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Background & Aims: Colonoscopy-based surveillance to prevent colorectal cancer (CRC) causes substantial burden for patients and health care. Stool tests may help to reduce surveillance colonoscopies by limiting colonoscopies to individuals at increased risk of advanced neoplasia., Methods: This cross-sectional observational study included individuals aged 50-75 years with surveillance indication. Before bowel preparation, participants collected samples for a multitarget stool DNA test and 2 fecal immunochemical tests (FITs). Test accuracy was calculated for all surveillance indications. For the post-polypectomy indication only, which is the most common and is associated with a relatively low CRC risk, long-term impact of stool-based surveillance was evaluated with the Adenoma and Serrated Pathway to Colorectal Cancer (ASCCA) model. Stool-based strategies were simulated to tune each test's positivity threshold to obtain strategies at least as effective as colonoscopy surveillance., Results: There were 3453 individuals with results for all stool tests and colonoscopy; 2226 had previous polypectomy, 1003 had previous CRC, and 224 had a familial risk. Areas under the receiver operating characteristic curve for advanced neoplasia were 0.72 (95% CI, 0.69-0.75) for the multitarget stool DNA test, 0.61 (95% CI, 0.58-0.64) for the FIT OC-SENSOR (Eiken Chemical Co, Tokyo, Japan) and 0.59 (95% CI, 0.56-0.61) for the FIT FOB-Gold (Sentinel, Milan, Italy). Stool-based post-polypectomy surveillance strategies at least as effective as colonoscopy surveillance reduced the number of colonoscopies by 15%-41% and required 5.6-9.5 stool tests over a person's lifetime. Multitarget stool DNA-based surveillance was more costly than colonoscopy surveillance, whereas FIT-based surveillance saved costs., Conclusions: This study found that stool-based post-polypectomy surveillance strategies can be safe and cost-effective, with potential to reduce the number of colonoscopies by up to 41%., Clinicaltrials: gov, Number: NCT02715141., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background & Aims: The authors assessed whether familial colorectal cancer (FCRC) surveillance in individuals without hereditary CRC can be optimized METHODS: The Adenoma and Serrated Pathway to Colorectal Cancer (ASCCA)-FCRC model simulates CRC development in individuals with a family history of CRC at 2-fold and 4-fold increased CRC risk compared with the general population. The authors simulated a strategy without surveillance, the current Dutch guideline (5-yearly colonoscopy between ages 45 and 75 years), and the following 3 sets of alternative strategies: colonoscopy surveillance, surveillance combining colonoscopy and fecal immunochemical testing (FIT), and FIT-based surveillance. Each set included a range of strategies differing in age range and test interval. The optimal strategy was defined as the strategy with highest quality-adjusted life-years (QALYs) satisfying all of the following criteria: in the (near-)efficiency area of the cost-effectiveness frontier and compared with current surveillance; noninferior effectiveness; no substantial increase in colonoscopy burden; and not more expensive., Results: The optimal strategy was 10-yearly colonoscopy with 2-yearly FIT between colonoscopies from ages 40 to 80 years for both 2-fold and 4-fold increased CRC risk. At 2-fold risk, this strategy prevented 0.8 more CRC deaths, gained 15.8 more QALYs at 731 fewer colonoscopies, and saved €98,000 over the lifetime of 1000 individuals compared with current surveillance. At 4-fold risk, figures were 2.1 more CRC deaths prevented, 37.0 more QALYs gained at 567 fewer colonoscopies, and €127,000 lower costs. Current surveillance was not (near-)efficient., Conclusions: FIT could play an important role in FCRC surveillance. Surveillance with 10-yearly colonoscopy and 2-yearly FIT between colonoscopies from ages 40 to 80 years increased QALYs and reduced colonoscopy burden and costs compared with current FCRC surveillance., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Current patient selection for adjuvant chemotherapy (ACT) after curative surgery for stage II colon cancer (CC) is suboptimal, causing overtreatment of high-risk patients and undertreatment of low-risk patients. Postoperative circulating tumor DNA (ctDNA) could improve patient selection for ACT., Objectives: We conducted an early model-based evaluation of the (cost-)effectiveness of ctDNA-guided selection for ACT in stage II CC in the Netherlands to assess the conditions for cost-effective implementation., Methods: A validated Markov model, simulating 1000 stage II CC patients from diagnosis to