Marjolein J. E. Greuter

Modeling the Adenoma and Serrated Pathway to Colorectal CAncer (ASCCA)

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.

Long-term evaluation of benefits, harms, and cost-effectiveness of the National Bowel Cancer Screening Program in Australia: a modelling study

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

The potential of imaging techniques as a screening tool for colorectal cancer: a cost-effectiveness analysis

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

Long-Term Impact of the Dutch Colorectal Cancer Screening Program on Cancer Incidence and Mortality—Model-Based Exploration of the Serrated Pathway

1·7 billion, AUS

Implementation of an optical diagnosis strategy saves costs and does not impair clinical outcomes of a fecal immunochemical test-based colorectal cancer screening program

2·0 billion, and AUS

Screening for Colorectal Cancer With Fecal Immunochemical Testing With and Without Postpolypectomy Surveillance Colonoscopy: A Cost-Effectiveness Analysis.

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.

Evaluation of the benefits, harms and cost-effectiveness of potential alternatives to iFOBT testing for colorectal cancer screening in Australia: Alternatives to iFOBT testing for bowel screening

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.

Impact of differences in adenoma and proximal serrated polyp detection rate on the long-term effectiveness of FIT-based colorectal cancer screening

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. Cancer Epidemiol Biomarkers Prev; 25(1); 135–44. ©2015 AACR.

Cost-effectiveness of response evaluation after chemoradiation in patients with advanced oropharyngeal cancer using (18)F-FDG-PET-CT and/or diffusion-weighted MRI

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.

Long-Term Impact of the Dutch Colorectal Cancer Screening Programme on Cancer Incidence: Exploration of the Serrated Pathway

