Exploring the relation of active surveillance schedules and prostate cancer mortality.

BACKGROUND: Active surveillance (AS), where treatment is deferred until cancer progression is detected by a biopsy, is acknowledged as a way to reduce overtreatment in prostate cancer. However, a consensus on the frequency of taking biopsies while in AS is lacking. In former studies to optimize biopsy schedules, the delay in progression detection was taken as an evaluation indicator and believed to be associated with the long-term outcome, prostate cancer mortality. Nevertheless, this relation was never investigated in empirical data. Here, we use simulated data from a microsimulation model to fill this knowledge gap. METHODS: In this study, the established MIcrosimulation SCreening Analysis model was extended with functionality to simulate the AS procedures. The biopsy sensitivity in the model was calibrated on the Canary Prostate Cancer Active Surveillance Study (PASS) data, and four (tri-yearly, bi-yearly, PASS, and yearly) AS programs were simulated. The relation between detection delay and prostate cancer mortality was investigated by Cox models. RESULTS: The biopsy sensitivity of progression detection was found to be 50%. The Cox models show a positive relation between a longer detection delay and a higher risk of prostate cancer death. A 2-year delay resulted in a prostate cancer death risk of 2.46%-2.69% 5 years after progression detection and a 10-year risk of 5.75%-5.91%. A 4-year delay led to an approximately 8% greater 5-year risk and an approximately 25% greater 10-year risk. CONCLUSION: The detection delay is confirmed as a surrogate for prostate cancer mortality. A cut-off for a "safe" detection delay could not be identified.

Breast Cancer Screening in Georgia: Choosing the Most Optimal and Cost-Effective Strategy.

OBJECTIVES: To define the optimal and cost-effective breast cancer screening strategy for Georgia. METHODS: We used the Microsimulation Screening Analysis-Breast (MISCAN-Breast) model that has been adapted to the Georgian situation to evaluate 736 mammography screening strategies varied by interval (biennial and triennial), starting ages (40-60 years), stopping ages (64-84 years), and screening modality (with and without clinical breast examination [CBE]). Quality-adjusted life-years (QALYs) and additional cost (healthcare perspective) compared with no screening per 1000 women were calculated with 3% discount. Major uncertainties (eg, costs) are addressed as sensitivity analyses. RESULTS: Strategies using a combination of mammography and CBE yielded in substantially higher costs with minimal differences in outcomes compared with mammography-only strategies. The current screening strategy, biennial mammography screening from the age of 40 until 70 years with CBE, is close to the frontier line but requires high additional cost given the QALY gains (€16 218/QALY), well above the willingness-to-pay threshold of €12 720. The optimal strategy in Georgia would be triennial mammography-only screening from age 45 to 66 years with an incremental cost-effectiveness ratio of €12 507. CONCLUSIONS: Biennial screening strategies are resource-intensive strategies and may not be feasible for Georgia. By switching to triennial mammography-only strategy from the age of 45 until 66 years, it is possible to offer screening to more eligible women while still gaining substantial screening benefits. This is to address capacity issues which is a common barrier for many Eastern European countries.

Modelling the cost-effectiveness of a newborn hearing screening programme; usability and pitfalls.

OBJECTIVE: The EUSCREEN project concerns the study of European vision and hearing screening programmes. Part of the project was the development of a cost-effectiveness model to analyse such programmes. We describe the development and usability of an online tool to enable stakeholders to design, analyse or modify a newborn hearing screening (NHS) programme. DESIGN: Data from literature, from existing NHS programmes, and observations by users were used to develop and refine the tool. Required inputs include prevalence of the hearing impairment, test sequence and its timing, attendance, sensitivity, and specificity of each screening step. Outputs include the number of cases detected and the costs of screening and diagnostics. STUDY SAMPLE: Eleven NHS programmes with reliable data. RESULTS: Three analyses are presented, exploring the effect of low attendance, number of screening steps, testing in the maternity ward, or screening at a later age, on the benefits and costs of the programme. Knowledge of the epidemiology of a staged screening programme is crucial when using the tool. CONCLUSIONS: This study presents a tool intended to aid stakeholders to design a new or analyse an existing hearing screening programme in terms of benefits and costs.

