Tuesday, March 26, 2013

Time for a Change

Since the end of World War II, Pap smear screening has markedly reduced the incidence and mortality of invasive cervical cancer in the United States, Canada, UK, Australia, and Western Europe. Interestingly, it’s one of the few widespread screening tests that have never been evaluated in a randomized clinical trial,yet it has undoubtedly forever changed women’s healthcare.

However, we may have reached the maximum benefit of Pap-based cervical cancer screening and have learned quite a bit about this diagnostic test in the last 20 years. Unfortunately, a single Pap smear has a false negative rate of 50% (yes, 50%!). That might be even higher in areas where prevalence of disease is low (i.e., an over-screened population or one with high HPV vaccination rates).

Counter to common belief, more Pap testing is not necessarily better for women. We have learned that over-screening, including annual screening, puts most low-risk women at considerable risk for unnecessary tests, procedures, and treatment. Some of this treatment may in fact jeopardize an individual woman’s future fertility and ability to carry a pregnancy to term. Thus, all professional societies, including the American Cancer Society, the American Society of Colposcopy and Cervical Pathology (ASCCP), the American Society of Clinical Pathology (ASCP), the American Congress of Obstetricians and Gynecologists (ACOG) as well as the United States Preventive Services Task Force (USPSTF), no longer recommend annual screening. Instead, women should start their screening at age 21, then be screened at three-year intervals with Pap testing alone from 21-29 years of age , and then at five-year intervals with Pap and HPV (provided that both results are normal). This is a marked departure from the age-old adage that women have learned, “Get your yearly Pap smear,” but it’s based on a high level of scientific evidence and correctly balances the benefits and risks of cervical cancer screening.

Testing for the human papillomavirus (HPV) has become an integral part of cervical cancer screening – we presently use it to figure out equivocal Pap smears and in conjunction with Pap smears in women less than 30 years of age. Persistent infection with HPV is a major risk factor for cervical cancer, and essentially all cervical cancers have identifiable DNA sequences of HPV – in other words, the development of cervical cancer without a preceding persistent HPV infection is exceedingly rare.

HPV testing has been shown to have a much higher sensitivity than Pap-based testing. More specifically, numerous trials have demonstrated a sensitivity in the mid to high 90% range (false negative rates of less than 5%). In fact, there have been eight randomized controlled trials (which included more than 270,000 women) that clearly demonstrate that HPV testing outperforms Pap testing for the detection of cervical pre-cancer and cancer.

At the recent 2013 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer in Los Angeles, end-of-study results were presented on the recently completed ATHENA trial (Addressing the Need for Advanced HPV Diagnostics) by Dr. Thomas C. Wright from Columbia University. (As disclosure, I served as senior author on this abstract and this study was funded by Roche Diagnostics.) This is the largest prospective registration study in the area of HPV diagnostics in the United States with more than 42,000 women enrolled.  At the end of the three-year follow-up period, here is what we learned: 1) The incidence of cervical pre-cancer and cancer in women who were HPV negative was a little more than half that of women who were Pap negative- these results indicate that HPV testing is superior to Pap testing for cervical cancer screening in a well-screened population, and 2) Testing with both Pap and HPV (as currently recommended) provides minimal benefit over HPV testing alone.

The bottom line is that these results are consistent with the other eight randomized controlled trials, all of which have been done outside of the U.S. So, these results were much needed to understand the value of this type of testing in a U.S. population.  Parts of Europe have started to embrace this concept of primary HPV screening, but unfortunately, we are well behind them. 

Although I do personally understand that it’s hard to imagine transitioning from a women’s healthcare standard like Pap testing (we may not like to admit it, but much of women’s healthcare revolves around the Pap test), it’s hard to ignore the facts. Why would we want to use a test that is less sensitive, particularly in the cancer screening setting, in lieu of one that picks up more disease and clearly outperforms the other?

It’s time for a change. The real question is whether we are ready for it.

Warner Huh, M.D., is a professor in the UAB Division of Gynecologic Oncology and a senior scientist in the UAB Comprehensive Cancer Center. He is a nationally recognized expert in the research and treatment of gynecologic cancers, with a particular emphasis on cervical cancer and the effects of the human papillomavirus. This blog was originally published on the Birmingham Medical News blog and can be found here.

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