By Will Boggs MD
NEW YORK (Reuters Health) - 16/5/2019
P16/Ki-67 dual-stain triage of women who test positive for human papillomavirus (HPV) in cervical cancer screening reduces referral to colposcopy without impairing detection of precancerous lesions, researchers report.
"Our findings demonstrate that dual stain can safely replace cytology testing as a triage strategy for HPV-positive women," Dr. Nicolas Wentzensen from the National Cancer Institute, in Bethesda, Maryland, told Reuters Health by email. "Our study also suggests that dual stain may perform even better than Pap cytology among vaccinated populations with reduced prevalence of HPV16/18 infections, the most carcinogenic HPV types."
The ideal cervical-cancer screening and triage approach would identify as many precancerous lesions as possible while minimizing the number of women referred for colposcopy. Dual staining of p16/Ki-67 and cytologic specimens has been shown to be an accurate marker for cervical precancerous lesions.
For their study, online May 13 in JAMA Internal Medicine, Dr. Wentzensen and colleagues used data on 3,225 HPV-positive women undergoing HPV and Papanicolaou cytologic testing with a valid dual staining (DS) result from September 16 to October 31, 2015. Follow-up lasted through 2018.
Both screening approaches showed similar sensitivity for detecting precancerous lesions, but the combination of DS with HPV16/18 genotyping proved positive in significantly fewer women (56.4%) than did the combination of partial genotyping and cytologic triage (66.0%).
DS showed better risk stratification for cervical intraepithelial neoplasia grade 3 or more (CIN3+) than did Papanicolaou cytologic testing for triage of HPV-positive women with partial genotyping and irrespective of genotyping; HPV16/18-negative women with negative DS results had a risk of CIN3 low enough to extend retesting intervals.
The strategy of HPV partial genotyping and triage based on Papanicolaou testing resulted in 66.0% of women having immediate referral to undergo colposcopy and 83.0% of women with overall referrals to colposcopy.
All DS strategies required substantially fewer colposcopies. The combination of partial genotyping and DS, with positive results for either test resulting in referral for colposcopy, for example, was associated with a 32.1% reduction in the number of colposcopies.
Even with fewer colonoscopies, the number of colposcopies required to detect one case of CIN3+ was lower with DS strategies (7.7-8.3 per case) than with HPV partial genotyping and Papanicolaou testing (9.7 per case).
"A cervical-cancer screening program combining HPV testing and dual stain can lead to better detection of cervical precancers compared to current standards, while sending fewer for colposcopies, biopsies and treatment procedures," Dr. Wentzensen said. "Therefore, diagnostic and therapeutic procedures can be better targeted to the women at highest risk of cervical pre-cancer."
"Cervical-cancer screening exemplifies the concept of precision prevention," he said. "The causal agent - human papillomaviral infection - is ubiquitous in the population, but few infections go on to cause pre-cancer. Novel risk markers allow clinical interventions to be tailored to an individual patient's risk."
In a separate study, Dr. George F. Sawaya of the University of California, San Francisco, and colleagues used a Markov decision model that used the preferences of a sociodemographically diverse group of 451 women (mean age, 38.2 years) to estimate the cost-effectiveness of 12 cervical cancer screening strategies. The team did not evaluate DS triage.
Cytologic testing every three years with repeat cytologic testing for atypical squamous cells of undetermined significance (ASC-US) yielded the most lifetime quality-adjusted life-years (28.9 QALYs).
Cytologic testing every three years with high-risk HPV triage of ASC-US was the lowest-cost strategy at $1,267 per woman. Cytologic testing every three years with repeat cytologic testing for ASC-US conferred more QALYs at higher costs ($2,166 per QALY).
Cotesting (preferred by the American College of Obstetricians and Gynecologists and the American Cancer Society) and primary high-risk HPV testing provided fewer QALYs at higher costs.
The analyses suggest that it is not cost-effective to begin primary high-risk HPV testing prior to age 30 years, to perform high-risk HPV testing every three years, or to perform cytologic testing annually.
Dr. Sawaya told Reuters Health, "Our study took into account patient preferences and economic costs of various cervical cancer screening strategies. Our findings suggest that Pap-based strategies provide the best balance of benefits, harms, and costs. This was surprising given the current high enthusiasm for using new HPV-based screening strategies. We believe that our observations were due in part to the lower cost and lower likelihood of false-positive testing seen with Pap tests compared with HPV tests."
"HPV test results are a powerful predictor of future cancer risk, but we need to better understand how to manage women with positive results in a manner that balances benefits, harms, and costs," he said. "Future work should focus on improved ways to manage these women."
Dr. Sawaya added, "Although we have new ways to screen, we have to remember that many women diagnosed with cervical cancer have never been screened. Access to screening of any kind would go a long way in decreasing the burden of cervical cancer in the U.S. and around the world."
Dr. Sarah Feldman from Brigham and Women's Hospital and Harvard Medical School, in Boston, who wrote an editorial related to this report, told Reuters Health by email, "Dual-stain technology offers a very exciting opportunity to easily assess a women's risk for severe dysplasia after abnormal primary HPV screening. However, although we will ultimately likely transition to primary HPV screening, we do not yet have that option available in many places."
"Although cotesting is not cost-effective, it is available everywhere and may be a good way for clinicians and patients to transition to becoming comfortable with HPV testing," she said. "Using dual stain on those cotests will allow clinicians to understand these results and ultimately transition to reflex cytology instead of the cotest."
"Vaccinate all children against HPV," Dr. Feldman said. "Ultimately early vaccination against the 9 highest risk HPV types may drastically reduce the risk of developing cervical cancer (as well as other HPV related cancers in both men and women) - but we are not there yet, so keep screening."
JAMA Intern Med 2019.