Cumulative risks of false positive recall and screen-detected breast cancer after multiple screening examinations.

Women tend to make a decision about participation in breast cancer screening and adhere to this for future invitations. Therefore, our study aimed to provide high-quality information on cumulative risks of false-positive (FP) recall and screen-detected breast cancer over multiple screening examinations. Individual Dutch screening registry data (2005-2018) were gathered on subsequent screening examinations of 92 902 women age 49 to 51 years in 2005. Survival analyses were used to calculate cumulative risks of a FP and a true-positive (TP) result after seven examinations. Data from 66 472 women age 58 to 59 years were used to extrapolate to 11 examinations. Participation, detection and additional FP rates were calculated for women who previously received FP results compared to women with true negative (TN) results. After 7 examinations, the cumulative risk of a TP result was 3.7% and the cumulative risk of a FP result was 9.1%. After 11 examinations, this increased to 7.1% and 13.5%, respectively. Following a FP result, participation was lower (71%-81%) than following a TN result (>90%). In women with a FP result, more TP results (factor 1.59 [95% CI: 1.44-1.72]), more interval cancers (factor 1.66 [95% CI: 1.41-1.91]) and more FP results (factor 1.96 [95% CI: 1.87-2.05]) were found than in women with TN results. In conclusion, due to a low recall rate in the Netherlands, the cumulative risk of a FP recall is relatively low, while the cumulative risk of a TP result is comparable. Breast cancer diagnoses and FP results were more common in women with FP results than in women with TN results, while participation was lower.

Overcoming barriers: Modelling the effect of potential future changes of organized breast cancer screening in Italy.

OBJECTIVES: Organized breast cancer screening may not achieve its full potential due to organizational and cultural barriers. In Italy, two identified barriers were low attendance in Southern Italy and, in Italy as a whole, underscreening and overscreening in parts of the eligible population. The objective of this study was to identify potential changes to overcome these barriers and to quantify their costs and effects. METHODS: To assess the impact of potential measures to improve breast cancer screening in Italy, we performed an evaluation of costs and effects for increasing adherence for Southern Italy and harmonizing screening intervals (biennial screening) for the whole of Italy, using an online tool (EU-TOPIA evaluation tool) based on the MIcrosimulation SCreening ANalysis (MISCAN) model. RESULTS: Increasing adherence in Southern Italy through investing in mobile screening units has an acceptable cost-effectiveness ratio of €9531 per quality-adjusted life year gained. Harmonizing the screening interval by investing in measures to reduce opportunistic screening and simultaneously investing in mobile screening units to reduce underscreening is predicted to gain 1% fewer life-years, while saving 19% of total screening costs compared to the current situation. CONCLUSIONS: Increasing adherence in Southern Italy and harmonizing the screening interval could result in substantial improvements at acceptable costs, or in the same benefits at lower costs. This example illustrates a systematic approach that can be easily applied to other European countries, as the online tools can be used by stakeholders to quantify effects and costs of a broad range of specific barriers, and ways to overcome them.

Concurrent participation in breast, cervical, and colorectal cancer screening in the Netherlands.

BACKGROUND: Many European countries offer organised population-based breast, cervical, and colorectal cancer screening programmes. Around age 55 and 60, Dutch women are invited to all three screening programmes. We examined the extent to which participation concurs and identified factors influencing concurrent participation. MATERIALS AND METHODS: Individual level data from breast, cervical, and colorectal cancer screening invitations between 2017 and 2019 were extracted from the Dutch screening registry. The percentages of women participating in all three, two, one, or none of the programmes around age 55 and 60, and before subsequent round invitation were determined. Multivariate ordinal regression analyses were performed to estimate whether population density, socio-economic status (SES) per postal code area, and time between the three invitations (<3, 3-6, >6 months) were associated with concurrent participation. RESULTS: Data from 332,484 women were analysed. At age 55, 53.7% participated in all three programmes, 22.1% in two, 11.7% in one, and 12.6% did not participate at all. At age 60, a similar participation pattern was observed. Women living in areas with higher population density were less likely (odds ratios 0.75-0.94) and women in higher SES groups were more likely (odds ratios 1.12-1.60) to participate in more screening programmes, although this positive association was smaller for the highest SES group. No substantial association was found between concurrent participation and timing of invitations. CONCLUSIONS: More than half of Dutch women participated in all three screening programmes and around 12% did not participate in any. Concurrent participation was lower in cities and lower SES groups.

