The Natural Disease Course of Pancreatic Cyst-Associated Neoplasia, Dysplasia, and Ductal Adenocarcinoma: Results of a Microsimulation Model.

BACKGROUND & AIMS: Estimates on the progression of precursor lesions to pancreatic cancer (PC) are scarce. We used microsimulation modeling to gain insight into the natural disease course of PC and its precursors. This information is pivotal to explore the efficacy of PC screening. METHODS: A Microsimulation Screening Analysis model was developed in which pancreatic intraepithelial neoplasms and cysts can evolve from low-grade dysplasia (LGD) to high-grade dysplasia (HGD) to PC. The model was calibrated to Dutch PC incidence data and Japanese precursor prevalence data (autopsy cases without PC) and provides estimates of PC progression (precursor lesion onset and stage duration). RESULTS: Mean LGD state durations of cysts and pancreatic intraepithelial neoplasms were 15.8 years and 17.1 years, respectively. Mean HGD state duration was 5.8 years. For lesions that progress to PC, the mean duration was 4.8-4.9 years for LGD lesions and 4.0-4.1 years for HGD lesions. In 13.7% of individuals who developed PC, the HGD state lasted less than 1 year. The probability that an individual at age 50 years developed PC in the next 20 years was estimated to be 1.8% in the presence of any cyst and 6.1% in case of an LGD mucinous cyst. This 20-year PC risk was estimated to be 5.1% for individuals with an LGD pancreatic intraepithelial neoplasm. CONCLUSIONS: Mean duration of HGD lesions before development of PC was estimated to be 4.0 years. This implies a window of opportunity for screening, presuming the availability of a reliable diagnostic test. The probability that an LGD cyst will progress to cancer was predicted to be low.

The impact of pancreatic cancer screening on life expectancy: A systematic review of modeling studies.

Evidence supporting the effectiveness of pancreatic cancer (PC) screening is scant. Most clinical studies concern small populations with short follow-up durations. Mathematical models are useful to estimate long-term effects of PC screening using short-term indicators. This systematic review aims to evaluate the impact of PC screening on life expectancy (LE) in model-based studies. Therefore, we searched four databases (Embase, Medline, Web-of-science, Cochrane) until 30 May 2022 to identify model-based studies evaluating the impact of PC screening on LE in different risk populations. Two authors independently screened identified papers, extracted data and assessed the methodological quality of studies. A descriptive analysis was performed and the impact of screening strategies on LE of different risk groups was reported. Our search resulted in 419 studies, of which eight met the eligibility criteria (mathematical model, PC screening, LE). Reported relative risks (RR) for PC varied from 1 to 70. In higher risk individuals (RR > 5), annual screening (by imaging with 56% sensitivity for HGD/early stage PC) predicted to increase LE of screened individuals by 20 to 260 days. In the general population, one-time PC screening was estimated to decrease LE (2-110 days), depending on the test characteristics and treatment mortality risk. In conclusion, although the models use different and sometimes outdated or unrealistic assumptions, it seems that PC screening in high-risk populations improves LE, and that this gain increases with a higher PC risk. Updated model studies, with data from large clinical trials are necessary to predict the long-term effect of PC screening more accurately.

Projections of costs and quality adjusted life years lost due to dementia from 2020 to 2050: A population-based microsimulation study.

INTRODUCTION: Efficient healthcare planning requires reliable projections of the future increase in costs and quality-adjusted life years (QALYs) lost due to dementia. METHODS: We used the microsimulation model MISCAN-Dementia to simulate life histories and dementia occurrence using population-based Rotterdam Study data and nationwide birth cohort demographics. We estimated costs and QALYs lost in the Netherlands from 2020 to 2050, incorporating literature estimates of cost and utility for patients and caregivers by dementia severity and care setting. RESULTS: Societal costs and QALYs lost due to dementia are estimated to double between 2020 and 2050. Costs are incurred predominantly through institutional (34%), formal home (31%), and informal home care (20%). Lost QALYs are mostly due to shortened life expectancy (67%) and, to a lesser extent, quality of life with severe dementia (14%). DISCUSSION: To limit healthcare costs and quality of life losses due to dementia, interventions are needed that slow symptom progression and reduce care dependency.

