Personalized Multilevel Intervention for Improving Appropriate Use of Colorectal Cancer Screening in Older Adults: A Cluster Randomized Clinical Trial.

Importance: Despite guideline recommendations, clinicians do not systematically use prior screening or health history to guide colorectal cancer (CRC) screening decisions in older adults. Objective: To evaluate the effect of a personalized multilevel intervention on screening orders in older adults due for average-risk CRC screening. Design, Setting, and Participants: Interventional 2-group parallel unmasked cluster randomized clinical trial conducted from November 2015 to February 2019 at 2 US Department of Veterans Affairs (VA) facilities: 1 academic VA medical center and 1 of its connected outpatient clinics. Randomization at the primary care physician/clinician (PCP) level, stratified by study site and clinical full-time equivalency. Participants were 431 average-risk, screen-due US veterans aged 70 to 75 years attending a primary care visit. Data analysis was performed from August 2018 to August 2023. Intervention: The intervention group received a multilevel intervention including a decision-aid booklet with detailed information on screening benefits and harms, personalized for each participant based on age, sex, prior screening, and comorbidity. The control group received a multilevel intervention including a screening informational booklet. All participants received PCP education and system-level modifications to support personalized screening. Main Outcomes and Measures: The primary outcome was whether screening was ordered within 2 weeks of clinic visit. Secondary outcomes were concordance between screening orders and screening benefit and screening utilization within 6 months. Results: A total of 436 patients were consented, and 431 were analyzed across 67 PCPs. Patients had a mean (SD) age of 71.5 (1.7) years; 424 were male (98.4%); 374 were White (86.8%); 89 were college graduates (21.5%); and 351 (81.4%) had undergone prior screening. A total of 258 (59.9%) were randomized to intervention, and 173 (40.1%) to control. Screening orders were placed for 162 of 258 intervention patients (62.8%) vs 114 of 173 control patients (65.9%) (adjusted difference, -4.0 percentage points [pp]; 95% CI, -15.4 to 7.4 pp). In a prespecified interaction analysis, the proportion receiving orders was lower in the intervention group than in the control group for those in the lowest benefit quartile (59.4% vs 71.1%). In contrast, the proportion receiving orders was higher in the intervention group than in the control group for those in the highest benefit quartile (67.6% vs 52.2%) (interaction P = .049). Fewer intervention patients (106 of 256 [41.4%]) utilized screening overall at 6 months than controls (96 of 173 [55.9%]) (adjusted difference, -13.4 pp; 95% CI, -25.3 to -1.6 pp). Conclusions and Relevance: In this cluster randomized clinical trial, patients who were presented with personalized information about screening benefits and harms in the context of a multilevel intervention were more likely to receive screening orders concordant with benefit and were less likely to utilize screening. Trial Registration: ClinicalTrials.gov Identifier: NCT02027545.

Cost-effectiveness of pembrolizumab for the first-line treatment of patients with unresectable or metastatic MSI-H/dMMR colorectal cancer in the United States.

