Michael Caruana

Primary HPV testing versus cytology-based cervical screening in women in Australia vaccinated for HPV and unvaccinated: effectiveness and economic assessment for the National Cervical Screening Program

BACKGROUND Australias National Cervical Screening Program currently recommends cytological screening every 2 years for women aged 18-69 years. Human papillomavirus (HPV) vaccination was implemented in 2007 with high population coverage, and falls in high-grade lesions in young women have been reported extensively. This decline prompted a major review of the National Cervical Screening Program and new clinical management guidelines, for which we undertook this analysis. METHODS We did effectiveness modelling and an economic assessment of potential new screening strategies, using a model of HPV transmission, vaccination, natural history, and cervical screening. First, we evaluated 132 screening strategies, including those based on cytology and primary HPV testing. Second, after a recommendation was made to adopt primary HPV screening with partial genotyping and direct referral to colposcopy of women positive for HPV16/18, we evaluated the final effect of HPV screening after incorporating new clinical guidelines for women positive for HPV. Both evaluations considered both unvaccinated and vaccinated cohorts. FINDINGS Strategies entailing HPV testing every 5 years and either partial genotyping for HPV16/18 or cytological co-testing were the most effective. One of the most effective and cost-effective strategies comprised primary HPV screening with referral of women positive for oncogenic HPV16/18 direct to colposcopy, with reflex cytological triage for women with other oncogenic types and direct referral for those in this group with high-grade cytological findings. After incorporating detailed clinical guidelines recommendations, this strategy is predicted to reduce cervical cancer incidence and mortality by 31% and 36%, respectively, in unvaccinated cohorts, and by 24% and 29%, respectively, in cohorts offered vaccination. Furthermore, this strategy is predicted to reduce costs by up to 19% for unvaccinated cohorts and 26% for cohorts offered vaccination, compared with the current programme. INTERPRETATION Primary HPV screening every 5 years with partial genotyping is predicted to be substantially more effective and potentially cost-saving compared with the current cytology-based screening programme undertaken every 2 years. These findings underpin the decision to transition to primary HPV screening with partial genotyping in the Australian National Cervical Screening Program, which will occur in May, 2017. FUNDING Department of Health, Australia.

Cervical screening with primary HPV testing or cytology in a population of women in which those aged 33 years or younger had previously been offered HPV vaccination: Results of the Compass pilot randomised trial

Background Using primary human papillomavirus (HPV) testing for cervical screening increases detection of high-grade cervical intraepithelial neoplastic lesions and invasive cancer (cervical intraepithelial neoplasia grade 2+ [CIN2+]) compared to cytology, but no evaluation has been conducted in a population previously offered HPV vaccination. We aimed to assess colposcopy referral and CIN2+ detection rates for HPV-screened versus cytology-screened women in Australia’s HPV-vaccinated population (by 2014, resident women ≤33 years had been age-eligible for HPV vaccination, with 3-dose uptake across age cohorts being about 50%–77%). Methods and findings Compass is an open-label randomised trial of 5-yearly HPV screening versus 2.5-yearly liquid-based cytology (LBC) screening. In the first phase, consenting women aged 25–64 years presenting for routine screening at 47 primary practices in Victoria, Australia, provided a cervical sample and were randomised at a central laboratory at a 1:2:2 allocation to (i) image-read LBC screening with HPV triage of low-grade cytology (‘LBC screening’), (ii) HPV screening with those HPV16/18 positive referred to colposcopy and with LBC triage for other oncogenic (OHR) types (‘HPV+LBC triage’), or (iii) HPV screening with those HPV16/18 positive referred to colposcopy and with dual-stained cytology triage for OHR types (‘HPV+DS triage’). A total of 5,006 eligible women were recruited from 29 October 2013 to 7 November 2014 (recruitment rate 58%); of these, 22% were in the group age-eligible for vaccination. Data on 4,995 participants were analysed after 11 withdrawals; 998 were assigned to, and 995 analysed (99.7%) in, the LBC-screened group; 1,996 assigned to and 1,992 analysed (99.8%) in the HPV+LBC triage group; and 2,012 assigned to and 2,008 analysed (99.8%) in the HPV+DS triage group. No serious trial-related adverse events were reported. The main outcomes were colposcopy referral and detected CIN2+ rates at baseline screening, assessed on an intention-to-treat basis after follow-up of the subgroup of triage-negative women in each arm referred to 12 months of surveillance, and after a further 6 months of follow-up for histological outcomes (dataset closed 31 August 2016). Analysis was adjusted for whether women had been age-eligible for HPV vaccination or not. For the LBC-screened group, the overall referral and detected CIN2+ rates were 27/995 (2.7% [95% CI 1.8%–3.9%]) and 1/995 (0.1% [95% CI 0.0%–0.6%]), respectively; for HPV+LBC triage, these were 75/1,992 (3.8% [95% CI 3.0%–4.7%]) and 20/1,992 (1.0% [95% CI 0.6%–1.5%]); and for HPV+DS triage, these were 79/2,008 (3.9% [95% CI 3.1%–4.9%]) and 24/2,008 (1.2% [95% CI 0.8%–1.6%]) (p = 0.09 for difference in referral rate in LBC versus all HPV-screened women; p = 0.003 for difference in CIN2+ detection rate in LBC versus all HPV-screened women, with p = 0.62 between HPV screening groups). Limitations include that the study population involved a relatively low risk group in a previously well-screened and treated population, that individual women’s vaccination status was unknown, and that long-term follow-up data on disease detection in screen-negative women are not yet available. Conclusions In this study, primary HPV screening was associated with significantly increased detection of high-grade precancerous cervical lesions compared to cytology, in a population where high vaccine uptake was reported in women aged 33 years or younger who were offered vaccination. It had been predicted that increased disease detection might be associated with a transient increase in colposcopy referral rates in the first round of HPV screening, possibly dampened by HPV vaccine effect; in this study, although the point estimates for referral rates in women in each HPV-screened group were 41%–44% higher than in cytology-screened women, the difference in referral rate between cytology- and HPV-screened women was not significant. These findings provide initial support for the implementation of primary HPV screening in vaccinated populations. Trial registration Australian New Zealand Clinical Trials Registry ACTRN12613001207707