Rapid elimination of cervical cancer while maintaining the harms and benefits ratio of cervical cancer screening: a modelling study.

BACKGROUND: Human papillomavirus (HPV) vaccination and intensifying screening expedite cervical cancer (CC) elimination, yet also deteriorate the balance between harms and benefits of screening. We aimed to find screening strategies that eliminate CC rapidly but maintain an acceptable harms-benefits ratio of screening. METHODS: Two microsimulation models (STDSIM and MISCAN) were applied to simulate HPV transmission and CC screening for the Dutch female population between 2022 and 2100. We estimated the CC elimination year and harms-benefits ratios of screening for 228 unique scenarios varying in vaccination (coverage and vaccine type) and screening (coverage and number of lifetime invitations in vaccinated cohorts). The acceptable harms-benefits ratio was defined as the number of women needed to refer (NNR) to prevent one CC death under the current programme for unvaccinated cohorts (82.17). RESULTS: Under current vaccination conditions (bivalent vaccine, 55% coverage in girls, 27.5% coverage in boys), maintaining current screening conditions is projected to eliminate CC by 2042, but increases the present NNR with 41%. Reducing the number of lifetime screens from presently five to three and increasing screening coverage (61% to 70%) would prevent an increase in harms and only delay elimination by 1 year. Scaling vaccination coverage to 90% in boys and girls with the nonavalent vaccine is estimated to eliminate CC by 2040 under current screening conditions, but exceeds the acceptable NNR with 23%. Here, changing from five to two lifetime screens would keep the NNR acceptable without delaying CC elimination. CONCLUSIONS: De-intensifying CC screening in vaccinated cohorts leads to little or no delay in CC elimination while it substantially reduces the harms of screening. Therefore, de-intensifying CC screening in vaccinated cohorts should be considered to ensure acceptable harms-benefits ratios on the road to CC elimination.

Shift in harms and benefits of cervical cancer screening in the era of HPV screening and vaccination: a modelling study.

OBJECTIVE: To calculate the changes in harms and benefits of cervical cancer screening over the first three screening rounds of the Dutch high-risk human papillomavirus (hrHPV) screening programme. DESIGN: Microsimulation study. SETTING: Dutch hrHPV screening programme; women are invited for screening every 5 or 10 years (depending on age and screening history) from age 30 to 65. POPULATION: Partly vaccinated population of 100 million Dutch women. METHODS: Microsimulation model MISCAN was used to estimate screening effects. Sensitivity analyses were performed on test characteristics and attendance. MAIN OUTCOME MEASURES: Harms (screening tests, unnecessary referrals, treatment-related health problems), benefits (CIN2+ diagnoses) and programme efficiency (number needed to screen [NNS]) over the first (period 2017-2021), second (period 2022-2026) and third (period 2027-2031) rounds of hrHPV-based screening. RESULTS: The number of screening tests and CIN2+ diagnoses decreased from the first to the second round (-25.8% and -23.6%, respectively). In the third screening round, these numbers decreased further, albeit only slightly (-2.7% and -5.3%, respectively). NNS to detect a CIN2+ remained constant over the rounds; however, it increased in younger age groups while decreasing in older age groups. CONCLUSION: Both harms and benefits of hrHPV screening decreased over the first screening rounds. For younger women, the efficiency would decrease, whereas longer screening intervals would lead to increased efficiency in older women. Programme efficiency overall remained stable, showing the importance of longer intervals for low-risk women. TWEETABLE ABSTRACT: Cervical cancer screening: both harms and benefits of hrHPV screening will decrease in the future.

Projected prevalence and incidence of dementia accounting for secular trends and birth cohort effects: a population-based microsimulation study.