death, was supplemented with ctDNA data. Five ACT selection strategies were evaluated: the current guideline (pT4, pMMR), ctDNA-only, and three strategies that combined ctDNA status with pT4 and pMMR status in different ways. For each strategy, the costs, life years, quality-adjusted life years (QALYs), recurrences, and CC deaths were estimated. Sensitivity analyses were performed to assess the impact of the costs of ctDNA testing, strategy adherence, ctDNA as a predictive biomarker, and ctDNA test performance., Results: Model predictions showed that compared to current guidelines, the ctDNA-only strategy was less effective (+2.2% recurrences, -0.016 QALYs), while the combination strategies were more effective (-3.6% recurrences, +0.038 QALYs). The combination strategies were not cost-effective, since the incremental cost-effectiveness ratio was €67,413 per QALY, exceeding the willingness-to-pay threshold of €50,000 per QALY. Sensitivity analyses showed that the combination strategies would be cost-effective if the ctDNA test costs were lower than €1500, or if ctDNA status was predictive of treatment response, or if the ctDNA test performance improved substantially., Conclusion: Adding ctDNA to current high-risk clinicopathological features (pT4 and pMMR) can improve patient selection for ACT and can also potentially be cost-effective. Future studies should investigate the predictive value of post-surgery ctDNA status to accurately evaluate the cost-effectiveness of ctDNA testing for ACT decisions in stage II CC., Competing Interests: S.J.S. received an institutional research grant from Personal Genome Diagnostics (PGDx). G.R.V. reported grants and/or nonfinancial support from BMS, Merck, Servier, Personal Genome Diagnostics, Bayer, Sirtex, Pierre Fabre, Lilly, Delfi Diagnostics, all outside the submitted work, and all financial supports transferred to the institute. J.P. is a founder of Delfi Diagnostics and owns Delfi Diagnostics stock. V.E.V. is a founder of Delfi Diagnostics, serves on the Board of Directors and as an officer for this organization, and owns Delfi Diagnostics stock, which is subject to certain restrictions under university policy. In addition, Johns Hopkins University owns equity in Delfi Diagnostics. V.E.V. divested his equity in Personal Genome Diagnostics (PGDx) to LabCorp in February 2022. V.E.V. is an inventor on patent applications submitted by Johns Hopkins University related to cancer genomic analyses and cell-free DNA for cancer detection that have been licensed to one or more entities, including Delfi Diagnostics, LabCorp, Qiagen, Sysmex, Agios, Genzyme, Esoterix, Ventana, and ManaT Bio. Under the terms of these license agreements, the University and inventors are entitled to fees and royalty distributions. V.E.V. is an advisor to Viron Therapeutics and Epitope. These arrangements have been reviewed and approved by Johns Hopkins University in accordance with its conflict-of-interest policies. D.v.d.B. has provided lectures, expert testimony, and advisory board presence, for Roche Diagnostics, all outside the submitted work and all financial supports transferred to the institute. M.K. reports having an advisory role for Eisai, Nordic Farma, Merck-Serono, Pierre Fabre, and Servier (vergoedingen naar instituut). Institutional scientific grants from Bayer, Bristol Myers Squibb, Merck, Personal Genome Diagnostics (PGDx), Pierre Fabre, Roche, Sirtex, and Servier. PI from the international cohort study PROMETCO with Servier as a sponsor. Non-financial interests: chair of the ESMO RWD-DH working group, co-chair DCCG, PI PLCRC (national observational cohort study), involved in several clinical trials as PI or co-investigator in CRC. G.A.M. is co-founder and board member (CSO) of CRCbioscreen BV, he has a research collaboration with CZ Health Insurances (cash matching to ZonMW grant), 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, and he has several patents pending/issued. J.M.L.R. is an advisory board and/or speaker at Bayer, BMS, Merck-Serono, Pierre Fabre, Servier, AMGEN, GSK, received research funding paid to the institution from BMS, Pierre Fabre, GSK, Servier, Cleara, HUB organoids B.V., Xilis, and is a board member of the Foundation Hubrecht Organoid Biobank. R.J.A.F. reports grants and nonfinancial support from Personal Genome Diagnostics (PGDx), DELFI Diagnostics, and Cergentis BV; grants from MERCK BV; and nonfinancial support from Pacific Biosciences, outside the submitted work. In addition, R.J.A.F. has several patents pending. V.P.R. received in the past 3 years an unrestricted grant from Intuitive BV, outside of the current work. The remaining authors declare no potential competing interests., (© The Author(s), 2024.)