Several countries have implemented a colorectal cancer (CRC) screening program, often in addition to an existing colonoscopy surveillance program. Although robust evidence shows that screening considerably reduces CRC mortality (13), the effect of surveillance is less clear. Observational studies have shown that persons who undergo polypectomy have an increased risk for CRC compared with the general population (4, 5). Standardized incidence ratios of 1.26 and 1.40 have been reported (6, 7), suggesting that surveillance is justified in this subgroup. Surveillance for persons with lesions at colonoscopy is recommended, but the benefit of surveillance in a screening setting has thus far not been assessed. Optimizing surveillance intervals in persons at different levels of CRC risk is challenging, as reflected by the variation in surveillance guidelines (812). The NPS (National Polyp Study), the only published trial to date that compared 2 different surveillance intervals, concluded that the interval can be at least 3 years (13). Ideally, the interval would be as long as possible while still being considered safe. The recently begun EPoS (European Polyp Surveillance) trial aims to determine the optimal surveillance strategy by randomly assigning participants to different surveillance intervals based on colonoscopy findings (14). Although the results are likely to increase our understanding of optimal surveillance strategies, data collection is scheduled to end no earlier than 2028. Given that prospective data on surveillance are limited and will remain so for some time, we used the ASCCA (Adenoma and Serrated pathway to Colorectal CAncer) model to address the following questions. First, what is the additional benefit of colonoscopy surveillance in a screening setting? Second, what is the colonoscopy demand associated with screening plus surveillance, and how does this relate to that of screening without surveillance? Finally, how do changes in surveillance intervals affect the benefit and colonoscopy demand associated with surveillance? Supplement. CHEERS Checklist Methods ASCCA Model The ASCCA model has been described extensively elsewhere (15). In brief, the model simulates Dutch persons from age 20 years to age 90 years or death, whichever comes first. During their lives, persons are at risk for up to 10 adenomas and 10 serrated lesions. When a colorectal lesion arises, it is assigned such characteristics as location, morphology, dysplasia, and histology. The development of each lesion in terms of growth and malignant characteristics is modeled independently. When a lesion progresses to advanced adenoma or arises as a sessile serrated adenoma, it can progress to CRC. We assumed that 15% of CRC cases develop from serrated lesions (serrated pathway) (1622). Each year, a tumor may be detected or may progress to a more advanced stage. Four stages for both asymptomatic and symptomatic CRC are included. An overview of natural history parameters is provided in Appendix Table 1, and a flow chart of the model is shown in Appendix Figure 1. The natural history model satisfactorily reproduces Dutch colorectal lesion prevalence rates (23) as well as Dutch CRC incidence and mortality rates in the absence of screening (Appendix Figures 2 and 3) (24). Of note, the lifetime CRC risk without screening in the U.S. population is similar to that in the Dutch population (23). The model is supplemented with a flexible screening-and-surveillance component that can evaluate a range of strategies. Parameters of the screening-and-surveillance component are updated regularly using the results of the national monitor of the Dutch CRC screening program. Appendix Table 1. Overview of Natural History Parameters of the ASCCA Model* Appendix Figure 1. Flow chart of the ASCCA model. Adapted from Greuter and colleagues (15). ASCCA = Adenoma and Serrated pathway to Colorectal CAncer; CRC = colorectal cancer; HP = hyperplastic polyp; SSA = sessile serrated adenoma. *Advanced adenoma is a definition and not a state in the model. Appendix Figure 2. Model-predicted prevalence of detected adenomas in men (top) and women (bottom) for the lowest and highest fitting incidence set and an intermediate set. Error bars indicate 95% CIs. Adapted from Greuter and colleagues (15). COCOS = COlonoscopy versus COlonography Screening trial. Appendix Figure 3. Model-predicted incidence of CRC in men (top) and women (bottom) for the lowest- and highest-prevalence parameter set that most closely approximates CRC incidence in 2009 according to the Netherlands Cancer Registry. Incidence curves from other years are similar to this one. Adapted from Greuter and colleagues (15). CRC = colorectal cancer. Strategies In the reference strategy, persons do not have screening or surveillance. Those who develop CRC may initiate treatment after becoming symptomatic. Five additional strategies were simulated: fecal immunochemical test (FIT) screening without colonoscopy surveillance; FIT screening plus colonoscopy surveillance performed according to the Dutch guideline; or FIT screening plus colonoscopy surveillance, with surveillance intervals extended to 5 years for all persons at increased risk, 5 years for those at high risk and 10 years for those at intermediate risk, or 10 years for all persons at increased risk. Screening Screening was modeled according to the Dutch CRC screening program. Model evaluations have shown that FIT screening is the strategy of choice in the Netherlands (25, 26). The Dutch screening program consists of biennial FIT screening in asymptomatic persons aged 55 to 75 years without a prior CRC diagnosis. We assumed a screening participation rate of 72.6% (27) (national monitor of the Dutch CRC screening program. Unpublished data). Persons with a positive FIT result are referred to screening colonoscopy (FIT-positive colonoscopy). Both the FIT and the FIT-positive colonoscopy are considered part of screening. During colonoscopy, all detected lesions are removed by polypectomy, except for small hyperplastic polyps located in the rectosigmoid (8, 28). We assumed that 92% of persons with a positive FIT result have this procedure (7) (national monitor of the Dutch CRC screening program. Unpublished data). No Surveillance In the strategy of FIT screening without colonoscopy surveillance, all persons considered to be at low risk for metachronous lesions after FIT-positive colonoscopy return for screening in 10 years. Those at intermediate or high risk for metachronous lesions return for screening immediately after polypectomy and are reinvited for FIT 2 years later. Surveillance The Dutch surveillance guideline recommends calculation of a risk score based on the number of colorectal lesions as well as the presence of large lesions, adenomas with villous components, and proximal adenomas detected during colonoscopy (Table 1) (8). Persons with a score of 0 at FIT-positive colonoscopy (low-risk persons) are referred back to screening after 10 years, and those at intermediate or high risk enter the surveillance program. The surveillance interval is 5 years for persons considered to be at intermediate risk (score of 1 to 2) and 3 years for those at high risk (score 3). Table 1. Dutch Surveillance Guideline* In addition to screening plus surveillance performed according to the Dutch guideline, we simulated 3 strategies that differed from the guideline with respect to surveillance intervals. First, we set the interval for the intermediate- and high-risk groups at 5 years. Second, we used intervals of 10 years for the intermediate-risk group and 5 years for the high-risk group. Finally, we set the interval for both groups at 10 years. For all surveillance colonoscopies, we assumed a 92% participation rate, identical to that for FIT-positive screening colonoscopy. We also assumed that surveillance ended when the patient had 2 negative results on surveillance colonoscopy in combination with risk scores less than 3 points or when the patient reached age 75 years. CRC Risk in the Surveillance Population The benefit of surveillance in addition to screening depends on the increase in adenoma and CRC risk in the surveillance population compared with the screening population. To allow appropriate judgment of the results of our study, we first obtained adenoma prevalence and CRC incidence curves for both the general population and the surveillance population by tracking the characteristics of persons considered to be at intermediate or high risk after FIT-positive colonoscopy. We then set up the model to simulate a cohort of 20000000 persons with these characteristics who did not undergo screening or surveillance. Outcomes were age-specific adenoma prevalence and CRC incidence. Test Characteristics Table 2 provides an overview of test characteristics related to screening, surveillance, and treatment. Lesion-specific test characteristics for FIT (cutoff of 75 ng/mL) were obtained from a Dutch FIT screening trial (32) following a previously reported calibration procedure (15). Colonoscopy detection rates were derived from a systematic review on adenoma miss rates (33). Because detection rates for serrated lesions are not reported but are likely to be lower than for adenomas (40, 41), we assigned a 10% lower detection rate to serrated lesions than for adenomas. We also assumed that colonoscopy was associated with a small risk for complications (38). Table 2. Participation Rates, Test Characteristics, and Costs Costs Costs were determined from a health care payer perspective (Appendix Figure 4) (42) and were converted to 2016 euros using the consumer price index for that year (43). To facilitate comparison of our results, costs are also reported in the tables in 2015 U.S. dollars using the purchasing power parity for that year (1 euro= 1.13 U.S. dollars) (44). Appendix Figure 4. Impact inventory for determining perspective of economic evaluation (42). NA = not applicable. *Categor