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Clinical Reviews


UPDATE ON CERVICAL DISEASE

The author revisits his declaration in the 2006 Update that “we’re on the way to ending cervical cancer.” What’s happened in 3 years with screening, HPV testing, and cancer prevention?

March 2009 · Vol. 21, No. 03

IN THIS ARTICLE

In the March 2006 “Update on Cervical Disease,” I began with Prof. Margaret Stanley’s exclamation “It could be the end of the affair with HPV!” That Update covered three major areas that have been nudging us closer to the possibility of someday ending cervical cancer.

I thought it time to revisit those three practical advances to see how we’re doing. As you’ll read, much has happened; one exciting prospect in 2006—human papillomavirus (HPV) vaccination—has become established in everyday practice. On the other hand, primary screening with an HPV plus a Pap test (so-called co-testing) has not yet fulfilled its promise, and type-specific HPV testing for HPV 16 and 18, expected in 2006 to be “just around the corner,” is still … just around that corner.

And it isn’t just medicine that has changed. The World of 2009 is a markedly different place than the World of 2006. The economy of the United States is rockier than at any time since the Great Depression, and the skyrocketing cost of medical care has made health-care cost containment more important a goal than it ever has been.

So, allow me to reexamine what was “new in 2006” for cervical cancer prevention and compare where we are in 2009—thanks to interesting, important research and the effects on health care of an economic squeeze that we could not have foretold 3 years ago. I’ll also make an educated prediction about where cervical cancer prevention may be headed in, say, the next 3 years or so.

1 “More sensitive and more objective screening” inches closer

Naucler P, Ryd W, Törnberg S, et al. Efficacy of HPV DNA testing with cytology triage and/or repeat HPV DNA testing in primary cervical cancer screening. J Natl Cancer Inst. 2009;101:88–99.

Solomon D, Breen N, McNeel T. Cervical cancer screening rates in the United States and the potential impact of implementation of screening guidelines. CA Cancer J Clin. 2007;57:105–111.

Dillner J, Rebolj M, Birembaut P, et al; Joint European Cohort Study. Long term predictive values of cytology and human papillomavirus testing in cervical cancer screening: joint European cohort study. BMJ. 2008;337:a1754.

Comforting combo: Negative Pap and HPV tests

In 2006, I discussed the Level-A evidence, cited in the 2005 ACOG Practice Bulletin, that women who have a negative HPV test and a negative Pap (i.e., a co-testing protocol) have a risk of approximately 1 in 1,000 of an unidentified CIN 2,3 or cervical cancer and, therefore, do not need another Pap or HPV test for at least another 3 years. This would seem compelling evidence of the efficacy and safety of co-testing, so the expectation might be that this cervical screening strategy would quickly become the primary protocol for women 30 years or older.

But not so fast! Even though a recent Centers for Disease Control and Prevention (CDC) survey indicates that 66% of clinicians who provide cervical screening already used co-testing by 2004, 1 recent estimates are that only one third or fewer of women 30 years or older are being screened with a Pap test + HPV test. What does this mean? Possibly, that co-testing is used by a majority of clinicians, but not routinely. There are, likely, a number of reasons that co-testing has not become standard, but hesitancy to move beyond the annual Pap test is at the top of the list.

Will we move beyond tradition?

Providing an annual Pap test to our patients has reduced the incidence of cervical cancer from second among cancers in women to 11th, and mortality from second to 113th. But a program of annual cervical cytology is not cost-efficient 2 even if it is protective for most women, and the degree of protection declines among women who are screened irregularly.

Screening can be made more cost-effective by extending the screening interval. One option is to repeat the Pap every 2 or 3 years, instead of annually, for women who have had three consecutive normal Pap tests. The additional risk of cervical cancer that results from extending the screening interval to 3 years is estimated to be 3 to 5 cases for every 100,000 women 3 —numbers that are small but that are unacceptable to many, considering the great potential for preventing cervical cancer.

The other option is to add HPV testing to screening. Because an HPV test is more sensitive for CIN 2,3, a negative result provides long-lasting reassurance against cancer risk.

Enter, economics. Adding an HPV test to the screen without increasing the interval is not cost-effective: It increases overdiagnosis and overmanagement and, thereby, harm.

Moving to less frequent screening is the only option for improving the cost effectiveness of cervical cancer prevention; less frequent screening reduces not only 1) the number of tests but also 2) detection of transient HPV infections not destined to progress and 3) overmanagement and treatment of such benign infections. And the high sensitivity and long-term predictive value of an HPV test ensures that moving to a longer interval isn’t likely to put women at more risk even if the next screen exceeds 3 years. Major studies confirm this margin of safety and validate a move to less frequent screening. Here’s what we learned in the past year.

