relative increase 1·0%) in Australia, and 2844 additional diagnoses (relative increase 0·3%) and 1319 additional deaths (relative increase 0·4%) in Canada between 2020 and 2050, compared with undisrupted screening. A 12-month disruption would result in 1619-3615 additional diagnoses (relative increase 0·4-0·9%) and 1360-1762 additional deaths (relative increase 0·8-1·2%) in the Netherlands, 7140 additional diagnoses (relative increase 1·2%) and 3968 additional deaths (relative increase 2·0%) in Australia, and 5212 additional diagnoses (relative increase 0·6%) and 2366 additional deaths (relative increase 0·8%) in Canada between 2020 and 2050, compared with undisrupted screening. Providing immediate catch-up screening could minimise the impact of the disruption, restricting the relative increase in colorectal cancer incidence and deaths between 2020 and 2050 to less than 0·1% in all countries. A post-disruption decrease in participation could increase colorectal cancer incidence by 0·2-0·9% and deaths by 0·6-1·6% between 2020 and 2050, compared with undisrupted screening., Interpretation: Although the projected effect of short-term disruption to colorectal cancer screening is modest, such disruption will have a marked impact on colorectal cancer incidence and deaths between 2020 and 2050 attributable to missed screening. Thus, it is crucial that, if disrupted, screening programmes ensure participation rates return to previously observed rates and provide catch-up screening wherever possible, since this could mitigate the impact on colorectal cancer deaths., Funding: Cancer Council New South Wales, Health Canada, and Dutch National Institute for Public Health and Environment., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objectives: Metamodeling can address computational challenges within decision-analytic modeling studies evaluating many strategies. This article illustrates the value of metamodeling for evaluating colorectal cancer screening strategies while accounting for colonoscopy capacity constraints., Methods: In a traditional approach, the best screening strategy was identified from a limited subset of strategies evaluated with the validated Adenoma and Serrated pathway to Colorectal CAncer model. In a metamodeling approach, metamodels were fitted to this limited subset to evaluate all potentially plausible strategies and determine the best overall screening strategy. Approaches were compared based on the best screening strategy in life-years gained compared with no screening. Metamodel runtime and accuracy was assessed., Results: The metamodeling approach evaluated >40 000 strategies in <1 minute with high accuracy after 1 adaptive sampling step (mean absolute error: 0.0002 life-years) using 300 samples in total (generation time: 8 days). Findings indicated that health outcomes could be improved without requiring additional colonoscopy capacity. Obtaining similar insights using the traditional approach could require at least 1000 samples (generation time: 28 days). Suggested benefits from screening at ages <40 years require adequate validation of the underlying Adenoma and Serrated pathway to Colorectal CAncer model before making policy recommendations., Conclusions: Metamodeling allows rapid assessment of a vast set of strategies, which may lead to identification of more favorable strategies compared to a traditional approach. Nevertheless, metamodel validation and identifying extrapolation beyond the support of the original decision-analytic model are critical to the interpretation of results. The screening strategies identified with metamodeling support ongoing discussions on decreasing the starting age of colorectal cancer screening., (Copyright © 2020 ISPOR–The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Background: Population-based metastatic recurrence rates for patients diagnosed with nonmetastatic colorectal cancer cannot be estimated directly from population-based cancer registries because recurrence information is not reported. We derived population-based colorectal cancer recurrence rates using disease-specific survival data based on our understanding of the colorectal cancer recurrence-death process., Methods: We used a statistical continuous-time multistate survival model to derive population-based annual colorectal cancer recurrence rates from 6 months to 10 years after colorectal cancer diagnosis using relative survival data from the Surveillance, Epidemiology, and End Results Program. The model was based on the assumption that, after 6 months of diagnosis, all colorectal cancer-related deaths occur only in patients who experience a metastatic recurrence first, and that the annual colorectal cancer-specific death rate among patients with recurrence was the same as in those diagnosed with de novo metastatic disease. We allowed recurrence rates to vary by post-diagnosis time, age, stage, and location for two diagnostic time periods., Results: In patients diagnosed in 1975-1984, annual recurrence rates 6 months to 5 years after diagnosis ranged from 0.054 to 0.060 in stage II colon cancer, 0.094 to 0.105 in stage II rectal cancer, and 0.146 to 0.177 in stage III colorectal cancer, depending on age. We found a statistically significant decrease in colorectal cancer recurrence among patients diagnosed in 1994-2003 compared with those diagnosed in 1975-1984 for 6 months to 5 years after diagnosis (hazard ratios between 0.43 and 0.70)., Conclusions: We derived population-based annual recurrence rates for up to 10 years after diagnosis using relative survival data., Impact: Our estimates can be used in decision-analytic models to facilitate analyses of colorectal cancer interventions that are more generalizable., (©2020 American Association for Cancer Research.)

