Search

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.

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 ep

Declining attendance in the Dutch cervical cancer screening programme was recently observed, coinciding with preparations for implementing primary hrHPV-based screening, which was implemented in January 2017. We aimed to investigate which factors were related to decreased attendance. We conducted a population-based cohort study including all women aged 30 to 60 years who were eligible for screening between 2014 and 2018. Attendance was defined as participation in the screening programme within 15 months of the start of the invitation-eligible year. We used data from the Dutch pathology archive (PALGA) linked with data from Statistics Netherlands to investigate population characteristics (position in the household, household income, socio-economic status, number of people in the household, migration background, age) and data from the five Dutch screening organisations (SO) to investigate the effect of cessing self-inviting GP's (‘inviting organisation’). SO's were termed SO 1 to 5. Higher attendance rates were observed in women who were employed (60.8%), married (62.9%), Dutch (61.2%), in the highest income bracket (63.4%), living in households with four persons (65.3%) and women who were invited by their GP (69.8%). Differences in personal characteristics did not explain the decline in attendance rates. By adjusting for whether the GP or the SO sent the invitation, the differences in attendance rates between 2014 and 2015 and 2016 and between 2014 and 2015 and 2017–2018 were explained in some screening organis

Declining attendance in the Dutch cervical cancer screening programme was recently observed, coinciding with preparations for implementing primary hrHPV-based screening, which was implemented in January 2017. We aimed to investigate which factors were related to decreased attendance. We conducted a population-based cohort study including all women aged 30 to 60 years who were eligible for screening between 2014 and 2018. Attendance was defined as participation in the screening programme within 15 months of the start of the invitation-eligible year. We used data from the Dutch pathology archive (PALGA) linked with data from Statistics Netherlands to investigate population characteristics (position in the household, household income, socio-economic status, number of people in the household, migration background, age) and data from the five Dutch screening organisations (SO) to investigate the effect of cessing self-inviting GP's (‘inviting organisation’). SO's were termed SO 1 to 5. Higher attendance rates were observed in women who were employed (60.8%), married (62.9%), Dutch (61.2%), in the highest income bracket (63.4%), living in households with four persons (65.3%) and women who were invited by their GP (69.8%). Differences in personal characteristics did not explain the decline in attendance rates. By adjusting for whether the GP or the SO sent the invitation, the differences in attendance rates between 2014 and 2015 and 2016 and between 2014 and 2015 and 2017–2018 were explained in some screening organis

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.

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.

Objective: We aim to compare the cost-effectiveness of the old cytology programme with the new high-risk human papillomavirus (hrHPV) screening programme, using performance indicators from the new Dutch hrHPV screening programme. Design: Model-based cost-effectiveness analysis. Setting: The Netherlands. Population: Dutch 30-year-old unvaccinated females followed up lifelong. Methods: We updated the microsimulation screening analysis (MISCAN) model using the most recent epidemiological and screening data from the Netherlands. We simulated both screening programmes, using the screening behaviour and costs observed in each programme. Sensitivity analyses were performed on screening behaviour, utility losses and discount rates. Main outcome measures: Cervical cancer incidence and mortality rates, number of screening tests and repeat tests, colposcopy referrals by lesion grade, costs from a societal perspective, quality-adjusted life years (QALYs) gained and cost-effectiveness. Results: The new Dutch cervical cancer screening programme decreased the cervical cancer mortality by 4% and the incidence by 1% compared with the old programme. Colposcopy referrals of women without cervical intra-epithelial neoplasia grade 2 or worse, increased by 172%, but 13% more QALYs were still achieved. Total costs were reduced by 21%, mainly due to fewer screening tests. Per QALY gained, the hrHPV programme cost 46% less (€12,225) than the cytology programme (€22,678), and hrHPV-based screening remained more cost-effective in all sensitivity analyses. Conclusions: The hrHPV-based screening programme was found to be more effective and cost-effective than the cytology programme. Alternatives for the current triage strategy should be considered to lower the number of unnecessary referrals. Tweetable abstract: First results after implementation confirm that HPV screening is more cost-effective than cytology screening.

