Pap Test Down but Far From Out
To take license with Samuel Clemens’ words, reports of the Pap test’s demise have been exaggerated, authorities agree in the aftermath of an FDA decision about HPV testing.
Roche’s Cobas HPV DNA test scored a regulatory hat trick, getting unanimous “yes” votes to the three key questionsaddressed by the FDA Medical Devices Advisory Committee Microbiology Panel. After reviewing data presented by the sponsor and by the FDA staff, the panel found that the test is safe, effective, and its benefits outweigh any risks.
If the FDA follows the panel’s recommendation — which it does in most cases — the HPV DNA test will supplant the Pap test as the initial screening test for cervical cancer, specialists in primary care, gynecology, and oncology told MedPage Today. However, the authorities agreed that the Pap test won’t disappear anytime soon, if ever.
“Even in the tentative algorithm that was discussed at the FDA panel’s meeting, cervical cytology is still being used,” saidWarner Huh, MD, of the University of Alabama Birmingham. “It’s being used as a triage test instead of a front-line test.”
In one triage scenario, a positive viral DNA test that triggers a Pap might lead to “cytology with prejudice,” meaning a specimen would be examined in light of information provided by the DNA test. The test results might lead a cytologist to perform a different type of specimen interrogation, as opposed to using a Pap specimen as the initial test.
Aside from the Pap test retaining a role in the screening process, consensus about the future of cervical cancer screening remains in flux, pending a final FDA decision and more information about cost and testing performance characteristics. Additionally, clinician and patient acceptance of the viral DNA test is assumed but not guaranteed.
“One of the barriers to HPV testing is the fact that it is a sexually transmitted infection,” said Huh, who spoke on behalf of the Society of Gynecologic Oncology at the FDA panel meeting. “Whether that will deter one from being screened and whether clinicians will take more time to explain that to patients more carefully — these are some of the things we’ll have to deal with.”
Cost always figures prominently in the adoption of new technology. To make a bare-bones cost comparison of viral DNA testing versus Pap test, the FAIR Health — a not-for-profit organization that maintains a database of costs for healthcare services — offers one potential starting point.
By pairing a ZIP code and a type of service, anyone can get a rough cost estimate from FAIR Health. Using a Houston ZIP code resulted in a base cost of about $50 for a Pap test and $150 for the viral DNA test. Those estimates assume the patient has to fork over the entire cost and do not take into account insurance coverage.
In the case of HPV testing, the base cost doesn’t take into consideration potential downstream effects of a testing protocol that begins with the viral DNA test. In an unselected population, most patients will test negative for HPV.
As discussed at the FDA panel hearing, a positive test for HPV16 or 18 will trigger colposcopy. However, studies have shown that the viral DNA test has greater accuracy compared with the Pap smear, which means and fewer unnecessary colposcopy procedures.
“The overall cost of screening will not increase,” said Nancy Khardori, MD, of Eastern Virginia Medical School in Norfolk. “Wider screening will actually lead to early diagnosis and intervention, saving the cost of more expensive later treatments.”
Initially, the cost of front-line viral testing could be higher, said Evan Myers, MD, of Duke University, but over the long term, the HPV DNA test should reduce the cost of screening.
“Tests for HPV DNA are more sensitive than cytology, which means the interval between screening can be safely lengthened,” said Myers. “Lengthening the interval will significantly decrease costs, both because fewer tests will be performed and because there will be fewer false-positive test results overall.”
Cost savings are less certain if screening continues at frequent intervals or if every positive result leads to aggressive management, he added.
From a Medicare perspective, the cost of a Pap test and the HPV DNA test are very similar, said Thomas C. Wright, MD, of Columbia University in New York City. Given the superior performance characteristics of the DNA test, the cost issue seems clearer.
Accurate numbers on participation in cervical screening, but appear to be on the order of 50 to 60 million. “If half of those women are getting cytology only, then they’re getting a test that, in every meta-analysis, is running at 50% sensitivity, which is what we had in the ATHENA trial, and we can replace that for almost the same amount of money for a test that has almost a 90% sensitivity; that’s a major win,” said Wright, an ATHENA investigator who spoke to the FDA panel.
Huh and colleagues have submitted a paper that addresses the cost implications of HPV DNA testing, but he declined to reveal details in advance of publication.
The interval between screening tests is a key variable that remains to be hashed out. The frequency of testing has implications for cost and adherence to screening recommendations.
“A majority of women screened for HPV will be negative” said Kevin Ault, MD, of Emory University in Atlanta. “It is likely these will not need to be tested for several years, because their risk of precancerous change or cervical cancer is very low for years after a negative test.
“Many women I see are uncomfortable with the long screening interval, and I am sure some doctors are as well.”
Wright, who speaks to numerous ob/gyn groups about HPV testing, said the reaction to a proposed screening interval of 5 years is a unanimous “are you out of your mind?”
According to a proposal submitted to the FDA panel, another outcome of viral DNA testing is a negative result for HPV16 and 18 but a positive result for another high-risk HPV strain (12 of which are included in the test panel, in addition to HPV16 and 18). In that case, patients would have a Pap test, after which a decision would be made about the need for colposcopy.
Within the ob/gyn community, the preferred method of screening for cervical cancer in women older than 30 is co-testing — use of the HPV DNA test and Pap test together, said David Chelmow, MD, of Virginia Commonwealth University in Richmond. Whether clinicians can be persuaded to drop the Pap component remains to be seen.
“The use of the HPV test as a first-line screen is promising and appears better than the Pap test used by itself,” said Chelmow, who spoke on behalf of the American College of Obstetricians and Gynecologists (ACOG) during the FDA panel hearing. “The real question is how it compares to co-testing.”
ACOG’s statement to the FDA highlighted four areas of uncertainty that are not addressed in the proposal to make vital DNA testing the first-line standard.
- Appropriate screening in women younger than 25
- Appropriate interval for repeat testing
- Criteria for ending screening
- Transitioning patients previously screened with the Pap smear alone or co-testing
How an FDA decision to extend the viral DNA test’s indication to front-line screening for cervical cancer also has implications for clinical guidelines.
“About half of the cervical cancers diagnosed in the U.S are found in women who were never screened for the disease,” said Chelmow. “At this time, primary screening is not part of any of the generally used clinical practice guidelines.”