Evaluation of Prostate Cancer Screening Strategies in a Low-Resource, High-risk Population in the Bahamas.

Importance: The benefit of prostate-specific antigen screening may be greatest in high-risk populations, including men of African descent in the Caribbean. However, organized screening may not be sustainable in low- and middle-income countries. Objective: To evaluate the expected population outcomes and resource use of conservative prostate-specific antigen screening programs in the Bahamas. Design Setting and Participants: Prostate cancer incidence from GLOBOCAN and prostate-specific antigen screening data for 4300 men from the Bahamas were used to recalibrate 2 decision analytical models previously used to study prostate-specific antigen screening for Black men in the United States. Data on age and results obtained from prostate-specific antigen screening tests performed in Nassau from 2004 to 2018 and in Freeport from 2013 to 2018 were used. Data were analyzed from January 15, 2021, to March 23, 2022. Interventions: One or 2 screenings for men aged 45 to 60 years and conservative criteria for biopsy (prostate-specific antigen level >10 ng/mL) and curative treatment (Gleason score ≥8) were modeled. Categories of Gleason scores were 6 or lower, 7, and 8 or higher, with higher scores indicating higher risk of cancer progression and death. Main Outcomes and Measures: Projected numbers of tests and biopsies, prostate cancer (over)diagnoses, lives saved, and life-years gained owing to screening from 2022 to 2040. Results: In this decision analytical modeling study, screening histories from 4300 men (median age, 54 years; range, 13-101 years) tested between 2004 and 2018 at 2 sites in the Bahamas were used to inform the models. Screening once at 60 years of age was projected to involve 40 000 to 42 000 tests (range between models) and prevent 500 to 600 of 10 000 to 14 000 prostate cancer deaths. Screening at 50 and 60 years doubled the number of tests but increased lives saved by only 15% to 16%. Among onetime strategies, screening once at 60 years of age involved the fewest tests per life saved (74-84 tests) and curative treatments per life saved (1.2-2.8 treatments). Conclusions and Relevance: The findings of this decision analytical modeling study of prostate cancer screening in the Bahamas suggest that limited screening offered modest benefits that varied with screening ages and number of tests. The results can be combined with data on capacity constraints and evaluated relative to competing national public health priorities.

The cost-effectiveness of different visual acuity screening strategies in three European countries: A microsimulation study.

Childhood vision screening programmes in Europe differ by age, frequency and location at which the child is screened, and by the professional who performs the test. The aim of this study is to compare the cost-effectiveness for three countries with different health care structures. We developed a microsimulation model of amblyopia. The natural history parameters were calibrated to a Dutch observational study. Sensitivity, specificity, attendance, lost to follow-up and costs in the three countries were based on the EUSCREEN Survey. Quality adjusted life-years (QALYs) were calculated using assumed utility loss for unilateral persistent amblyopia (1%) and bilateral visual impairment (8%). We calculated the cost-effectiveness of screening (with 3.5% annual discount) by visual acuity measurement at age 5 years or 4 and 5 years in the Netherlands by nurses in child healthcare centres, in England and Wales by orthoptists in schools and in Romania by urban kindergarten nurses. We compared screening at various ages and with various frequencies. Assuming an amblyopia prevalence of 36 per 1,000 children, the model predicted that 7.2 cases of persistent amblyopia were prevented in the Netherlands, 6.6 in England and Wales and 4.5 in Romania. The cost-effectiveness was €24,159, €19,981 and €23,589, per QALY gained respectively, compared with no screening. Costs/QALY was influenced most by assumed utility loss of unilateral persistent amblyopia. For all three countries, screening at age 5, or age 4 and 5 years were optimal. Despite differences in health care structure, vision screening by visual acuity measurement seemed cost-effective in all three countries.