Detection of KRAS, NRAS, and BRAF mutations in tumor tissue is currently used to predict resistance to treatment with anti-epidermal growth factor receptor (EGFR) antibodies in patients with metastatic colorectal cancer (mCRC). Liquid biopsies are minimally invasive, and cell-free circulating tumor DNA (ctDNA) mutation analyses may better represent tumor heterogeneity. This study examined the incorporation of liquid biopsy RAS/BRAF ctDNA analyses into diagnostic strategies to determine mCRC patient eligibility for anti-EGFR therapy. Tumor tissue and liquid biopsies were collected from 100 mCRC patients with liver-only metastases in a multicenter prospective clinical trial. Three diagnostic strategies incorporating droplet digital PCR ctDNA analyses were compared with routine tumor tissue RAS/BRAF mutation profiling using decision tree analyses. Tissue DNA mutations in KRAS, NRAS, and BRAF were present in 54%, 0%, and 3% of mCRC patients, respectively. A 93% concordance was observed between tissue DNA and liquid biopsy ctDNA mutations. The proportion of patients with RAS/BRAF alterations increased from 57% to 60% for diagnostic strategies that combined tissue and liquid biopsy mutation analyses. Consecutive RAS/BRAF ctDNA analysis followed by tissue DNA analysis in case of a liquid biopsy-negative result appeared to be the most optimal diagnostic strategy to comprehensively determine eligibility for anti-EGFR therapy in a cost-saving manner. These results highlight the potential clinical utility of liquid biopsies for detecting primary resistance to anti-EGFR-targeted therapies., (Copyright © 2020 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background . This study aimed to assess the validity of 2 microsimulation models of colorectal cancer (CRC), Policy1-Bowel and ASCCA. Methods . The model-estimated CRC risk in population subgroups with different health statuses, "dwell time" (time from incident precancerous polyp to symptomatically detected CRC), and reduction in symptomatically detected CRC incidence after a one-time complete removal of polyps and/or undetected CRC were compared with published findings from 3 well-established models ( MISCAN, CRC-SPIN , and SimCRC ). Furthermore, 6 randomized controlled trials (RCTs) that provided screening using a guaiac fecal occult blood test (Funen trial, Burgundy trial, and Minnesota Colon Cancer Control Study [MCCCS]) or flexible sigmoidoscopy (NORCCAP, SCORE, and UKFSST) with long-term follow-up were simulated. Model-estimated long-term relative reductions of CRC incidence (RR inc ) and mortality (RR mort ) were compared with the RCTs' findings. Results . The Policy1-Bowel and ASCCA estimates showed more similarities to CRC-SPIN and SimCRC . For example, overall dwell times estimated by Policy1-Bowel (24.0 years) and ASCCA (25.3) were comparable to CRC-SPIN (25.8) and SimCRC (25.2) but higher than MISCAN (10.6). In addition, ∼86% of Policy1-Bowel 's and ∼74% of ASCCA 's estimated RR inc and RR mort were consistent with the RCTs' long-term follow-up findings. For example, at 17 to 18 years of follow-up, the MCCCS reported RR mort of 0.67 (95% confidence interval [CI], 0.51-0.83) and 0.79 (95% CI, 0.62-0.97) for the annual and biennial screening arm, respectively, and the UKFSST reported RR mort of 0.70 (95% CI, 0.62-0.79) for CRC at all sites and 0.54 (95% CI, 0.46-0.65) for distal CRC. The corresponding model estimates were 0.65, 0.74, 0.81, and 0.61, respectively, for Policy1-Bowel and 0.65, 0.70, 0.75, and 0.58, respectively, for ASCCA . Conclusion . Policy1-Bowel and ASCCA 's estimates are largely consistent with the data included for comparisons, which indicates good model validity.

Background: Faecal occult blood testing is widely used in colorectal cancer screening. However, there is little empirical long-term evidence on the accumulation of false-positive test results over several screening rounds. We aimed to systematically explore and quantify the cumulative false-positive rate for various scenarios of colorectal cancer screening., Methods: Using a Markov analysis, we estimated the lifetime cumulative number of false-positive test results (cumFP) per 100 000 50-year-old persons. We varied the screening interval and the specificity of a single screening test and the starting age of screening., Results: For a test with a specificity of 98% used from 50 to 74 years, the cumFP at age 74 was 26 260 (1-year interval), 15 102 (2-year interval), and 10 819 (3-year interval), respectively. For a test with a specificity of, respectively, 95 and 92% used at a 2-year interval, the cumFP at age 74 was 2.2 times and 3.0 times higher as compared to a test with a specificity of 98%. The cumFP at age 74 was 18% lower for screening persons aged 54-74 years vs. 50-74 years., Conclusion: Our findings quantitatively illustrate the large variation of the cumFP in colorectal cancer screening between screening strategies, which is relevant to informed decision making and adequate resource planning.

Background: Decision-making about palliative care for metastatic colorectal cancer (mCRC) consists of many different treatment-related decisions, and there generally is no best treatment option. Decision support systems (DSS), e.g., prognostic calculators, can aid oncologists' decision-making. DSS that contain features tailored to the needs of oncologists are more likely to be implemented in clinical practice. Therefore, our aim is to inventory colorectal cancer specialists' unmet decision support needs., Methods: We asked oncologists from the Dutch colorectal cancer group (DCCG), to participate in an online inventory questionnaire on their unmet decision support needs. To get more in-depth insight in required features of the DSS they need, we also conducted semi-structured telephone interviews., Results: Forty-one oncologists started the inventory questionnaire, and 27 of them completed all items. Of all respondents, 18 were surgeons (44%), 22 were medical oncologists (54%), and 28 (68%) had more than 10 years of experience treating mCRC. In both the inventory questionnaire and interviews, respondents expressed a need for an overarching DSS incorporating multiple treatment options, and presenting both the treatment benefits and harms. Respondents found it relevant for other outcomes, such as cost-effectiveness of treatment or quality of life, to be incorporated in DSS. There was also a wish for DSS incorporating an up-to-date "personalized" overview of the ongoing trials for which a specific patient is eligible., Conclusions: Experienced oncologists indicate that their treatment advice is currently almost solely based on the available clinical guidelines. They experience a lack of good quality DSS to help them personalize their treatment advice. New tools integrating multiple treatment options and providing a broad range of clinically relevant outcomes are urgently needed to stimulate and safeguard more personalized treatment decision-making.