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.)

Objectives: Self-monitoring and patient-initiated care (PIC) leads to fewer outpatient clinic visits in patients with established RA with low disease activity (LDA) while healthcare outcomes are similar. This study assesses the cost-effectiveness of PIC with self-monitoring., Methods: A 12-month randomized controlled trial was performed with 49 patients in the PIC with self-monitoring group (app-group) and 53 in usual care. The usual care group continued with preplanned visits. The app group had one planned follow-up visit after 12 months and monitored their RA disease activity in a smartphone app. Both groups could make additional appointments at liberty. We included adult RA patients with a disease duration of over 2 years, a disease activity score 28 (DAS28) below 3.2 that were stable on medication for at least 6 months. The effect measure, the DAS28, was measured at 12 months and healthcare resource usage and productivity losses were measured at 3, 6, 9 and 12 months., Results: There was no significant difference in mean change of DAS28 (-0.04 mean difference, 95% CI: -0.39, 0.30), nor a statistically significant difference in total costs (mean difference €514, 95% CI:-€266, €3690) in the app group compared with the usual care group. The probability that the app was cost-effective was 0.37 and 0.57 at a willingness-to-pay threshold of 0 and 50 000 €/point improvement DAS28, respectively., Conclusion: Although rheumatic care costs were significantly lower in the app group, total costs and effects of PIC with self-monitoring were not different from usual care in RA patients with LDA., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Background: Screening for colorectal cancer (CRC) decreases cancer burden through removal of precancerous lesions and early detection of cancer. The COVID-19 pandemic has disrupted organised CRC screening programs worldwide, with some programs completely suspending screening and others experiencing significant decreases in participation and diagnostic follow-up. This study estimated the global impact of screening disruptions on CRC outcomes, and potential effects of catch-up screening., Methods: Organised screening programs were identified in 29 countries, and data on participation rates and COVID-related changes to screening in 2020 were extracted where available. Four independent microsimulation models (ASCCA, MISCAN-Colon, OncoSim, and Policy1-Bowel) were used to estimate the long-term impact on CRC cases and deaths, based on decreases to screening participation in 2020. For countries where 2020 participation data were not available, changes to screening were approximated based on excess mortality rates. Catch-up strategies involving additional screening in 2021 were also simulated., Findings: In countries for which direct data were available, organised CRC screening volumes at a country level decreased by an estimated 1.3-40.5% in 2020. Globally, it is estimated that COVID-related screening decreases led to a deficit of 7.4 million fewer faecal screens performed in 2020. In the absence of any organised catch-up screening, this would lead to an estimated 13,000 additional CRC cases and 7,900 deaths globally from 2020 to 2050; 79% of the additional cases and 85% of additional deaths could have been prevented with catch-up screening, respectively., Interpretation: COVID-19-related disruptions to screening will cause excess CRC cases and deaths, but appropriately implemented catch-up screening could have reduced the burden by over 80%. Careful management of any disruption is key to improving the resilience of colorectal cancer screening programs., Funding: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by Cancer Council New South Wales, Health Canada, and Dutch National Institute for Public Health and Environment., Competing Interests: Karen Canfell is co-PI of an investigator-initiated trial of cervical screening, “Compass”, run by the Australian Centre for Prevention of Cervical Cancer (ACPCC), which is a government-funded not-for-profit charity. Compass receives infrastructure support from the Australian government and the ACPCC has received equipment and a funding contribution from Roche Molecular Diagnostics, USA. Karen Canfell is co-PI on a major implementation program Elimination of Cervical Cancer in the Western Pacific which has received support from the Minderoo Foundation and the Frazer Family Foundation and equipment donations from Cepheid Inc. Dr. Lew reports grants from National Health and Medical Research Council, during the conduct of the study. Dr. Feletto reports grants from National Health and Medical Research Council, outside the submitted work. Dr Coupé reports grants from Dutch Cancer Foundation, grants from Netherlands Organisation for Health Research and Development, and from Maag Lever Darm Stichting MLDS, outside the submitted work., (© 2023 The Authors.)

