Women screened for cervical cancer via primary HPV testing had a lower likelihood of developing grade 3 cervical intraepithelial neoplasia lesions at 48 months than women who underwent standard cytology testing, according to results from the randomized HPV FOCAL clinical trial.
“HPV is the cause of 99% of cervical cancers. In this study, we show that by using HPV testing as the primary screening for cervical precancer lesions, we are better able to detect the precancers earlier compared with using Pap tests,” Gina S. Ogilvie, MD, FCFP, DrPH, professor in the school of population and public health at University of British Columbia in Vancouver, Canada, and a tier 1 Canada Research Chair in Global Control of HPV related diseases and prevention, told HemOnc Today. “In addition, women who have a negative HPV test are much less likely to develop cervical precancer 4 years later.”
Previous studies have shown HPV testing alone or combined with cytology for cervical screening is associated with increased detection of precancerous lesions in the first round of screening, as well as a subsequent reduction in precancerous lesions, compared with cytology alone.
ASCO, the U.S. Preventive Services Task Force, and American Society for Colposcopy and Cervical Pathology have called for clinical trials to be performed on primary HPV testing alone with more than one round of screening to further advise on application of primary HPV screening for cervical cancer.
Researchers of the HPV FOCAL study compared the effect of primary HPV testing alone with liquid-based cytology screening for the prevention of grade 3 or higher cervical intraepithelial neoplasia within an organized cervical cancer screening program in Canada.
Researchers recruited women through 224 collaborative clinicians between January 2008 and May 2012, with follow-up through December 2016. Investigators randomly assigned 19,009 women (mean age, 45 years) to HPV screening (n = 9,552) or liquid-based cytology screening (n = 9,457).
Women who underwent HPV screening and had negative results returned at 48 months. Women who underwent cytology and had negative results returned at 24 months to undergo cytology and again at 48 months if results remained negative. At the 48-month exit, all patients received HPV and cytology co-testing.
Cumulative incidence of grade 3 or higher CIN 48 months after randomization served as the primary objective. Cumulative incidence of grade 2 or higher CIN served as a secondary objective.
Among all patients, 86.9% in the HPV screening group and 85.4% in the cytology group completed the study.
Median follow-up was 77.1 months for the HPV screening group and 76.8 months for the cytology group.
Previous data from the first round of screening showed greater detection of grade 3 or higher CIN among patients who underwent HPV screening compared with cytology screening (RR = 1.61; 95% CI, 1.09-2.37). The absolute difference in the incidence rate was 2.67 (95% CI, 0.53-4.88) per 1,000.
At 48 months, significantly fewer grade 3 or higher CIN were detected in the HPV screening group. Researchers reported an incidence rate for grade 3 or higher CIN of 2.3 (95% CI, 1.5-3.5) per 1,000 patients who underwent HPV screening compared with 5.5 (95% CI, 4.2-7.2) per 1,000 patients who underwent cytology screening (RR = 0.42; 95% CI, 0.25-0.69).
“This shows that HPV testing is a better screening test than Pap tests,” Ogilvie said. “Women who receive HPV testing have more reassurance with a negative test and can likely get screened less frequently.”
Among HPV- or liquid-based cytology-negative women at baseline, rates of grade 3 CIN positivity at 48 months appeared significantly higher in the cytology group than the HPV group across all age groups. The RR for HPV vs. cytology was 0.25 (95% CI, 0.13-0.48), and the absolute difference in the incidence rate of grade 3 CIN was –4.03 (95% CI, –5.88 to –2.41) per 1,000.
After the first round of screening, more grade 2 CIN cases also were detected with HPV testing. The RR for grade 2 CIN with HPV vs. cytology was 1.61 (95% CI, 1.24-2.09), with an absolute difference in the incidence rate of 5.84 (95% CI, 2.7-9.07) per 1,000.
By 48 months, significantly fewer grade 2 CIN cases were observed in the HPV group. The incidence rate was 5 (95% CI, 3.8-6.7) per 1,000 patients who underwent HPV screening compared with 10.6 (95% CI, 8.7-12.9) per 1,000 patients who underwent cytology screening (RR = 0.47; 95% CI, 0.34-0.67).
Among HPV- or liquid-based cytology-negative women at baseline, the RR for grade 2 CIN with HPV testing vs. cytology was 0.36 (95% CI,0.24-0.54), for an absolute difference in incidence rate of –6.38 (95% CI, –8.91 to –4.02) per 1,000.
Cumulative incidence curves showed HPV-negative women at baseline had a significantly lower risk for grade 2 and grade 3 CIN at 48 months compared with cytology-negative women.
By the end of trial follow-up at 72 months, incidence of grade 2 and grade 3 CIN was similar across both groups.
Ogilvie acknowledged the cohort population as a limitation in the study.
“This was done in a Canadian population and the women tended to be more educated,” she said.
Organizations that develop cancer screening guidelines are still grappling with whether to recommend replacing cytology and HPV co-testing with primary HPV testing as the absolute screening strategy for cervical cancer, according to L. Stewart Massad, MD, professor of obstetrics and gynecology at Washington University School of Medicine in St. Louis.
“A draft recommendation on cervical screening from the USPSTF recommended either cytology testing at 3-year intervals or primary HPV testing at 5-year intervals for women 30 to 65 years of age, but the final recommendation statement has not yet been released,” Massad wrote in a related editorial. “Fortunately for women, both modalities are so effective for cancer screening that an adequately powered comparative effectiveness trial is likely impossible.”
Still, the declining prevalence of HPV disease following HPV vaccination will make the sensitivity of co-testing irrelevant, Massad said.
“Until that occurs, clinicians will have to choose between primary HPV testing and co-testing based on modeling and cost-effectiveness studies, against the backdrop of intensive marketing by test manufacturers.” – by Melinda Stevens
For more information:
Gina Suzanne Ogilvie, MD, FCFP, DrPH, BC, can be reached at Women’s Hospital and Health Centre, 4500 Oak St., Room H203G (Box 42), Vancouver, BC V6H 3N1, Canada; email: firstname.lastname@example.org.
Disclosures: Ogilvie reports a coinvestigator role on adjunct studies to the HPV FOCAL trial funded by Hologic Inc and Roche. Please see the study for a list of all other authors’ relevant financial disclosures. Massad reports a consultant role with malpractice attorneys in cases alleging missed cervical cancer; honoraria and travel expenses for educational activities and development of management guidelines; a panel member role that recommended FDA approval for the first HPV-based cervical cancer screening test and developed interim guidance for its application; and a panel member role on the American Cancer Society cervical cancer screening guidelines.