AIMS: Approximately, 4% of Stage IV colorectal cancers (CRC) are microsatellite instability-high (MSI-H)/deficient mismatch repair (dMMR) tumors. Patients with metastatic MSI-H/dMMR CRC receiving conventional therapies experience lower response rates and tend to have worse overall survival compared with patients with microsatellite stable (MSS)/proficient mismatch repair (pMMR) CRC. Pembrolizumab received FDA approval in 2020 for first-line treatment of Stage IV MSI-H/dMMR CRC based on significantly longer progression-free survival versus standard of care (SoC, 5-fluorouracil-based therapy with or without bevacizumab or cetuximab). This study evaluated the cost-effectiveness of pembrolizumab vs. SoC as per KEYNOTE-177 and other first-line treatments for MSI-H/dMMR CRC from a US healthcare system perspective. METHODS: A three-health-state partitioned-survival model was built using progression-free and overall survival data from KEYNOTE-177 and a network meta-analysis. Utilities were derived from KEYNOTE-177 EQ-5D-3L data. Drug acquisition, administration, AE, surgery, monitoring, subsequent treatment, and terminal care costs were included. Sensitivity and scenario analyses were performed, including utilizing a state-transition model structure and adopting a societal perspective. RESULTS: Over a lifetime time horizon, pembrolizumab and SoC were associated with total QALYs of 4.85 and 3.23, and total costs of $381,735 and $370,465, respectively, resulting in an ICER of $6,984 per QALY. QALY gains were mainly driven by extended survival with pembrolizumab. Pembrolizumab incurred higher drug acquisition costs relative to SoC but was cost-saving in terms of drug administration, AE, monitoring, subsequent treatment, and terminal care. Pembrolizumab dominated FOLFOX + panitumumab, FOLFOXIRI, and FOLFOXIRI + bevacizumab, and presented ICERs of $35,220 and $276 against XELOX and XELOX + bevacizumab. Results were robust to sensitivity and scenario analyses. CONCLUSION: Pembrolizumab is highly cost-effective for the first-line treatment of unresectable or metastatic MSI-H/dMMR CRC in the US at a willingness-to-pay threshold of $100,000/QALY.Key messagesPembrolizumab is a highly cost-effective option for the first-line treatment of patients with unresectable or metastatic MSI-H/dMMR colorectal cancer in the United States at a willingness-to-pay threshold of $100,000. Compared with the current standard of care for these patients, pembrolizumab:Increases survival due to delaying and preventing progression;Increases QALYs due to longer survival, improvement in HRQoL in the progression-free health state, and fewer Grade 3+ adverse events;Reduces costs associated with administering treatment, managing adverse events, monitoring post-progression disease, providing subsequent treatment, and providing terminal care; andReduces indirect health care costs when taking a societal perspective due to productivity gains from delaying and preventing progression and death, less frequent treatment administration and less frequent Grade 3+ adverse events.

Real-Time Monitoring of Results During First Year of Dutch Colorectal Cancer Screening Program and Optimization by Altering Fecal Immunochemical Test Cut-Off Levels.

BACKGROUND & AIMS: After careful pilot studies and planning, the national screening program for colorectal cancer (CRC), with biennial fecal immunochemical tests (FITs), was initiated in The Netherlands in 2014. A national information system for real-time monitoring was developed to allow for timely evaluation. Data were collected from the first year of this screening program to determine the importance of planning and monitoring for optimal screening program performance. METHODS: The national information system of the CRC screening program kept track of the number of invitations sent in 2014, FIT kits returned, and colonoscopies performed. Age-adjusted rates of participation, the number of positive test results, and positive predictive values (PPVs) for advanced neoplasia were determined weekly, quarterly, and yearly. RESULTS: In 2014, there were 741,914 persons invited for FIT; of these, 529,056 (71.3%; 95% CI, 71.2%-71.4%) participated. A few months into the program, real-time monitoring showed that rates of participation and positive test results (10.6%; 95% CI, 10.5%-10.8%) were higher than predicted and the PPV was lower (42.1%; 95% CI, 41.3%-42.9%) than predicted based on pilot studies. To reduce the burden of unnecessary colonoscopies and alleviate colonoscopy capacity, the cut-off level for a positive FIT result was increased from 15 to 47 µg Hb/g feces halfway through 2014. This adjustment decreased the percentage of positive test results to 6.7% (95% CI, 6.6%-6.8%) and increased the PPV to 49.1% (95% CI, 48.3%-49.9%). In total, the first year of the Dutch screening program resulted in the detection of 2483 cancers and 12,030 advanced adenomas. CONCLUSIONS: Close monitoring of the implementation of the Dutch national CRC screening program allowed for instant adjustment of the FIT cut-off levels to optimize program performance.

Developing a score chart to improve risk stratification of patients with colorectal adenoma.

