Cost-effectiveness of pembrolizumab compared with chemotherapy in the US for women with previously treated deficient mismatch repair or high microsatellite instability unresectable or metastatic endometrial cancer.

AIMS: There is limited published evidence for the cost-effectiveness of treatments for unresectable or metastatic endometrial cancer (mEC). The objective of this analysis was to assess the cost-effectiveness of pembrolizumab versus chemotherapy for previously treated unresectable or mEC, in women whose tumors have deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H). The analysis was carried out from a US healthcare payer perspective. MATERIALS AND METHODS: A lifetime partitioned survival model comprising three health states (progression-free, progressed disease and death) was constructed. Chemotherapy was represented by single-agent paclitaxel or doxorubicin. Overall survival, progression-free survival and time on treatment data for pembrolizumab were obtained from a Phase II clinical study that included women with previously treated dMMR/MSI-H unresectable or mEC (KEYNOTE-158, NCT02628067). Survival data for chemotherapy were obtained from a published Phase III study for previously treated advanced endometrial cancer. Costs included were drug acquisition and administration, health-state, end-of-life, and adverse event management. Costs were presented in 2019 US$. Outcomes were calculated as quality-adjusted life-years (QALYs), using EQ-5D data from KEYNOTE-158. Model results were tested extensively in deterministic and probabilistic sensitivity analyses. RESULTS: Results demonstrated that pembrolizumab is a highly cost-effective treatment option when compared with chemotherapy, with estimated deterministic and probabilistic incremental cost-effectiveness ratios (ICERs) of $58,165 and $57,668 per QALY gained, respectively. Pembrolizumab was associated with a large QALY and life-year gain per person versus chemotherapy over the model time horizon (deterministic 4.68 life year gain, 3.80 QALYs), with the majority of QALYs accrued in the progression-free health state. LIMITATIONS: The key limitation of the analysis was the lack of comparative effectiveness data for pembrolizumab versus chemotherapy. CONCLUSIONS: Pembrolizumab is a highly cost-effective treatment option when compared with chemotherapy for women with previously treated dMMR/MSI-H unresectable or mEC. Results were robust to the changes in parameters and assumptions explored.

Estimating the Natural History of Cervical Carcinogenesis Using Simulation Models: A CISNET Comparative Analysis.

BACKGROUND: The natural history of human papillomavirus (HPV)-induced cervical cancer (CC) is not directly observable, yet the age of HPV acquisition and duration of preclinical disease (dwell time) influences the effectiveness of alternative preventive policies. We performed a Cancer Intervention and Surveillance Modeling Network (CISNET) comparative modeling analysis to characterize the age of acquisition of cancer-causing HPV infections and implied dwell times for distinct phases of cervical carcinogenesis. METHODS: Using four CISNET-cervical models with varying underlying structures but fit to common US epidemiological data, we estimated the age of acquisition of causal HPV infections and dwell times associated with three phases of cancer development: HPV, high-grade precancer, and cancer sojourn time. We stratified these estimates by HPV genotype under both natural history and CC screening scenarios, because screening prevents cancer development that affects the mix of detected cancers. RESULTS: The median time from HPV acquisition to cancer detection ranged from 17.5 to 26.0 years across the four models. Three models projected that 50% of unscreened women acquired their causal HPV infection between ages 19 and 23 years, whereas one model projected these infections occurred later (age 34 years). In the context of imperfect compliance with US screening guidelines, the median age of causal infection was 4.4-15.9 years later compared with model projections in the absence of screening. CONCLUSIONS: These validated CISNET-CC models, which reflect some uncertainty in the development of CC, elucidate important drivers of HPV vaccination and CC screening policies and emphasize the value of comparative modeling when evaluating public health policies.

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.

The health impact of human papillomavirus vaccination in the situation of primary human papillomavirus screening: A mathematical modeling study.

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 mortality, prevention can be further improved by increasing vaccination uptake and extending vaccination to boys. As not all cervical cancer deaths will be prevented, screening participation should still be encouraged.

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 5 924 474 normal screening samples (23 833 123 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 100 000 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 cytology and conventional cytology.

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.

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, 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 pre-vaccination 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.

Population-level impact, herd immunity, and elimination after human papillomavirus vaccination: a systematic review and meta-analysis of predictions from transmission-dynamic models.