Alzheimer’s disease (AD) is a complex, multicausal disorder involving several spatiotemporal scales and scientific domains. While many studies focus on specific parts of this system, the complexity of AD is rarely studied as a whole. In this work, we apply systems thinking to map out known causal mechanisms and risk factors ranging from intracellular to psychosocial scales in sporadic AD. We report on the first systemic causal loop diagram (CLD) for AD, which is the result of an interdisciplinary group model building (GMB) process. The GMB was based on the input of experts from multiple domains and all proposed mechanisms were supported by scientific literature. The CLD elucidates interaction and feedback mechanisms that contribute to cognitive decline from midlife onward as described by the experts. As an immediate outcome, we observed several non-trivial reinforcing feedback loops involving factors at multiple spatial scales, which are rarely considered within the same theoretical framework. We also observed high centrality for modifiable risk factors such as social relationships and physical activity, which suggests they may be promising leverage points for interventions. This illustrates how a CLD from an interdisciplinary GMB process may lead to novel insights into complex disorders. Furthermore, the CLD is the first step in the development of a computational model for simulating the effects of risk factors on AD.

Background. To interpret cervical cancer screening model results, we need to understand the influence of model structure and assumptions on cancer incidence and mortality predictions. Cervical cancer cases and deaths following screening can be attributed to 1) (precancerous or cancerous) disease that occurred after screening, 2) disease that was present but not screen detected, or 3) disease that was screen detected but not successfully treated. We examined the relative contributions of each of these using 4 Cancer Intervention and Surveillance Modeling Network (CISNET) models. Methods. The maximum clinical incidence reduction (MCLIR) method compares changes in the number of clinically detected cervical cancers and mortality among 4 scenarios: 1) no screening, 2) one-time perfect screening at age 45 that detects all existing disease and delivers perfect (i.e., 100% effective) treatment of all screen-detected disease, 3) one-time realistic-sensitivity cytological screening and perfect treatment of all screen-detected disease, and 4) one-time realistic-sensitivity cytological screening and realistic-effectiveness treatment of all screen-detected disease. Results. Predicted incidence reductions ranged from 55% to 74%, and mortality reduction ranged from 56% to 62% within 15 years of follow-up for scenario 4 across models. The proportion of deaths due to disease not detected by screening differed across the models (21%–35%), as did the failure of treatment (8%–16%) and disease occurring after screening (from 1%–6%). Conclusions. The MCLIR approach aids in the interpretation of variability across model results. We showed that the reasons why screening failed to prevent cancers and deaths differed between the models. This likely reflects uncertainty about unobservable model inputs and structures; the impact of this uncertainty on policy conclusions should be examined via comparing findings from different well-calibrated and validated model platforms.

Background: Organised cervical cancer (CC) screening programmes are delivered in many different ways across the European Union and its regions. Our aim was to systematically review the impact of these programs on CC mortality. Methods: Two independent reviewers identified all eligible studies investigating the effect of organised screening on CC mortality in Europe. Six databases including Embase, Medline and Web of Science were searched (March 2018) with predefined inclusion and exclusion criteria. Only original studies with at least five years of follow-up were considered. Validated tools

Objective To maximize benefits and reduce potential harms of organized cancer screening programs in Europe, monitoring, quality assurance, and evaluation of long-term impact are required. We aimed to identify the most important indicators to be collected and reported. The study was designed to establish a consensus within a European-level working group and suggest a manageable list of key indicators. Methods We conducted a Delphi study among p

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 intraep

Objective: Several studies have shown that there is an upward shift in the classification of cervical cytology when high-risk human papillomavirus (hrHPV) status is known to be positive. The Netherlands implemented primary hrHPV screening with reflex cytology as the primary screening test in 2017. Prior to implementation of the new programme, we investigated whether knowledge of hrHPV status influences cytology rating. Methods: Using a set of 200 cytology slides that had been previously tested, two pairs of cytotechnicians rated 100 slides per pair twice: first without knowledge of hrHPV status and t

