Emily Annika Burger

A cost-effectiveness analysis of sentinel lymph node biopsy compared with lymphadenectomy in intermediate- and high- risk endometrial carcinoma

Sentinel lymph node biopsy (SLN) is increasingly used for surgical staging of endometrial carcinoma. To estimate the effect and cost-effectiveness of the implementation of an SLN algorithm for surgical staging in patients with intermediate- and high-risk endometrial carcinoma compared with lymphadenectomy. We performed a model-based, cost-effectiveness analysis using primary data from a tertiary referral hospital that included 829 patients with endometrial carcinoma undergoing surgical staging. We quantified the health and economic outcomes from two time periods, before and after implementation of the SLN algorithm by robotic surgery. Costs were measured directly from the hospital's financial department, while long-term health outcomes were estimated using self-reported lymphedema and health-related quality-of-life among survivors. Sensitivity analyses were conducted to evaluate uncertainty. We projected that the SLN implementation period, predominately reflecting use of robotic SLN, simultaneously improved health outcomes (0.08 incremental quality-adjusted life-years) and lowered costs (US$1051) compared with the prior period involving robotic or open lymphadenectomy. SLN remained more beneficial and less costly across key sensitivity analyses-namely, varying the cost of the robotic platform, surgical equipment, number of yearly robotic procedures, percentage of robotic procedures versus percentage of laparotomies, length of stay, and lymphedema development. After 1000 simulations of the model, SLN implementation provided greater health benefits for lower costs (ie, cost saving) in 89% of simulations. Implementation of an SLN algorithm in the staging of intermediate- and high-risk endometrial carcinoma improved health outcomes for lower costs compared with lymphadenectomy. Cost-effectiveness could further improve by continuing to increase the proportion of robotic procedures.

Population-level impact of switching to 1-dose human papillomavirus vaccination in high-income countries: examining uncertainties using mathematical modeling

Abstract Background A concern in high-income countries is that switching to 1-dose human papillomavirus (HPV) vaccination could cause a rebound in HPV infection and cervical cancer if 1-dose efficacy or duration were inferior to 2 doses. Using mathematical modeling and up-to-date trial-based data, we projected the population-level effectiveness of switching from 2-dose to 1-dose vaccination under different vaccine efficacy and duration assumptions in high-income countries. Methods We used HPV-ADVISE (Agent-based Dynamic model for VaccInation and Screening Evaluation), a transmission-dynamic model of HPV infection and cervical cancer, varying key model assumptions to identify those with the greatest impact on projections of HPV-16 and cervical cancer incidence over time: 1) 1-dose vaccine efficacy and vaccine duration, 2) mechanisms of vaccine efficacy and duration over time, 3) midadult (>30 years of age) sexual behavior, 4) progression to cervical cancer among midadults, and 5) vaccination coverage and programs. Results In high-income countries, 1-dose vaccination would cause no appreciable rebound in HPV-16 infection, except for a limited rebound under the most pessimistic assumptions of vaccine duration (average, 25 years), because 1) the switch would occur when HPV prevalence is low because of high 2-dose vaccination coverage and 2) individuals would be protected during their peak ages of sexual activity (<35 to 40 years of age). Our model projects a more limited rebound in cervical cancer because of a shift to older age at infection, resulting in fewer life-years left to potentially develop cancer. Projections were robust when varying key model assumptions. Conclusions High protection during peak ages of sexual activity in high-income countries would likely mitigate any potential rebounds in HPV infection and cervical cancer under the most pessimistic assumptions of 1-dose efficacy and duration.

Population-level health impact of hypothetical waning 1-dose human papillomavirus vaccination and 2-dose mitigation strategies in a high cervical cancer burden setting

