HPV Testing May Reduce Incidence Of Cervical Cancer But Evidence Is Not Yet Strong Enough To Support Its Routine Use In Screening Programmes

Main Category: Cervical Cancer / HPV Vaccine
Also Included In: Cancer / Oncology;  Women's Health / Gynecology
Article Date: 30 Oct 2007 - 3:00 PDT

email to a friend   printer friendly   opinions  

Conducting cervical cancer screening programmes by detecting the DNA of human papilloma virus (HPV), the causative agent of this type of cancer, could protect women for longer than the currently-used method, meaning intervals between screening rounds could be lengthened, according to the results of two studies published in the New England Journal of Medicine.

Most developed countries have national screening programmes for cervical cancer that make use of the Pap smear, a technique developed over 50 years ago in which a sample of cells from the cervix is examined under a microscope for any abnormalities in their look and shape. Women with any abnormal looking cells---and indication of cancer or pre-cancer---are either screened again or referred for colposcopy. It is the best screening tool introduced for any cancer and has helped reduce the incidence of cervical cancer in developed countries dramatically. However, this test produces a high number of false negative results, so women must be screened at regular intervals to ensure any cases of cancer are not missed---usually one every 3-5 years after women first become sexually active.

Because infection with HPV has been identified as the underlying cause of cervical cancer, it has been suggested that HPV testing should be the primary screening test for cervical cancer, replacing the traditional Pap smear. Some non-randomised studies suggest that HPV tests are substantially more sensitive than traditional cytological testing (looking at the cells) for detecting high-grade cervical intraepithelial neoplasia---the type of lesions that progresses to cancer. However, the decision about whether to switch screening programmes from the Pap smear to HPV testing is complicated by the fact that the latter has a lower specificity than cytological testing, which means that women will falsely test positive and will therefore be referred for coloscopy, thus increasing health care costs.

So should government screening programmes switch to the new technique? Or is there a way in which these two tests can be combined to provide the most effective preventive measure for cervical cancer? Two trials looking at this issue have been published this month. The first, a randomised study from Canada , involved the first screening round of the Canadian Cervical Cancer Screening Trial. Women who went for testing at any of 30 clinics in Montreal or St John's were recruited to the trial, which was designed to compare HPV testing and Pap testing for their ability to identify cervical cancers and high-grade precancers.

Between September 26, 2002, and February 3, 2005, 10,154 women aged 30 to 69 years were randomly assigned to screening with both tests in different orders. Half received the Pap test first and the other half HPV first (the investigators decided it would have been unethical not to have given both groups both tests). Participants were referred for colposcopy, involving biopsy of abnormal and normal regions, if they had a positive Pap or HPV screening test. A random sample of women with negative tests were also referred in order to eliminate verification bias in the results.

By analysing the data on the basis of the first test received by the women, the investigators found that the sensitivity of the Pap test was significantly lower than the sensitivity of the HPV test (ie, the former resulted in more false negative results), as previous studies had indicated, but that the specificity of the Pap test was slightly higher than the HPV test (the Pap test caused fewer false positives). Use of both tests achieved 100% sensitivity.

The researchers concluded that their data show the HPV test should mean women can safely be screened less frequently than with Pap smear, and because of this finding, the increased costs likely to be incurred by a higher rate of false positives---which would lead to higher rates of referrals and expensive colposcopies---would be offset. However, they say it remains unclear whether HPV testing will further reduce the rates of death from cervical cancer although they are convinced that the test would lead to "more efficient control of cervical cancer."

In the other study, a Swedish research group tested a very sensitive method of HPV DNA detection, which is not widely available, and went further that the Canadian study in following up the women, which allowed the researchers to speculate on the effect of the addition of HPV to screening examinations on the incidence of high-grade intraepithelial neoplasia (precancer). The study involved 12 527 women 32-38 years old from a population-based screening program in Sweden . They were randomly assigned to have an HPV test plus a Pap test or a Pap test alone. Women with a positive HPV test and a normal Pap test result were offered a second HPV test at least 1 year later, and those who were found to be persistently infected with the same high-risk type of HPV were then offered colposcopy with cervical biopsy. One of the main differences to the other study was that comprehensive registry data were used to follow the women for a mean of 4.1 years.

The primary outcome of the trial was the incidence of grade 2 or 3 cervical intraepithelial neoplasia lesions or cancers and the researchers found that the addition of an HPV test to the Pap test resulted in a reduction of lesions detected by subsequent screening examinations. However, it was unclear whether the increased detection of high-grade cervical intraepithelial neoplasia offered by the HPV test represented overdiagnosis of lesions that might have regressed spontaneously. The authors say the extent of over-diagnosis and long-term protection against grade three neoplasia is an area that will need additional study.

There are limitations to the generalisability of both studies, however, because they used conventional cytological testing as opposed to liquid-based cytology, which is standard in the US and the UK . The liquid-based technique is more sensitive than conventional cytology so if this approach had been tested, the gain in sensitivity for HPV DNA testing may have been less. Furthermore, neither or these studies provides the crucial data necessary to prompt a change in European guidelines about screening for cervical cancer. For that to happen, regulators have specified that they need information on the effect of HPV-based cervical screening on the incidence of grade 3 cervical intraepithelial neoplasia or cancer detected by subsequent screening. And HPV testing will not be adopted as a routine screening tool until that data is available.

Human papillomavirus DNA versus Papanicolaou screening tests for cervical cancer
Mayrand M-H, Duarte-Franco E, Rodrigues I, Walter SD, Hanley J, Ferenczy A, Ratnam S, Coutlée F, Franco EL, for the Canadian Cervical Cancer Screening Trial Study Group
N Engl J Med 2007; 357:1579-88.

http://www.esoncology.org

• Additional
• References
• Citations