The projected health and economic impact of increased colorectal cancer screening participation among Canadians by income quintile.

OBJECTIVES: Disparities in colorectal cancer (CRC) screening uptake by socioeconomic status have been observed in Canada. We used the OncoSim-Colorectal model to evaluate the health and economic outcomes associated with increasing the participation rates of CRC screening programs to 60% among Canadians in different income quintiles. METHODS: Baseline CRC screening participation rates were obtained from the 2017 Canadian Community Health Survey. The survey participants were categorized into income quintiles using their reported household income and 2016 Canadian Census income quintile thresholds. Within each quintile, the participation rate was the proportion of respondents aged 50-74 who reported having had a fecal test in the past two years. Using the OncoSim-Colorectal model, we simulated an increase in CRC screening uptake to 60% across income quintiles to assess the effects on CRC incidence, mortality, and associated economic costs from 2024 to 2073. RESULTS: Increasing CRC screening participation rates to 60% across all income quintiles would prevent 69,100 CRC cases and 36,600 CRC deaths over 50 years. The improvement of clinical outcomes would also translate to increased person-years and health-adjusted person-years. The largest impact was observed in the lowest income group, with 22,200 cases and 11,700 deaths prevented over 50 years. Increased participation could lead to higher screening costs ($121 million CAD more per year) and lower treatments costs ($95 million CAD less per year), averaged over the period 2024-2073. CONCLUSION: Increased screening participation will improve clinical outcomes across all income groups while alleviating associated treatment costs. The benefits of increased participation will be strongest among the lowest income quintile.

RéSUMé: OBJECTIFS: Des disparités dans le recours au dépistage du cancer colorectal (CCR) selon le statut socioéconomique sont observées au Canada. Nous avons utilisé le modèle OncoSim-Colorectal pour évaluer les résultats cliniques et économiques associés à une augmentation à 60 % des taux de participation aux programmes de dépistage du CCR chez les Canadiennes et les Canadiens appartenant à différents quintiles de revenu. MéTHODE: Les taux de participation de référence au dépistage du CCR provenaient de l'Enquête sur la santé dans les collectivités canadiennes de 2017. Nous avons catégorisé les participantes et les participants de l'enquête en quintiles de revenu à l'aide du revenu du ménage déclaré et des seuils de quintiles de revenu du Recensement du Canada de 2016. Dans chaque quintile, le taux de participation était la proportion des répondantes et des répondants de 50 à 74 ans ayant dit avoir subi un test fécal au cours des deux années antérieures. À l'aide du modèle OncoSim-Colorectal, nous avons simulé une augmentation à 60 % du recours au dépistage du CCR dans tous les quintiles de revenu pour en évaluer les effets sur l'incidence, la mortalité et les coûts économiques associés du CCR entre 2024 et 2073. RéSULTATS: L'augmentation des taux de participation au dépistage du CCR à 60 % dans tous les quintiles de revenu préviendrait 69 100 cas de CCR et 36 600 décès dus au CCR sur 50 ans. L'amélioration des résultats cliniques se traduirait aussi par une augmentation des personnes-années et des personnes-années corrigées en fonction de la santé. Nous avons observé l'effet le plus marquant dans la catégorie de revenu inférieure, avec la prévention de 22 200 cas et de 11 700 décès sur 50 ans. La participation accrue pourrait entraîner une hausse des coûts de dépistage (121 millions de dollars canadiens de plus par année) et une baisse des coûts de traitement (95 millions de dollars canadiens de moins par année), en moyenne, sur la période de 2024 à 2073. CONCLUSION: La participation accrue au dépistage améliorera les résultats cliniques dans toutes les catégories de revenu tout en réduisant les coûts de traitement associés. Les avantages d'une participation accrue seront les plus marquants dans le quintile de revenu inférieur.

Association of Reducing the Recommended Colorectal Cancer Screening Age With Cancer Incidence, Mortality, and Costs in Canada Using OncoSim.

Importance: Recent US guideline updates have advocated for colorectal cancer (CRC) screening to begin at age 45 years in average-risk adults, whereas Canadian screening programs continue to begin screening at age 50 years. Similarities in early-onset CRC rates in Canada and the US warrant discussion of earlier screening in Canada, but there is a lack of Canadian-specific modeling data to inform this. Objective: To estimate the association of a lowered initiation age for CRC screening by biennial fecal immunochemical test (FIT) with CRC incidence, mortality, and health care system costs in Canada. Design, Setting, and Participants/Exposures: This economic evaluation computational study used microsimulation modeling via the OncoSim platform. Main Outcomes and Measures: Modeled rates of CRC incidence, mortality, and health care costs in Canadian dollars. Results: This analysis included 4 birth cohorts (1973-1977, 1978-1982, 1983-1987, and 1988-1992) representative of the Canadian population accounting for previously documented effects of increasing CRC incidence in younger birth cohorts. Screening initiation at age 45 years resulted in a net 12 188 fewer CRC cases, 5261 fewer CRC deaths, and an added 92 112 quality-adjusted life-years (QALYs) to the cohort population over a 40-year period relative to screening from age 50 years. Screening initiation at age 40 years yielded 18 135 fewer CRC cases, 7988 fewer CRC deaths, and 150 373 QALYs. The cost per QALY decreased with younger birth cohorts to a cost of $762 per QALY when Canadians born in 1988 to 1992 began screening at age 45 years or $2622 per QALY with screening initiation at age 40 years. Although costs associated with screening and resulting therapeutic interventions increased with earlier screening, the overall health care system cost of managing CRC decreased. Conclusions and Relevance: This economic evaluation study using microsimulation modeling found that earlier screening may reduce CRC disease burden and add life-years to the Canadian population at a modest cost. Guideline changes suggesting earlier CRC screening in Canada may be justified, but evaluation of the resulting effects on colonoscopy capacity is necessary.