BACKGROUND: Modelling studies have been widely used to inform human papillomavirus (HPV) vaccination policy decisions; however, many models exist and it is not known whether they produce consistent predictions of population-level effectiveness and herd effects. We did a systematic review and meta-analysis of model predictions of the long-term population-level effectiveness of vaccination against HPV 16, 18, 6, and 11 infection in women and men, to examine the variability in predicted herd effects, incremental benefit of vaccinating boys, and potential for HPV-vaccine-type elimination. METHODS: We searched MEDLINE and Embase for transmission-dynamic modelling studies published between Jan 1, 2009, and April 28, 2015, that predicted the population-level impact of vaccination on HPV 6, 11, 16, and 18 infections in high-income countries. We contacted authors to determine whether they were willing to produce new predictions for standardised scenarios. Strategies investigated were girls-only vaccination and girls and boys vaccination at age 12 years. Base-case vaccine characteristics were 100% efficacy and lifetime protection. We did sensitivity analyses by varying vaccination coverage, vaccine efficacy, and duration of protection. For all scenarios we pooled model predictions of relative reductions in HPV prevalence (RRprev) over time after vaccination and summarised results using the median and 10th and 90th percentiles (80% uncertainty intervals [UI]). FINDINGS: 16 of 19 eligible models from ten high-income countries provided predictions. Under base-case assumptions, 40% vaccination coverage and girls-only vaccination, the RRprev of HPV 16 among women and men was 0·53 (80% UI 0·46-0·68) and 0·36 (0·28-0·61), respectively, after 70 years. With 80% girls-only vaccination coverage, the RRprev of HPV 16 among women and men was 0·93 (0·90-1·00) and 0·83 (0·75-1·00), respectively. Vaccinating boys in addition to girls increased the RRprev of HPV 16 among women and men by 0·18 (0·13-0·32) and 0·35 (0·27-0·39) for 40% coverage, and 0·07 (0·00-0·10) and 0·16 (0·01-0·25) for 80% coverage, respectively. The RRprev were greater for HPV 6, 11, and 18 than for HPV 16 for all scenarios investigated. Finally at 80% coverage, most models predicted that girls and boys vaccination would eliminate HPV 6, 11, 16, and 18, with a median RRprev of 1·00 for women and men for all four HPV types. Variability in pooled findings was low, but increased with lower vaccination coverage and shorter vaccine protection (from lifetime to 20 years). INTERPRETATION: Although HPV models differ in structure, data used for calibration, and settings, our population-level predictions were generally concordant and suggest that strong herd effects are expected from vaccinating girls only, even with coverage as low as 20%. Elimination of HPV 16, 18, 6, and 11 is possible if 80% coverage in girls and boys is reached and if high vaccine efficacy is maintained over time. FUNDING: Canadian Institutes of Health Research.

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.

The estimated impact of natural immunity on the effectiveness of human papillomavirus vaccination.

BACKGROUND: Mathematical modelling is used to estimate the effectiveness of HPV vaccination. These estimates depend strongly on herd immunity and thus on naturally acquired immunity, a mechanism of which little is known. We estimated the impact of different vaccination strategies on HPV-16 and HPV-18 transmission and cervical cancer incidence in the Netherlands, considering different acquired immunity mechanisms. METHODS: We used the STDSIM microsimulation model, and considered two mechanisms for acquired immunity after infection: (I) full immunity with variable duration; (II) cumulatively decreasing susceptibility to reinfection. Girls aged 13-16 years received vaccination (94.7% efficacy for HPV-16 and 92.3% for HPV-18) during a once-off catch-up campaign with 50% coverage, followed by annual vaccination of 12-year-old girls (60% coverage). Alternative vaccination scenarios included increased coverage, including boys, and lower vaccine efficacy. RESULTS: HPV-16 incidence reduced by 64% under mechanism I and 75% under mechanism II; HPV-18 incidence reduced by 58% and 73%, respectively, and these reductions lead to 48-56% fewer cervical cancer cases. Increasing coverage can lead to over 96% reduction in HPV incidence. Vaccinating boys reduced incidence by 79-89% for HPV-16 and 83-98% for HPV-18 in women. CONCLUSIONS: Effectiveness estimates of HPV vaccination differ slightly between different acquired immunity mechanisms, yet these differences are unlikely to affect policy decisions. Offering vaccination to boys as well may be considered to further reduce cancer incidence.

Exploring the trend of increased cervical intraepithelial neoplasia detection rates in the Netherlands.

OBJECTIVE: Over the last decade, cervical intraepithelial neoplasia (CIN) detection has increased in the Netherlands. We investigated the underlying mechanism by quantifying the increase, and analyzing patterns of CIN and cervical cancer detection over time. METHODS: We observed annual CIN and cervical cancer detection rates (DRs) per 10,000 primary smears within the Dutch screening programme for 2000-2011. Joinpoint analyses were performed to determine changes in time trends, logistic regression analyses to assess the relative risk of calendar time on histological outcomes, adjusted for demographic factors and type of primary cytology test used. RESULTS: Trends of increased detection occurred for all CIN grades (ie. DRs increased from 17.8 to 36.1, from 21.0 to 35.5, and from 43.4 to 64.6 for CIN I, II, and III from 2003 to 2009). After adjusting for demographic factors, DRs were still 2.11 (95% confidence interval (CI): 1.95, 2.29), 1.79 (95% CI: 1.66, 1.92) and 1.59 (95% CI: 1.50, 1.67) times larger in 2009. When also adjusting for the type of cytology test, DRs were 1.90 (95% CI: 1.62, 2.22), 1.48 (95% CI: 1.22, 1.79) and 1.55 (95% CI: 1.39, 1.73) times larger. No trends in cervical cancer DRs were found. CONCLUSIONS: The implementation of liquid-based cytology contributed to the CIN increase. If some of these extra detected CIN are regressive this leads to overdiagnosis. Other factors, such as an increased cervical cancer risk, and implementation of imaging-assisted reading, could also have contributed.

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.