Background: Radiofrequency ablation (RFA) and microwave ablation (MWA) are widely accepted techniques to eliminate small unresectable colorectal liver metastases (CRLM). Although previous studies labelled thermal ablation inferior to surgical resection, the apparent selection bias when comparing patients with unresectable disease to surgical candidates, the superior safety profile, and the competitive overall survival results for the more recent reports mandate the setup of a randomized controlled trial. The objective of the COLLISION trial is to prove non-inferiority of thermal ablation compared to hepatic resection in patients with at least one resectable and ablatable CRLM and no extrahepatic disease., Methods: In this two-arm, single-blind multi-center phase-III clinical trial, six hundred and eighteen patients with at least one CRLM (≤3 cm) will be included to undergo either surgical resection or thermal ablation of appointed target lesion(s) (≤3 cm). Primary endpoint is OS (overall survival, intention-to-treat analysis). Main secondary endpoints are overall disease-free survival (DFS), time to progression (TTP), time to local progression (TTLP), primary and assisted technique efficacy (PTE, ATE), procedural morbidity and mortality, length of hospital stay, assessment of pain and quality of life (QoL), cost-effectiveness ratio (ICER) and quality-adjusted life years (QALY)., Discussion: If thermal ablation proves to be non-inferior in treating lesions ≤3 cm, a switch in treatment-method may lead to a reduction of the post-procedural morbidity and mortality, length of hospital stay and incremental costs without compromising oncological outcome for patients with CRLM., Trial Registration: NCT03088150 , January 11th 2017.

Introduction: Cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) improve the survival of colorectal cancer (CRC) patients with peritoneal metastases. Patient selection is key since this treatment is associated with high morbidity. Patients with peritoneal recurrence within 1 year after previous adjuvant chemotherapy are thought to benefit less from HIPEC treatment; however, no published data are available to assist in clinical decision making. This study assessed whether peritoneal recurrence within 1 year after adjuvant chemotherapy was associated with survival after HIPEC treatment., Methods: Peritoneal recurrence within 1 year after adjuvant chemotherapy, as well as other potentially prognostic clinical and pathological variables, were tested in univariate and multivariate analysis for correlation with primary outcomes, i.e. overall survival (OS) and disease-free survival (DFS). Two prospectively collected databases from the VU University Medical Center Amsterdam and Catherina Hospital Eindhoven containing 345 CRC patients treated with the intent of HIPEC were utilized., Results: High Peritoneal Cancer Index (PCI) scores were associated with worse DFS [hazard ratio (HR) 1.04, 95% confidence interval (CI) 1.00-1.08, p = 0.040] and OS (HR 1.11, 95% CI 1.07-1.15, p < 0.001) in multivariate analysis. Furthermore, patients with peritoneal recurrence within 1 year following adjuvant chemotherapy had worse DFS (HR 2.13, 95% CI 1.26-3.61, p = 0.005) and OS (HR 2.76, 95% CI 1.45-5.27, p = 0.002) than patients who did not receive adjuvant chemotherapy or patients with peritoneal recurrence after 1 year., Conclusion: Peritoneal recurrence within 1 year after previous adjuvant chemotherapy, as well as high PCI scores, are associated with poor survival after cytoreduction and HIPEC. These factors should be considered in order to avoid high-morbidity treatment in patients who might not benefit from such treatment.

The Australian National Bowel Cancer Screening Program (NBCSP) will fully roll-out 2-yearly screening using the immunochemical Faecal Occult Blood Testing (iFOBT) in people aged 50 to 74 years by 2020. In this study, we aimed to estimate the comparative health benefits, harms, and cost-effectiveness of screening with iFOBT, versus other potential alternative or adjunctive technologies. A comprehensive validated microsimulation model, Policy1-Bowel, was used to simulate a total of 13 screening approaches involving use of iFOBT, colonoscopy, sigmoidoscopy, computed tomographic colonography (CTC), faecal DNA (fDNA) and plasma DNA (pDNA), in people aged 50 to 74 years. All strategies were evaluated in three scenarios: (i) perfect adherence, (ii) high (but imperfect) adherence, and (iii) low adherence. When assuming perfect adherence, the most effective strategies involved using iFOBT (annually, or biennially with/without adjunct sigmoidoscopy either at 50, or at 54, 64 and 74 years for individuals with negative iFOBT), or colonoscopy (10-yearly, or once-off at 50 years combined with biennial iFOBT). Colorectal cancer incidence (mortality) reductions for these strategies were 51-67(74-80)% in comparison with no screening; 2-yearly iFOBT screening (i.e. the NBCSP) would be associated with reductions of 51(74)%. Only 2-yearly iFOBT screening was found to be cost-effective in all scenarios in context of an indicative willingness-to-pay threshold of A$50,000/life-year saved (LYS); this strategy was associated with an incremental cost-effectiveness ratio of A$2,984/LYS-A$5,981/LYS (depending on adherence). The fully rolled-out NBCSP is highly cost-effective, and is also one of the most effective approaches for bowel cancer screening in Australia., (© 2018 UICC.)

About 5% of colorectal adenomas are estimated to progress to colorectal cancer. However, it is important to identify which adenomas actually carry a high risk of progression, because these serve as intermediate endpoints, for example, in screening programs. In clinical practice, adenomas with a size of ≥10 mm, villous component and/or high-grade dysplasia, called advanced adenomas, are considered high risk, although solid evidence for this classification is lacking. Specific DNA copy number changes are associated with adenoma-to-carcinoma progression. We set out to determine the prevalence of cancer-associated events (CAE) in advanced and nonadvanced adenomas. DNA copy number analysis was performed on archival tissues from three independent series of, in total, 297 adenomas (120 nonadvanced and 177 advanced) using multiplex ligation-dependent probe amplification or low-coverage whole-genome DNA sequencing. Alterations in two or more CAEs were considered to mark adenomas as high risk. Two or more CAEs were overall present in 25% (95% CI, 19.0-31.8) of advanced adenomas; 23% (11/48), 36% (12/33), and 23% (22/96) of the advanced adenomas in series 1, 2, and 3, respectively, and 1.7% (1/58) and 4.8% (3/62) of the nonadvanced adenomas, in series 1 and 2, respectively. The majority of advanced adenomas do not show CAEs, indicating that only a subset of these lesions is to be considered high risk. Nonadvanced adenomas have very low prevalence of CAEs, although those with CAEs should be considered high risk as well. Specific DNA copy number alterations may better reflect the true progression risk than the advanced adenoma phenotype. Cancer Prev Res; 11(7); 403-12. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Background: Both the adenoma detection rate (ADR) and proximal serrated polyp detection rate (PSPDR) vary among endoscopists. It is unclear how these variations influence colorectal cancer (CRC) screening effectiveness. We evaluated the effect of variation in these detection rates on the long-term impact of fecal immunochemical test (FIT) based screening., Methods: The Adenoma and Serrated pathway to Colorectal CAncer (ASCCA) model was set up to simulate the Dutch national biennial FIT-based CRC screening program between 2014 and 2044. Adherence to FIT and colonoscopy was 73 and 92%. Besides a 'no screening scenario', several screening scenarios varying in ADR and PSPDR were evaluated. Using the available literature on colonoscopy miss rates led to a base-case ADR of 59% and PSPDR of 11%, which were varied with intervals of 3 and 2%., Results: Compared to no screening, FIT-screening in the base-case scenario reduced long-term mortality with 51.8%. At a fixed PSPDR of 11%, an increase in ADR from 44 to 62% would result in a 10.7% difference in mortality reduction. Using a fixed ADR of 59%, changing the PSPDR from 3 to 15% did not substantially influence long-term mortality (51.0 to 52.3%)., Conclusions: An increase in ADR gradually reduces CRC burden in a FIT-based screening program, whereas an increase in PSPDR only minimally influences long-term outcomes at a population-level. The limited effect of the PSPDR can be explained by the limited sensitivity of FIT for serrated polyps (SPs). Other triage modalities aiming to detect relevant SPs should be explored.