BACKGROUND AND STUDY AIMS: Current surveillance guidelines risk stratify patients with adenoma by using only one or two factors: adenoma multiplicity or presence of an advanced adenoma characteristic. Combinations of adenoma characteristics are not considered, which limits the predictive value of these guidelines. The aim of the study was to develop a scoring system for more refined risk stratification of patients with adenoma. PATIENTS AND METHODS: The Dutch Pathology Registry (PALGA) was used to identify newly diagnosed patients with adenoma in 10 Dutch hospitals between 1988 and 2002. Medical records were reviewed until 1 December 2008 for follow-up. Logistic regression analysis was used to assess patient- and adenoma-related predictors of metachronous advanced neoplasia. The prediction model was validated by bootstrapping and cross-validation. A score chart was developed based on identified adenoma-related predictors. The discriminative ability of the prediction model was compared with currently used risk stratifications in surveillance guidelines. RESULTS: A total of 2914 patients with adenoma were included (mean age 61 years; 55 % male). The score chart consisted of characteristics that contributed 1 point (size ≥ 10 mm, villous histology, proximal location, having 2 - 4 adenomas) or 2 points (having ≥ 5 adenomas). A patient's adenoma risk score could range from 0 to 5 points. A score of 5 for a 75-year-old man implied a 5-year risk of advanced neoplasia of 46 %. The discriminative ability of the model was moderate (c-statistic 0.712) but better than risk stratifications in current international guidelines, which had c-statistics of 0.642 - 0.674. CONCLUSION: A score chart that combines adenoma-related predictors of advanced colorectal neoplasia optimized the risk stratification of patients with adenoma for appropriate surveillance colonoscopy intervals.

Calibrating Parameters for Microsimulation Disease Models: A Review and Comparison of Different Goodness-of-Fit Criteria.

BACKGROUND: Calibration (estimation of model parameters) compares model outcomes with observed outcomes and explores possible model parameter values to identify the set of values that provides the best fit to the data. The goodness-of-fit (GOF) criterion quantifies the difference between model and observed outcomes. There is no consensus on the most appropriate GOF criterion, because a direct performance comparison of GOF criteria in model calibration is lacking. METHODS: We systematically compared the performance of commonly used GOF criteria (sum of squared errors [SSE], Pearson chi-square, and a likelihood-based approach [Poisson and/or binomial deviance functions]) in the calibration of selected parameters of the MISCAN-Colon microsimulation model for colorectal cancer. The performance of each GOF criterion was assessed by comparing the 1) root mean squared prediction error (RMSPE) of the selected parameters, 2) computation time of the calibration procedure of various calibration scenarios, and 3) impact on estimated cost-effectiveness ratios. RESULTS: The likelihood-based deviance resulted in the lowest RMSPE in 4 of 6 calibration scenarios and was close to best in the other 2. The SSE had a 25 times higher RMSPE in a scenario with considerable differences in the values of observed outcomes, whereas the Pearson chi-square had a 60 times higher RMSPE in a scenario with multiple studies measuring the same outcome. In all scenarios, the SSE required the most computation time. The likelihood-based approach estimated the cost-effectiveness ratio most accurately (up to -0.15% relative difference versus 0.44% [SSE] and 13% [Pearson chi-square]). CONCLUSIONS: The likelihood-based deviance criteria lead to accurate estimation of parameters under various circumstances. These criteria are recommended for calibration in microsimulation disease models in contrast with other commonly used criteria.

Personalizing colonoscopy screening for elderly individuals based on screening history, cancer risk, and comorbidity status could increase cost effectiveness.

BACKGROUND & AIMS: Colorectal cancer (CRC) screening decisions for elderly individuals are often made primarily on the basis of age, whereas other factors that influence the effectiveness and cost effectiveness of screening are often not considered. We investigated the relative importance of factors that could be used to identify elderly individuals most likely to benefit from CRC screening and determined the maximum ages at which screening remains cost effective based on these factors. METHODS: We used a microsimulation model (Microsimulation Screening Analysis-Colon) calibrated to the incidence of CRC in the United States and the prevalence of adenomas reported in autopsy studies to determine the appropriate age at which to stop colonoscopy screening in 19,200 cohorts (of 10 million individuals), defined by sex, race, screening history, background risk for CRC, and comorbidity status. We applied a willingness-to-pay threshold of $100,000 per quality-adjusted life-year (QALY) gained. RESULTS: Less intensive screening history, higher background risk for CRC, and fewer comorbidities were associated with cost-effective screening at older ages. Sex and race had only a small effect on the appropriate age to stop screening. For some individuals likely to be screened in current practice (for example, 74-year-old white women with moderate comorbidities, half the average background risk for CRC, and negative findings from a screening colonoscopy 10 years previously), screening resulted in a loss of QALYs, rather than a gain. For some individuals unlikely to be screened in current practice (for example, 81-year-old black men with no comorbidities, an average background risk for CRC, and no previous screening), screening was highly cost effective. Although screening some previously screened, low-risk individuals was not cost effective even when they were 66 years old, screening some healthy, high-risk individuals remained cost effective until they reached the age of 88 years old. CONCLUSIONS: The current approach to CRC screening in elderly individuals, in which decisions are often based primarily on age, is inefficient, resulting in underuse of screening for some and overuse of screening for others. CRC screening could be more effective and cost effective if individual factors for each patient are considered.