The aim of this study was to identify barriers to effective breast, cervical and colorectal cancer screening programmes throughout the whole of the European region using the Barriers to Effective Screening Tool (BEST). The study was part of the scope of the EU-TOPIA (TOwards imProved screening for breast, cervical and colorectal cancer In All of Europe) project and respondents were European screening organisers, researchers and policymakers taking part in a workshop for the project in Budapest in September 2017. 67 respondents from 31 countries responded to the online survey. The study found that there are many barriers to effective screening throughout the system from identification of the eligible population to ensuring appropriate follow-up and treatment for the three cancers. The most common barriers were opportunistic screening, sub-optimal participation, limited capacity (including trained human resource), inadequate and/or disjointed information technology s

The aim of this study was to identify barriers to effective cervical and colorectal cancers screening programmes in Europe. The Barriers to Effective Screening Tool (BEST), based on a health systems approach, was completed by teams of three to six experts on cancer screening in each of the six countries involved in leading the EU-TOPIA project (TOwards imProved screening for breast, cervical and colorectal cancer In All of Europe). While the basic components of screening systems and the challenges they face, such as low participation, are similar, there are also many differences, both in the structures underpinning particular functions, such as maintenance of populationregisters and monitoring outcomes, and the ways that they operate. Many of these lie outside the strict organisational boundaries of screening programmes. BEST offers a means to identify and prioritise issues for further detailed exploration. The holistic health systems approach to assessing barriers differs from previous approaches. Those focus on individual characteristics that determine participation. The approach described here provides additional opportunities to improve outcomes with measures that are largely within the control of those managing the health system.

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.

Background Human papillomavirus (HPV) vaccination and the implementation of primary HPV screening in the Netherlands will lead to a lower cervical disease burden. For evaluation and further improvement of prevention, it is important to estimate the magnitude and timing of health benefits of current and alternative vaccination strategies such as vaccination of boys or adults. Methods and findings We evaluated the impact of the current girls-only vaccination program and alternative strategies on cervical disease burden among the first four vaccinated five-year birth cohorts, given the context of primary HPV screening. We integrated the existing microsimulation models STDSIM (HPV transmission model) and MISCAN-Cervix (cervical cancer screening model). Alternative vaccination strategies include: improved vaccination uptake, including routine boys vaccination, and offering adult vaccination at sexual health clinics. Our models show that the current vaccination program is estimated to reduce cervical cancers and cancer deaths by about 35% compared to primary HPV screening in the absence of vaccination. The number needed to vaccinate (NNV) to gain 1 life year is 45. The most efficient alternative vaccination strategies are: 1) improving coverage of girls to 80% (NNV = 42); and 2) routine vaccination for girls and boys at 80% coverage (incremental NNV = 155), with cervical cancer mortality reductions estimated at 50% and 60% respectively. Conclusions While the current program already substantially reduces cervical cancer incidence and morta

Objective: Women exposed to diethylstilbestrol in utero (DES) have an increased risk of clear cell adenocarcinoma (CCA) of the vagina and cervix, while their risk of non-CCA invasive cervical cancer is still unclear. Methods: We studied the risk of pre-cancerous (CIN) lesions and non-CCA invasive cervical cancer in a prospective cohort of 12,182 women with self-reported DES exposure followed from 2000 till 2008. We took screening behavior carefully into account. Incidence was obtained through linkage with the Netherlands Nationwide Pathology database (PALGA). General population data were also derived from PALGA. Results: The incidence of CIN1 was increased (Standardized Incidence Ratio (SIR). =2.8, 95% Confidence Interval (CI). =2.3 to 3.4), but no increased risk was observed for CIN2. + (CIN2, CIN3 or invasive cancer) compared to the screened general population (SIR. =1.1, 95% CI. =0.95 to1.4). Women with DES-related malformations had increased risks of both CIN1 and CIN2. + (SIR. =4.1, 95%CI. =3.0 to 5.3 and SIR. =1.5, 95%CI. =1.1 to 2.0, respectively). For CIN2. +, this risk increase was largely restricted to women with malformations who were more intensively screened. Conclusions: An increased risk of CIN1 among DES daughters was obse

