STD Quarterly-HPV DNA tests: Studies target use for cancer screening

Evaluating new weapon in cervical cancer fight

Cervical cancer is a leading cause of cancer in women worldwide, with an estimated 400,000 cases diagnosed each year.1 The cause of most of those cases? Researchers now point to human papillomavirus (HPV).2

While there are more than 30 genital types of HPV, only 10 to 15 types cause cancer.3 The prevalence of HPV in the United States is high: More than one-third of the estimated 15.3 million new cases of sexually transmitted diseases (STDs) in the United States in 1996 were attributed to HPV.4

While most HPV infections do not lead to serious problems, high-risk HPV types are responsible for nearly all cervical cancers. Now that scientists have firmly established the link between cervical cancer and HPV, they are turning their attention on how to use that information to decrease the morbidity and mortality associated with the disease.

The federal Food and Drug Administration gave approval in March 1999 to the Hybrid Capture II HPV Test, a DNA-based technology that can detect 13 high-risk types of HPV. The test is manufactured by Digene Corp. of Beltsville, MD. (Contraceptive Technology Update reported on the Hybrid Capture II and its predecessor in April 1998, p. 48.)

HPV DNA testing should become a routine way of screening women over the ages of 35-40 in the United States as soon as clinical trials can be conducted in this country, asserts Thomas Wright Jr., MD, associate professor in the department of pathology in the College of Physicians and Surgeons at Columbia University in New York City. Wright served as lead author for a recently published study on HPV testing of self-collected vaginal swabs in a periurban population of South African women.5 Results from the cross-sectional observational study, which screened more than 1,400 women ages 35 to 65, indicate that HPV testing of such swabs is less specific than but as sensitive as Pap smears for detecting high-grade lesions in women ages 35 and older.

"[HPV DNA testing] is more sensitive than routine cytology, and I doubt much less specific in a low- or intermediate-risk U.S. older population," Wright observes. "In women, I would hope we would go to a combination of HPV and cytology and use a management algorithm in which the women negative on both tests get interval screening, whereas the women who are HPV DNA positive/Pap negative get repeat screens at six- to 12-month intervals until they become either HPV DNA negative or develop an abnormal smear."

HPV testing can accurately identify most precancerous changes in the cervix and may be a useful screening tool in some populations, according to recent research that looked at DNA testing in women in a high-risk province of Costa Rica.6

"Our findings suggest that HPV testing is a viable technology worthy of consideration in cervical cancer prevention programs," states Mark Schiffman, MD, an epidemiologist at the National Cancer Institute in Bethesda and the study's principal investigator. However, study authors also caution that the usefulness of HPV testing will vary according to the population being screened and other factors, such as prevalence of other screening methods and cost.

"Decisions on optimal methods of screening will probably have to be made on a regional or national basis and depend on health economic analyses," Schiffman says.

ASCUS, LSIL questions

Providers are familiar with the Pap smear, which is the most common tool in the fight against cervical cancer. It is estimated that early detection of pre-malignant lesions by Pap smears prevents at least 70% of potential cervical cancers.7 The incidence of invasive cervical cancer has decreased significantly over the last 40 years, in large part due to early detection efforts. The National Breast and Cervical Cancer Early Detection Program, operated by the Centers for Disease Control and Prevention in Atlanta, estimates 12,800 new cases in 1999, with 4,800 deaths attributed to the infection.

Providers are familiar with two of the classifications for reporting cervical and vaginal cytologic diagnoses: ASCUS (atypical squamous cells of undetermined significance) and LSIL (low-grade squamous intraepithelial lesions). Uncertainty about the management of such mild cervical lesions has caused provider headaches because most lesions regress and do not cause disease.8 Providers are puzzled about which lesions can be safely tracked with follow-up Pap tests and which may require immediate biopsy and follow-up.