Abstract Background We simulated the impact of hypothetical waning scenarios of a 1-dose human papillomavirus (HPV) vaccination paired with switching to 2-dose mitigation strategies guided by empirical vaccine trial reporting timelines. Methods Using 2 independent mathematical models fitted to a high-burden setting, we projected the cumulative cervical cancer cases averted over 85 years for alternative HPV vaccination scenarios under 2 program adoption timelines: 1) de novo introduction of a 1-dose HPV vaccination and 2) a switch from an existing 2-dose HPV vaccination program to a 1-dose vaccination. We assumed 80% vaccination coverage with the bivalent vaccine and an average duration of a 1-dose HPV vaccine protection of either 30 or 25 years with 100% efficacy. We varied the eligible age group(s) at program introduction and the 2-dose mitigation (single-age cohort or multi-age cohort). If needed for mitigation, reintroduction of 2-dose vaccination was assumed to occur in 2036 (ie, 30 years after initiation of the Costa Rica Vaccine Trial). Results Under both vaccine adoption timelines, the models projected that countries could achieve the same level of health benefits by switching to 2 doses in 2036 using a multi-age cohort approach as with initiating a 2-dose or 1-dose vaccination program with no waning. With only a single-age cohort 2-dose mitigation approach, 98%-99% of cases would be prevented compared with the health benefits of 2 doses or a noninferior, durable 1 dose. Conclusions Countries hesitant to adopt a 1-dose HPV vaccination program may have opportunities to leverage the benefits and efficiency of a 1-dose schedule while awaiting longer-term reporting from 1-dose durability studies, including Costa Rica Vaccine Trial.

Disparities in cervical cancer elimination time frames in the United States: a comparative modeling study

Abstract Population-level estimates in time frames for reaching cervical cancer elimination (ie, <4 cases per 100 000 women) in the United States may mask potential disparities in achieving elimination among subpopulations. We used 3 independent Cancer Intervention and Surveillance Modeling Network models to estimate differences in the time to cervical cancer elimination across 7 strata of correlated screening and human papillomavirus vaccination uptake, based on national survey data. Compared with the average population, elimination was achieved at least 22 years earlier for the high-uptake strata and at least 27 years later for the most extreme low-uptake strata. Accounting for correlated uptake impacted the population average time frame by no more than 1 year. Consequently, national average elimination time frames mask substantial disparities in reaching elimination among subpopulations. Addressing inequalities in cervical cancer control could shorten elimination time frames and would ensure more equitable elimination across populations. Furthermore, country-level elimination monitoring could be supplemented by monitoring progress in subpopulations.

Sociodemographic characteristics associated with cervical cancer screening participation by send‐to‐all and opt‐in HPV self‐sampling: Who benefits? Results from a randomized controlled trial among long‐term non‐attending women in Norway

AbstractWith the objective to investigate associations between sociodemographic characteristics and participation in interventions designed to increase participation in cervical cancer screening among under‐screened women, we randomized a random sample of 6000 women in Norway aged 35–69 years who had not attended cervical screening for ≥10 years to receive either (i) a reminder to attend regular screening (control), (ii) an offer to order a self‐sampling kit (opt‐in), or (iii) a self‐sampling kit unsolicited (send‐to‐all). We analyzed how sociodemographic characteristics were associated with screening participation within and between screening arms. In the send‐to‐all arm, increased screening participation ranged from 17.1% (95% confidence interval [95% CI] = 10.3% to 23.8%) to 30.0% (95% CI = 21.5% to 38.6%) between sociodemographic groups. In the opt‐in arm, we observed smaller, and at times, non‐significant increases within the range 0.7% (95% CI = −5.8% to 7.3%) to 19.1% (95% CI = 11.6% to 26.7%). In send‐to‐all versus control comparisons, there was greater increase in participation for women in the workforce versus not (6.1%, 95% CI = 1.6% to 10.6%), with higher versus lower income (7.6%, 95% CI = 2.2% to 13.1%), and with university versus primary education (8.5%, 95% CI = 2.4% to 14.6%). In opt‐in versus control comparisons, there was greater increase in participation for women in the workforce versus not (4.6%, 95% CI = 0.7% to 8.5%), with higher versus lower income (6.3%, 95% CI = 1.5% to 11.1%), but lower increase for Eastern European versus Norwegian background (−12.7%, 95% CI = −19.7% to −5.7%). Self‐sampling increased cervical screening participation across all sociodemographic levels, but inequalities in participation should be considered when introducing self‐sampling, especially with the goal to reach long‐term non‐attending women.

