Sandra D. Isidean

Human papillomavirus testing versus cytology in primary cervical cancer screening: End-of-study and extended follow-up results from the Canadian cervical cancer screening trial

The Canadian Cervical Cancer Screening Trial was a randomized controlled trial comparing the performance of human papillomavirus (HPV) testing and Papanicolaou cytology to detect cervical intraepithelial neoplasia of grades 2 or worse (CIN2+) among women aged 30–69 years attending routine cervical cancer screening in Montreal and St. Johns, Canada (n = 10,154). We examined screening and prognostic values of enrollment cytologic and HPV testing results. Extended follow‐up data were available for St. Johns participants (n = 5,754; 501,682.6 person‐months). HPV testing detected more CIN2+ than cytology during protocol‐defined (82.9 vs. 44.4%) and extended (54.2 vs. 19.3%) follow‐up periods, respectively. Three‐year risks ranged from 0.87% (95% CI: 0.37–2.05) for HPV‐/Pap‐ women to 35.77% (95% CI: 25.88–48.04) for HPV+/Pap+ women. Genotype‐specific risks ranged from 0.90% (95% CI: 0.40–2.01) to 43.84% (95% CI: 32.42–57.24) among HPV− and HPV16+ women, respectively, exceeding those associated with Pap+ or HPV+ results taken individually or jointly. Ten‐year risks ranged from 1.15% (95% CI: 0.60–2.19) for HPV−/Pap− women to 26.05% (95% CI: 15.34–42.13) for HPV+/Pap+ women and genotype‐specific risks ranged from 1.13% (95% CI: 0.59–2.14) to 32.78% (95% CI: 21.15–48.51) among women testing HPV− and HPV16+, respectively. Abnormal cytology stratified risks most meaningfully for HPV+ women. Primary HPV testing every 3 years provided a similar or greater level of reassurance against disease risks as currently recommended screening strategies. HPV‐based cervical screening may allow for greater disease detection than cytology‐based screening and permit safe extensions of screening intervals; genotype‐specific testing could provide further improvement in the positive predictive value of such screening.

cobas® 4800 HPV Test, a real-time polymerase chain reaction assay for the detection of human papillomavirus in cervical specimens

Cervical cancer screening incorporating high-risk human papillomavirus (HPV) detection has become the preferred screening strategy in some countries and is increasingly more widespread in other countries with organized or opportunistic screening programs. Given knowledge that high-risk HPV genotypes differ in their oncogenic potential, commercial HPV assays with genotyping capabilities have been developed and have garnered attention in the recent literature. The cobas® 4800 HPV Test is a qualitative multiplex assay that provides specific genotyping information for HPV types 16 and 18, while concurrently detecting 12 other high-risk HPV genotypes as a pooled result. It is currently the only clinically validated, US FDA-approved assay with this capability. Since HPV types 16 and 18 have been designated as conferring the greatest risk for cervical disease, their detection may prove useful in guiding patient management.

Counterpoint: Cervical Cancer Screening Guidelines—Approaching the Golden Age

Changes in screening guidelines that imply suppression of procedures once recommended are always controversial because of the perception that benefits are being curtailed. Prior to 2012, cervical cancer screening guidelines issued by US-based expert bodies differed in several decision areas, making clinicians essentially cherry-pick among recommendations. To some extent, this approach to screening practices also served to shield clinicians from litigation. It implied starting screening earlier, doing it more frequently, and stopping later in life than necessary. This state of affairs changed in 2012, when the most influential professional groups updated their cervical screening guidelines, and recommendations became essentially unified. All groups recommended that women older than 65 years of age discontinue cervical cancer screening on the basis of evidence that screening benefits in this age group were minor and far outweighed by harms. The guidelines are very specific about the exceptions, which ensure acceptable safety. It is expected that the new guidelines will permit less wasteful cervical screening, while fostering the opportunity to direct resources towards ensuring adequate coverage of high-risk women.

Human papillomavirus vaccines: key factors in planning cost-effective vaccination programs.

Prophylactic HPV vaccines hold tremendous potential for reducing cervical and non-cervical HPV-related disease burden worldwide. To maximize on this potential, policy officials will need to carefully consider available evidence, existing uncertainties and the cost–effectiveness of mass HPV vaccination programs in the context of their respective nations and/or regions. Proper harmonization of primary prevention strategies with secondary prevention efforts will also be important. Decisions following such considerations may ultimately depend on programmatic objectives, infrastructure and available resources. Continued research and surveillance surrounding HPV vaccination will be essential for filling current knowledge gaps, and forcing ongoing reconsiderations of selected immunization strategies.

