The recent draft Recommendation Statement on cervical cancer screening by the United States Preventive Services Task Force (USPSTF)1 and the publication of the analysis of one of the most extensive sources of data in the United States regarding cervical cancer screening2 follow on the heels of guidance from professional associations3-5 and large-scale clinical studies here and abroad.6-8 They present an opportunity to reflect on the scientific evidence, consider the clinical and health economic rationale, and map a path forward for clinicians and laboratories to continue the decline in cervical cancer through efficacious, cost-effective screening with maximal benefit and minimal harm to the patient.
Screening vs. diagnostics
The goal of cervical cancer screening is prevention—early identification of patients at risk in order to slow or halt disease progression while avoiding invasive interventions. Screening implies testing a large number of asymptomatic individuals and favors using a methodology that is noninvasive and low-cost. Sensitivity is important so that potential disease is not missed.
The goal of diagnostic testing, by contrast, is to establish the presence or absence of disease in symptomatic individuals and those who test positive during screening. The importance of timely diagnosis sometimes justifies invasive procedures as well as higher costs.
Putting the goals of screening vs. diagnosis into proper context is helpful in assessing test strategies. For example, extended time intervals may be less intrusive to patients and thus improve adherence. Fewer tests can also help lower costs.
What the USPSTF is saying
In 2017, following a review of outcomes from trials and cohort studies in high-resource countries comparing screening with high-risk human papillomavirus (hrHPV) testing alone, cytology alone, and cotesting, the USPSTF posted a draft Recommendation for public comments. Table 1 compares the 2017 draft Recommendation and the 2012 Recommendation.
The 2017 draft Recommendation is based in part on the review of three randomized, controlled trials (RCTs) comparing screening with hrHPV screening alone (primary screening) vs. cytology alone and four RCTs comparing screening with cytology alone vs. cotesting (cytology plus hrHPV testing). The USPSTF concluded that all three screening strategies offer substantial benefit in terms of reducing cancer incidence and mortality compared with no screening. Primary screening or cotesting leads to slightly higher detection rates of CIN3 (Cervical Intra-epithelial Neoplasia) compared with cytology alone but also more tests and procedures. The USPSTF noted that “cotesting does not offer any benefit in terms of cancer reduction or life-years gained over hrHPV testing alone but increases the number of tests and procedures (such as colposcopies) per each cancer case averted.” The USPSTF concluded there is convincing evidence that screening with either cytology alone or hrHPV testing alone provides substantial benefit and did not include cotesting in the 2017 draft Recommendation.
Guidelines from professional associations
The most recent societal practice recommendations were announced by the American Society of Clinical Oncology (ASCO) in 2016.3 The ASCO guidelines recommend hrHPV DNA testing to be used for all resource settings (basic, limited, enhanced, and maximal), with an age range of 25 to 65 and frequency of every five years for the maximal setting. “Maximal” refers to developed countries such as the United States. The ASCO guidelines note that “cotesting is an option…however, the added value on the basis of increased costs is limited.” The guidelines further note that the hrHPV testing component has been shown to provide most of the reassurance from a co-test6 and that the cost- effectiveness analysis from the ARTISTIC (A Randomized Trial In Screening To Improve Cytology) trial suggests that primary hrHPV screening would be more cost-effective than cervical cytology screening.7
In 2016, in a revised Practice Bulletin, the American College of Obstetricians and Gynecologists (ACOG) provided clinical practice guidance supporting the use of the FDA-approved hrHPV test for primary screening as an alternative to current cytology-based cancer screening methods in women aged 25 years and older.5
Together with the Society of Gynecologic Oncology (SGO), the American Society for Colposcopy and Cervical Pathology (ASCCP) led the publication of interim clinical guidance also supporting the use of primary hrHPV testing in cervical cancer screening in 2015.4
Clinical outcomes from cancer screening database2
In 2003, Kaiser Permanente Northern California (KPNC), an integrated healthcare organization, introduced three-year cotesting. Data from the 1,208,710 women aged 30 or older who underwent cotesting from January 1, 2003, to December 31, 2015, was analyzed to assess the relative performance of HPV and cytology components of cotesting.