Choosing the optimal HPV vaccine: The health impact and economic value of the nonavalent and bivalent HPV vaccines in 48 Gavi‐eligible countries

AbstractThe human papillomavirus (HPV) vaccines may provide some level of cross‐protection against high‐risk HPV genotypes not directly targeted by the vaccines. We evaluated the long‐term health and economic impacts of routine HPV vaccination using either the nonavalent HPV vaccine or the bivalent HPV vaccine in the context of 48 Gavi‐eligible countries. We used a multi‐modeling approach to compare the bivalent with or without cross‐protection and the nonavalent HPV vaccine. The optimal, that is, most cost‐effective, vaccine was the vaccine with an incremental cost‐effectiveness ratio below the per‐capita gross domestic product (GDP) for each country. By 2100 and assuming 70% HPV vaccination coverage, a bivalent vaccine without cross‐protection, a bivalent vaccine with favorable cross‐protection and the nonavalent vaccine were projected to avert 14.9, 17.2 and 18.5 million cumulative cases of cervical cancer across all 48 Gavi‐eligible countries, respectively. The relative value of the bivalent vaccine compared to the nonavalent vaccine increased assuming a bivalent vaccine conferred high cross‐protection. For example, assuming a cost‐effectiveness threshold of per‐capita GDP, the nonavalent vaccine was optimal in 83% (n = 40) of countries if the bivalent vaccine did not confer cross‐protection; however, the proportion of countries decreased to 63% (n = 30) if the bivalent vaccine conferred high cross‐protection. For lower cost‐effectiveness thresholds, the bivalent vaccine was optimal in a greater proportion of countries, under both cross‐protection assumptions. Although the nonavalent vaccine is projected to avert more cases of cervical cancer, the bivalent vaccine with favorable cross‐protection can prevent a considerable number of cases and would be considered a high‐value vaccine for many Gavi‐eligible countries.

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

Abstract 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.

Potential effectiveness of a therapeutic HPV intervention campaign in Uganda

AbstractCervical cancer is a major source of morbidity and mortality in Uganda. In addition to prophylactic HPV vaccination, secondary prevention strategies are needed to reduce cancer burden. We evaluated the potential cancer reductions associated with a hypothetical single‐contact therapeutic HPV intervention—with 70% coverage and variable efficacy [30%‐100%]—using a three‐stage HPV modeling framework reflecting HPV and cervical cancer burden in Uganda. In the reference case, we assumed prophylactic preadolescent HPV vaccination starting in 2020 with 70% coverage. A one‐time therapeutic intervention targeting 35‐year‐old women in 2025 (not age‐eligible for prophylactic vaccination) averted 1801 cervical cancers per 100 000 women over their lifetime (100% efficacy) or 533 cancers per 100 000 (30% efficacy). Benefits were considerably smaller in birth cohorts eligible for prophylactic HPV vaccination (768 cases averted per 100 000 at 100% efficacy). Evaluating the population‐level impact over 40 years, we found introduction of a therapeutic intervention in 2025 with 100% efficacy targeted annually to 30‐year‐old women averted 139 000 incident cervical cancers in Uganda. This benefit was greatly reduced if efficacy was lower (30% efficacy; 41 000 cases averted), introduction was delayed (2040 introduction; 72 000 cases averted) or both (22 000 cases averted). We demonstrate the potential benefits of a single‐contact HPV therapeutic intervention in a low‐income setting, but show the importance of high therapeutic efficacy and early introduction timing relative to existing prophylactic programs. Reduced benefits from a less efficacious intervention may be somewhat offset if available within a shorter time frame.

Switching clinic‐based cervical cancer screening programs to human papillomavirus self‐sampling: A cost‐effectiveness analysis of vaccinated and unvaccinated Norwegian women

AbstractSeveral countries have implemented primary human papillomavirus (HPV) testing for cervical cancer screening. HPV testing enables home‐based, self‐collected sampling (self‐sampling), which provides similar diagnostic accuracy as clinician‐collected samples. We evaluated the impact and cost‐effectiveness of switching an entire organized screening program to primary HPV self‐sampling among cohorts of HPV vaccinated and unvaccinated Norwegian women. We conducted a model‐based analysis to project long‐term health and economic outcomes for birth cohorts with different HPV vaccine exposure, that is, preadolescent vaccination (2000‐ and 2008‐cohorts), multiage cohort vaccination (1991‐cohort) or no vaccination (1985‐cohort). We compared the cost‐effectiveness of switching current guidelines with clinician‐collected HPV testing to HPV self‐sampling for these cohorts and considered an additional 44 strategies involving either HPV self‐sampling or clinician‐collected HPV testing at different screening frequencies for the 2000‐ and 2008‐cohorts. Given Norwegian benchmarks for cost‐effectiveness, we considered a strategy with an additional cost per quality‐adjusted life‐year below $55 000 as cost‐effective. HPV self‐sampling strategies considerably reduced screening costs (ie, by 24%‐40% across cohorts and alternative strategies) and were more cost‐effective than clinician‐collected HPV testing. For cohorts offered preadolescent vaccination, cost‐effective strategies involved HPV self‐sampling three times (2000‐cohort) and twice (2008‐cohort) per lifetime. In conclusion, we found that switching from clinician‐collected to self‐collected HPV testing in cervical screening may be cost‐effective among both highly vaccinated and unvaccinated cohorts of Norwegian women.