Background: Decision-making regarding palliative treatment for patients with metastatic colorectal cancer (mCRC) is complex and comprises numerous decisions. Decision-making should be guided by the premise of maintaining and/or improving patients' quality of life, by patient preference, and by the trade-off between treatment benefits and harm. Decision support systems (DSSs) for clinicians (eg, nomograms) can assist in this process. The present systematic review aimed to provide a comprehensive overview of the available DSSs for incurable mCRC and to assess their clinical usefulness., Materials and Methods: A systematic literature search was performed in PubMed, Embase, and the Cochrane Library. We extracted information on the DSS characteristics and their discriminatory ability, calibration, and user-friendliness., Results: From 5205 studies, we identified 14 DSSs for decisions regarding palliative resection of the primary tumor (n = 3), radiotherapy for metastases (n = 2), treatment type (invasive vs. symptomatic only; n = 7), and selection of chemotherapy (n = 2). The predictors varied greatly among the DSSs, and only 1 DSS incorporated a genetic marker (ie, UGT1A1). None of the DSSs included > 1 treatment option, nor did any DSS present estimates of treatment benefits and harms. Five tools had not been externally validated, two had only been validated in < 35 patients, and the rest had only been validated in populations similar to the population used for their development. Discriminatory accuracy was generally moderate to poor. Calibration measures were only reported for 2 tools., Conclusion: A limited number of DSSs are available to support palliative treatment decisions for patients with mCRC, and the evidence regarding their discriminatory ability and calibration is too limited to recommend their use. New DSSs comparing multiple treatment options and presenting both treatment benefits and harms are needed., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The fecal immunochemical test (FIT) for detecting hemoglobin is used widely for noninvasive colorectal cancer (CRC) screening, but its sensitivity leaves room for improvement., Objective: To identify novel protein biomarkers in stool that outperform or complement hemoglobin in detecting CRC and advanced adenomas., Design: Case-control study., Setting: Colonoscopy-controlled referral population from several centers., Participants: 315 stool samples from one series of 12 patients with CRC and 10 persons without colorectal neoplasia (control samples) and a second series of 81 patients with CRC, 40 with advanced adenomas, and 43 with nonadvanced adenomas, as well as 129 persons without colorectal neoplasia (control samples); 72 FIT samples from a third independent series of 14 patients with CRC, 16 with advanced adenomas, and 18 with nonadvanced adenomas, as well as 24 persons without colorectal neoplasia (control samples)., Measurements: Stool samples were analyzed by mass spectrometry. Classification and regression tree (CART) analysis and logistic regression analyses were performed to identify protein combinations that differentiated CRC or advanced adenoma from control samples. Antibody-based assays for 4 selected proteins were done on FIT samples., Results: In total, 834 human proteins were identified, 29 of which were statistically significantly enriched in CRC versus control stool samples in both series. Combinations of 4 proteins reached sensitivities of 80% and 45% for detecting CRC and advanced adenomas, respectively, at 95% specificity, which was higher than that of hemoglobin alone (P < 0.001 and P = 0.003, respectively). Selected proteins could be measured in small sample volumes used in FIT-based screening programs and discriminated between CRC and control samples (P < 0.001)., Limitation: Lack of availability of antibodies prohibited validation of the top protein combinations in FIT samples., Conclusion: Mass spectrometry of stool samples identified novel candidate protein biomarkers for CRC screening. Several protein combinations outperformed hemoglobin in discriminating CRC or advanced adenoma from control samples. Proof of concept that such proteins can be detected with antibody-based assays in small sample volumes indicates the potential of these biomarkers to be applied in population screening., Primary Funding Source: Center for Translational Molecular Medicine, International Translational Cancer Research Dream Team, Stand Up to Cancer (American Association for Cancer Research and the Dutch Cancer Society), Dutch Digestive Foundation, and VU University Medical Center.