In search of an optimal protocol

Most research on co-testing continues to come from Europe, where organized screening programs have facilitated large studies.

Compared with screening by cytology alone, co-testing that included 1) referral to colposcopy of all women who had an abnormal Pap and 2) testing for type-specific HPV persistence at 12 months for women who initially had a normal Pap and a positive HPV test resulted in a 35% increase in sensitivity for detecting CIN 3+, with only a modest reduction in positive predictive value. The researchers noted, however, that the gain in sensitivity came at the expense of doubling screening tests because screening in Sweden already occurs at a 3-year interval.

Naucler and colleagues used the database from the intervention arm (n=6,257 women) of a population-based randomized trial (the Swedescreen Trial), in which a conventional Pap smear and HPV test were obtained from women 32 to 38 years old, to evaluate the efficacy of 10 cervical screening strategies based on HPV DNA testing alone, cytology alone, and co-testing with both tests.

Solomon and co-workers estimated that, in the very near future, 75 million Paps will be performed each year if we don’t change our screening strategy from annual cervical cytology. If all screened women younger than 30 years had a liquid-based Pap every 2 years as recommended by the ACS, however, and if all screened women 30 years or older had a Pap test and an HPV test every 3 years, the number of annual Paps would decline to 34 million. Because this protocol requires a similar number of HPV tests for women older than 30 years, the total number of primary screening tests (HPV + Pap tests) would be only marginally less than the Paps performed at the present interval. But it is expected that less frequent screening would also reduce the number of transient HPV-induced cytologic events detected that require follow-up.

Are there other options?

Additional savings are possible if 1) both the Pap test and the HPV test did not need to be performed together or 2) the screening interval could be longer than Solomon described.

Naucler and colleagues clearly demonstrated that the most effective of the 10 screening options they evaluated was screening with an HPV test first (the most sensitive test) followed by a Pap test (the most specific test) only on women who have a positive HPV test. This protocol increased the sensitivity for CIN 3+ by 30% over the detection rate when the Pap was the only screening test, maintained a high positive predictive value, and increased the number of screening tests over the triennial “Pap-only” protocol by just 12%. In the United States, this approach would significantly decrease the number of screening tests, and should decrease costs, compared with the number of tests and costs associated with the traditional annual Pap test.

However, whether co-testing will ever be replaced by an HPV test as the sole primary screen depends on whether we are willing to accept a small decrement in protection in exchange for a major gain in cost effectiveness. In the past, safety has trumped but, in every aspect of health care to come, this will be the trade-off debated if, as a nation, we are to make our health care more affordable.

Can a longer HPV screening interval adequately protect patients?

A basic concern that clinicians have with the 3-year screening interval is that some women may not come in for screening until 4 or 5, or even more, years. Their concern is justified; numerous studies have confirmed that extending the screening interval beyond 3 years for women screened by cytology significantly decreases protection.

How protected would women be if they were screened with an HPV test? Dillner and colleagues demonstrated in their study that women who have a negative HPV test could have their interval safely extended for at least 6 years. Their work suggests that women who are screened infrequently would be significantly protected well beyond the 3-year interval now recommended in the United States with co-testing. However, it is important to point out that no screening test is perfect, and the reduction of cancer risk to zero is unlikely.

WHAT THIS MEANS FOR PRACTICE

Although the recommended screening interval is 3 years after a negative co-test, women screened by HPV testing have a margin of safety for at least 6 years. Irregularly screened women are therefore likely to be better protected even if the next screen surpasses 3 years.

2 “Better management of screen positives”—we wait for new testing technology

Ginocchio CC, Barth D, Zhang F. Comparison of the Third Wave Invader human papillomavirus (HPV) assay and the Digene HPV hybrid capture 2 assay for detection of high-risk HPV DNA. J Clin Microbiol. 2008;46:1641–1646.

Wong AK, Chan RC, Nichols WS, Bose S. Invader human papillomavirus (HPV) type 16 and 18 assays as adjuncts to HPV screening of cervical Papanicolaou smears with atypical squamous cells of undetermined significance. Cancer. 2009;115:823–832.

Castle PE, Dockter J, Giachetti C, et al. A cross-sectional study of a prototype carcinogenic human papillomavirus E6/E7 messenger RNA assay for detection of cervical precancer and cancer. Clin Cancer Res. 2007;13:2599–2605.

Type-specific HPV testing identifies highest risk

By 2006, it had become clear that testing for HPV types 16 and 18 would identify those HPV-positive women who are at highest risk of CIN 2,3+. Investigators introduced a potential management algorithm that would likely alter the care of Pap-/HPV+ women once such testing became available.

Three years later, however, type-specific HPV testing still isn’t available. Why not?

Continued...
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