The predicted effect and cost-effectiveness of tailoring colonoscopic surveillance according to mismatch repair gene in patients with Lynch syndrome.

PURPOSE: Lynch syndrome-related colorectal cancer (CRC) risk substantially varies by mismatch repair (MMR) gene. We evaluated the health impact and cost-effectiveness of MMR gene-tailored colonoscopic surveillance. METHODS: We first estimated sex- and MMR gene-specific cumulative lifetime risk of first CRC without colonoscopic surveillance using an optimization algorithm. Next, we harnessed these risk estimates in a microsimulation model, "Policy1-Lynch," and compared 126 colonoscopic surveillance strategies against no surveillance. RESULTS: The most cost-effective strategy was 3-yearly surveillance from age 25 to 70 years (pathogenic variants [path_] in MLH1 [path_MLH1], path_MSH2) with delayed surveillance for path_MSH6 (age 30-70 years) and path_PMS2 (age 35-70 years) heterozygotes (incremental cost-effectiveness ratio = Australian dollars (A) $8,833/life-year saved). This strategy averted 60 CRC deaths (153 colonoscopies per death averted) over the lifetime of 1000 confirmed patients with Lynch syndrome (vs no surveillance). This also reduced colonoscopies by 5% without substantial change in health outcomes (vs nontailored 3-yearly surveillance from 25-70 years). Generally, starting surveillance at age 25 (vs 20) years was more cost-effective with minimal effect on life-years saved and starting 5 to 10 years later for path_MSH6 and path_PMS2 heterozygotes (vs path_MLH1 and path_MSH2) further improved cost-effectiveness. Surveillance end age (70/75/80 years) had a minor effect. Three-yearly surveillance strategies were more cost-effective (vs 1 or 2-yearly) but prevented 3 fewer CRC deaths. CONCLUSION: MMR gene-specific colonoscopic surveillance would be effective and cost-effective.

Human papillomavirus vaccination for adults aged 30 to 45 years in the United States: A cost-effectiveness analysis.

BACKGROUND: A nonavalent human papillomavirus (HPV) vaccine has been licensed for use in women and men up to age 45 years in the United States. The cost-effectiveness of HPV vaccination for women and men aged 30 to 45 years in the context of cervical cancer screening practice was evaluated to inform national guidelines. METHODS AND FINDINGS: We utilized 2 independent HPV microsimulation models to evaluate the cost-effectiveness of extending the upper age limit of HPV vaccination in women (from age 26 years) and men (from age 21 years) up to age 30, 35, 40, or 45 years. The models were empirically calibrated to reflect the burden of HPV and related cancers in the US population and used standardized inputs regarding historical and future vaccination uptake, vaccine efficacy, cervical cancer screening, and costs. Disease outcomes included cervical, anal, oropharyngeal, vulvar, vaginal, and penile cancers, as well as genital warts. Both models projected higher costs and greater health benefits as the upper age limit of HPV vaccination increased. Strategies of vaccinating females and males up to ages 30, 35, and 40 years were found to be less cost-effective than vaccinating up to age 45 years, which had an incremental cost-effectiveness ratio (ICER) greater than a commonly accepted upper threshold of $200,000 per quality-adjusted life year (QALY) gained. When including all HPV-related outcomes, the ICER for vaccinating up to age 45 years ranged from $315,700 to $440,600 per QALY gained. Assumptions regarding cervical screening compliance, vaccine costs, and the natural history of noncervical HPV-related cancers had major impacts on the cost-effectiveness of the vaccination strategies. Key limitations of the study were related to uncertainties in the data used to inform the models, including the timing of vaccine impact on noncervical cancers and vaccine efficacy at older ages. CONCLUSIONS: Our results from 2 independent models suggest that HPV vaccination for adult women and men aged 30 to 45 years is unlikely to represent good value for money in the US.

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

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

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

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

The predicted impact and cost-effectiveness of systematic testing of people with incident colorectal cancer for Lynch syndrome.