There is need for accurate projections of the future dementia burden to prepare healthcare systems and policymakers. Existing projections only account for population ageing, not for observed declines in age-specific dementia incidence of 13% per decade. We developed a dementia microsimulation model that synthesizes population-based data from the Rotterdam Study with changes in demographics between birth cohorts from the early 1900s onwards. We determined dementia prevalence and incidence until 2050 for three different dementia incidence trend scenarios: (1) stable age-specific incidence, (2) linear decline by 13% per decade, (3) nonlinear declines averaging 13% per decade. Assuming a stable age-specific incidence resulted in a 130% increase in incidence and 118% in prevalence between 2020 and 2050. By contrast, the linearly declining trend resulted in substantially smaller increases of 58% in incidence (95%CI: 29-87%), and 43% in prevalence (95%CI: 13-66%), corresponding to 39% lower incidence and 36% lower prevalence by 2050 than in the stable-incidence scenario. Results for various non-linear declines fell between the stable and linear trend. The future burden of dementia is highly susceptible to achievable changes in age-specific incidence. Extension of previously established secular trends globally would reduce widely upheld projections of new dementia cases until 2050 by 39%.

The potential of breast cancer screening in Europe.

Currently, all European countries offer some form of breast cancer screening. Nevertheless, disparities exist in the status of implementation, attendance and the extent of opportunistic screening. As a result, breast cancer screening has not yet reached its full potential. We examined how many breast cancer deaths could be prevented if all European countries would biennially screen all women aged 50 to 69 for breast cancer. We calculated the number of breast cancer deaths already prevented due to screening as well as the number of breast cancer deaths which could be additionally prevented if the total examination coverage (organised plus opportunistic) would reach 100%. The calculations are based on total examination coverage in women aged 50 to 69, the annual number of breast cancer deaths for women aged 50 to 74 and the maximal possible mortality reduction from breast cancer, assuming similar effectiveness of organised and opportunistic screening. The total examination coverage ranged from 49% (East), 62% (West), 64% (North) to 69% (South). Yearly 21 680 breast cancer deaths have already been prevented due to mammography screening. If all countries would reach 100% examination coverage, 12 434 additional breast cancer deaths could be prevented annually, with the biggest potential in Eastern Europe. With maximum coverage, 23% of their breast cancer deaths could be additionally prevented, while in Western Europe it could be 21%, in Southern Europe 15% and in Northern Europe 9%. Our study illustrates that by further optimising screening coverage, the number of breast cancer deaths in Europe can be lowered substantially.

Identifying key factors for the effectiveness of pancreatic cancer screening: A model-based analysis.

Pancreatic cancer (PC) survival is poor, as detection usually occurs late, when treatment options are limited. Screening of high-risk individuals may enable early detection and a more favorable prognosis. Knowledge gaps prohibit establishing the effectiveness of screening. We developed a Microsimulation Screening Analysis model to analyze the impact of relevant uncertainties on the effect of PC screening in high-risk individuals. The model simulates two base cases: one in which lesions always progress to PC and one in which indolent and faster progressive lesions coexist. For each base case, the effect of annual and 5-yearly screening with endoscopic ultrasonography/magnetic resonance imaging was evaluated. The impact of variance in PC risk, screening test characteristics and surgery-related mortality was evaluated using sensitivity analyses. Screening resulted in a reduction of PC mortality by at least 16% in all simulated scenarios. This reduction depended strongly on the natural disease course (annual screening: -57% for "Progressive-only" vs -41% for "Indolent Included"). The number of screen and surveillance tests needed to prevent one cancer death was impacted most by PC risk. A 10% increase in test sensitivity reduced mortality by 1.9% at most. Test specificity is important for the number of surveillance tests. In conclusion, screening reduces PC mortality in all modeled scenarios. The natural disease course and PC risk strongly determines the effectiveness of screening. Test sensitivity seems of lesser influence than specificity. Future research should gain more insight in PC pathobiology to establish the true value of PC screening in high-risk individuals.

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.

Molecular markers for cervical cancer screening.