Background: Many screening programs for colorectal cancer (CRC) use the fecal immunochemical test (FIT) to triage individuals for colonoscopy. Although these programs reduce CRC incidence and CRC-related mortality, the detection of advanced precursor lesions (advanced adenomas and advanced serrated polyps) by FIT could be improved. As an alternative for FIT, the antibody-based multitargetFIT (mtFIT) has been proposed. The mtFIT measures three protein markers: hemoglobin, calprotectin, and serpin family F member 2. In a retrospective diagnostic accuracy study in a large colonoscopy-controlled series (n = 1284), mtFIT showed increased sensitivity for advanced neoplasia (AN), at equal specificity, compared to FIT (42.9% versus 37.3%; p = 0.025). This increase was mainly due to a higher sensitivity of mtFIT for advanced adenomas (37.8% versus 28.1% for FIT; p = 0.006). The present mtFIT study aims to prospectively validate these findings in the context of the Dutch national CRC screening program., Method: The mtFIT study is a cross-sectional intervention study with a paired design. Eligible subjects for the Dutch FIT-based national CRC screening program are invited to perform mtFIT in addition to FIT. Samples are collected at home, from the same bowel movement, and are shipped to a central laboratory by postal mail. If either one or both tests are positive, participants are referred for colonoscopy. Detailed colonoscopy and pathology data are centrally stored in a national screening database (ScreenIT; Topicus, Deventer, the Netherlands) that is managed by the screening organization, and will be retrieved for this study. We aim to determine the relative sensitivity for AN, comprising of CRC, advanced adenomas and advanced serrated polyps, of mtFIT compared to FIT at an equal positivity rate. Additionally, we will use the Adenoma and Serrated Pathway to Colorectal CAncer model to predict lifetime health effects and costs for programmatic mtFIT- versus FIT-based screening. The target sample size is 13,131 participants., Discussion: The outcome of this study will inform on the comparative clinical utility of mtFIT versus FIT in the Dutch national CRC screening program and is an important step forward in the development of a new non-invasive stool test for CRC screening., Trial Registration: Clinicaltrials.gov ; NCT05314309, registered April 6th 2022, first inclusions March 25th 2022 https://clinicaltrials.gov/ct2/results?cond=&term=NCT05314309&cntry=&state=&city=&dist =., (© 2022. The Author(s).)

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.)