OBJECTIVES: To evaluate the health impact and cost-effectiveness of systematic testing for Lynch syndrome (LS) in people with incident colorectal cancer (CRC) in Australia. DESIGN, SETTING, PARTICIPANTS: We investigated the impact of LS testing strategies in a micro-simulation model (Policy1-Lynch), explicitly modelling the cost of testing all patients diagnosed with incident CRC during 2017, with detailed modelling of outcomes for patients identified as LS carriers (probands) and their at-risk relatives throughout their lifetimes. For people with confirmed LS, we modelled ongoing colonoscopic surveillance. MAIN OUTCOME MEASURES: Cost-effectiveness of six universal tumour testing strategies (testing for DNA mismatch repair deficiencies) and of universal germline gene panel testing of patients with incident CRC; impact on cost-effectiveness of restricting testing by age at CRC diagnosis (all ages, under 50/60/70 years) and of colonoscopic surveillance interval (one, two years). RESULTS: The cost-effectiveness ratio of universal tumour testing strategies (annual colonoscopic surveillance, no testing age limit) compared with no testing ranged from $28 915 to $31 904/life-year saved (LYS) (indicative willingness-to-pay threshold: $30 000-$50 000/LYS). These strategies could avert 184-189 CRC deaths with an additional 30 597-31 084 colonoscopies over the lifetimes of 1000 patients with incident CRC with LS and 1420 confirmed LS carrier relatives (164-166 additional colonoscopies/death averted). The most cost-effective strategy was immunohistochemistry and BRAF V600E testing (incremental cost-effectiveness ratio [ICER], $28 915/LYS). Universal germline gene panel testing was not cost-effective compared with universal tumour testing strategies (ICER, $2.4 million/LYS). Immunohistochemistry and BRAF V600E testing was cost-effective at all age limits when paired with 2-yearly colonoscopic surveillance (ICER, $11 525-$32 153/LYS), and required 4778-15 860 additional colonoscopies to avert 46-181 CRC deaths (88-103 additional colonoscopies/death averted). CONCLUSIONS: Universal tumour testing strategies for guiding germline genetic testing of people with incident CRC for LS in Australia are likely to be cost-effective compared with no testing. Universal germline gene panel testing would not currently be cost-effective.

Pathways to a cancer-free future: A protocol for modelled evaluations to maximize the future impact of interventions on cervical cancer in Australia.

OBJECTIVE: Australia's HPV vaccination and HPV-based cervical screening programs are changing the landscape in cervical cancer prevention. We aim to identify areas which can make the biggest further impact on cervical cancer burden. This protocol describes the first stage of a program of work called Pathways-Cervix that aims to generate evidence from modelled evaluations of interventions across the cervical cancer spectrum. METHODS: Based on evidence from literature reviews and guidance from a multi-disciplinary Scientific Advisory Committee (SAC), the most relevant evaluations for prevention, diagnosis and treatment were identified. RESULTS: Priority evaluations agreed by the SAC included: increasing/decreasing and retaining vaccination uptake at the current level; vaccinating older women; increasing screening participation; methods for triaging HPV-positive women; improving the diagnosis of cervical intraepithelial neoplasia (CIN) and cancer; treating cervical abnormalities and cancer; and vaccinating women treated for CIN2/3 to prevent recurrence. Evaluations will be performed using a simulation model, Policy1-Cervix previously used to perform policy evaluations in Australia. Exploratory modelling of interventions using idealised scenarios will initially be conducted in single birth cohorts. If these have a significant impact on findings then evaluations with more realistic assumptions will be conducted. Promising strategies will be investigated further by multi-cohort simulations predicting health outcomes, resource use and cost outcomes. CONCLUSIONS: Pathways-Cervix will assess the relative benefits of strategies and treatment options in a systematic and health economic framework, producing a list of 'best buys' for future decision-making in cervical cancer control.

Thoracic paravertebral blockade in breast surgery: Is pneumothorax an appreciable concern? A review of over 1000 cases.

There has been a substantial increase in ambulatory day-case breast surgery in recent decades. This has been largely due to improvements in anesthetic procedures and pre-emptive analgesia. Thoracic paravertebral blockade (TPVB) is increasing in popularity, though concerns over iatrogenic injury remain, especially pneumothorax. The purpose of this study was to conduct a review of the incidence of pneumothorax following TPVB prior to breast surgery. Data from of a consecutive series of patients having TPVB prior to breast surgery between 2009 and 2014 were reviewed. TPVB were used prior to unilateral and bilateral procedures. Medical records were retrospectively assessed for any complication including pleural punctures, pneumothorax, hypotension, bradycardia as well as signs and symptoms of local anesthetic toxicity. 1152 patients underwent a total of 1322 TPVB injections (982 unilateral and 340 bilateral). Clinically significant hypotension and/or bradycardia occurred in 26 patients (2.2%). Two patients (0.17%) had a suspected toxicity from the local anesthetic. Incidence of pleural puncture was 0.6% (n=9) and pneumothorax 0.26% (n=3). All pneumothoraxes were managed conservatively. There was no statistical difference in complication rates in those that had unilateral vs bilateral TPVB or those that had ultrasound guidance (P=.09). Good pre-emptive analgesia is pertinent to prevent acute postoperative pain. TPVB have been shown to be successful in reducing rescue analgesia. This study shows TPVB is a well-tolerated procedure, with a low associated incidence of iatrogenic injury and complication.

A modelled analysis of the impact of COVID-19-related disruptions to HPV vaccination.