Background: Population-based screening to prevent colorectal cancer (CRC) death is effective, but the effectiveness of postpolypectomy surveillance is unclear., Objective: To evaluate the additional benefit in terms of cost-effectiveness of colonoscopy surveillance in a screening setting., Design: Microsimulation using the ASCCA (Adenoma and Serrated pathway to Colorectal CAncer) model., Data Sources: Dutch CRC screening program and published literature., Target Population: Asymptomatic persons aged 55 to 75 years without a prior CRC diagnosis., Time Horizon: Lifetime., Perspective: Health care payer., Intervention: Fecal immunochemical test (FIT) screening with colonoscopy surveillance performed according to the Dutch guideline was simulated. The comparator was no screening or surveillance. FIT screening without colonoscopy surveillance and the effect of extending surveillance intervals were also evaluated., Outcome Measures: CRC burden, colonoscopy demand, life-years, and costs., Results of Base-Case Analysis: FIT screening without surveillance reduced CRC mortality by 50.4% compared with no screening or surveillance. Adding surveillance to FIT screening reduced mortality by an additional 1.7% to 52.1% but increased lifetime colonoscopy demand by 62% (from 335 to 543 colonoscopies per 1000 persons) at an additional cost of €68 000, for an increase of 0.9 life-year. Extending the surveillance intervals to 5 years reduced CRC mortality by 51.8% and increased colonoscopy demand by 42.7% compared with FIT screening without surveillance. In an incremental analysis, incremental cost-effectiveness ratios (ICERs) for screening plus surveillance exceeded the Dutch willingness-to-pay threshold of €36 602 per life-year gained., Results of Sensitivity Analysis: When using a parameter set representing low colorectal lesion prevalence or when colonoscopy costs were halved or colorectal lesion incidence was doubled, screening plus surveillance became cost-effective compared with screening without surveillance., Limitation: Limited data on FIT performance and background CRC risk in the surveillance population., Conclusion: Adding surveillance to FIT screening is not cost-effective based on the Dutch ICER threshold and substantially increases colonoscopy demand. Extending surveillance intervals to 5 years would decrease colonoscopy demand without substantial loss of effectiveness., Primary Funding Source: Alpe d'HuZes, Dutch Cancer Society, and Stand Up To Cancer.

Background: No assessment of the National Bowel Screening Program (NBCSP) in Australia, which considers all downstream benefits, costs, and harms, has been done. We aimed to use a comprehensive natural history model and the most recent information about cancer treatment costs to estimate long-term benefits, costs, and harms of the NBCSP (2 yearly immunochemical faecal occult blood testing screening at age 50-74 years) and evaluate the incremental effect of improved screening participation under different scenarios., Methods: In this modelling study, a microsimulation model, Policy1-Bowel, which simulates the development of colorectal cancer via both the conventional adenoma-carcinoma and serrated pathways was used to simulate the NBCSP in 2006-40, taking into account the gradual rollout of NBCSP in 2006-20. The base-case scenario assumed 40% screening participation (currently observed behaviour) and two alternative scenarios assuming 50% and 60% participation by 2020 were modelled. Aggregate year-by-year screening, diagnosis, treatment and surveillance-related costs, resource utilisation (number of screening tests and colonoscopies), and health outcomes (incident colorectal cancer cases and colorectal cancer deaths) were estimated, as was the cost-effectiveness of the NBCSP., Findings: With current levels of participation (40%), the NBCSP is expected to prevent 92 200 cancer cases and 59 000 deaths over the period 2015-40; an additional 24 300 and 37 300 cases and 16 800 and 24 800 deaths would be prevented if participation was increased to 50% and 60%, respectively. In 2020, an estimated 101 000 programme-related colonoscopies will be done, associated with about 270 adverse events; an additional 32 500 and 49 800 colonoscopies and 88 and 134 adverse events would occur if participation was increased to 50% and 60%, respectively. The overall number needed to screen (NNS) is 647-788 per death prevented, with 52-59 colonoscopies per death prevented. The programme is cost-effective due to the cancer treatment costs averted (cost-effectiveness ratio compared with no screening at current participation, AUS$3014 [95% uncertainty interval 1807-5583] per life-year saved) in the cost-effectiveness analysis. In the budget impact analysis, reduced annual expenditure on colorectal cancer control is expected by 2030, with expenditure reduced by a cumulative AUS$1·7 billion, AUS$2·0 billion, and AUS$2·1 billion (2015 prices) between 2030 and 2040, at participation rates of 40%, 50%, and 60%, respectively., Interpretation: The NBCSP has potential to save 83 800 lives over the period 2015-40 if coverage rates can be increased to 60%. By contrast, the associated harms, although an important consideration, are at a smaller magnitude at the population level. The programme is highly cost-effective and within a decade of full roll-out, there will be reduced annual health systems expenditure on colorectal cancer control due to the impact of screening., Funding: Australia Postgraduate Award PhD Scholarship, Translational Cancer Research Network Top-up scholarship (supported by Cancer Institute NSW) and Cancer Council NSW., (Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: As in many other European countries, a nationwide screening program for colorectal cancer (CRC) has recently been introduced in the Netherlands. As a side effect, such a screening program will inherently yield an increase in the demand for surveillance after removal of polyps/adenomas or CRC. Although these patients are at increased risk of metachronous colorectal neoplasia, solid evidence on CRC-related mortality reduction as a result of colonoscopy-based surveillance programs is lacking. Furthermore, colonoscopy-based surveillance leads to high patient burden, high logistic demands and high costs. Therefore, new surveillance strategies are needed. The aim of the present study, named Molecular stool testing for Colorectal CAncer Surveillance (MOCCAS), is to determine the performance characteristics of two established non-invasive tests, i.e., the multitarget stool DNA test Cologuard® and the faecal immunochemical test (FIT) in the detection of CRC and advanced adenomas as an alternative for colonoscopy surveillance., Methods: In this observational cross-sectional cohort study, subjects aged 50 to 75 years will be approached to collect (whole-) stool samples for molecular testing and a FIT prior to their scheduled surveillance colonoscopy. The results of the tests will allow calculation of test sensitivities and specificities in the context of surveillance. This will provide the required input for the Dutch ASCCA model (Adenoma and Serrated pathway to Colorectal CAncer) to simulate surveillance strategies differing in frequency and duration. The model will allow predictions of lifetime health effects and costs. Multiple centres in the Netherlands will participate in the study that aims to include 4,000 individuals., Discussion: The outcome of this study will inform on the (cost-) effectiveness of stool based molecular testing as an alternative for colonoscopy in the rapidly expanding surveillance population., Trial Registration: ClinicalTrials.gov ( https://clinicaltrials.gov/ ): NCT02715141 . Retrospectively registered 17 February 2016.