Results of the study, published in 2018, confirm the sensitivity advantage of hrHPV testing by showing that hrHPV testing identified more women subsequently diagnosed with cancer and pre-cancer, compared with cytology. The authors noted that hrHPV testing alone as a cervical cancer screening option would perform nearly the same as hrHPV and cytology cotesting. In the context of screening frequency (three vs. five years), the authors noted the harms associated with excessive screening, including identification and overtreatment of potentially regressive CIN2 lesions and possible risk of negative reproductive outcomes such as preterm delivery. Furthermore, issues related to design and resulting bias of previous analyses of other databases, sometimes without the goal of screening (to identify pre-cancer) put in proper context, may have exaggerated the contribution of cytology (and thus the value of cotesting).
Converging conclusions
The three-year prospective ATHENA (Addressing the Need for Advanced HPV Diagnostics) study of 42,209 women aged over 25 years showed that primary hrHPV screening has the highest sensitivity for the detection of CIN3, the highest grade of cervical pre-cancer, over three years, compared with cytology alone or cotesting with both cytology and hrHPV.6 Because it identifies CIN3+ earlier, hrHPV screening is associated with fewer cases of cervical cancer or CIN3 in subsequent rounds of screening. The cost-effectiveness analysis from the ARTISTIC trial suggests that hrHPV screening would be more cost-effective compared with cervical cytology screening.7 Another study of 176,464 women aged 20-to-64 years in Sweden, the Netherlands, England, and Italy concluded that “HPV-based cervical screening provides 60–70% greater protection against invasive cancer compared with cytology-based screening” and that the findings “support HPV-based screening with triage at prolonged intervals, starting at age 30 years.”8
From clinical guidelines to patient care
Currently, there are two hrHPV DNA tests approved by the FDA for primary screening in the U.S., as well as an approved primary screening algorithm that specifies triage to cytology or colposcopy depending on the HPV result and genotype (i.e., 16, 18 or other 12 high-risk types). These developments, along with mounting evidence of the role of primary screening in the prevention of cervical cancer, have prompted many of my colleagues to embrace hrHPV testing. However, barriers to widespread adoption of HPV primary screening remain. In the laboratory, the transition to primary screening may mean changes in lab workflow, which is not an insignificant concern. In parallel, the lab needs to establish a testing code for primary screening to facilitate physician ordering and reimbursement. The laboratory can also take an active role in disseminating new scientific data and helping clinicians give their patients a better option for their fight to prevent and eradicate cervical cancer.
REFERENCES
- Draft Recommendation Statement: Cervical Cancer: Screening. U.S. Preventive Services Task Force. Published September 2017. https://www.uspreventiveservicestaskforce.org/Page/Document/draft-recommendation-statement/cervical-cancer-screening2 .
- Schiffman M, Kinney WK, Cheung L, et al. Relative performance of HPV and cytology components of cotesting in cervical screening. J Natl Cancer Inst. 2017; Nov 14. doi.org/10.1093/jnci/djx225.
- Jeronimo J, Castle PE, Temin S, et al. Secondary prevention of cervical cancer: ASCO resource-stratified clinical practice guideline. Published online October 12, 2016. doi: 10.1200/JGO.2016.006577. http://www.asco.org/practice-guidelines/quality-guidelines/guidelines/gynecologic-cancer#/14021.
- Huh WK, Ault KA, Chelmow D, et al. Use of primary high-risk human papillomavirus testing for cervical cancer screening: Interim clinical guidance. Gynecol Oncol. 2015; Jan 6. pii: S0090-8258(14)01577-7.
- Cervical Cancer Screening and Prevention. ACOG Practice Bulletin No. 157. January 2016.
- Wright TC, Stoler MH, Behrens CM, Sharma A, Zhang G, Wright TL.
Primary cervical cancer screening with human papillomavirus: End of study results from the ATHENA study using HPV as the first-line screening test. Gynecol Oncol. 2015 Jan 6. pii: S0090-8258(14)01549-2. - Kitchener HC, Canfell K, Gilham C, et al. The clinical effectiveness and cost-effectiveness of primary human papillomavirus cervical screening in England: Extended follow-up of the ARTISTIC randomised trial cohort through three screening rounds. Health Technol Assess. 2014;18:1-196.
- Ronco G, Dillner J, Elfström KM, et al. Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials. Lancet. 2014;383:524-532.
Lee P. Shulman, MD, is Chief of Clinical Genetics in the Department of Obstetrics and Gynecology and the Anna Lapham Professor of Obstetrics and Gynecology at Northwestern University Feinberg School of Medicine.