COVID-19 disrupted school attendance in many countries, delaying routine adolescent vaccination against human papillomavirus (HPV) in some settings. We used Policy1-Cervix, a dynamic model simulating HPV transmission, natural history, vaccination, cervical screening, and diagnosis of HPV-related cancers, to estimate the impact on HPV-related cancers from disruptions to HPV vaccination in a high-income setting. A baseline scenario of no disruption to HPV vaccination was modelled, which assumed uptake of the nonavalent vaccine at the age of 12 by 82.4% of females and 75.5% of males, as is the coverage in Australia. Additional lifetime HPV-related cancer cases were calculated for three disruption scenarios affecting one birth cohort (2008; aged 12 in 2020) compared to the baseline scenario: (1) 1-year delay (no doses missed); (2) 1- to 7-year delay (slow catch-up); (3) no catch-up (herd effects only). A fourth scenario assumed no catch-up HPV vaccination for two birth cohorts, that is all individuals born in 2008 and in 2009 missed vaccination (worst-case scenario). Compared to 1532 HPV-related cancer cases estimated for the baseline no disruption scenario, we found a 1-year delay could result in ≤0.3% more HPV-related cancers (n = 4) but the increase would be greater if catch-up was slower (5%; n = 70), and especially if there was no catch-up (49%; n = 750). Additional cancers for a single missed cohort were most commonly cervical (23% of the additional cases) and anal cancers (16%) in females and oropharyngeal cancers in males (20%). In the worst-case scenario of two birth cohorts missing vaccination, ≤62% more HPV-related cancers would be diagnosed (n = 1892). In conclusion, providing catch-up of missed HPV vaccines is conducted, short-term delays in vaccinating adolescents are unlikely to have substantial long-term effects on cancer.

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.

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

Background: 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. Methods: 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 HPV-based screening. Results: 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 under-screened women whose last cytology screen was 5 years prior to the disruption period compared with guidelines-compliant women (i.e., last screen three 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. Conclusions: 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 under-screened women, underpinning the importance of reaching such women as a critical area of focus, regardless of temporary disruptions. Funding: This study was supported by funding from the National Cancer Institute (U01CA199334). The contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute. Megan A Smith receives salary support from the National Health and Medical Research Council, Australia (APP1159491) and Cancer Institute NSW (ECF181561). Matejka Rebolj is funded by Cancer Research UK (reference: C8162/A27047). James O'Mahony is funded by Ireland's Health Research Board (EIA2017054). Karen Canfell receives salary support from the National Health and Medical Research Council, Australia (APP1194679). Emily A. Burger receives salary support from the Norwegian Cancer Society.

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.

Projected time to elimination of cervical cancer in the USA: a comparative modelling study.

BACKGROUND: In May, 2018, the Director-General of WHO issued a global call to eliminate cervical cancer as a public health problem, which will involve ambitious screening and vaccination coverage targets. We aimed to assess the potential for, and timing of, cervical cancer elimination in the USA and whether this could be expedited by adopting ambitious coverage targets, using two cervical cancer simulation models. METHODS: In this modelling study, we used two independently-developed cervical cancer microsimulation models-Harvard and Policy1-Cervix-to estimate changes in the incidence of human papillomavirus (HPV)-induced cervical cancer over time in the USA, including herd effects from vaccination. We compared nine alternative scenarios for prophylactic HPV vaccination and cervical screening scale-up with a status quo scenario that involved no additional interventions in the context of a threshold for cervical cancer elimination of four or fewer cases per 100 000 women-years. We also estimated the number of cervical cancer cases that could be averted between 2019 and 2100 associated with the adoption of ambitious goals for cervical cancer screening and vaccination coverage, and other potential strategies. FINDINGS: Under status quo assumptions, the Havard and Policy1-Cervix models projected that cervical cancer incidence would decrease to less than four or fewer new cases per 100 000 women-years by the 2038 and 2046, respectively. Scaling up screening coverage to 90% in 2020, was the most effective intervention to expedite time to elimination (10-13-year reduction), averting a mean of 1400-2088 additional cases annually between 2019 and 2100. Increasing HPV vaccination coverage to 90% or vaccinating adults aged 26-45 years had relatively little effect on cervical cancer incidence. Sensitivity analysis using different population structures resulted in differences in time to elimination (range -10 years to +27 years) compared with status quo predictions. INTERPRETATION: The USA is on track to eliminate cervical cancer as a public health problem in the next two to three decades. Time to elimination could be expedited by 10-13 years by achieving higher screening coverage. Targeting of underscreened and under-vaccinated women remains key to achieving cervical cancer elimination for all women. FUNDING: US National Cancer Institute.

The Impact of Different Screening Model Structures on Cervical Cancer Incidence and Mortality Predictions: The Maximum Clinical Incidence Reduction (MCLIR) Methodology.

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.

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.