Objective: Imaging may be promising for colorectal cancer (CRC) screening, since it has test characteristics comparable with colonoscopy but is less invasive. We aimed to assess the potential of CT colonography (CTC) and MR colonography (MRC) in terms of (cost-effectiveness) using the Adenoma and Serrated pathway to Colorectal CAncer model., Methods: We compared several CTC and MRC strategies with 5- or 10-yearly screening intervals with no screening, 10-yearly colonoscopy screening and biennial faecal immunochemical test (FIT) screening. We assumed trial-based participation rates in the base-case analyses and varied the rates in sensitivity analyses. Incremental lifetime costs and health effects were estimated from a healthcare perspective., Results: The health gain of CTC and MRC was similar and ranged from 0.031 to 0.048 life-year gained compared with no screening, for 2-5 screening rounds. Lifetime costs per person for MRC strategies were €60-110 higher than those for CTC strategies with an equal number of screening rounds. All imaging-based strategies were cost-effective compared with no screening. FIT screening was the dominant screening strategy, leading to most LYG and highest cost-savings. Compared with three rounds of colonoscopy screening, CTC with five rounds was found to be cost-effective in an incremental analysis of imaging strategies. Assumptions on screening participation have a major influence on the ordering of strategies in terms of costs and effects., Conclusion: CTC and MRC have potential for CRC screening, compared with no screening and compared with three rounds of 10-yearly colonoscopy screening. When taking FIT screening as the reference, imaging is not cost-effective. Participation is an important driver of effectiveness and cost estimates., Advances in Knowledge: This is the first study to assess the cost-effectiveness of MRC screening for CRC.

Background: Prognosis of patients with colorectal cancer liver metastasis (CRCLM) is estimated based on clinicopathological models. Stratifying patients based on tumor biology may have additional value., Methods: Tissue micro-arrays (TMAs), containing resected CRCLM and corresponding primary tumors from a multi-institutional cohort of 507 patients, were immunohistochemically stained for 18 candidate biomarkers. Cross-validated hazard rate ratios (HRRs) for overall survival (OS) and the proportion of HRRs with opposite effect (P(HRR < 1) or P(HRR > 1)) were calculated. A classifier was constructed by classification and regression tree (CART) analysis and its prognostic value determined by permutation analysis. Correlations between protein expression in primary tumor-CRCLM pairs were calculated., Results: Based on their putative prognostic value, EGFR (P(HRR < 1) = .02), AURKA (P(HRR < 1) = .02), VEGFA (P(HRR < 1) = .02), PTGS2 (P(HRR < 1) = .01), SLC2A1 (P(HRR > 1) < 01), HIF1α (P(HRR > 1) = .06), KCNQ1 (P(HRR > 1) = .09), CEA (P (HRR > 1) = .05) and MMP9 (P(HRR < 1) = .07) were included in the CART analysis (n = 201). The resulting classifier was based on AURKA, PTGS2 and MMP9 expression and was associated with OS (HRR 2.79, p < .001), also after multivariate analysis (HRR 3.57, p < .001). The prognostic value of the biomarker-based classifier was superior to the clinicopathological model (p = .001). Prognostic value was highest for colon cancer patients (HRR 5.71, p < .001) and patients not treated with systemic therapy (HRR 3.48, p < .01). Classification based on protein expression in primary tumors could be based on AURKA expression only (HRR 2.59, p = .04)., Conclusion: A classifier was generated for patients with CRCLM with improved prognostic value compared to the standard clinicopathological prognostic parameters, which may aid selection of patients who may benefit from adjuvant systemic therapy.

Background: We aimed to predict the long-term colorectal cancer incidence, mortality, and colonoscopy demand of the recently implemented Dutch colorectal cancer screening program., Methods: The Adenoma and Serrated pathway to Colorectal Cancer model was set up to simulate the Dutch screening program consisting of biennial fecal immunochemical testing combined with the new Dutch surveillance guidelines, between 2014 and 2044. The impact of screening and surveillance was evaluated under three sets of natural history assumptions differing in the contribution of the serrated pathway to colorectal cancer incidence. In sensitivity analyses, other assumptions concerning the serrated pathway were varied. Model-predicted outcomes were yearly colorectal cancer incidence, mortality, and colonoscopy demand per year., Results: Assuming an aging population, colorectal cancer incidence under 30 years of screening is predicted to decrease by 35% and 31% for a contribution of 0% and 30% of the serrated pathway to colorectal cancer, respectively. For colorectal cancer mortality, reductions are 47% and 45%. In 2044, 110,000 colonoscopies will be required annually assuming no contribution of the serrated pathway (27 per 1,000 individuals in the screening age range). Including the serrated pathway influences predicted screening effectiveness if serrated lesions are neither detected nor treated at colonoscopy, and/or if colorectal cancers arising from serrated lesions have substantially lower survival rates than those arising from adenomas., Conclusions: The Dutch screening program will markedly decrease colorectal cancer incidence and mortality but considerable colonoscopy resources will be required., Impact: Predictions of long-term screening effectiveness are preferably based on both pathways to colorectal cancer to transparently describe the impact of uncertainties regarding the serrated pathway on long-term predictions., (©2015 American Association for Cancer Research.)