Finding the optimal mammography screening strategy: A cost-effectiveness analysis of 920 modelled strategies.

Breast cancer screening policies have been designed decades ago, but current screening strategies may not be optimal anymore. Next to that, screening capacity issues may restrict feasibility. This cost-effectiveness study evaluates an extensive set of breast cancer screening strategies in the Netherlands. Using the Microsimulation Screening Analysis-Breast (MISCAN-Breast) model, the cost-effectiveness of 920 breast cancer screening strategies with varying starting ages (40-60), stopping ages (64-84) and intervals (1-4 years) were simulated. The number of quality adjusted life years (QALYs) gained and additional net costs (in €) per 1000 women were predicted (3.5% discounted) and incremental cost-effectiveness ratios (ICERs) were calculated to compare screening scenarios. Sensitivity analyses were performed using different assumptions. In total, 26 strategies covering all four intervals were on the efficiency frontier. Using a willingness-to-pay threshold of €20 000/QALY gained, the biennial 40 to 76 screening strategy was optimal. However, this strategy resulted in more overdiagnoses and false positives, and required a high screening capacity. The current strategy in the Netherlands, biennial 50 to 74 years, was dominated. Triennial screening in the age range 44 to 71 (ICER 9364) or 44 to 74 (ICER 11144) resulted in slightly more QALYs gained and lower costs than the current Dutch strategy. Furthermore, these strategies were estimated to require a lower screening capacity. Findings were robust when varying attendance and effectiveness of treatment. In conclusion, switching from biennial to triennial screening while simultaneously lowering the starting age to 44 can increase benefits at lower costs and with a minor increase in harms compared to the current strategy.

Cost-Effectiveness of Magnetic Resonance Imaging Screening for Women With Extremely Dense Breast Tissue.

BACKGROUND: Extremely dense breast tissue is associated with increased breast cancer risk and limited sensitivity of mammography. The DENSE trial showed that additional magnetic resonance imaging (MRI) screening in women with extremely dense breasts resulted in a substantial reduction in interval cancers. The cost-effectiveness of MRI screening for these women is unknown. METHODS: We used the MISCAN-breast microsimulation model to simulate several screening protocols containing mammography and/or MRI to estimate long-term effects and costs. The model was calibrated using results of the DENSE trial and adjusted to incorporate decreases in breast density with increasing age. Screening strategies varied in the number of MRIs and mammograms offered to women ages 50-75 years. Outcomes were numbers of breast cancers, life-years, quality-adjusted life-years (QALYs), breast cancer deaths, and overdiagnosis. Incremental cost-effectiveness ratios (ICERs) were calculated (3% discounting), with a willingness-to-pay threshold of €22 000. RESULTS: Calibration resulted in a conservative fit of the model regarding MRI detection. Both strategies of the DENSE trial were dominated (biennial mammography; biennial mammography plus MRI). MRI alone every 4 years was cost-effective with €15 620 per QALY. Screening every 3 years with MRI alone resulted in an incremental cost-effectiveness ratio of €37 181 per QALY. All strategies with mammography and/or a 2-year interval were dominated because other strategies resulted in more additional QALYs per additional euro. Alternating mammography and MRI every 2 years was close to the efficiency frontier. CONCLUSIONS: MRI screening is cost-effective for women with extremely dense breasts, when applied at a 4-year interval. For a willingness to pay more than €22 000 per QALY gained, MRI at a 3-year interval is cost-effective as well.

Extending Age Ranges in Breast Cancer Screening in Four European Countries: Model Estimations of Harm-to-Benefit Ratios.

The main benefit of breast cancer (BC) screening is a reduction in mortality from BC. However, screening also causes harms such as overdiagnosis and false-positive results. The balance between benefits and harms varies by age. This study aims to assess how harm-to-benefit ratios of BC screening vary by age in the Netherlands, Finland, Italy and Slovenia. Using microsimulation models, we simulated biennial screening with 100% attendance at varying ages for cohorts of women followed over a lifetime. The number of overdiagnoses, false-positive diagnoses, BC deaths averted and life-years gained (LYG) were calculated per 1000 women. We compared four strategies (50-69, 45-69, 45-74 and 50-74) by calculating four harm-to-benefit ratios, respectively. Compared to the reference strategy 50-69, screening women at 45-74 or 50-74 years would be less beneficial in any of the four countries than screening women at 45-69, which would result in relatively fewer overdiagnoses per death averted or LYG. At the same time, false-positive results per death averted would increase substantially. Adapting the age range of BC screening is an option to improve harm-to-benefit ratios in all four countries. Prioritization of considered harms and benefits affects the interpretation of results.

