Cotesting for cervical cancer using both Pap smear testing and human papillomavirus (HPV) testing does not improve cancer detection to any great degree in comparison with using HPV testing alone, say the authors of a new study.
Using HPV testing alone as a cervical cancer screening option would be nearly as effective as the combination HPV and cytology cotesting; in fact, cotesting may lead to overscreening, says lead author Mark Schiffman, MD, MPH, Division of Cancer Epidemiology and Genetics at the National Cancer Institute, and colleagues.
The new study was published online November 14 in the Journal of the National Cancer Institute.
It found that HPV testing alone identified more women who were subsequently diagnosed with cervical cancer (P < .001) and precancer (P < .001) as compared with cytology. An HPV test result was also statistically significantly more likely to be positive for cancer at almost all points in time (P < .001).
In cases in which HPV testing results were negative and cytology results were positive, only 3.5% were found to be precancer; 5.9% were found to be cancer cases. In this group of malignancies, cases were more likely to be regional or of distant stage with squamous histopathology, as compared with other cases.
Overall, adding cytology to screening resulted in earlier disease detection of at most only 5 cases per million women per year, the authors note.
Approached for comment, Karen Canfell, DPhil, director, Cancer Research Division, Cancer Council NSW, Sydney, Australia, said this new study “is a very important new source of evidence on the relative performance of cotesting and HPV testing.
“This major analysis demonstrated that HPV testing identified more women subsequently diagnosed with invasive cervical cancer and with precancer ― CIN3 and adenocarcinoma in situ ― compared with cytology,” she commented.
Only small incremental benefits are achieved by using cotesting vs primary HPV screening alone.
“These results confirm prior findings that only small incremental benefits are achieved by using cotesting vs primary HPV screening alone,” Dr Canfell told Medscape Medical News.
Other Countries Already Transitioning
A number of countries around the world (excluding the United States) are in the process of transitioning, or have already transitioned, to using HPV as the sole primary screening test, Dr Canfell commented.
“This has been motivated by the evidence of the increased effectiveness of HPV testing compared to cytology,” she said.
“In Australia, for example, the National Cervical Screening Program, which has been established for 25 years, will transition to HPV screening in 2 weeks’ time,” she noted.
Next month, Australia will also switch from use of Pap smears every 2 years for women aged 18 to 69 years to the use of HPV testing every 5 years for women aged 25 to 74 years. In Australia as well as several other countries, such as the Netherlands and Italy, she explained, cytology will be used as a secondary test only for women who are already found to be HPV positive.
“However, as HPV screening is being introduced in various countries, there has also been debate, mostly in the US, about the role of cotesting, which has been driven by reports of rare, HPV-negative cancers,” said Dr. Canfell .
Direction the World Is Heading
In the United States, HPV testing alone as an alternative method of screening for cervical cancer in women aged 25 years and older has not become the preferred modality in any major society’s guidelines, noted Dr Schiffman.
For example, the American College of Obstetricians and Gynecologists (ACOG) updated its guidelines in 2015. They noted that the HPV test can be considered an alternative to current cytology-based cancer in women aged 25 years and older.
Nevertheless, the ACOG still recommends cytology testing alone every 3 years for women aged 21 to 29 years as well as for those aged 30 to 65 years, and says that cotesting with cytology and HPV testing every 5 years is preferred. Screening with cytology alone every 3 years is also acceptable.
However, there are changes afoot, Dr Schiffman commented in an interview with Medscape Medical News.
He noted that the US Preventive Services Task Force (USPSTF) now recommends HPV testing alone for most age groups. The USPSTF issued new draft guidelines a few months ago, in which the USPSTF stated that testing for high-risk HPV strains alone is now recommended as an alternative to cytology or Pap screening alone beginning at age 30 years. Cotesting is no longer recommended.
As in its previous guidelines, issued in 2012, the USPSTF continues to recommend that women aged 21 to 29 years undergo Pap screening every 3 years.
The recommendations for women aged 30 to 65 years were changed because the existing literature shows that screening with cytology alone and testing for high-risk strains of HPV alone “offer a reasonable balance between benefits and harms” in this age group, wrote the authors of the draft guideline.
Dr Schiffman welcomed the move but pointed out that this is a draft guideline and has yet to be finalized, and that the comment period for this draft closed only recently, on October 9.
Dr Schiffman pointed that there are “a lot of disruptive aspects from backing away from Pap smears and using HPV alone. It’s not that simple, as it requires a lot of regulatory and structural changes.
“But it’s certainly the direction that the world is heading,” he said. “You can do self-sampling with an HPV test that’s as good as clinician collected. To reach the hundreds of millions of women, it’s just not really feasible in many places to do a speculum exam.”
It’s certainly the direction that the world is heading.
For the United States, Dr Schiffman believes there will eventually be three screening options: the Pap smear, the HPV test, and cotesting.
“The NCI is collaborating with the consensus guidelines group at the American Society for Colposcopy and Cervical Pathology to develop guidelines on screening and management of abnormalities,” he added. “This is really what the discussion is about now ― what’s state of the art and how to move medicine along.”
HPV Test Highly Effective
In their study, Dr Schiffman and his colleagues quantified the detection of cervical precancer and cancer by cotesting as compared with HPV testing alone at Kaiser Permanente Northern California (KPNC), a large integrated healthcare organization. KPNC introduced cotesting every 3 years in 2003. Thus far, 1,208,710 women aged 30 years and older have been tested.
The authors examined screening histories that preceded detection of both cervical cancers (n = 623) and precancers (n = 5369) to assess the relative contribution of the Pap test and HPV test components in identifying cases.
Overall, prediagnostic HPV testing results (76.7%) were more likely to be positive and thus more clinically sensitive as compared to cytology results (59.1%, P < .001 for paired comparison) for cancer diagnosis. The majority (82.6%) of all prediagnostic cotest results were positive by HPV testing or cytology, whereas only 5.9% were positive by cytology alone and negative by HPV testing.
For precancers, prediagnostic HPV testing (83.8%) was more likely to be positive than cytology (61.9%, P < .001); 87.3% of prediagnostic cotests were positive by HPV and/or cytology; 3.5% of cotests were positive by cytology and negative by HPV testing.
Compared to cytology, HPV testing was more likely to be positive prior to cervical intraepithelial neoplasia 3 (83.9% vs 62.8%, P < .001) and adenocarcinoma in situ (82.2% vs 53.2%, P < .001).
However, the authors observed that an increasing percentage of cancers were cytology positive/HPV negative in cases of more severe stage (5.1% for localized, 11.8% for regional, and 17.2% for distant spread). This trend was opposite for HPV positive/cytology negative cases (10.2% for localized, 6.5% for regional, and 0.0% for distant) (P trend = .002).
Therefore, with respect to the last cotest before diagnosis, HPV testing appeared more sensitive for detecting localized cancer (90.7% vs 85.6%, P = .02) and marginally less sensitive for distant disease (51.7% vs 69.0%, P = .06) vs cytology.
The analysis was supported through the Intramural Research Program of the National Cancer Institute. Coauthor Philip E. Castle, MD, received partial support by the Intergovernmental Personnel Act mobility program.
J Natl Cancer Inst. Published online November 14, 2017. Abstract
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