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Studies Outline Outcomes Associated With Cervical Cancer Screening, Triage Strategies

NEW YORK (GenomeWeb) – New research is helping to narrow in on optimal screening approaches — and appropriate screening intervals — for preventing cervical cancer in women with or without positive genetic tests for risky human papillomavirus (HPV) strains.

For one of two related studies published online today in JAMA Internal Medicine, a University of California at San Francisco-led team compared a dozen cervical cancer screening strategies, including cytologic testing and high-risk HPV (hrHPV) testing alone or in combination every three or five years with distinct management or triage strategies for those with positive test results.

The researchers analyzed various screening strategies in 451 English- or Spanish-speaking women between the ages of 21 and 65 years old who were enrolled at San Francisco health clinics tested, taking into account the women's screening preferences, direct medical costs and the cost-effectiveness of each approach, the estimated quality of life associated with each strategy, and other outcomes.

Authors of that study noted that hrHPV was approved by the US Food and Drug Administration as a primary cervical cancer screening approach for women over 25 around five years ago. The US Preventive Services Task Force has since suggested that hrHPV testing every five years may be used in women who have reached 30 years old in combination with cytologic screens at three-year intervals in women aged 21 to 65 years. Even so, no single screening protocol is favored across the board.

"With various possible test combinations, screening frequencies, and ages to switch from one screening strategy to another, many different cervical cancer screening strategies are now being recommended in the United States," first and corresponding author George Sawaya, an obstetrics, gynecology, and reproductive sciences researcher at UCSF, and his co-authors, wrote. "In an effort to contribute to policy discussions regarding high-value cervical cancer screening, we estimated quality of life and economic outcomes associated with 12 strategies by measuring women's preferences and incorporating them into a cost-effectiveness analysis."

In their own cohort, the researchers saw the highest number of quality-adjusted life years (QALYs) in women who had cytologic testing done every three years, with follow-up cytologic testing when atypical squamous cells of undetermined significance (ASC-US) turned up. Still, they noted, the cost of this approach — estimated at almost $2,200 for each QALY — appeared to exceed the price of cytologic testing every three years with ASC-US follow up by hrHPV test triage (the lowest-cost screening combination considered).

The team found that annual cytologic testing, the most expensive approach, seemed to result in fewer QALYs than cytologic testing done more infrequently (every three years). Likewise, cytologic and hrHPV co-testing approaches were typically pricier, but provided fewer additional QALY.

"Both the American College of Obstetricians and Gynecologists and the American Cancer Society consider co-testing the preferred cervical cancer screening strategy, and the US Preventive Services Task Force considers it an alternative strategy," the authors wrote. "Our findings challenge these endorsements."

Testing with hrHPV alone once every five years, in combination with an HPV genotype-based triage for ASC-US, appeared to be the lowest cost option when started at age 30, the investigators explained, and showed higher sensitivity than the cytologic test. They noted that all of the screening strategies considered appeared to save money compared with no screening.

"Cytologic testing every three years for women aged 21 to 29 years with either continued cytologic testing every three years, or switching to a low-cost hrHPV test every five years, confers a reasonable balance of benefits, harms, and costs," the authors wrote, adding that "[c]omparative modeling is needed to confirm the association of these novel utilities with cost-effectiveness."

For their own JAMA Internal Medicine study, researchers from the National Cancer Institute, Kaiser Permanente, and elsewhere outlined their own cervical cancer screening prospective observation study, which focused on 3,225 women who tested positive for HPV with Qiagen's hybrid capture 2 test and were triaged to p16/Ki-67 dual stain (DS) and HPV genotyping at the Kaiser Permanente Northern California health system.

"Although a negative HPV test result provides reassurance against prevalent pre-cancerous lesions or cancer, most HPV-positive women have transient infections that are not associated with cervical precancerous lesions, highlighting the need for additional triage tests," first and corresponding author Nicolas Wentzensen, a cancer epidemiology and genetics researcher at NCI, and his colleagues explained.

When the team compared outcomes — namely progression to grade 2 or grade 3 cervical intraepithelial neoplasia (CIN) in the three years following sample collection — it found that the DS approach appeared more apt to pick up and risk stratify women who went on to develop grade 3 CIN (CIN3+) lesions than Papanicolaou-based cytologic testing, even without HPV16/18 genotypes.

Roughly half of the HPV-positive women had positive DS tests, including 96 percent of women with high-grade squamous intraepithelial lesions and more than 88 percent of women with CIN3+ or adenocarcinoma in situ.

Nevertheless, the researchers noted that the women with the lowest risk of advanced, CIN3+ over three years of follow up were those who tested negative on both the DS test and the HPV16/18 test, suggesting the partial genotyping approach can provide insights into those cases.

From these and other results, the authors concluded that "DS can safely replace Papanicolaou cytologic testing as a triage strategy for primary HPV screening, and that retesting intervals in HPV16/18-negative women with negative DS results can be safely extended to three years."

In a related commentary in JAMA Internal Medicine, Sarah Feldman, a gynecologic oncology researcher at Brigham and Women's Hospital noted that the pair of newly-published studies "will inform continuing efforts to improve the effectiveness of cervical cancer screening."

She emphasized the importance of identifying low-risk women who are eligible for less frequent cervical cancer screening, which may ultimately be trickier than focusing in on a specific test type. 

In the long term, Feldman noted that primary HPV screening could well become the standard of care for women over 30, but she cautioned that "challenges remain," citing "clinician and patient education and acceptance; access to primary HPV tests; the development of simple, easily implementable, and evidence-based management advice; and systems-based approaches to help clinicians implement optimal care."

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