Embracing a new era in cervical cancer screening

www.thelancet.com Vol 383 February 8, 2014 493 Despite its low sensitivity, conventional cytology for cervical cancer (the Papanicolaou test) is one of the most successful cancer screening tests of all time. In countries with high-quality and broad-coverage screening programmes using this test, invasive cervical cancer incidence and mortality rates have plummeted. Why change a good thing? After human papillomavirus (HPV) was identifi ed as a cause of invasive cervical cancer, HPV DNA testing was developed to screen for the disease. Molecular techniques are better than cervical cytology with respect to diagnostic sensitivity and reproducibility to detect cervical intraepithelial neoplasia grade 2 (CIN2) or grade 3 (CIN3)—the high-grade lesion precursors of invasive cervical cancer. However, to be better at detecting these intermediate endpoints is not enough. Treatment of screen-detected lesions by ablative or excisional procedures must also stop the natural history of invasive cervical cancer and reduce incidence of and mortality from the disease. Findings of randomised controlled trials need to show that HPV testing is more effi cacious than cytologybased testing for prevention of subsequent invasive cervical cancer and related death. Up to now, such proof of the value of HPV testing has only been recorded in a population in rural India that did not benefi t from routine high-quality screening. Moreover, most randomised con trolled trials of cervical screening have taken place in developed countries, where cytological screening has long been practised and invasive cervical cancer morbidity and mortality are low. As a result, detection of CIN2 and CIN3 is mainly reported as the predefi ned study endpoint. Since most CIN2 and CIN3 lesions never become invasive or lead to death from cervical cancer, further evidence is needed about these vitally important, longitudinal outcomes before updated recommendations can be made about HPV-based screening. In The Lancet, Guglielmo Ronco and colleagues pool individual-level data from four European randomised trials comparing HPV-based with cytology-based cervical cancer screening. In Swedescreen, POBASCAM, ARTISTIC, and NTCC more than 175 000 women were randomised in total and accrued second-round screening outcomes. Linkage to screening, pathology, and cancer registries permitted Ronco and colleagues to extend follow-up of these enrolled women. HPV-based screening resulted in a 60–70% reduction in invasive cervical cancer incidence, compared with cytology-based screening. The decrease in incidence of invasive cervical cancer with HPV testing was not signifi cant within 2·5 years of enrolment (rate ratio 0·79, 95% CI 0·46–1·36) but the eff ect became decisive with longer follow-up (0·45, 0·25–0·81). These fi ndings highlight the opportunity that HPV testing aff ords to permit enhanced detection of CIN2 and CIN3 in screened women, therefore enabling early treatment and reduction of invasive cervical cancer risk. However, the most important property of HPV-based screening is the safety it brings to most women who have a negative HPV test. Ronco and colleagues showed that the observed cumulative incidence of invasive cervical cancer was lower 5·5 years after a negative HPV test than 3·5 years after a negative cytology test, indicating that 5-year screen intervals with HPV-based testing are safer than 3-year intervals with conventional cytology. Despite various diff erences in study features among the four randomised controlled trials, particularly with respect to management protocols triggered by test results, Ronco and colleagues noted very little heterogeneity between trials, with consistently lower overall detection of invasive cervical cancer in HPVscreened groups. This fi nding seems to indicate that the eff ect of HPV-based screening on invasive cervical cancer incidence is much larger than any potential eff ect of diff ering management protocols from the trials. As shown by this work, sound meta-analytical pooling of data can provide more insightful, powerful, and precise estimates of an eff ect of interest than can be otherwise obtained, to inform future policy and practice. The future of cervical cancer screening in highresource settings will most probably incorporate primary HPV testing, a science-driven change in strategy that particularly befi ts the post-HPV vaccination era. With economies of scale that come with broad implementation of primary HPV testing (which will foster competition among various HPV tests) and the lengthening of screen intervals, cervical cancer screening might end up costing countries less money while providing greater safety than with conventional cervical cytology. To reap the benefi ts of this implementation, however, nations will need to consider important Embracing a new era in cervical cancer screening

COMPARISON OF TRIAGE STRATEGIES FOR HPV POSITIVE WOMEN: CANADIAN CERVICAL CANCER SCREENING TRIAL RESULTS.