Interventions to improve the quality of screening-related colonoscopy: protocol for a systematic review and network meta-analysis of randomised controlled trials.

INTRODUCTION: Colonoscopy quality can vary depending on endoscopist-related factors. Quality indicators, such as adenoma detection rate (ADR), have been adopted to reduce variations in care. Several interventions aim to improve ADR, but these fall into several domains that have traditionally been difficult to compare. We will conduct a systematic review and network meta-analysis of randomised controlled trials evaluating the efficacies of interventions to improve colonoscopy quality and report our findings according to clinically relevant interventional domains. METHODS AND ANALYSIS: We will search MEDLINE (Ovid), PubMed, EMBASE, CINAHL, Web of Science, Scopus and Evidence-Based Medicine from inception to September 2022. Four reviewers will screen for eligibility and abstract data in parallel, with two accordant entries establishing agreement and with any discrepancies resolved by consensus. The primary outcome will be ADR. Two authors will independently conduct risk of bias assessments. The analyses of the network will be conducted under a Bayesian random-effects model using Markov-chain Monte-Carlo simulation, with 10 000 burn-ins and 100 000 iterations. We will calculate the ORs and corresponding 95% credible intervals of network estimates with a consistency model. We will report the impact of specific interventions within each domain against standard colonoscopy. We will perform a Bayesian random-effects pairwise meta-analysis to assess heterogeneity based on the I2 statistic. We will assess the certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework for network meta-analyses. ETHICS AND DISSEMINATION: Our study does not require research ethics approval given the lack of patient-specific data being collected. The results will be disseminated at national and international gastroenterology conferences and peer-reviewed journals. PROSPERO REGISTRATION NUMBER: CRD42021291814.

Simulation study on the validity of the average risk approach in estimating population attributable fractions for continuous exposures.

BACKGROUND: The population attributable fraction (PAF) is an important metric for estimating disease burden associated with causal risk factors. In an International Agency for Research on Cancer working group report, an approach was introduced to estimate the PAF using the average of a continuous exposure and the incremental relative risk (RR) per unit. This 'average risk' approach has been subsequently applied in several studies conducted worldwide. However, no investigation of the validity of this method has been done. OBJECTIVE: To examine the validity and the potential magnitude of bias of the average risk approach. METHODS: We established analytically that the direction of the bias is determined by the shape of the RR function. We then used simulation models based on a variety of risk exposure distributions and a range of RR per unit. We estimated the unbiased PAF from integrating the exposure distribution and RR, and the PAF using the average risk approach. We examined the absolute and relative bias as the direct and relative difference in PAF estimated from the two approaches. We also examined the bias of the average risk approach using real-world data from the Canadian Population Attributable Risk of Cancer study. RESULTS: The average risk approach involves bias, which is underestimation or overestimation with a convex or concave RR function (a risk profile that increases more/less rapidly at higher levels of exposure). The magnitude of the bias is affected by the exposure distribution as well as the value of RR. This approach is approximately valid when the RR per unit is small or the RR function is approximately linear. The absolute and relative bias can both be large when RR is not small and the exposure distribution is skewed. CONCLUSIONS: We recommend that caution be taken when using the average risk approach to estimate PAF.

Estimating the future cancer management costs attributable to modifiable risk factors in Canada.