#### Objective To compare the cumulative incidence of cervical cancer diagnosed within 72 months after a normal screening sample between conventional cytology and liquid based cytology tests SurePath and ThinPrep. #### Design Retrospective population based cohort study. #### Setting Nationwide network and registry of histo- and cytopathology in the Netherlands (PALGA), January 2000 to March 2013. #### Population Women with 5924474 normal screening samples (23833123 person years). #### Exposure Use of SurePath or ThinPrep versus conventional cytology as screening test. #### Main outcome measure 72 month cumulative incidence of invasive cervical cancer after a normal screening sample for each screening test. Cox regression analyses assessed the hazard ratios, adjusted for calendar time, age, screening history, and socioeconomic status and including laboratories as random effects. #### Results The 72 month cumulative cancer incidence was 58.5 (95% confidence interval 54.6 to 62.7) per 100000 normal conventional cytology samples, compared with 66.8 (56.7 to 78.7) for ThinPrep and 44.6 (37.8 to 52.6) for SurePath. Compared with conventional cytology, the hazard of invasive cancer was 19% lower (hazard ratio 0.81, 95% confidence interval 0.66 to 0.99) for SurePath, mainly caused by a 27% lower hazard (0.73, 0.57 to 0.93) of a clinically detected cancer. For ThinPrep, the hazard was on average 15% higher (hazard ratio 1.15, 0.95 to 1.38), mainly caused by a 56% higher hazard of a screen detected cancer (1.56, 1.17 to 2.08). #### Conclusions These findings should provoke reconsideration of the assumed similarity in sensitivity to detect progressive cervical intraepithelial neoplasia between different types of liquid based cyt

Purpose: Within the last decade, SurePath and ThinPrep [both liquid-based cytology (LBC) tests] have replaced conventional cytology (CC) as primary test method in cervical cancer screening programs of multiple countries. The aim of our study was to examine the effect in the Dutch screening program. Methods: All primary smears taken within this program from 2000 to 2011 were analyzed using the nationwide registry of histo- and cytopathology (PALGA) with a follow-up until March 2013. The percentage of smears classified as borderline/mildly dyskaryotic (BMD) and >BMD as well as CIN and cervical cancer detection rates were compared between SurePath and ThinPrep versus CC by logistic regression analyses (adjusted for age, screen region, socioeconomic status, and calendar time). Results: We included 3,118,685 CC, 1,313,731 SurePath, and 1,584,587 ThinPrep smears. Using SurePath resulted in an increased rate of primary smears classified as >BMD [odds ratio (OR) = 1.12 (95% confidence interval (CI) 1.09–1.16)]. CIN I and II+ detection rates increased by 14 % [OR = 1.14 (95% CI 1.08–1.20)] and 8 % [OR = 1.08 (95% CI 1.05–1.12)]. Cervical cancer detection rates were unaffected. Implementing ThinPrep did not result in major alterations of the cytological classification of smears, and it did not affect CIN detection rates. While not significant, cervical cancer detection rates were lower [OR = 0.87 (95% CI 0.75–1.01)]. Conclusions: The impact of replacing CC by LBC as primary test method depends on the type of LBC test used. Only the use of SurePath was associated with increased CIN II+ detection, although it simultaneously increased the detection of CIN I.