Background: High-risk human papillomavirus (HR-HPV) testing has become a preferred cervical cancer screening strategy in some countries due to its superior sensitivity over cytology-based methods for identifying cervical intraepithelial neoplasia of grade 2 or worse (CIN2+). Improved sensitivity has been accompanied by reductions in specificity and concerns regarding overscreening and overtreatment of women with transient or nonprogressing HR-HPV infections. Triage of HR-HPV+ women to colposcopy is, thus, warranted for appropriate management and treatment. Methods: Using data from the Canadian Cervical Cancer Screening Trial (CCCaST), we compared the performance of cytology and HR-HPV strategies to detect CIN2+ among HR-HPV+ women (age, 30–69 years). Colposcopy referral rates and performance gains from adding other HR-HPV genotypes to HPV16/18+ triage were also evaluated. Results: A strategy referring all women HPV16/18+ and HPV16/18−, but with atypical squamous cells of undetermined significance or worse cytology (ASC-US+) had the highest sensitivity [82.5%; 95% confidence interval (CI), 70.9%–91.0%] but yielded the highest colposcopy referral rate. HPV16/18+ triage was the next most sensitive strategy (64.1%; 95% CI, 51.1%–75.7%). Low-grade squamous intraepithelial lesion or worse cytology (LSIL+) triage yielded a low sensitivity (32.8%; 95% CI, 21.9%–45.4%) but had the most favorable specificity (93.6%; 95% CI, 91.0%–95.6%), positive predictive value (41.5%; 95% CI, 28.1%–55.9%), and colposcopy referral rate of strategies examined. HPV viral load triage strategies did not perform optimally overall. Inclusion of HR-HPV genotypes 31 and 52 to HPV16/18+ triage provided the highest sensitivities. Conclusion: Concerns surrounding HPV-based screening can be effectively mitigated via triage. Impact: Balancing the benefits of HPV-based primary cervical screening with informed management recommendations for HR-HPV+ women may decide the success of its widening utilization. Cancer Epidemiol Biomarkers Prev; 26(6); 923–9. ©2017 AACR.

Striving for excellence while adapting to change: redefining our mission of serving the preventive medicine community.

As we prepared for the launch of a new journal, Preventive Medicine Reports (PMR), we asked Professor Olli S. Miettinen to write candidly and provocatively on what he thought was the mission of preventive medicine. Actually, we could have left these adverbs out in our invitation to him; a ‘candid and provocative Miettinen’ is a tautology. Miettinens writings exude candor and elicit intellectual discomfort. The latter comes from his erudite and probing narrative with its ostensive revisionism of what many readers of Preventive Medicine consider as concepts and principles written in stone. As Preventive Medicine and its offshoot scholarly companion PMR begin to be published in parallel at the end of the summer of 2014 it is only fitting that we begin our own assessment of the editorial vision we want to impart to both journals. Professor Miettinens body of work and public persona are uniquely impressive. The epidemiology and biostatistics toolbox and how it produces the knowledge base used in preventive medicine have been the focus of Miettinens attention for nearly 50 years. His scholarly work from the late 1960s and culminating with the publication of ‘Theoretical Epidemiology’, his 1985 textbook (Miettinen, 1985), brought together the theory and underlying mathematics that gave birth to what became known as modern epidemiology (Morabia, 2004). Miettinen is credited with having developed the mathematical underpinnings for the notion of incidence density sampling, which underscored the soundness of the case–control study as a sampling strategywithin an underlying cohort and provided a unified framework for risk ratio estimation (Miettinen, 1976). He provided a cogent formulation for our understanding of confounding and effect modification (Miettinen, 1972, 1974a) and developed a handy by-product of the risk ratio, thepopulation attributable risk (Miettinen, 1974b), ameasure of great value to policymakers in setting empirically valid targets for disease prevention and control. The latter four contributions and others related to study design, selection of controls, statistical comparison of rates, and a variety of estimation problems are classics that have greatly inspired subsequent thinking by other giants of epidemiologic theory and methods. Over time his writings became more complex and acquired a tinge of feistiness, as he exhibited displeasure with what he viewed as inappropriate understanding of fundamental principles. Miettinen coined many terms and concepts himself and is opposed to much of the mainstream lexicon of epidemiologists. His insistence on the need for precise technical language comes fromhis broad epistemological vision of how epidemiology, statistics, medicine, and the scientific method are related in general (Miettinen, 2011a).