OBJECTIVES: An estimated 33-37% of incident cancers in Canada are attributable to modifiable risk factors. Interventions targeting these risk factors would minimize the substantial health and economic burdens Canadians face due to cancer. We estimate the future health and economic burden of cancer in Canada by incorporating data from the Canadian Population Attributable Risk of Cancer (ComPARe) study into OncoSim, a web-based microsimulation tool. METHODS: Using the integrated OncoSim population attributable risk and population impact measures, we evaluated risk factor-targeted intervention scenarios implemented in 2020, assuming the targeted risk factor prevalence reduction would be achieved by 2032 with a 12-year latency period. RESULTS: We estimate that smoking will be the largest contributor to cancer-related costs, with a cost of CAD $44.4 billion between 2032 and 2044. An estimated CAD $3.3 billion of the cost could be avoided with a 30% reduction in smoking prevalence by 2022. Following smoking, the next highest cancer management costs are associated with inadequate physical activity and excess body weight, accounting for CAD $10.7 billion ($2.7 billion avoidable) and CAD $9.8 billion ($3.2 billion avoidable), respectively. Avoidable costs for other risk factors range from CAD $90 million to CAD $2.5 billion. CONCLUSION: Interventions targeting modifiable cancer risk factors could prevent a substantial number of incident cancer cases and billions of dollars in cancer management costs. With limited budgets and rising costs in cancer care in Canada, these simulation models and results are valuable for researchers and policymakers to inform decisions and prioritize and evaluate intervention programs.

RéSUMé: OBJECTIFS: Il est estimé que de 33 % à 37 % des cancers incidents au Canada sont imputables à des facteurs de risque modifiables. Des interventions ciblant ces facteurs de risque réduiraient le fardeau sanitaire et économique considérable du cancer dans la population canadienne. Nous avons estimé le futur fardeau sanitaire et économique du cancer au Canada en intégrant les données de l'étude ComPARe (Canadian Population Attributable Risk of Cancer) dans l'outil de microsimulation en ligne OncoSim. MéTHODE: À l'aide des indicateurs d'impact dans la population et du risque attribuable dans la population intégrés dans OncoSim, nous avons évalué des scénarios d'intervention mis en œuvre en 2020 axés sur les facteurs de risque, en partant de l'hypothèse que la réduction de la prévalence des facteurs de risque ciblés serait atteinte d'ici 2032 avec une période de latence de 12 ans. RéSULTATS: Nous estimons que le tabagisme sera le facteur qui contribuera le plus aux coûts du cancer, avec un coût de 44,4 milliards $ CA entre 2032 et 2044. Il est estimé qu'une part de 3,3 milliards $ CA de ce coût pourrait être évitée en réduisant de 30 % la prévalence du tabagisme d'ici 2022. Après le tabagisme, les coûts de prise en charge du cancer les plus élevés sont associés à l'inactivité physique et au surpoids, qui représentent respectivement 10,7 milliard $ CA (dont 2,7 milliards $ évitables) et 9,8 milliards $ CA (dont 3,2 milliards $ évitables). Les coûts évitables pour d'autres facteurs de risque vont de 90 millions $ CA à 2,5 milliards $ CA. CONCLUSION: Des interventions ciblant les facteurs de risque de cancer modifiables pourraient prévenir un nombre considérable de cas de cancers incidents et épargner des milliards de dollars en coûts de prise en charge du cancer. Avec les budgets serrés et la hausse des coûts des soins du cancer au Canada, ces modèles de simulation et leurs résultats permettent aux chercheurs et aux responsables des politiques d'éclairer les décisions et de hiérarchiser et d'évaluer les programmes d'intervention.

Profiling pathway-specific novel therapeutics in preclinical assessment for central nervous system atypical teratoid rhabdoid tumors (CNS ATRT): favorable activity of targeting EGFR- ErbB2 signaling with lapatinib.

Despite intensifying multimodal treatments, children with central nervous system atypical teratoid/rhabdoid tumor (CNS ATRT) continue to endure unacceptably high mortality rates. At present, concerted efforts are focusing on understanding the characteristic INI1 mutation and its implications for the growth and survival of these tumors. Additionally, pharmaceutical pipeline libraries constitute a significant source of potential agents that can be taken to clinical trials in a timely manner. However, this process requires efficient target validation and relevant preclinical studies. As an initial screening approach, a panel of 129 small molecule inhibitors from multiple pharmaceutical pipeline libraries was tested against three ATRT cell lines by in vitro cytotoxicity assays. Based on these data, agents that have strong activity and corresponding susceptible cellular pathways were identified. Target modulation, antibody array analysis, drug combination and in vivo xenograft studies were performed on one of the pathway inhibitors found in this screening. Approximately 20% of agents in the library showed activity with IC(50) values of 1 µM or less and many showed IC(50) values less than 0.05 µM. Intra cell line variability was also noted among some of the drugs. However, it was determined that agents capable of affecting pathways constituting ErbB2, mTOR, proteasomes, Hsp90, Polo like kinases and Aurora kinases were universally effective against the three ATRT cell lines. The first target selected for further analysis, the inhibition of ErbB2-EGFR pathway by the small molecule inhibitor lapatinib, indicated inhibition of cell migration properties and the initiation of apoptosis. Synergy between lapatinib and IGF-IR inhibition was also demonstrated by combination index (CI) values. Xenograft studies showed effective antitumor activity of lapatinib in vivo. We present an experimental approach to identifying agents and drug combinations for future clinical trials and provide evidence for the potential of lapatinib as an effective agent in the context of the biology and heterogeneity of its targets in ATRT.