Measurable residual disease (MRD) measured using multiparameter flow-cytometry (MFC) has proven to be an important prognostic biomarker in acute myeloid leukemia (AML). In addition, MRD is increasingly used to guide consolidation treatment towards a non-allogenic stem cell transplantation treatment for MRD-negative patients in the ELN-2017 intermediate risk group. Currently, measurement of MFC-MRD in bone marrow is used for clinical decision making after 2 cycles of induction chemotherapy. However, measurement after 1 cycle has also been shown to have prognostic value, so the optimal time point remains a question of debate. We assessed the independent prognostic value of MRD results at either time point and concordance between these for 273 AML patients treated within and according to the HOVON-SAKK 92, 102, 103 and 132 trials. Cumulative incidence of relapse, event free survival and overall survival were significantly better for MRD-negative (<0.1%) patients compared to MRD-positive patients after cycle 1 and cycle 2 ( p ≤ 0.002, for all comparisons). A total of 196 patients (71.8%) were MRD-negative after cycle 1, of which the vast majority remained negative after cycle 2 (180 patients; 91.8%). In contrast, of the 77 MRD-positive patients after cycle 1, only 41 patients (53.2%) remained positive. A cost reduction of -€571,751 per 100 patients could be achieved by initiating the donor search based on the MRD-result after cycle 1. This equals to a 50.7% cost reduction compared to the current care strategy in which the donor search is initiated for all patients. These results show that MRD after cycle 1 has prognostic value and is highly concordant with MRD status after cycle 2. When MRD-MFC is used to guide consolidation treatment (allo vs non-allo) in intermediate risk patients, allogeneic donor search may be postponed or omitted after cycle 1. Since the majority of MRD-negative patients remain negative after cycle 2, this could safely reduce the number of allogeneic donor searches and reduce costs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tettero, Al-Badri, Ngai, Bachas, Breems, van Elssen, Fischer, Gjertsen, van Gorkom, Gradowska, Greuter, Griskevicius, Juliusson, Maertens, Manz, Pabst, Passweg, Porkka, Löwenberg, Ossenkoppele, Janssen and Cloos.)

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.)

Competing Interests: R. Bisschops has received consultancy and speaker’s fees from Fujifilm and Pentax (both 2015 to present); his department has received research grants from Fujifilm and Pentax (both 2015 to present). 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). C. Hassan has received research support from Fujifilm (2017 to present); his department has received support from Sonoscape. M. Dinis-Ribeiro is co-editor in-chief of Endoscopy. V.M.H. Coupé, M.J.E. Greuter, Y. Hazewinkel, B.B.S.L. Houwen, and J.L.A. Vleugels declare that they have no conflict of interest.

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.

Background: To explore the potential value of consensus molecular subtypes (CMS) in stage II colon cancer treatment selection, we carried out an early cost-effectiveness assessment of a CMS-based strategy for adjuvant chemotherapy., Methods: We used a Markov cohort model to evaluate three selection strategies: (i) the Dutch guideline strategy (MSS+pT4), (ii) the mutation-based strategy (MSS plus a BRAF and/or KRAS mutation or MSS plus pT4), and (iii) the CMS-based strategy (CMS4 or pT4). Outcomes were number of colon cancer deaths per 1,000 patients, total discounted costs per patient (pp), and quality-adjusted life-years (QALY) pp. The analyses were conducted from a Dutch societal perspective. The robustness of model predictions was assessed in sensitivity analyses. To evaluate the value of future research, we performed a value of information (VOI) analysis., Results: The Dutch guideline strategy resulted in 8.10 QALYs pp and total costs of €23,660 pp. The CMS-based and mutation-based strategies were more effective and more costly, with 8.12 and 8.13 QALYs pp and €24,643 and €24,542 pp, respectively. Assuming a threshold of €50,000/QALY, the mutation-based strategy was considered as the optimal strategy in an incremental analysis. However, the VOI analysis showed substantial decision uncertainty driven by the molecular markers (expected value of partial perfect information: €18M)., Conclusions: On the basis of current evidence, our analyses suggest that the mutation-based selection strategy would be the best use of resources. However, the extensive decision uncertainty for the molecular markers does not allow selection of an optimal strategy at present., Impact: Future research is needed to eliminate decision uncertainty driven by molecular markers., (©2021 American Association for Cancer Research.)

