High-risk human papillomavirus testing is acceptable as a primary approach to cervical cancer screening in women aged 25 years and older, according to interim clinical guidance from an expert panel convened by the Society of Gynecologic Oncology and the American Society for Colposcopy and Cervical Pathology.
Based on several large studies published since 2011 when screening guidelines were last updated, the panel concluded that a negative high-risk HPV (hrHPV) test provides greater reassurance of low cervical intraepithelial neoplasia grade 3–positive (CIN3+) risk than does a negative cytology result, and that “because of equivalent or superior effectiveness, primary hrHPV screening can be considered as an alternative to current U.S. cytology-based cervical cancer screening methods.”
The guidance was simultaneously published on Jan. 8 in Gynecologic Oncology (2015 [ doi:10.1016/j.ygyno.2014.12.022 ]), the Journal of Lower Genital Tract Disease, and Obstetrics & Gynecology (2015;125:330-7 [ doi:10.1097/AOG.0000000000000669 ]).
The 13-member panel was convened when an application was submitted to the U.S. Food and Drug Administration for a currently marketed HPV test to be labeled for the indication of primary cervical cancer screening; that application was approved in April 2013.
The panel included representatives from the American Society for Colposcopy and Cervical Pathology, the American College of Obstetricians and Gynecologists, the American Cancer Society, the American Society of Cytopathology, the College of American Pathologists, and the American Society for Clinical Pathology.
Cytology alone and cotesting remain the screening options specifically recommended in existing major guidelines. The interim guidance does not supplant those guidelines, but provides clinicians with an additional screening tool, Dr. Warner K. Huh of the University of Alabama at Birmingham, and his colleagues reported.
“The scientific evidence clearly demonstrates that primary HPV testing outperforms cytology or Pap as a screening test. This has been confirmed from numerous European and Canadian studies as well as the ATHENA trial. There are going to be fewer false negatives with HPV, and arguably, we have been using a less sensitive test for screening for a while now,” Dr. Huh said in a statement , adding that “pap smears miss a fair number of adenocarcinomas.”
The ATHENA HPV trial is a longitudinal study of the HPV test sponsored by Roche Diagnostics, and the end-of-study results, which were used along with other study data and expert opinion in the guidance panel’s deliberations, were published in Gynecologic Oncology 2014 [ doi:10.1016/j.ygyno.2014.11.076 ].
Previously approved labeling for HPV tests included triage of equivocal cytology and as an adjunct to cytology in women aged 30 years and older – two uses that are “widely recommended by numerous stakeholder societies and organizations, as well as the U.S. Preventive Services Task Force,” the authors noted, adding that hrHPV testing was also approved for identifying specific high-risk types of HPV for triage in select settings.
Primary hrHPV testing was not indicated “in most clinical settings,” mainly due to substantial concerns about the specificity of primary hrHPV screening and the potential harms, the lack of a well-defined and evaluated strategy to manage hrHPV-positive women, and inadequate information to define appropriate screening intervals for those who test negative, the panel wrote.
But since that time, several large studies have been published strengthening the evidence in support of primary hrHPV screening. The new studies “consistently demonstrate an improved sensitivity of primary hrHPV screening for detecting cervical cancer precursor lesions, compared with cytology alone,” the panel wrote.
Based on this evidence, the expert panel also concluded that:
• Triage of hrHPV-positive women using a combination of genotyping for HPV-16 and -18, and reflex cytology for women positive for the 12 other hrHPV genotypes appears to be a reasonable approach to managing hrHPV-positive women.
• Rescreening after a negative primary hrHPV screen should occur no sooner than every 3 years.
• Primary hrHPV screening should not be initiated before age 25.
The panel called primary hrHPV screening “an important scientific and clinical advance in cervical cancer screening because it offers better reassurance of low cancer risk, compared with cytology-only screening conducted at the same interval.”
More data on triage options should be available soon and could lead to updated triage recommendations, the panel noted.
“Primary hrHPV screening at 25-29 years of age may lead to increased CIN 3 detection, but the impact of increased number of colposcopies, integration with screening before age 25, and actual impact on cancer prevention needs further investigation,” the panel wrote. “While there continue to be numerous practical and research questions, primary hrHPV testing has the potential to further reduce morbidity and mortality of cervical cancer in the United States. However, to achieve the maximum benefit of screening, we need to continue to identify women who are either unscreened or under-screened.”
In fact, most women who have cervical cancer have not been screened or have not been adequately screened, according to Dr. Andrew Menzin , associate chief of gynecologic oncology at North Shore LIJ Health System, and professor of obstetrics and gynecology at Hofstra University, Hempstead, N.Y.
“That’s still the challenge, and I expect that having the opportunity to use a primary HPV test will facilitate enhanced screening,” he said in an interview.
Dr. Menzin said that use and acceptance of cotesting has been widespread, and predicts that the 3-year minimum testing interval for primary hrHPV testing recommended by the guidance panel could serve to ease some of the discomfort that many clinicians felt as guidelines expanded screening intervals from 1 year to 3 years, and then to 5 years with cotesting, thereby promoting acceptance of primary hrHPV testing.
“The information provided in the interim guidance speaks to a trend in the advancement of cervical cancer screening of allowing technological advances to be coupled with ongoing evolution in our knowledge of the natural history of disease and to focus on tests that have high accuracy and important predictive value,” he said. “The inclusion of the hrHPV test as an additional primary screening tool in the cervical cancer screening armamentarium will also help to evolve the triage of testing to focus on patients at greatest risk while minimizing the burden of testing and evaluation on those who are low risk, thereby optimizing care delivery.”
The panel’s work was funded by the Society of Gynecologic Oncology and the American Society for Colposcopy and Cervical Pathology. Dr. Huh is on the scientific advisory board of Merck. Dr. Menzin said he had no financial disclosures.
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