Background: Vaccination against the oncogenic human papillomavirus (HPV) types 16 and 18 will reduce the prevalence of these types, thereby also reducing cervical cancer risk in unvaccinated women. This (measurable) herd effect will be limited at first, but is expected to increase over time. At a certain herd immunity level, tailoring screening to vaccination status may no longer be worth the additional effort. Moreover, uniform screening may be the only viable option. We therefore investigated at what level of herd immunity it is cost-effective to also reduce screening intensity in unvaccinated women. Methods: We used the MISCAN-Cervix model to determine the optimal screening strategy for a prevaccination population and for vaccinated women (∼80% decreased risk), assuming a willingness- to-pay of €50,000 per quality-adjusted life year gained. We considered HPV testing, cytology testing and co-testing and varied the start age of screening, the screening interval and the number of lifetime screens. We then calculated the incremental cost-effectiveness ratio (ICER) of screening unvaccinated women with the strategy optimized to the pre-vaccination population as compared to with the strategy optimized to vaccinated women, assuming different herd immunity levels. Results: Primary HPV screening with cytology triage was the optimal strategy, with 8 lifetime screens for the pre-vaccination population and 3 for vaccinated women. The ICER of screening unvaccinated women 8 times instead of 3 was €28,085 in the absence of herd immunity. At around 50% herd immunity, the ICER reached €50,000. Conclusion: From a herd immunity level of 50% onwards, screening intensity based on the pre-vaccination risk level becomes cost-ineffective for unvaccinated women. Reducing the screening intensity of uniform screening may then be considered.

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.

__Background:__ Knowledge of the natural history of human papillomavirus (HPV), in particular the role of immunity, is crucial in estimating the (cost-) effectiveness of HPV vaccination and cervical cancer screening strategies, because naturally acquired immunity after clearing an infection may already protect part of the risk population against new HPV infections. __Methods:__ We used STDSIM, an established stochastic microsimulation model, quantified to the Netherlands. We explored different assumptions regarding the natural history of HPV-16 and HPV-18, and estimated the transmission probabilities and durations of acquired immunity necessary to reproduce age-specific prevalence. __Results:__ A model without acquired immunity cannot reproduce the age-specific patterns of HPV. Also, it is necessary to assume a high degree of individual variation in the duration of infection and acquired immunity. According to the model estimates, on average 20% of women are immune for HPV-16 and 15% for HPV-18. After an HPV-16 infection, 50% are immune for less than 1 year, whereas 20% exceed 30 years. For HPV-18, up to 12% of the individuals are immune for less than 1 year, and about 50% over 30 years. Almost half of all women will never acquire HPV-16 or HPV-18. __Conclusions:__ Acquired immunity likely plays a major role in HPV epidemiology, but its duration shows substantial variation. Combined with the lifetime risk, this explains to a large extent why many women will never develop cervical cancer.

The human papilloma virus (HPV) DNA test has higher sensitivity than cytology for cervical cancer screening. Therefore, cervical cancer cases that are missed by cytology could potentially be identified if we use primary HPV testing. Studies showed that HPV screening is the preferred primary test at age 35 and over. Given the high prevalence of harmless HPV infections, the use of HPV testing at younger age is less obvious. The number of cancers in young age is often mentioned to indicate the possible benefits of a more sensitive test. We actually estimated the proportion of those cases that is potentially preventable in The Netherlands by the use of a more sensitive screen-test at the first screening age 30, given that the more sensitive test is used at age 35 and over. We analysed the screening history of women diagnosed with cervical cancer in the period 2004 to March 2009, using data from the Dutch National Pathology Registry. Only 15-30% (two to four cases per 100,000 women) of the cases was preceded by negative cytology under age 35 and therefore could have been prevented by a more sensitive test at age 30. The lower the screening coverage and the shorter the screening interval in those screened at young age, the smaller the gain of a more sensitive test. So, as long as the current screening pattern is not changed, the majority of the cervical cancer cases at young age would still occur even when applying a more sensitive test at the younger ages.