Identifying high risk individuals for targeted lung cancer screening: Independent validation of the PLCOm2012 risk prediction tool

Lung cancer screening with computerised tomography holds promise, but optimising the balance of benefits and harms via selection of a high risk population is critical. PLCOm2012 is a logistic regression model based on U.S. data, incorporating sociodemographic and health factors, which predicts 6‐year lung cancer risk among ever‐smokers, and thus may better predict those who might benefit from screening than criteria based solely on age and smoking history. We aimed to validate the performance of PLCOm2012 in predicting lung cancer outcomes in a cohort of Australian smokers. Predicted risk of lung cancer was calculated using PLCOm2012 applied to baseline data from 95,882 ever‐smokers aged ≥45 years in the 45 and Up Study (2006–2009). Predictions were compared to lung cancer outcomes captured to June 2014 via linkage to population‐wide health databases; a total of 1,035 subsequent lung cancer diagnoses were identified. PLCOm2012 had good discrimination (area under the receiver‐operating‐characteristic‐curve; AUC 0.80, 95%CI 0.78–0.81) and excellent calibration (mean and 90th percentiles of absolute risk difference between observed and predicted outcomes: 0.006 and 0.016, respectively). Sensitivity (69.4%, 95%CI, 65.6–73.0%) of the PLCOm2012 criteria in the 55–74 year age group for predicting lung cancers was greater than that using criteria based on ≥30 pack‐years smoking and ≤15 years quit (57.3%, 53.3‐61.3%; p < 0.0001), but specificity was lower (72.0%, 71.7–72.4% versus 75.2%, 74.8–75.6%, respectively; p < 0.0001). Targeting high risk people for lung cancer screening using PLCOm2012 might improve the balance of benefits versus harms, and cost‐effectiveness of lung cancer screening.

Long-term evaluation of benefits, harms, and cost-effectiveness of the National Bowel Cancer Screening Program in Australia: a modelling study