Researchers hope that results from the ASCUS/LSIL Triage Study (ALTS) sponsored by the National Cancer Institute will yield the answers needed for developing clinical guidelines for managing mild lesions. A multisite investigation initiated in 1995, the study is looking at three ways to manage lesions:

1. watchful waiting with a follow-up Pap smear every six months;

2. immediate colposcopy and biopsy;

3. use of HPV DNA testing to identify women most likely to benefit from immediate colposcopy (HPV positive) and women most likely to be normal (HPV negative) who do not need colposcopy and can be reassured.8

Approximately 2% of the 50 million Pap smears performed each year in the United States are categorized as LSIL, with the average cost of management for such cases estimated at $1,000 per woman.9 Because the majority of those lesions disappear spontaneously, identifying those that are most likely to progress would help to minimize patient anxiety and inconvenience, lower use of invasive testing, and save money.9

The latest report from the ALTS trial addresses the question of whether testing women who have LSIL diagnoses for HPV DNA is useful as a triage strategy.10 Women with a LSIL diagnosis were enrolled in clinical centers in Birmingham, Oklahoma City, Pittsburgh, and Seattle. Within six months of their diagnosis, women completed a standardized questionnaire and underwent a pelvic examination in which cervical specimens were collected for HPV DNA testing and Pap smears were repeated.

Cells taken from each woman were analyzed for HPV DNA using the Hybrid Capture II assay. In addition, cells from 210 of the women were tested for HPV DNA by polymerase chain reaction assays. The commercial technique detected HPV DNA in 82.9% of the specimens, while 81.4% of the specimens tested by both methods were positive by both methods.

Because a very high percentage of women with an LSIL diagnosis from Pap smears tested positive with the HPV DNA assay, there is limited potential for HPV DNA testing to help direct decisions about the clinical management of women with LSIL, researchers conclude.

The role of HPV testing in the management of women with ASCUS is still under study by the ALTS group.

The ALTS study also will offer a thorough understanding of the screening process and how it affects women, says J. Thomas Cox, MD, executive medical director of the National HPV & Cervical Cancer Prevention Resource Center. (The center, launched by the Research Triangle Park, NC-based American Social Health Association, offers information for providers and patients. See CTU, April 2000, p. 46.) Testing for HPV has been proposed as a less invasive way of resolving the persistent anxiety that often accompanies the prolonged uncertainty of cytologic follow-up and the more acute high anxiety generated among women referred for colposcopy.11

"I think we will have a much better understanding of what is most anxiety-producing in women," Cox notes. "It is all anxiety-producing, but is it harder to go directly to colposcopy, or have an HPV test and find out that you have this STD, or to not really know what is going on for a couple of years in conservative management? I think we will have some terrific information when the study is completed."

References

1. Parkin DM, Pisani P, Ferlay J. Global cancer statistics. CA Cancer J Clin 1999; 49:33-64.

2. International Agency for Research on Cancer. Human Papillomaviruses. Lyon, France: IARC Monographs on the Evaluation of Carcinogenic Risks to Humans 64; 1995.

3. Bosch FX, Manos MM, Munoz N, et al. Prevalence of human papillomavirus in cervical cancer: A worldwide perspective. J Natl Cancer Inst 1995; 87:796-802.

4. American Social Health Association and the Kaiser Family Foundation. Sexually Transmitted Diseases in America: How Many Cases and at What Cost? Menlo Park: Kaiser Family Foundation; 1998.

5. Wright TC, Denny L, Kuhn L, et al. HPV DNA testing of self-collected vaginal samples compared with cytologic screening to detect cervical cancer. JAMA 2000; 283:81-86.

6. Schiffman M, Herrero R, Hildesheim A, et al. HPV DNA testing in cervical cancer screening: Results from women in a high-risk province of Costa Rica. JAMA 2000; 283:87-93.

7. Hatcher RA, Trussell J, Stewart F, et al. Contraceptive Technology. 17th ed. New York City: Ardent Media; 1998.

8. McNeil C. Getting a handle on ASCUS: A new clinical trial could show how. J Natl Cancer Inst 1995; 87:787-790.

9. Arnold K, Eckstein D. Limited potential for human papillomavirus (HPV) testing for women with low-grade Pap smears. J Natl Cancer Inst memorandum; Feb. 29, 2000.

10. The Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesions Triage Study (ALTS) Group. Human papillomavirus testing for triage of women with cytologic evidence of low-grade squamous intraepithelial lesions: Baseline data from a randomized trial. J Natl Cancer Inst 2000; 92:397-402.

11. Cox JT. Evaluating the role of HPV testing for women with equivocal Papanicolaou test findings. JAMA 1999; 281:1,645-1,647.