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.)

Background: We aimed to evaluate the cost-effectiveness of risk-based strategies to improve the selection of surgically treated stage II colon cancer (CC) patients for adjuvant chemotherapy., Methods: Using the 'Personalized Adjuvant TreaTment in EaRly stage coloN cancer' (PATTERN) model, we evaluated five selection strategies: (1) no chemotherapy, (2) Dutch guideline recommendations assuming observed adherence, (3) Dutch guideline recommendations assuming perfect adherence, (4) biomarker mutation OR pT4 stage strategy in which patients with MSS status combined with a pT4 stage or a mutation in BRAF and/or KRAS receive chemotherapy assuming perfect adherence and (5) biomarker mutation AND pT4 stage strategy in which patients with MSS status combined with a pT4 stage tumor and a BRAF and/or KRAS mutation receive chemotherapy assuming perfect adherence. Outcomes were number of CC deaths per 1000 patients and total discounted costs and quality-adjusted life-years (QALYs) per patient (pp). Analyses were conducted from a societal perspective. The robustness of model predictions was assessed in sensitivity analyses., Results: The reference strategy, that is, no adjuvant chemotherapy, resulted in 139 CC deaths in a cohort of 1000 patients, 8.077 QALYs pp and total costs of €22,032 pp. Strategies 2-5 were more effective (range 8.094-8.217 QALYs pp and range 118-136 CC deaths per 1000 patients) and more costly (range €22,404-€25,102 pp). Given a threshold of €50,000/QALY, the optimal use of resources would be to treat patients with either the full adherence strategy and biomarker mutation OR pT4 stage strategy., Conclusion: Selection of stage II CC patients for chemotherapy can be improved by either including biomarker status in the selection strategy or by improving adherence to the Dutch guideline recommendations., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest., (© The Author(s), 2021.)

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.)

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: Our aim was to evaluate the cost effectiveness of 3 months' adjuvant chemotherapy versus 6 months in high-risk (T4 stage + microsatellite stable) stage II colon cancer (CC) patients., Methods: Using the validated PATTERN Markov cohort model, which simulates the disease progression of stage II CC patients from diagnosis to death, we first evaluated a reference strategy in which high-risk patients were treated with chemotherapy for 6 months. In the second strategy, treatment duration was shortened to 3 months. Both strategies were evaluated for CAPOX (capecitabine plus oxaliplatin) and FOLFOX (fluorouracil, leucovorin and oxaliplatin). Based on trial data, we assumed that shortened treatment duration compared with a 6-month regimen was equally effective for CAPOX and less effective for FOLFOX. Adverse events were highest in the 6-month strategy. Analyses were conducted from a societal perspective using a lifelong time horizon. Outcomes were number of CC deaths per 1000 patients and total discounted costs and quality-adjusted life-years (QALYs) per patient (pp). Incremental net monetary benefit (iNMB) was calculated using a willingness-to-pay value of €50,000/QALY., Results: For CAPOX, the 6-month strategy resulted in 316 CC deaths per 1000 patients, 6.71 QALYs pp and total costs of €41,257 pp. The 3-month strategy resulted in an equal number of CC deaths, but higher QALYs (6.80 pp) and lower costs (€37,645 pp), leading to a iNMB of €8454 per person for 3 months versus 6 months. For FOLFOX, the 6-month strategy resulted in 316 CC deaths per 1000 patients, 6.71 QALYs pp and total costs of €47,135 pp. The 3-month strategy resulted in more CC deaths (393), lower QALYs (6.19 pp) and lower costs (€44,389 pp). An iNMB of -€23,189 was found for 3 months versus 6 months., Conclusion: Our findings indicate that 3 months' adjuvant chemotherapy should be considered as standard of care in high-risk stage II CC patients for CAPOX, but not for FOLFOX., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest., (© The Author(s), 2020.)

