Vaccination and Screening for the Prevention of Cervical Cancer: Health Effects and Cost-effectiveness

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

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

Cervical cancer screening in partly HPV vaccinated cohorts - A cost-effectiveness analysis

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

The role of acquired immunity in the spread of human papillomavirus (HPV): Explorations with a microsimulation model

__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

Predictors of HPV vaccination uptake: A longitudinal study among parents

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 s

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

Increasing girls' knowledge about human papillomavirus vaccination with a pre-test and a national leaflet: A quasi-experimental study

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

Comparing SurePath, ThinPrep, and conventional cytology as primary test method: SurePath is associated with increased CIN II+ detection rates

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

Effect of organised cervical cancer screening on cervical cancer mortality in Europe: a systematic review

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 were used to assess the risk of bias of the included studies. Results: Ten observational studies were included: seven cohort and three case-control studies. No randomised controlled trials were found, and there were no eligible studies from the eastern and southern part of Europe. Among the eligible studies, seven were conducted in the twentieth century; they scored lower on the risk of bias assessment. CC mortality reduction for women attending organised screening vs. non-attenders ranged from 41% to 92% in seven studies. Reductions were similar in Western (45–92%) and Northern (41–8

Cervical cancer incidence after normal cytological sample in routine screening using SurePath, ThinPrep, and conventional cytology: population based study

#### 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 cy