To assess among parents longitudinal predictors of human papillomavirus (HPV) vaccination uptake for their daughters, random samples of parents were identified via municipal services and sent baseline questionnaires in June 2009 and follow-up questionnaires in November 2011 after their uptake decision. Hierarchical logistic regression analysis was used to assess whether demographic characteristics, and affective and social cognitive factors, predicted uptake at follow-up. Response rates of the baseline and follow-up questionnaire were 29.8% (1762/5918) and 74.3% (793/1067), respectively. Uptake was predicted by a later (2011) versus earlier (2010) decision about uptake as HPV vaccination implementation [odds ratio (OR) 2.48; 95% confidence interval (CI) 1.11-5.52], anticipated regret about no uptake (OR 1.43; 95% CI 1.08-1.89) and intention (OR 2.61; 95% CI 1.47-4.61). There was an interaction between ambivalence and attitude (OR 1.68; 95% CI 1.14-2.47); parents with a positive attitude and a high ambivalence toward vaccination were more likely to have their daughter vaccinated than parents with a positive attitude and a low ambivalence. An informed choice about uptake (5/7 correct items) was made by 44%. In conclusion, uptake was predicted by intention, a later (2011) versus earlier (2010) decision and by anticipated regret about no uptake. Decisions regarding new vaccines are difficult to make, we recommend a well-balanced implementation process.

Background: Adolescent girls are at an age to be involved in the decision about HPV vaccination uptake and therefore need adequate information about the vaccination. This study assesses to what extent reading an official information leaflet about HPV contributes to girls' knowledge levels, and to what extent an increase in knowledge is boosted by a pre-test measurement. Methods. Participants (girls aged 11-14 years) were systematically allocated to group A that completed a pre-test measurement (12 true/false statements) or to group B that did not complete it. Subsequently, both groups read the HPV leaflet and completed the post-test measurement. Results: The response rate was 237/287 (83%). Pre-test scores in group A (M = 3.6, SD = 1.81, p < 0.001) were lower than post-test mean knowledge scores (0-10) in group B (M = 4.6, SD = 2.05). Post-test knowledge scores in group A were higher than those in group B [6.2 (SD = 2.06) versus 4.6 (SD = 2.05), p < 0.001]. In the post-test measurement, about a third of both groups knew that vaccinations do not give 100% protection against cervical cancer and that the duration of protection is unknown. Conclusions: Reading the information leaflet had a positive effect on knowledge, even more so when boosted by a pre-test measurement. However, knowledge on the degree and duration of protection against cervical cancer remained limited. Focusing girls' attention on important aspects before they start reading the leaflet (e.g. by including a quiz on the first page) may serve to raise their awareness of these aspects.

Objective To determine the most cost-effective screening programme for cervical cancer. Design Cost-effectiveness analysis from a societal perspective. Setting The Netherlands. Population Dutch women who have not been invited for human papillomavirus (HPV) vaccination. Methods We calibrated the microsimulation screening analysis (MISCAN) model to Dutch epidemiological data. We used this model to consider nine screening strategies that use: (i) cytological testing with cytology triage for borderline/mildly abnormal smears; (ii) HPV testing with cytology triage for HPV-positive smears; or (iii) cytological testing with HPV triage for borderline/mildly abnormal smears. For each strategy, we varied the number of screening rounds, the time interval, the age of the first screening, and the type of cytological testing (conventional or liquid-based cytology). Main outcome measures Quality-adjusted life years (QALYs) gained and costs from a societal perspective. Results Under the base-case assumptions, primary HPV testing with cytology triage is the most cost-effective strategy. Using cost-effectiveness thresholds of a€20 000 and a€50 00