INTRODUCTION: Cervical cancer remains a significant healthcare problem, notably in low- to middle-income countries. While a negative test for hrHPV has a predictive value of more than 99.5%, its positive predictive value is less than 10% for CIN2+ stages. This makes the use of a so-called triage test indispensable for population-based screening to avoid referring women, that are ultimately at low risk of developing cervical cancer, to a gynecologist. This review will give an overview of tests that are based on epigenetic marker panels and protein markers. AREAS COVERED: There is a medical need for molecular markers with a better predictive value to discriminate hrHPV-positive women that are at risk of developing cervical cancer from those that are not. Areas covered are epigenetic and protein markers as well as health economic considerations in view of the fact that most cases of cervical cancer arise in low-to-middle-income countries. EXPERT OPINION: While there are biomarker assays based on changes at the nucleic acid (DNA methylation patterns, miRNAs) and at the protein level, they are not widely used in population screening. Combining nucleic acid-based and protein-based tests could improve the overall specificity for discriminating CIN2+ lesions that carry a low risk of progressing to cervical cancer within the screening interval from those that carry an elevated risk. The challenge is to reduce unnecessary referrals without an undesired increase in false-negative diagnoses resulting in cases of cervical cancer that could have been prevented. A further challenge is to develop tests for low-and middle-income countries, which is critical to reduce the worldwide burden of cervical cancer.

Reducing unnecessary referrals for colposcopy in hrHPV-positive women within the Dutch cervical cancer screening programme: A modelling study.

BACKGROUND: With the implementation of primary high-risk human papillomavirus (hrHPV) screening in the Netherlands, an increase was observed in the number of unnecessary referrals (≤Cervical Intraepithelial Neoplasia (CIN) 1) to colposcopy. We aimed to investigate which alternative triage strategies safely reduce unnecessary referrals in HPV-based cervical cancer screening programmes. METHODS: Microsimulation model MISCAN was used to simulate an unvaccinated cohort of ten million 30-year old Dutch women. We calculated unnecessary referrals, cervical cancer incidence, mortality, costs and QALYs for 24 triage strategies. Condition for direct referral (atypical squamous cells of undetermined significance (ASC-US), low-grade squamous intraepithelial lesions (LSIL), high-grade squamous intraepithelial lesions (HSIL), conditional on HPV-genotype 16/18/other high risk (OHR)), type of triage test (cytology alone or combined with hrHPV) and time to triage test (6 or 12 months) was varied. RESULTS: The 24 triage strategies had varying effects on the number of unnecessary referrals ranging from -72% to +35%. Adjusting conditions for referral to 'HPV16/18+ and ASC-US+' and 'HPVOHR+ and HSIL+' and extending the interval between tests to 12 months resulted in a reduction in unnecessary referrals of 40% (incidence +0%, mortality -1%). Reduction in unnecessary referrals without genotyping was achieved by adjusting conditions for direct referral to LSIL (12 months to repeat test) (unnecessary referrals -37%, incidence +2%, mortality +0%). CONCLUSIONS: To reduce the number of unnecessary referrals without increasing incidence and mortality by more than 2% in the Dutch cervical cancer screening programme, genotyping for HPV16 or HPV16/18 should be implemented with 12 months to repeat testing.

The optimal HPV-screening protocol in Eastern-Europe: The example of Slovenia.

OBJECTIVE: Eastern European countries are contemplating to introduce the high-risk Human Papillomavirus (HPV)-test as the primary screening test for their cervical cancer screening programme, but its optimal protocol is yet unknown. The aim of this study was to compare the costs, effects and cost-effectiveness of different primary HPV-screening protocols in Eastern Europe, using Slovenia as an example and with respect of local preferences for screening. METHODS: We evaluated 968 HPV-screening protocols, which varied by screening ages, triage tests (i.e. cytology, repeat HPV and/or genotyping) and strategy for women under 35 years old, using the microsimulation model MISCAN-Cervix. RESULTS: Within the subset of strategies that would be acceptable for Slovenian women, the optimal HPV-screening protocol is to start with two cytology tests at age 25 and 28 and switch to 5-yearly HPV screening from age 30 to 65. When also other protocols were considered, the optimal screening strategy would be 5-yearly HPV screening from age 30 to 65 only, improving the cost-effectiveness with 5%. Adding genotyping in the triage algorithm consistently improved cost-effectiveness. Sensitivity analyses showed the robustness of the results for other situations in Eastern Europe. CONCLUSIONS: Despite differences in cervical cancer epidemiology between Eastern and Western European regions where HPV screening was evaluated, the optimal screening protocol was found to be very similar. Furthermore, strategies that were considered socially acceptable to the population were found to be almost as cost-effective as less acceptable strategies and can therefore be considered a viable alternative to prevent opportunistic screening.