The EU-TOPIA evaluation tool: An online modelling-based tool for informing breast, cervical, and colorectal cancer screening decisions in Europe.

BACKGROUND: Aiming to support European countries in improving their breast, cervical, and colorectal cancer (CRC) screening programmes, the EU-TOPIA consortium has developed an online user-friendly tool (the EU-TOPIA evaluation tool; https://miscan.eu-topia.org) based on the Microsimulation Screening Analysis (MISCAN) model. METHODS: We designed an online platform that allows stakeholders to use their country-specific data (demographic, epidemiological, and cancer screening information) to quantify future harms and benefits of different cancer screening scenarios in their country. Current cancer screening programmes and impacts of potential changes in screening protocols (such as extending target ages or increasing screening attendance) can be simulated. Results are scaled to the country-specific population. To illustrate the tool, we used the tool to simulate two different CRC screening scenarios in the Netherlands: biennial fecal immunochemical testing (FIT) in ages 55-75 and colonoscopy every ten years in ages 55-75. Data from the Dutch screening programme was used to inform both scenarios. RESULTS: A total of 482,700 CRC cases and 178,000 CRC deaths were estimated in the Netherlands with FIT screening (for individuals aged 40-100 years, 2018-2050), with 47.3 million FITs performed (1.92 million positives of which 1.64 million adhered to diagnostic colonoscopy). With colonoscopy screening, CRC incidence and mortality were, respectively, up to 17% and 14% lower than in the current FIT screening programme, requiring, however, a colonoscopy demand that was 7-fold higher. CONCLUSIONS: Our study presents an essential online tool for stakeholders and medical societies to quantify estimates of benefits and harms of early cancer detection in Europe.

The Impact of Intensifying Prostate Cancer Screening in Black Men: A Model-Based Analysis.

BACKGROUND: Black men in the United States have markedly higher rates of prostate cancer than the general population. National guidelines for prostate-specific antigen (PSA) screening do not provide clear guidance for this high-risk population. The purpose of this study is to estimate the benefit and harm of intensified PSA screening in Black men. METHODS: Two microsimulation models of prostate cancer calibrated to incidence from the Surveillance, Epidemiology, and End Results program among Black men project the impact of different screening strategies (varying screening intervals, starting and stopping ages, and biopsy utilization following an abnormal PSA) on disease-specific mortality and overdiagnosis. Each strategy induces a mean lead time (MLT) for detected cases. A longer MLT reduces mortality according to estimates combining the US and European prostate cancer screening trials but increases overdiagnosis. RESULTS: Under historical population screening, Black men had similar MLT to men of all races and similar mortality reduction (range between models = 21%-24% vs 20%-24%) but a higher frequency of overdiagnosis (75-86 vs 58-60 per 1000 men). Screening Black men aged 40-84 years annually would increase both mortality reduction (29%-31%) and overdiagnosis (112-129 per 1000). Restricting screening to ages 45-69 years would still achieve substantial mortality reduction (26%-29%) with lower overdiagnosis (51-61 per 1000). Increasing biopsy utilization to 100% of abnormal tests would further reduce mortality but substantially increase overdiagnosis. CONCLUSIONS: Annual screening in Black men is expected to reduce mortality more than that estimated under historical screening. Limiting screening to men younger than 70 years is expected to help reduce overdiagnosis.

Effects of cancer screening restart strategies after COVID-19 disruption.