Impact of COVID-19-related care disruptions on cervical cancer screening in the United States

Objectives To quantify the secondary impacts of the COVID-19 pandemic disruptions to cervical cancer screening in the United States, stratified by step in the screening process and primary test modality, on cervical cancer burden. Methods We conducted a comparative model-based analysis using three independent NCI Cancer Intervention and Surveillance Modeling Network cervical models to quantify the impact of eight alternative COVID-19-related screening disruption scenarios compared to a scenario of no disruptions. Scenarios varied by the duration of the disruption (6 or 24 months), steps in the screening process being disrupted (primary screening, surveillance, colposcopy, excisional treatment), and primary screening modality (cytology alone or cytology plus human papillomavirus “cotesting”). Results The models consistently showed that COVID-19-related disruptions yield small net increases in cervical cancer cases by 2027, which are greater for women previously screened with cytology compared with cotesting. When disruptions affected all four steps in the screening process under cytology-based screening, there were an additional 5–7 and 38–45 cases per one million screened for 6- and 24-month disruptions, respectively. In contrast, under cotesting, there were additional 4–5 and 35–45 cases per one million screened for 6- and 24-month disruptions, respectively. The majority (58–79%) of the projected increases in cases under cotesting were due to disruptions to surveillance, colposcopies, or excisional treatment, rather than to primary screening. Conclusions Women in need of surveillance, colposcopies, or excisional treatment, or whose last primary screen did not involve human papillomavirus testing, may comprise priority groups for reintroductions.

A model-based analysis of the health impacts of COVID-19 disruptions to primary cervical screening by time since last screen for current and future disruptions

We evaluated how temporary disruptions to primary cervical cancer (CC) screening services may differentially impact women due to heterogeneity in their screening history and test modality. We used three CC models to project the short- and long-term health impacts assuming an underlying primary screening frequency (i.e., 1, 3, 5, or 10 yearly) under three alternative COVID-19-related screening disruption scenarios (i.e., 1-, 2-, or 5-year delay) versus no delay in the context of both cytology-based and human papillomavirus (HPV)-based screening. Models projected a relative increase in symptomatically detected cancer cases during a 1-year delay period that was 38% higher (Policy1-Cervix), 80% higher (Harvard), and 170% higher (MISCAN-Cervix) for underscreened women whose last cytology screen was 5 years prior to the disruption period compared with guidelines-compliant women (i.e., last screen 3 years prior to disruption). Over a woman’s lifetime, temporary COVID-19-related delays had less impact on lifetime risk of developing CC than screening frequency and test modality; however, CC risks increased disproportionately the longer time had elapsed since a woman’s last screen at the time of the disruption. Excess risks for a given delay period were generally lower for HPV-based screeners than for cytology-based screeners. Our independent models predicted that the main drivers of CC risk were screening frequency and screening modality, and the overall impact of disruptions from the pandemic on CC outcomes may be small. However, screening disruptions disproportionately affect underscreened women, underpinning the importance of reaching such women as a critical area of focus, regardless of temporary disruptions.

Now or later: Health impacts of delaying single‐dose HPV vaccine implementation in a high‐burden setting

AbstractWe aimed to quantify the health impact of immediate introduction of a single‐dose human papillomavirus (HPV) vaccination program in a high‐burden setting, as waiting until forthcoming trials are completed to implement single‐dose HPV vaccination may result in health losses, particularly for cohorts who would age‐out of vaccination eligibility. Two mathematical models fitted to a high‐burden setting projected cervical cancer incidence rates associated with (a) immediate implementation of one‐dose HPV vaccination vs (b) waiting 5 years for evidence from randomized trials to determine if one‐ or two‐doses should be implemented. We conducted analyses assuming a single dose was either noninferior or inferior to two doses. The models projected that immediate implementation of a noninferior single‐dose vaccine led to a 7.2% to 9.6% increase in cancers averted between 2021 to 2120, compared to waiting 5 years. Health benefits remained greater with immediate implementation despite an inferior single‐dose efficacy (80%), but revaccination of one‐dose recipients became more important assuming vaccine waning. Under most circumstances, immediate vaccination avoided health losses for those aging out of vaccine eligibility, leading to greater health benefits than waiting for more information in 5 years.

