Ask Dr. Mark Schiffman about the strategy behind screening for cervical cancer and he'll tell you it boils down to one thing.

"It all comes back to an underlying knowledge of persistence," explains Dr. Schiffman, from NCI's Division of Cancer Epidemiology and Genetics, and one of the world's foremost experts on cervical cancer and its cause, the human papillomavirus (HPV). "We only want to catch persistent infections."

The reason is simple: It's the persistent infections with 1 of approximately 15 "oncogenic" types of HPV that are responsible for virtually all cases of cervical cancer worldwide. In the vast majority of cases, however, HPV infections, and any associated cervical lesions, make only a cameo appearance before being suppressed or dispatched by the immune system. This is particularly true in women under 30, who are typically more sexually active and thus at higher risk than older women for new and multiple HPV infections (brief HPV infections are the most common sexually transmitted infections).

With this knowledge and the results of a number of studies over the past several years, experts on cervical cancer and HPV have begun to shift their thinking about the best way to weed out persistent infections via screening. The studies - including three published in October - have suggested that testing women 30 or older every few years for the presence of HPV using a DNA test may be a more clinically effective option than what has almost become a ritual for many American women, an annual Pap test.

But, when the time comes - and consensus is mounting that eventually it will - the switch, says Dr. Schiffman, will have to be done very carefully.

"We're not talking about abandoning a poor strategy for a good one," he says. "We're talking about moving from a very good strategy to an even better one."

Taking Advantage of Persistence
Heralded by some as the single most successful cancer prevention technique ever developed, annual Pap screening has cut cervical cancer rates in the U.S. by more than half since it came into widespread use in the 1960s, and it has had equal success in other, primarily developed countries with organized national screening programs.

The persistence factor also lies at the root of the Pap's success. For any single test, the Pap is not particularly sensitive in detecting underlying, persistent HPV infection or precancer. But when performed annually, typically as part of a routine gynecologic check-up, the Pap test eventually catches most precancerous lesions before they become life threatening.

The need for such regular testing, however, has been criticized.

"Compensating for the poor sensitivity of cytology through frequent screening makes it difficult to assure that all women at risk are properly screened," wrote Dr. Thomas C. Wright of Columbia University in a recent commentary. Of the 10,000 cervical cancer diagnoses each year, he noted, half are in women who have not had a recent Pap test. The cost-effectiveness of such frequent testing also has been challenged.

Studies have consistently demonstrated that the HPV DNA test - of which only one is currently approved by the FDA - has a very high sensitivity, meaning a negative result provides great assurance that no dangerous infection is present.

But the concern with the HPV DNA test, which is more expensive than the Pap test, is exactly how to address positive results on a single test - results that usually represent a transient, and thus harmless, infection.

"It might mean a single HPV test doesn't refer to colposcopy," says Dr. Diane Solomon, from NCI's Division of Cancer Prevention, a co-author of a recently released risk-assessment guide for cervical cancer. During colposcopy, clinicians can more closely examine the cervix for lesions and, if necessary, take a biopsy. "Two positive HPV DNA tests a certain length of time apart might be required before triggering colposcopy. Such a strategy would capitalize on the increased sensitivity provided by HPV testing while targeting persistence."

The Interval Is the Thing
This leads to a subject researchers are now more closely investigating: screening intervals. In other words, how long should a woman who tests HPV-negative wait before being tested again?

"It hasn't been published how long this 'protection' [from risk of a positive result] lasts," says Dr. Carolyn Runowicz, director of the Carole and Ray Neag Comprehensive Cancer Center in Connecticut and a gynecologic oncologist. "Can you go 3 years or 5 years? We need to work that out. We need to wait for the data from serial and longer follow-up periods."

The Kaiser Permanente's Northern California Region has spearheaded the movement toward longer screening intervals using HPV testing. In 2004, the region became the first health plan in the nation to offer - but not require - the HPV DNA test as front-line screening to all women 30 and older, but only in combination with the Pap test, which is consistent with its FDA-approved indication. It's also approved for use as a triage test after an "equivocal" Pap result.

Women who are negative on both tests do not undergo cervical cancer screening again for 3 years. A Pap-negative/HPV-positive result, on the other hand, elicits a recommendation for retesting 12 months later. If they get the same result, colposcopy is recommended.

Expanding the testing intervals for women who are negative on both screens has worked well, says Dr. Walter Kinney. "More than 90 percent of our members opt for both tests at 3-year intervals instead of annual Pap smears," he says.

It's too soon after initiating the dual-test approach to know if it has affected the Kaiser region's incidence rates. And Dr. Kinney and his colleagues have not reviewed the number of advanced cervical lesions detected using the combination approach since 2005. However, he says, they hope to receive approval from Kaiser's Institutional Review Board to do so next year.

"We have been very pleased with this approach," Dr. Kinney says, "and at no point have we contemplated moving away from it."

— Carmen Phillips