BACKGROUND: Many breast, cervical, and colorectal cancer screening programmes were disrupted due to the COVID-19 pandemic. This study aimed to estimate the effects of five restart strategies after the disruption on required screening capacity and cancer burden. METHODS: Microsimulation models simulated five restart strategies for breast, cervical, and colorectal cancer screening. The models estimated required screening capacity, cancer incidence, and cancer-specific mortality after a disruption of 6 months. The restart strategies varied in whether screens were caught up or not and, if so, immediately or delayed, and whether the upper age limit was increased. RESULTS: The disruption in screening programmes without catch-up of missed screens led to an increase of 2.0, 0.3, and 2.5 cancer deaths per 100 000 individuals in 10 years in breast, cervical, and colorectal cancer, respectively. Immediately catching-up missed screens minimised the impact of the disruption but required a surge in screening capacity. Delaying screening, but still offering all screening rounds gave the best balance between required capacity, incidence, and mortality. CONCLUSIONS: Strategies with the smallest loss in health effects were also the most burdensome for the screening organisations. Which strategy is preferred depends on the organisation and available capacity in a country.

Screening for cancers with a good prognosis: The case of testicular germ cell cancer.

BACKGROUND: To determine, using testicular germ cell cancer screening as an example, whether screening can also be effective for cancers with a good prognosis. METHODS: Based on the Dutch incidence, stage distribution, and survival and mortality data of testicular germ cell cancer, we developed a microsimulation model. This model simulates screening scenarios varying in screening age, interval, self-examination or screening by the general practitioner (GP), and screening of a defined high-risk group (cryptorchidism). For each scenario, the number of clinically and screen-detected cancers by stage, referrals, testicular germ cell cancer deaths, and life-years gained were projected. RESULTS: Annual self-examination from age 20 to 30 years resulted in 767 cancers detected per 100,000 men followed over life-time, of which 123 (16%) by screening. In this scenario, 19.2 men died from the disease, 4.7 (20%) less than without screening, and 230 life-years were gained. Around 14,000 visits to the GP and 2080 visits to an urologist were required. This scenario resulted in the most favorable ratio between extra visits to the GP or urologist and deaths prevented (1418 and 116 respectively). Monthly screening, or screening until age 40 resulted in less favorable ratios. Self-examination by only the high-risk population prevented 1.0 death per 100,00 men in the general population. In all scenarios, 46-50 life-years were gained for each testicular germ cell cancer death prevented. CONCLUSION: Despite the good prognosis, self-examination at young ages for testicular germ cell cancer could be considered.

The comparative effectiveness of mpMRI and MRI-guided biopsy vs regular biopsy in a population-based PSA testing: a modeling study.

The benefit of prostate cancer screening is counterbalanced by the risk of overdiagnosis and overtreatment. The use of a multi-parametric magnetic resonance imaging (mpMRI) test after a positive prostate-specific antigen (PSA) test followed by magnetic resonance imaging-guided biopsy (MRIGB) may reduce these harms. The aim of this study was to determine the effects of mpMRI and MRIGB vs the regular screening pathway in a population-based prostate cancer screening setting. A micro-simulation model was used to predict the effects of regular PSA screening (men with elevated PSA followed by TRUSGB) and MRI based screening (men with elevated PSA followed by mpMRI and MRIGB). We predicted reduction of overdiagnosis, harm-benefit ratio (overdiagnosis per cancer death averted), reduction in number of biopsies, detection of clinically significant cancer, prostate cancer death averted, life-years gained (LYG), and quality adjusted life years (QALYs) gained for both strategies. A univariate sensitivity analysis and threshold analysis were performed to assess uncertainty around the test sensitivity parameters used in the MRI strategy.In the MRI pathway, we predicted a 43% reduction in the risk of overdiagnosis, compared to the regular pathway. Similarly a lower harm-benefit ratio (overdiagnosis per cancer death averted) was predicted for this strategy compared to the regular screening pathway (1.0 vs 1.8 respectively). Prostate cancer mortality reduction, LY and QALYs gained were also slightly increased in the MRI pathway than the regular screening pathway. Furthermore, 30% of men with a positive PSA test could avoid a biopsy as compared to the regular screening pathway. Compared to regular PSA screening, the use of mpMRI as a triage test followed by MRIGB can substantially reduce the risk of overdiagnosis and improve the harm-benefit balance, while maximizing prostate cancer mortality reduction and QALYs gained.