Impact of disruptions and recovery for established cervical screening programs across a range of high-income country program designs, using COVID-19 as an example: A modelled analysis.

COVID-19 has disrupted cervical screening in several countries, due to a range of policy-, health-service and participant-related factors. Using three well-established models of cervical cancer natural history adapted to simulate screening across four countries, we compared the impact of a range of standardised screening disruption scenarios in four countries that vary in their cervical cancer prevention programs. All scenarios assumed a 6- or 12-month disruption followed by a rapid catch-up of missed screens. Cervical screening disruptions could increase cervical cancer cases by up to 5-6%. In all settings, more than 60% of the excess cancer burden due to disruptions are likely to have occurred in women aged less than 50 years in 2020, including settings where women in their 30s have previously been offered HPV vaccination. Approximately 15-30% of cancers predicted to result from disruptions could be prevented by maintaining colposcopy and precancer treatment services during any disruption period. Disruptions to primary screening had greater adverse effects in situations where women due to attend for screening in 2020 had cytology (vs. HPV) as their previous primary test. Rapid catch-up would dramatically increase demand for HPV tests in 2021, which it may not be feasible to meet because of competing demands on the testing machines and reagents due to COVID tests. These findings can inform future prioritisation strategies for catch-up that balance potential constraints on resourcing with clinical need.

Historical and projected hysterectomy rates in the USA: Implications for future observed cervical cancer rates and evaluating prevention interventions.

BACKGROUND: SEER-reported cervical cancer incidence rates reflect the total female population including women no longer at risk due to hysterectomy. Hysterectomy rates have been declining in the United States as alternative treatments have become available, which could result in an apparent increase in SEER-reported cervical cancer rates. We aimed to obtain nationally representative historical data on hysterectomy rates in USA, use trends analysis to project rates back to 1935 and forward to 2035, and then predict the impact of changing hysterectomy rates on SEER-reported cervical cancer rates. METHODS: We performed a systematic search of Medline, Embase, Premedline, Cochrane Central databases and extracted nationally-representative hysterectomy incidence data from 1965 to 2009, including data on the number of cervix-preserving (subtotal) procedures. We then projected rates back to 1935, and forward to 2035 based on trends from joinpoint regression. These rates were then used to estimate hysterectomy prevalence out to 2035, and then to predict the impact of changing hysterectomy rates on SEER-reported cervical cancer rates to 2035. We examined alternative assumptions regarding projected hysterectomy incidence rates out to 2035, including a scenario in which rates decline no further from 2009 rates, and a scenario where rates decline at twice the baseline rate. RESULTS: Estimated age-standardized hysterectomy incidence increased from 2.4 to 10.6 per 1000 women between 1935 and 1975. Thereafter, rates are predicted to fall to 3.9 per 1000 by 2035. Subtotal hysterectomy procedures declined from being the predominant method in 1935 to less than 12% of procedures from 1970 onwards. Consequently, holding all else constant, an increase in SEER-reported age-standardized cervical cancer incidence rates (ages 0-85+) of 9% is expected from 2009 to 2035. The predictions were minimally impacted by alternative scenarios for future hysterectomy rates. CONCLUSIONS: Declining hysterectomy rates have implications for the interpretation of SEER-reported cervical cancer rates. A background increase in cervical cancer rates due to decreasing population hysterectomy exposure may partially offset expected decreases from recent cervical screening changes recommended by the US Preventive Services Task Force. Evaluations of new cervical cancer prevention opportunities should consider the background impact of historical and projected hysterectomy rates.

Introduction of primary screening using high-risk HPV DNA detection in the Dutch cervical cancer screening programme: a population-based cohort study.