Background: Faecal immunochemical tests (FITs) are commonly used in colorectal cancer (CRC) screening. Diagnostic accuracy of FIT differs between males and females. This so far unexplained difference could result in a dissimilarity in screening outcome between both sexes. The aim of this study is to compare sensitivity and specificity of a FIT between males and females, and study potential explanatory variables., Methods: In this cross-sectional study, data were prospectively collected. 3,022 subjects performed a FIT prior to complete colonoscopy. Sensitivity, specificity, and ROC curves were compared for both sexes. Potential explanatory variables of the relation between sensitivity and sex were explored., Results: At all cut-off values, FIT sensitivity for CRC was higher (range 13-23%) and specificity was lower (range 2-4%) in males compared to females. At 75 ng/ml, sensitivity for CRC was 93% in males compared to 71% in females (p = 0.03), and specificity was 90% in males compared to 93% in females (p = <0.05). For advanced adenomas, males had a slightly higher sensitivity and lower specificity (not significant). At 75 ng/ml, sensitivity for advanced adenomas was 33% in males compared to 29% in females (p = 0.46), and specificity was 93% in males compared to 95% in females (p = 0.22). ROC curves were similar for both sexes, and equal combinations of sensitivity and specificity could be achieved by adjusting the cut-off values. For CRC, the difference in sensitivity could not be explained by age or location of the tumour., Conclusions: FIT has a higher sensitivity and a lower specificity for CRC in males than in females. Equal test characteristics can be achieved by allowing separate cut-off values for both sexes. Location and age do not explain the observed differences in sensitivity.

Several colorectal cancer (CRC) screening models have been developed describing the progression of adenomas to CRC. Currently, there is increasing evidence that serrated lesions can also develop into CRC. It is not clear whether screening tests have the same test characteristics for serrated lesions as for adenomas, but lower sensitivities have been suggested. Models that ignore this type of colorectal lesions may provide overly optimistic predictions of the screen-induced reduction in CRC incidence. To address this issue, we have developed the Adenoma and Serrated pathway to Colorectal CAncer (ASCCA) model that includes the adenoma-carcinoma pathway and the serrated pathway to CRC as well as characteristics of colorectal lesions. The model structure and the calibration procedure are described in detail. Calibration resulted in 19 parameter sets for the adenoma-carcinoma pathway and 13 for the serrated pathway that match the age- and sex-specific adenoma and serrated lesion prevalence in the COlonoscopy versus COlonography Screening (COCOS) trial, Dutch CRC incidence and mortality rates, and a number of other intermediate outcomes concerning characteristics of colorectal lesions. As an example, we simulated outcomes for a biennial fecal immunochemical test screening program and a hypothetical one-time colonoscopy screening program. Inclusion of the serrated pathway influenced the predicted effectiveness of screening when serrated lesions are associated with lower screening test sensitivity or when they are not removed. To our knowledge, this is the first model that explicitly includes the serrated pathway and characteristics of colorectal lesions. It is suitable for the evaluation of the (cost)effectiveness of potential screening strategies for CRC., (© 2013 Society for Risk Analysis.)

Background: Given the increasing burden on colonoscopy capacity, it has been suggested that faecal immunochemical test (FIT) results could guide surveillance colonoscopy intervals. Against this background, we have evaluated the test accuracy of single and double FIT sampling to detect colorectal cancer (CRC) and/or advanced adenomas in an asymptomatic colonoscopy-controlled high-risk population., Methods: Cohort study of asymptomatic high-risk patients (personal history of adenomas/CRC or family history of CRC), who provided one or two FITs before elective colonoscopy. Test accuracy of FIT for detection of CRC and advanced adenomas was determined (cut-off level 50 ng/ml)., Results: 1,041 patients provided a FIT (516 personal history of adenomas, 172 personal history of CRC and 353 family history of CRC). Five CRCs (0.5%) and 101 advanced adenomas (9.7%) were detected by colonoscopy. Single FIT sampling resulted in a sensitivity, specificity, PPV and NPV for CRC of 80%, 89%, 3% and 99.9%, respectively, and for advanced adenoma of 28%, 91%, 24% and 92%, respectively. Double FIT sampling did not result in a significantly higher sensitivity for advanced neoplasia. Simulation of multiple screening rounds indicated that sensitivity of FIT for advanced adenoma could reach 81% after 5 screening rounds., Conclusions: In once-only FIT sampling before surveillance colonoscopy, 70% of advanced neoplasia were missed. A simulation approach indicates that multiple screening rounds may be more promising in detecting advanced neoplasia and could potentially alleviate endoscopic burden.

Background: Colorectal cancer screening by fecal immunochemical tests (FITs) is hampered by frequent false-positive (FP) results and thereby the risk of complications and strain on colonoscopy capacity. Hemorrhoids might be a plausible cause of FP results., Objective: To determine the contribution of hemorrhoids to the frequency of FP FIT results., Design: Retrospective analysis from prospective cohort study., Setting: Five large teaching hospitals, including 1 academic hospital., Patients: All subjects scheduled for elective colonoscopy., Interventions: FIT before bowel preparation., Main Outcome Measurements: Frequency of FP FIT results in subjects with hemorrhoids as the only relevant abnormality compared with FP FIT results in subjects with no relevant abnormalities. Logistic regression analysis to determine colonic abnormalities influencing FP results., Results: In 2855 patients, 434 had positive FIT results: 213 had advanced neoplasia and 221 had FP results. In 9 individuals (4.1%; 95% CI, 1.4-6.8) with an FP FIT result, hemorrhoids were the only abnormality. In univariate unadjusted analysis, subjects with hemorrhoids as the only abnormality did not have more positive results (9/134; 6.7%) compared with subjects without any abnormalities (43/886; 4.9%; P = .396). Logistic regression identified hemorrhoids, nonadvanced polyps, and a group of miscellaneous abnormalities, all significantly influencing false positivity. Of 1000 subjects with hemorrhoids, 67 would have FP results, of whom 18 would have FP results because of hemorrhoids only., Limitations: Potential underreporting of hemorrhoids; high-risk individuals., Conclusions: Hemorrhoids in individuals participating in colorectal cancer screening will probably not lead to a substantial number of false-positive test results., (Copyright © 2012 American Society for Gastrointestinal Endoscopy. Published by Mosby, Inc. All rights reserved.)