Context: This article compares cervical cancer screening intensity and cervical cancer mortality trends in the United States and the Netherlands to illustrate the potential of cross-national comparative studies. We discuss the lessons that can be learned from the comparison as well as the challenges in each country to effective and efficient screening. Methods: We used nationally representative data sources in the United States and the Netherlands to estimate the number of Pap smears and the cervical cancer mortality rate since 1950. The following questions are addressed: How do differences in intensity of Pap smear use between the countries translate into differences in mortality trends? Can population coverage rates (the proportion of eligible women who had a Pap smear within a specified period) explain the mortality trends better than the total intensity of Pap smear use? Findings: Even though three to four times more Pap smears per woman were conducted in the United States than in the Netherlands over a period of three decades, the two countries' mortality trends were quite similar. The five-year coverage rates for women aged thirty to sixty-four were quite comparable at 80 to 90 percent. Because screening in the Netherlands was limited to ages thirty to sixty, screening rates for women under thirty and over sixty were much higher in the United States. These differences had consequences for age-specific mortality trends. The relatively good coverage rate in the Netherlands can be traced back to a nationwide invitation system based on municipal population registries. While both countries followed a "policy cycle" involving evidence review, surveillance of screening practices and outcomes, clinical guidelines, and reimbursement policies, the components of this cycle were more systematically linked and implemented nationwide in the Netherlands than in the United States. To a large extent, this was facilitated by a public health model of screening in the Netherlands

[to follow]

Cancer of the cervix uteri is the third most common cancer among women worldwide. The incidence and mortality in the Netherlands, however, are very low, partly because of an effective screening programme. Next to the well-known conventional Pap smear, other medical interventions are available and have been developed more recently to prevent death from cervical cancer. This is, amongst others, liquid-based cytology, HPV DNA screening, and HPV vaccination. This thesis presents health effects and cost-effectiveness of cervical cancer screening and HPV vaccination, in the Netherlands as well as internationally.

It is under debate whether healthcare costs related to death and in life years gained (LysG) due to life saving interventions should be included in economic evaluations. We estimated the impact of including these costs on cost-effectiveness of cancer screening. We obtained health insurance, home care, nursing homes, and mortality data for 2.1 million inhabitants in the Netherlands in 1998-1999. Costs related to death were approximated by the healthcare costs in the last year of life (LastYL), by cause and age of death. Costs in LYsG were estimated by calculating the healthcare costs in any life year. We calculated the change in cost-effectiveness ratios (CERs) if unrelated healthcare costs in the LastYL or in LYsG would be included. Costs in the LastYL were on average 33% higher for persons dying from cancer than from any cause. Including costs in LysG incr

Background and aims Over the past decades, incidence trends of colorectal cancer are sharply increased in Singapore. In this population-based study we describe changes in colorectal cancer incidence in Singapore and explore the reasons behind these changes through age-period cohort (APC) modeling. Methods We included all 22,609 colorectal cancer cases reported to the Singapore Cancer Registry between 1968 and 2002. Poisson regression, using age-period (AP) and age-cohort (AC) models was used to determine the effects of age at diagnosis, calendar period, and birth cohort. Results Male colorectal cancer rates between 1968 and 2002 from 20 to 40 per 100,000 person years. The increase was sharpest among older men, for whom there was a significant AC effect. Female colorectal cancer rates increased until 1992 (from 16 to 29 per 100,000 person years) and stabilized afterward. For women under 65 years, we observed a significant AP effect, corresponding to a sudden rise in colorectal cancer incidence around 1978. Conclusions This study demonstrates important gender differences in colorectal cancer incidence in Singapore, with increasing rates among men, and stabilized rates in women. The increase in men is mainly attributable to an incidence increase in the oldest age groups, probably due to increased exposure to dietary and lifestyle risk factors earlier in life. The stab

Despite increased recognition of the importance of investigating socio-economic inequalities in health from a life course perspective, little is known about the influence of childhood socio-economic position (SEP) on cancer incidence. The authors studied the association between father's occupation and adult cancer incidence by linking information from the longitudinal GLOBE study with the regional population-based Eindhoven Cancer Registry (the Netherlands) over a period of 14 years. In 1991, 18,973 participants (response rate 70.1%) of this study responded to a postal questionnaire, including questions on SEP in youth and adulthood. Respondents above the age of 24 were