Identifying a Single Optimal Integrated Cervical Cancer Prevention Policy in Norway: A Cost-Effectiveness Analysis

Background Interventions targeting the same disease but at different points along the disease continuum (e.g., screening and vaccination to prevent cervical cancer [CC]) are often evaluated in isolation, which can affect cost-effectiveness profiles and policy conclusions. We evaluated nonavalent human papillomavirus (HPV) vaccine (9vHPV) compared with bivalent HPV vaccine (2vHPV) alongside deintensified screening intervals for a vaccinated birth cohort to inform a single optimal integrated CC prevention policy. Methods Using a multimodeling approach, we evaluated the health and economic impacts of alternative CC screening strategies for a Norwegian birth cohort eligible for HPV vaccination in 2021 assuming they received 1) 2vHPV or 2) 9vHPV. We conducted 1) a restricted analysis that evaluated the optimal HPV vaccine under current screening guidelines; and 2) a comprehensive analysis including alternative screening and vaccination strategy combinations. We calculated incremental cost-effectiveness ratios (ICERs) and evaluated them according to different cost-effectiveness thresholds. Results Assuming a cost-effectiveness threshold of $40,000 per quality-adjusted life year (QALY) gained, we found that, while holding screening intensity fixed, switching the routine vaccination program in Norway from 2vHPV to 9vHPV would not be considered cost-effective (ICER of $132,700 per QALY gained). However, when allowing for varying intensities of CC screening, we found that switching to 9vHPV would be cost-effective compared with 2vHPV under an alternative threshold of $55,000 per QALY gained, if coupled with reductions in the number of lifetime screens. Conclusions Our analysis highlights the importance of evaluating the full potential policy landscape for country-level decision makers considering policy adoption, including nonindependent primary and secondary prevention efforts, to draw appropriate conclusions and avoid sub-optimal outcomes. Highlights Without evaluating the full potential policy landscape, including primary and secondary prevention efforts, country-level decision makers may not be able to draw appropriate policy conclusions, resulting in suboptimal outcomes. An applied example from cervical cancer prevention in Norway compared a restricted analysis of current screening guidelines to a comprehensive analysis including alternative screening and vaccination strategy combinations. We found that a switch from bivalent to nonavalent human papillomavirus vaccine would be considered cost-effective in Norway if coupled with reductions in the number of lifetime screens compared with the current screening strategy. A comprehensive analysis that considers how different types of interventions along the disease continuum affect each other will be critical for decision makers interpreting cost-effectiveness analysis results.

Cost‐effectiveness of primary human papillomavirus triage approaches among vaccinated women in Norway: A model‐based analysis

AbstractAs Norway considers revising triage approaches following their first adolescent cohort with human papillomavirus (HPV) vaccination entering the cervical cancer screening program, we analyzed the health impact and cost‐effectiveness of alternative primary HPV triage approaches for women initiating cervical cancer screening in 2023. We used a multimodeling approach that captured HPV transmission and cervical carcinogenesis to evaluate the health benefits, harms and cost‐effectiveness of alternative extended genotyping and age‐based triage strategies under five‐yearly primary HPV testing (including the status‐quo screening strategy in Norway) for women born in 1998 (ie, age 25 in 2023). We examined 35 strategies that varied alternative groupings of high‐risk HPV genotypes (“high‐risk” genotypes; “medium‐risk” genotypes or “intermediate‐risk” genotypes), number and types of HPV included in each group, management of HPV‐positive women to direct colposcopy or active surveillance, wait time for re‐testing and age at which the HPV triage algorithm switched from less to more intensive strategies. Given the range of benchmarks for severity‐specific cost‐effectiveness thresholds in Norway, we found that the preferred strategy for vaccinated women aged 25 years in 2023 involved an age‐based switch from a less to more intensive follow‐up algorithm at age 30 or 35 years with HPV‐16/18 genotypes in the “high‐risk” group. The two potentially cost‐effective strategies could reduce the number of colposcopies compared to current guidelines and simultaneously improve health benefits. Using age to guide primary HPV triage, paired with selective HPV genotype and follow‐up time for re‐testing, could improve both the cervical cancer program effectiveness and efficiency.