The value of models in informing resource allocation in colorectal cancer screening: the case of The Netherlands.

In May 2011, the Dutch government decided to implement a national programme for colorectal cancer (CRC) screening using biennial faecal immunochemical test screening between ages 55 and 75. Decision modelling played an important role in informing this decision, as well as in the planning and implementation of the programme afterwards. In this overview, we illustrate the value of models in informing resource allocation in CRC screening using the role that decision modelling has played in the Dutch CRC screening programme as an example.

The impact of stratifying by family history in colorectal cancer screening programs.

In the province-wide colorectal cancer (CRC) screening program in Ontario, Canada, individuals with a family history of CRC are offered colonoscopy screening and those without are offered guaiac fecal occult blood testing (gFOBT, Hemoccult II). We used microsimulation modeling to estimate the cumulative number of CRC deaths prevented and colonoscopies performed between 2008 and 2038 with this family history-based screening program, compared to a regular gFOBT program. In both programs, we assumed screening uptake increased from 30% (participation level in 2008 before the program was launched) to 60%. We assumed that 11% of the population had a family history, defined as having at least one first-degree relative diagnosed with CRC. The programs offered screening between age 50 and 74 years, every two years for gFOBT, and every ten years for colonoscopy. Compared to opportunistic screening (2008 participation level kept constant at 30%), the gFOBT program cumulatively prevented 6,700 more CRC deaths and required 570,000 additional colonoscopies by 2038. The family history-based screening program increased these numbers to 9,300 and 1,100,000, a 40% and 93% increase, respectively. If biennial gFOBT was replaced with biennial fecal immunochemical test (FIT), annual Hemoccult Sensa or five-yearly sigmoidoscopy screening, both the added benefits and colonoscopies required would decrease. A biennial gFOBT screening program that identifies individuals with a family history of CRC and recommends them to undergo colonoscopy screening would prevent 40% (range in sensitivity analyses: 20-51%) additional deaths while requiring 93% (range: 43-116%) additional colonoscopies, compared to a regular gFOBT screening program.

Optimal colorectal cancer screening in states' low-income, uninsured populations­the case of South Carolina.

OBJECTIVE: To determine whether, given a limited budget, a state's low-income uninsured population would have greater benefit from a colorectal cancer (CRC) screening program using colonoscopy or fecal immunochemical testing (FIT). DATA SOURCES/STUDY SETTING: South Carolina's low-income, uninsured population. STUDY DESIGN: Comparative effectiveness analysis using microsimulation modeling to estimate the number of individuals screened, CRC cases prevented, CRC deaths prevented, and life-years gained from a screening program using colonoscopy versus a program using annual FIT in South Carolina's low-income, uninsured population. This analysis assumed an annual budget of $1 million and a budget availability of 2 years as a base case. PRINCIPAL FINDINGS: The annual FIT screening program resulted in nearly eight times more individuals being screened, and more important, approximately four times as many CRC deaths prevented and life-years gained than the colonoscopy screening program. Our results were robust for assumptions concerning economic perspective and the target population, and they may therefore be generalized to other states and populations. CONCLUSIONS: A FIT screening program will prevent more CRC deaths than a colonoscopy-based program when a state's budget for CRC screening supports screening of only a fraction of the target population.

The appropriateness of more intensive colonoscopy screening than recommended in Medicare beneficiaries: a modeling study.