BACKGROUND: In January 2017, the Dutch cervical cancer screening programme transitioned from cytomorphological to primary high-risk HPV (hrHPV) DNA screening, including the introduction of self-sampling, for women aged between 30 and 60 years. The Netherlands was the first country to switch to hrHPV screening at the national level. We investigated the health impact of this transition by comparing performance indicators from the new hrHPV-based programme with the previous cytology-based programme. METHODS: We obtained data from the Dutch nationwide network and registry of histo- and cytopathology (PALGA) for 454,573 women eligible for screening in 2017 who participated in the hrHPV-based programme between 1 January 2017 and 30 June 2018 (maximum follow-up of almost 21 months) and for 483,146 women eligible for screening in 2015 who participated in the cytology-based programme between 1 January 2015 and 31 March 2016 (maximum follow-up of 40 months). We compared indicators of participation (participation rate), referral (screen positivity; referral rate) and detection (cervical intraepithelial neoplasia (CIN) detection; number of referrals per detected CIN lesion). RESULTS: Participation in the hrHPV-based programme was significantly lower than that in the cytology-based programme (61% vs 64%). Screen positivity and direct referral rates were significantly higher in the hrHPV-based programme (positivity rate: 5% vs 9%; referral rate: 1% vs 3%). CIN2+ detection increased from 11 to 14 per 1000 women screened. Overall, approximately 2.2 times more clinical irrelevant findings (i.e. ≤CIN1) were found in the hrHPV-based programme, compared with approximately 1·3 times more clinically relevant findings (i.e. CIN2+); this difference was mostly due to a national policy change recommending colposcopy, rather than observation, of hrHPV-positive, ASC-US/LSIL results in the hrHPV-based programme. CONCLUSIONS: This is the first time that comprehensive results of nationwide implementation of hrHPV-based screening have been reported using high-quality data with a long follow-up. We have shown that both benefits and potential harms are higher in one screening round of a well-implemented hrHPV-based screening programme than in an established cytology-based programme. Lower participation in the new hrHPV programme may be due to factors such as invitation policy changes and the phased roll-out of the new programme. Our findings add further to evidence from trials and modelling studies on the effectiveness of hrHPV-based screening.

Management and treatment of cervical intraepithelial neoplasia in the Netherlands after referral for colposcopy.

INTRODUCTION: The aim of this study was to describe trends in the diagnosis and treatment of women referred from the national screening program with cervical intraepithelial neoplasia (CIN) in the Netherlands, and to compare these trends with national guidelines and identify potential areas for improvement for the new primary high-risk HPV screening program. MATERIAL AND METHODS: We conducted a population-based cohort study using data from the Dutch pathology archive. Women aged 29-63 years who took part in the Dutch cervical screening program between 1 January 2005 and 31 December 2014 were selected. Three referral groups were identified: direct referrals and those referred after either one (first indirect referrals) or two (second indirect referrals) repeat cytology tests, totaling 85 239 referrals for colposcopy. The most invasive management technique and the most severe diagnosis of each screening episode was identified. Rates of management techniques were calculated separately by referral type, highest CIN diagnosis and age group. RESULTS: In all, 85.1% of CIN 3 lesions were treated with excision (either large excision or hysterectomy) and 26.4% of CIN 1 lesions were treated with large excision. Rates of overtreatment (CIN 1 or less) in see-and-treat management were higher for indirect referrals than for direct referrals and increased with age. Large excision rates increased with CIN diagnosis severity. CONCLUSIONS: Despite guideline recommendations not to treat, CIN 1 lesions were treated in just over 25% of cases and approximately 15% of CIN 3 lesions were possibly undertreated. Given the expected increase in CIN detection in the new primary high-risk HPV screening program, reduction in CIN 1 treatment and CIN 2 treatment in younger women is needed to avoid an increase in potential harm.

Quality of life assumptions determine which cervical cancer screening strategies are cost-effective.