Aim: To develop a decision model for the population-level evaluation of strategies to improve the selection of stage II colon cancer (CC) patients who benefit from adjuvant chemotherapy., Methods: A Markov cohort model with a one-month cycle length and a lifelong time horizon was developed. Five health states were included; diagnosis, 90-day mortality, death other causes, recurrence and CC death. Data from the Netherlands Cancer Registry were used to parameterize the model. Transition probabilities were estimated using parametric survival models including relevant clinical and pathological covariates. Subsequently, biomarker status was implemented using external data. Treatment effect was incorporated using pooled trial data. Model development, data sources used, parameter estimation, and internal and external validation are described in detail. To illustrate the use of the model, three example strategies were evaluated in which allocation of treatment was based on (A) 100% adherence to the Dutch guidelines, (B) observed adherence to guideline recommendations and (C) a biomarker-driven strategy., Results: Overall, the model showed good internal and external validity. Age, tumor growth, tumor sidedness, evaluated lymph nodes, and biomarker status were included as covariates. For the example strategies, the model predicted 83, 87 and 77 CC deaths after 5 years in a cohort of 1000 patients for strategies A, B and C, respectively., Conclusion: This model can be used to evaluate strategies for the allocation of adjuvant chemotherapy in stage II CC patients. In future studies, the model will be used to estimate population-level long-term health gain and cost-effectiveness of biomarker-based selection strategies.

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.

There is an ongoing discussion regarding the impact of adjuvant chemotherapy in Stage II colon cancer. We therefore estimated adjuvant treatment effect in Stage II colon cancer using pooled disease-free survival (DFS) data from randomized clinical trials (RCT approach) and compared this to real-world data (RWD approach) estimates. First, we estimated the treatment effect in RCTs by (i) searching relevant trials reporting DFS data, (ii) generating patient-level data from reported DFS data and (iii) estimating treatment effect in the patient-level data. Second, the treatment effect was estimated in an observational cohort of 1,947 patients provided by the Netherlands Cancer Registry using three propensity score methods; matching, weighting and stratification. In the RCT approach, patient-level data of 4,489 patients (events: 853) were generated from seven trials which compared two of the following treatment arms: control, 5FU/LV or FOLFOX. A Cox model was used to estimate a hazard ratio (HR) of 0.77 (0.43;1.10) for 5FU/LV vs. control and 0.93 (0.72;1.15) for FOLFOX vs. 5FU/LV. In the RWD approach, HRs for any adjuvant treatment vs. control were 0.95 (0.50;1.80), 0.88 (0.24;3.21) and 1.05 (0.04;2.06) using matching, weighting and stratification, respectively. There was no significant difference with the estimates from the RCT approach (interaction test, p > 0.10). The RCT data suggest a clinically relevant benefit of adjuvant chemotherapy in terms of DFS, but the estimate did not reach statistical significance. Stratified analyses are required to evaluate whether treatment effect differs in specific subgroups., (© 2019 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Multiple platforms are commercially available for the detection of circulating cell-free tumour DNA (ctDNA) from liquid biopsies. Since platforms have different input and output variables, deciding what platform to use for a given clinical or research question can be daunting. This study aimed to provide insight in platform selection criteria by comparing four commercial platforms that detect KRAS ctDNA hotspot mutations: Bio-Rad droplet digital PCR (ddPCR), BioCartis Idylla, Roche COBAS z480 and Sysmex BEAMing. Platform sensitivities were determined using plasma samples from metastatic colorectal cancer (mCRC) patients and synthetic reference samples, thereby eliminating variability in amount of plasma analysed and ctDNA isolation methods. The prevalence of KRAS nucleotide alterations was set against platform-specific breadth of target. Platform comparisons revealed that ddPCR and BEAMing detect more KRAS mutations amongst mCRC patients than Idylla and COBAS z480. Maximum sample throughput was highest for ddPCR and COBAS z480. Total annual costs were highest for BEAMing and lowest for Idylla and ddPCR. In conclusion, when selecting a platform for detection of ctDNA hotspot mutations the desired test sensitivity, breadth of target, maximum sample throughput, and total annual costs are critical factors that should be taken into consideration. Based on the results of this study, laboratories will be able to select the optimal platform for their needs.

