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6. What were the results of these studies?

In their analysis of ALTS data, Castle et al. found that 542 women in the study group developed CIN3 or cervical cancer. Those who tested positive for HPV16 had 38 times the risk for CIN3 or cervical cancer than women in the study who were HPV negative. Women who tested positive for other oncogenic HPV types had seven times the risk for these conditions than women who tested HPV negative. The authors concluded that patients with a positive HPV16 diagnosis may require more aggressive management than those who test positive for another oncogenic HPV type or who are HPV negative.

Khan et al. found that women in the Portland study who tested positive for HPV16 or HPV18 were diagnosed with CIN3 or cervical cancer more often than women who tested positive for another oncogenic HPV type, or women who tested negative for HPV. Additional analysis of women with normal Pap smear results at study enrollment provided further evidence for the observed risk differences. The authors concluded that screening for HPV16 and HPV18 separately from other oncogenic HPV types may identify women at the greatest risk of CIN3 and cervical cancer, while allowing for less aggressive management of cases of other oncogenic HPV infections.

The authors note that an elevated risk for HPV16 also was observed in a natural history study in Guanacaste, Costa Rica (Schiffman, Virology, 2005)***.

7. How were these studies performed?

The ALTS study compared three different management strategies for 5,060 women with Pap tests that either showed ambiguous cytologic abnormalities (ASCUS, 3,488 women), or low-grade squamous intraepithelial lesions (LSIL, 1,572 women). The study referred one-third of the women to an immediate colposcopy, regardless of their Pap test results; one-third to colposcopy if their initial HPV test was positive or if their Pap test showed high-grade squamous intraepithelilal lesions (HSIL); and one-third to colposcopy if their Pap test showed HSIL at their enrollment in the study or during follow-up. All three groups received additional tests every six months for two years of follow-up and a colposcopy at the end of the trial. Women whose test results showed cervical intraepithelial neoplasia grade 2 (CIN2) or higher received treatment for the condition.

The Portland study examined data on 20,514 women who received routine cytologic screening through a prepaid health plan in Oregon. Women included in this analysis had negative, equivocal, or mildly abnormal baseline cervical Pap smears; suitable samples for HPV testing; and type-specific HPV test results. Study participants received regular follow-up cytology testing for up to 10 years following their enrollment. Practice guidelines at the time of the study mandated treatment for women whose Pap smears showed CIN2 or higher, but some physicians also treated some patients with cervical intraepithelial neoplasia grade 1 (CIN1).

8. What were the limitations of these studies?

ALTS was a clinical trial and, consequently, the participants in the trial may have been screened more regularly than patients in everyday clinical management. Additionally, the women in this study were relatively young, with a median age of 25. A population of older women might lead to different results.

Women with cellular abnormalities in the Portland study received very aggressive treatment -- more than was mandated by clinical standards at the time or today. Thus, results in this study may actually underestimate the risk attributable to HPV16 and to HPV18 because of over-treatment. Additionally, there were relatively few cases to analyze despite the study size, possibly leading to some imprecise estimates of risk.

9. What are the next steps in this area of research?

Twenty organizations - including the American Society for Colposcopy and Cervical Pathology (ASCCP), the American Cancer Society, and the National Cancer Institute (NCI) - will participate in a conference in September 2005 to discuss the use of HPV DNA testing for screening and for triage of equivocal (ASCUS) Pap smears. One of the topics of discussion is likely to be the utility of HPV genotype detection in screening and clinical management.

The data from these recent two studies should be confirmed in other larger studies and in other populations, perhaps even in some of the clinical trials that are evaluating HPV DNA tests to develop more precise estimates of risk. Also, subsequent evaluations will need to examine this question in women who are newly infected.

To perform HPV genotyping, a reliable, FDA-approved test to distinguish these specific HPV types will need to be developed and validated. When FDA-approved tests that provide genotype information become available, researchers will be better able to identify women with persistent infection, an important risk factor for the development of precancer and cancer. Understanding the risks associated with a persistent HPV infection and the appropriate clinical management of these women is critical to preventing cervical cancer.

Future research will help to demonstrate whether women who test negative for HPV16 and HPV18 can be followed and treated less aggressively than women who test positive for these HPV types, thereby reducing the number of clinical visits, potential over-treatment of these women, and increasing the cost effectiveness of such testing.

Tags: Cervical Cancer

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