Quality-adjusted life years are used in cost-effectiveness analyses (CEAs). To calculate QALYs, a "utility" (0-1) is used for each health state induced or prevented by the intervention. We aimed to estimate the impact of quality of life (QoL) assumptions (utilities and durations of health states) on CEAs of cervical cancer screening. To do so, 12 alternative sets of utility assumptions were retrieved from published cervical cancer screening CEAs. Two additional sets were based on empirical QoL data that were integrally obtained through two different measures (SF-6D and EQ-5D) from eight groups of women (total n = 3,087), from invitation for screening to diagnosis with cervical cancer. Per utility set we calculated the number of quality-adjusted days lost (QADL) for each relevant health state in cervical cancer screening, by multiplying the study-specific assumed disutilities (i.e., 1-utility) with study-specific durations of the loss in QoL, resulting in 14 "QADL-sets." With microsimulation model MISCAN we calculated cost-effectiveness of 342 alternative screening programs (varying in primary screening test [Human Papillomavirus (HPV) vs. cytology], starting ages, and screening interval) for each of the 14 QADL-sets. Utilities used in CEAs appeared to differ largely. We found that ten QADL-sets from the literature resulted in HPV and two in cytology as preferred primary test. The SF-6D empirical QADL-set resulted in cytology and the EQ-5D one in HPV as preferred primary test. In conclusion, assumed utilities and health state durations determine cost-effectiveness of cervical cancer screening. Also, the measure used to empirically assess utilities can be crucial for CEA conclusions.

Public Health Benefits of Routine Human Papillomavirus Vaccination for Adults in the Netherlands: A Mathematical Modeling Study.

BACKGROUND: Expanding routine human papillomavirus (HPV) vaccination to adults could be an effective strategy to improve prevention of HPV infection and cervical cancer. METHODS: We evaluated the following adult vaccination strategies for women only and for both women and men in addition to the current girls-only vaccination program in the Netherlands, using the established STDSIM microsimulation model: one-time mass campaign, vaccination at the first cervical cancer screening visit, vaccination at sexual health clinics, and combinations of these strategies. RESULTS: The estimated impact of expanding routine vaccination to adult women is modest, with the largest incremental reductions in the incidence of HPV infection occurring when offering vaccination both at the cervical cancer screening visit and during sexually transmitted infection (STI) consultations (about 20% lower after 50 years for both HPV-16 and HPV-18). Adding male vaccination during STI consultations leads to more-substantial incidence reductions: 63% for HPV-16 and 84% for HPV-18. The incremental number needed to vaccinate among women is 5.48, compared with 0.90 for the current vaccination program. CONCLUSIONS: Offering vaccination to adults, especially at cervical cancer screening visits (for women) and during STI consultations (for both sexes), would substantially reduce HPV incidence and would be an efficient policy option to improve HPV prevention and subsequently avert cervical and possibly male HPV-related cancers.

The potential harms of primary human papillomavirus screening in over-screened women: a microsimulation study.

BACKGROUND: It is well acknowledged that HPV testing should not be performed at young age and at short intervals. Cytological screening practices have shown that over-screening, i.e., from a younger age and at shorter intervals than recommended, is hard to avoid. We quantified the consequences of a switch to primary HPV screening for over-screened women, taking into account its higher sensitivity but lower specificity than cytology. METHODS: The health effects of using the HPV test instead of cytology as the primary screening method were determined with the MISCAN-Cervix model. We varied the age women start screening and the interval between screens. In the sensitivity analyses, we varied the background risk of cervical cancer, the HPV prevalence, the discount rate, the triage strategy after cytology, and the test characteristics of both cytology and the HPV test. RESULTS: For women screened 5 yearly from age 30, 32 extra deaths per 100,000 simulated women were prevented when switching from primary cytology to primary HPV testing. For annual screening from age 20, such a switch resulted in 6 extra deaths prevented. It was associated with 9,044 more positive primary screens in the former scenario versus 76,480 in the latter. Under all conditions, for women screened annually, switching to HPV screening resulted in a net loss of quality-adjusted life years. CONCLUSION: For over-screened women, the harms associated with a lower test specificity outweigh the life years gained when switching from primary cytology to primary HPV testing. The extent of over-screening should be considered when deciding on inclusion of primary HPV screening in cervical cancer screening guidelines.