BACKGROUND No assessment of the National Bowel Screening Program (NBCSP) in Australia, which considers all downstream benefits, costs, and harms, has been done. We aimed to use a comprehensive natural history model and the most recent information about cancer treatment costs to estimate long-term benefits, costs, and harms of the NBCSP (2 yearly immunochemical faecal occult blood testing screening at age 50-74 years) and evaluate the incremental effect of improved screening participation under different scenarios. METHODS In this modelling study, a microsimulation model, Policy1-Bowel, which simulates the development of colorectal cancer via both the conventional adenoma-carcinoma and serrated pathways was used to simulate the NBCSP in 2006-40, taking into account the gradual rollout of NBCSP in 2006-20. The base-case scenario assumed 40% screening participation (currently observed behaviour) and two alternative scenarios assuming 50% and 60% participation by 2020 were modelled. Aggregate year-by-year screening, diagnosis, treatment and surveillance-related costs, resource utilisation (number of screening tests and colonoscopies), and health outcomes (incident colorectal cancer cases and colorectal cancer deaths) were estimated, as was the cost-effectiveness of the NBCSP. FINDINGS With current levels of participation (40%), the NBCSP is expected to prevent 92 200 cancer cases and 59 000 deaths over the period 2015-40; an additional 24 300 and 37 300 cases and 16 800 and 24 800 deaths would be prevented if participation was increased to 50% and 60%, respectively. In 2020, an estimated 101 000 programme-related colonoscopies will be done, associated with about 270 adverse events; an additional 32 500 and 49 800 colonoscopies and 88 and 134 adverse events would occur if participation was increased to 50% and 60%, respectively. The overall number needed to screen (NNS) is 647-788 per death prevented, with 52-59 colonoscopies per death prevented. The programme is cost-effective due to the cancer treatment costs averted (cost-effectiveness ratio compared with no screening at current participation, AUS

Cost-effectiveness of the next generation nonavalent human papillomavirus vaccine in the context of primary human papillomavirus screening in Australia: a comparative modelling analysis

3014 [95% uncertainty interval 1807-5583] per life-year saved) in the cost-effectiveness analysis. In the budget impact analysis, reduced annual expenditure on colorectal cancer control is expected by 2030, with expenditure reduced by a cumulative AUS

How will transitioning from cytology to HPV testing change the balance between the benefits and harms of cervical cancer screening? Estimates of the impact on cervical cancer, treatment rates and adverse obstetric outcomes in Australia, a high vaccination coverage country

1·7 billion, AUS

Estimating the cost-effectiveness of lung cancer screening with low dose computed tomography for high risk smokers in Australia

2·0 billion, and AUS

Factors associated with prostate specific antigen testing in Australians: Analysis of the New South Wales 45 and Up Study

2·1 billion (2015 prices) between 2030 and 2040, at participation rates of 40%, 50%, and 60%, respectively. INTERPRETATION The NBCSP has potential to save 83 800 lives over the period 2015-40 if coverage rates can be increased to 60%. By contrast, the associated harms, although an important consideration, are at a smaller magnitude at the population level. The programme is highly cost-effective and within a decade of full roll-out, there will be reduced annual health systems expenditure on colorectal cancer control due to the impact of screening. FUNDING Australia Postgraduate Award PhD Scholarship, Translational Cancer Research Network Top-up scholarship (supported by Cancer Institute NSW) and Cancer Council NSW.

Lung cancer mortality in Australia: Projected outcomes to 2040

BACKGROUND First generation bivalent and quadrivalent human papillomavirus (HPV) vaccines have been introduced in most developed countries. A next generation nonavalent vaccine (HPV9) has become available, just as many countries are considering transitioning from cytology-based to HPV-based cervical screening. A key driver for the cost-effectiveness of HPV9 will be a reduction in screen-detected abnormalities and surveillance tests. We aimed to evaluate the cost-effectiveness of HPV9 in Australia, a country with HPV vaccination of both sexes that is transitioning to 5-yearly HPV-based screening. METHODS We used Policy1-Cervix and HPV-ADVISE-two dynamic models of HPV transmission, vaccination, and cervical screening-to estimate the cost-effectiveness of HPV9 versus quadrivalent vaccine (HPV4), assuming lifelong vaccine protection, two vaccine doses, and that additional costs were incurred in girls only. Policy1-Cervix was used to estimate the lifetime risk of cervical cancer diagnosis and death. Probabilistic sensitivity analysis of the cost-effectiveness outcomes was done with both models, and results are presented as the median and 10th to 90th percentiles of simulation runs (referred to as 80% uncertainty intervals [UIs]). FINDINGS Compared with cytology-based screening, HPV screening is predicted to reduce lifetime risk of cervical cancer diagnosis by 18% and of death by 20%, even in unvaccinated cohorts. Under base-case assumptions (lifelong protection, full efficacy at two doses), HPV4 will provide a further reduction in diagnosis of 54% and in death of 53% and HPV9 will provide a further reduction in both diagnosis and death of 11%, compared with cytology-based screening in unvaccinated cohorts. For HPV9 to remain a cost-effective alternative to HPV4, the incremental cost per dose in girls should not exceed a median of AUS

Evaluation of the benefits, harms and cost-effectiveness of potential alternatives to iFOBT testing for colorectal cancer screening in Australia: Alternatives to iFOBT testing for bowel screening

35·99 (80% UI 28·47-41·18) with Policy1-Cervix or AUS