IMPORTANCE: Many Medicare beneficiaries undergo more intensive colonoscopy screening than recommended. Whether this is favorable for beneficiaries and efficient from a societal perspective is uncertain. OBJECTIVE: To determine whether more intensive colonoscopy screening than recommended is favorable for Medicare beneficiaries (ie, whether it results in a net health benefit) and whether it is efficient from a societal perspective (ie, whether the net health benefit justifies the additional resources required). DESIGN, SETTING, AND PARTICIPANTS: Microsimulation modeling study of 65-year-old Medicare beneficiaries at average risk for colorectal cancer (CRC) and with an average life expectancy who underwent a screening colonoscopy at 55 years with negative results. INTERVENTIONS: Colonoscopy screening as recommended by guidelines (ie, at 65 and 75 years) vs scenarios with a shorter screening interval (5 or 3 instead of 10 years) or in which screening was continued to 85 or 95 years. MAIN OUTCOMES AND MEASURES: Quality-adjusted life-years (QALYs) gained (measure of net health benefit); additional colonoscopies required per additional QALY gained and additional costs per additional QALY gained (measures of efficiency). RESULTS: Screening previously screened Medicare beneficiaries more intensively than recommended resulted in only small increases in CRC deaths prevented and life-years gained. In comparison, the increases in colonoscopies performed and colonoscopy-related complications experienced were large. As a result, all scenarios of more intensive screening than recommended resulted in a loss of QALYs, rather than a gain (ie, a net harm). The only exception was shortening the screening interval from 10 to 5 years, which resulted in 0.7 QALYs gained per 1000 beneficiaries. However, this scenario was inefficient because it required no less than 909 additional colonoscopies and an additional $711 000 per additional QALY gained. Results in previously unscreened beneficiaries were slightly less unfavorable, but conclusions were identical. CONCLUSIONS AND RELEVANCE: Screening Medicare beneficiaries more intensively than recommended is not only inefficient from a societal perspective; often it is also unfavorable for those being screened. This study provides evidence and a clear rationale for clinicians and policy makers to actively discourage this practice.

Should colorectal cancer screening be considered in elderly persons without previous screening? A cost-effectiveness analysis.

BACKGROUND: The U.S. Preventive Services Task Force recommends against routine screening for colorectal cancer (CRC) in adequately screened persons older than 75 years but does not address the appropriateness of screening in elderly persons without previous screening. OBJECTIVE: To determine at what ages CRC screening should be considered in unscreened elderly persons and to determine which test is indicated at each age. DESIGN: Microsimulation modeling study. DATA SOURCES: Observational and experimental studies. TARGET POPULATION: Unscreened persons aged 76 to 90 years with no, moderate, and severe comorbid conditions. TIME HORIZON: Lifetime. PERSPECTIVE: Societal. INTERVENTION: One-time colonoscopy, sigmoidoscopy, or fecal immunochemical test (FIT) screening. OUTCOME MEASURES: Quality-adjusted life-years gained, costs, and costs per quality-adjusted life-year gained. RESULTS OF BASE-CASE ANALYSIS: In unscreened elderly persons with no comorbid conditions, CRC screening was cost-effective up to age 86 years. Screening with colonoscopy was indicated up to age 83 years, sigmoidoscopy was indicated at age 84 years, and FIT was indicated at ages 85 and 86 years. In unscreened persons with moderate comorbid conditions, screening was cost-effective up to age 83 years (colonoscopy indicated up to age 80 years, sigmoidoscopy at age 81 years, and FIT at ages 82 and 83 years). In unscreened persons with severe comorbid conditions, screening was cost-effective up to age 80 years (colonoscopy indicated up to age 77 years, sigmoidoscopy at age 78 years, and FIT at ages 79 and 80 years). RESULTS OF SENSITIVITY ANALYSES: Results were most sensitive to assuming a lower willingness to pay per quality-adjusted life-year gained. LIMITATION: Only persons at average risk for CRC were considered. CONCLUSION: In unscreened elderly persons CRC screening should be considered well beyond age 75 years. A colonoscopy is indicated at most ages. PRIMARY FUNDING SOURCE: National Cancer Institute.