Using a bioinformatics-based strategy, we set out to identify hypermethylated genes that could serve as biomarkers for early detection of colorectal cancer (CRC) in stool. In addition, the complementary value to a Fecal Immunochemical Test (FIT) was evaluated. Candidate genes were selected by applying cluster alignment and computational analysis of promoter regions to microarray-expression data of colorectal adenomas and carcinomas. DNA methylation was measured by quantitative methylation-specific PCR on 34 normal colon mucosa, 71 advanced adenoma, and 64 CRC tissues. The performance as biomarker was tested in whole stool samples from in total 193 subjects, including 19 with advanced adenoma and 66 with CRC. For a large proportion of these series, methylation data for GATA4 and OSMR were available for comparison. The complementary value to FIT was measured in stool subsamples from 92 subjects including 44 with advanced adenoma or CRC. Phosphatase and Actin Regulator 3 (PHACTR3) was identified as a novel hypermethylated gene showing more than 70-fold increased DNA methylation levels in advanced neoplasia compared with normal colon mucosa. In a stool training set, PHACTR3 methylation showed a sensitivity of 55% (95% CI: 33-75) for CRC and a specificity of 95% (95% CI: 87-98). In a stool validation set, sensitivity reached 66% (95% CI: 50-79) for CRC and 32% (95% CI: 14-57) for advanced adenomas at a specificity of 100% (95% CI: 86-100). Adding PHACTR3 methylation to FIT increased sensitivity for CRC up to 15%. PHACTR3 is a new hypermethylated gene in CRC with a good performance in stool DNA testing and has complementary value to FIT.

Background: A single sampled faecal immunochemical test (FIT) has moderate sensitivity for colorectal cancer and advanced adenomas. Repeated FIT sampling could improve test sensitivity. The aim of the present study is to determine whether any of three different strategies of double FIT sampling has a better combination of sensitivity and specificity than single FIT sampling., Methods: Test performance of single FIT sampling in subjects scheduled for colonoscopy was compared to double FIT sampling intra-individually. Test positivity of double FIT sampling was evaluated in three different ways: 1) "one of two FITs+" when at least one out of two measurements exceeded the cut-off value, 2) "two of two FITs+" when both measurements exceeded the cut-off value, 3) "mean of two FITs+" when the geometric mean of two FITs exceeded the cut-off value. Receiver operator curves were calculated and sensitivity of single and the three strategies of double FIT sampling were compared at a fixed level of specificity., Results: In 124 of 1096 subjects, screen relevant neoplasia (SRN) were found (i.e. early stage CRC or advanced adenomas). At any cut-off, "two of two FITs+" resulted in the lowest and "one of two FITs+" in the highest sensitivity for SRN (range 35-44% and 42%-54% respectively). ROC's of double FIT sampling were similar to single FIT sampling. At specificities of 85/90/95%, sensitivity of any double FIT sampling strategy did not differ significantly from single FIT (p-values 0.07-1)., Conclusion: At any cut off, "one of two FITs+" is the most sensitive double FIT sampling strategy. However, at a given specificity level, sensitivity of any double FIT sampling strategy for SRN is comparable to single FIT sampling at a different cut-off value. None of the double FIT strategies has a superior combination of sensitivity and specificity over single FIT., (© 2011 Oort et al; licensee BioMed Central Ltd.)

Background: Adjusting the threshold for positivity of quantitative fecal immunochemical tests (FIT) allows for controlling the number of follow-up colonoscopies in a screening program. However, it is unknown to what extent higher cutoff levels affect detection rates of screen-relevant neoplasia. This study aimed to assess the effect of higher cutoff levels of a quantitative FIT on test positivity rate and detection rate of early-stage colorectal cancers (CRC)., Methods: Subjects above 40 years old scheduled for colonoscopy in 5 hospitals were asked to sample a single FIT (OC sensor) before colonoscopy. Screen-relevant neoplasia were defined as advanced adenoma or early-stage cancer (stage I and II). Positivity rate, sensitivity, and specificity were evaluated at increasing cutoff levels of 50 to 200 ng/mL., Results: In 2,145 individuals who underwent total colonoscopy, 79 patients were diagnosed with CRC, 38 of which were with early-stage disease. Advanced adenomas were found in 236 patients. When varying cutoff levels from ≥ 50 to ≥ 200 ng/mL, positivity rates ranged from 16.5% to 10.2%. With increasing cutoff levels, sensitivity for early-stage CRCs and for screen-relevant neoplasia ranged from 84.2% to 78.9% and 47.1% to 37.2%, respectively., Conclusions: Higher FIT cutoff levels substantially decrease test positivity rates with only limited effects on detection rates of early-stage CRCs. However, spectrum bias resulting in higher estimates of sensitivity than would be expected in a screening population may be present., Impact: Higher cutoff levels can reduce strain on colonoscopy capacity with only a modest decrease in sensitivity for curable cancers., (©2010 AACR.)

Background: Diagnosing colorectal cancer (CRC) at an early stage improves survival. To what extent any delay affects outcome once patients are symptomatic is still unclear.Our objectives were to evaluate the association between diagnostic delay and survival in symptomatic patients with early stage CRC and late stage CRC., Methods: Prospective population-based observational study evaluating daily clinical practice in Northern Holland. Diagnostic delay was determined through questionnaire-interviews. Dukes' stage was classified into two groups: early stage (Dukes A or B) and late stage (Dukes C or D) cancer. Patients were followed up for 3.5 years after diagnosis., Results: In total, 272 patients were available for analysis. Early stage CRC was present in 136 patients while 136 patients had late stage CRC. The mean total diagnostic delay (SE) was 31 (1.5) weeks in all CRC patients. No significant difference was observed in the mean total diagnostic delay in early versus late stage CRC (p = 0.27).In early stage CRC, no difference in survival was observed between patients with total diagnostic delay shorter and longer than the median (Kaplan-Meier, log-rank p = 0.93).In late stage CRC, patients with a diagnostic delay shorter than the median had a shorter survival than patients with a diagnostic delay longer than the median (log-rank p = 0.01). In the multivariate Cox regression model with survival as dependent variable and median delay, age, open access endoscopy, number and type of symptoms as independent variables, the odd's ratio for survival in patients with long delay (>median) versus short delay (