Background: The Australian National Bowel Cancer Screening Program (NBCSP) is rolling out 2-yearly immunochemical fecal occult blood test screening in people aged 50 to 74 years. This study aimed to evaluate the benefits, harms, and cost-effectiveness of extending the NBCSP to younger and/or older ages., Methods: A comprehensive validated microsimulation model, Policy1-Bowel, was used to simulate the fully rolled-out NBCSP and alternative strategies assuming screening starts at 40 or 45 years and/or ceases at 79 or 84 years given three scenarios: (i) perfect adherence (100%), (ii) high adherence (60%), and (ii) low adherence (40%, as currently achieved)., Results: The current NBCSP will reduce colorectal cancer incidence (mortality) by 23% to 51% (36% to 74%) compared with no screening (range reflects participation); extending screening to younger or older ages would result in additional reductions of 2 to 6 (2 to 9) or 1 to 3 (3 to 7) percentage points, respectively. With an indicative willingness-to-pay threshold of A$50,000/life-year saved (LYS), only screening from 50 to 74 years [incremental cost-effective ratio (ICER): A$2,984-5,981/LYS) or from 45 to 74 years (ICER: A$17,053-29,512/LYS) remained cost-effective in all participation scenarios. The number-needed-to-colonoscope to prevent a death over the lifetime of a cohort in the current NBCSP is 35 to 49. Starting screening at 45 years would increase colonoscopy demand for program-related colonoscopies by 3% to 14% and be associated with 55 to 170 additional colonoscopies per additional death prevented., Conclusions: Starting screening at 45 years could be cost-effective, but it would increase colonoscopy demand and would be associated with a less favorable incremental benefits-to-harms trade-off than screening from 50 to 74 years., Impact: The study underpins recently updated Australian colorectal cancer management guidelines that recommend that the NBCSP continues to offer bowel screening from 50 to 74 years., (©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 and Study Aims:  In an optical diagnosis strategy, diminutive polyps that are endoscopically characterized with high confidence are removed without histopathological analysis and distal hyperplastic polyps are left in situ. We evaluated the effectiveness and costs of optical diagnosis., Methods:  Using the Adenoma and Serrated pathway to Colorectal CAncer (ASCCA) model, we simulated biennial fecal immunochemical test (FIT) screening in individuals aged 55 - 75 years. In this program, we compared an optical diagnosis strategy with current histopathology assessment of all diminutive polyps. Base-case assumptions included 76 % high-confidence predictions and sensitivities of 88 %, 91 %, and 88 % for endoscopically characterizing adenomas, sessile serrated polyps, and hyperplastic polyps, respectively. Outcomes were colorectal cancer burden, number of colonoscopies, life-years, and costs., Results:  Both the histopathology strategy and the optical diagnosis strategy resulted in 21 life-days gained per simulated individual compared with no screening. For optical diagnosis, €6 per individual was saved compared with the current histopathology strategy. These cost savings were related to a 31 % reduction in colonoscopies in which histopathology was needed for diminutive polyps. Projecting these results onto the Netherlands (17 million inhabitants), assuming a fully implemented FIT-based screening program, resulted in an annual undiscounted cost saving of € 1.7 - 2.2 million for optical diagnosis., Conclusion:  Implementation of optical diagnosis in a FIT-based screening program saves costs without decreasing program effectiveness when compared with current histopathology analysis of all diminutive polyps. Further work is required to evaluate how endoscopists participating in a screening program should be trained, audited, and monitored to achieve adequate competence in optical diagnosis.

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.)