Data spark new directions in cervical cancer

“Furthermore, our findings suggest . . . that HPV testing without adjunctive cytology might be sufficiently sensitive for primary cervical cancer screening.”

In the Kaiser data, Dr. Austin says, among women who developed invasive cancer in the next five years after cotesting, 31 percent had a baseline negative HPV result. If persistent HPV infections—10 years and longer—are assumed and if FDA-approved HPV tests are reliable, then why do women developing cervical cancer over the next several years test negative at baseline? Sampling challenges and low and fluctuating viral load in cancers probably account for this, he says, “and the false-negative results represent a patient safety hazard for patients screened with extended intervals.”

Dr. Austin also argued that a short-term trial like ATHENA cannot establish that a screening strategy can prevent cancer. “A lot of people don’t even think about the fact that screening is all about protection from cervical cancer,” he says. “They look only at rates of detection of CIN2 and CIN3. The only way to document protection from cervical cancer is long-term observational studies on populations. You can’t conclude anything about protection from cancer in a three-year trial.”

FDA advisory committee member Dr. Massad says cancer protection was addressed: “CIN3+ is the standard surrogate marker for cancer throughout the world. HPV screening has been shown to prevent cancer in the Ronco trial, and early detection/treatment of CIN3 worked in that study” (Ronco G, et al. Lancet Oncol. 2010; 11:249–257).

Commenting on the deliberation phase that will follow the FDA’s approval, Dr. Crothers says one trial is not enough. “Most of the time, CAP and other professional organizations like to have lots of solid evidence, that maybe doesn’t come from the vendor, that this is an appropriate algorithm for our patients. At this time that evidence is lacking.”

In addition to the Kaiser study, several European trials have demonstrated the efficacy of a primary HPV screening approach (e.g., Naucler P, et al. J Natl Cancer Inst. 2009;101:88–99; Dillner J, et al. BMJ. 2008;337:a1754; also the Ronco trial cited previously). Do these qualify as part of the evidence base? “Those were done in national screening programs where women receive notification that they require followup and have access to that health care at very low cost,” Dr. Crothers says.

She notes another possible drawback to the proposed program. “One of the advantages of implementing primary HPV screening is the cost savings, since you can extend the screening interval to three years,” she says. But the United States doesn’t have a national screening program. Without such a program, she notes, “we cannot be certain that women will have access to and return at appropriate intervals for screening, and longer intervals could result in women inadvertently delaying appropriate screening.”

Dr. Massad notes that the currently recommended interval for Pap screening is three years. “Both the U.S. Preventive Services Task Force and the American Cancer Society recommend against annual cervical screening based on extensive evidence assessment,” he says. “Annual screening will increase the detection of lesions fated to regress if left undiagnosed. Women and the clinicians who care for them will believe they’ve averted cancer by treating these, without actually having any impact.”

“In my opinion,” Dr. Massad says, “based on data from trials other than ATHENA, the optimal interval for primary HPV screening is five years, not three years. European studies suggest that five-year followup is optimal, with strong NPV out to at least five years following a negative HPV test, as do data presented from the Kaiser Permanente Northern California database used to calculate risk estimates for the American Society for Colposcopy and Cervical Pathology’s management guidelines. These studies were with other assays, but the performance of the Cobas HPV test at three years seems to be at least as good.”

Dr. Crothers says several organizations have assembled a working group to look at interim guidelines. The Society of Gynecologic Oncology and the ASCCP are leading the effort to review the efficacy of primary HPV screening and to suggest how to incorporate the HPV test into screening practice. “I believe that primary HPV screening will be an option for a subset of women,” Dr. Crothers says.

If primary HPV screening does move into practice, it will have a major impact on cytopathology practice. In the core population—25 to 65 years—15 percent of women will be HPV positive. “So 85 percent of Pap smears will drop out,” Dr. Stoler says. Authors of the Kaiser study estimated a 95 percent reduction (see page 48).

Taking Pap tests and HPV tests together, Dr. Stoler says, “Integrated labs will do about the same number of tests. At any academic institution you have a cytology lab and a clinical molecular pathology lab or a cytology lab doing HPV testing. The only places that will lose out on test volume are labs that only do cytology.”

Dr. Crothers notes the importance of any situation in which the result of only one test is relied on to make a primary decision. “[The Roche assay] is the only FDA-approved test for primary HPV screening. That is critically important,” she says. “Most clinicians and even some pathologists may not be aware of that. There are a number of platforms for HPV testing. However, we should not be using other methods at this point, only this Roche method, since it has been validated in a clinical trial. We don’t know how those other methods perform in a clinical setting.”

Dr. Stoler agrees. He was asked about this issue after his symposium presentation. “We can’t say, Do HPV screening with any test you want,” he responded. While some HPV tests have been shown to have 90 percent to 95 percent equivalence to the Roche Cobas assay, he said, “The bar for HPV tests in cervical screening is higher than that.” In an interview, he added: “In primary HPV screening, where you don’t have cytology as your backup, you really want to know you are performing like the HPV assay performed in the ATHENA trial.”

“The FDA held Roche to this very high standard of doing a clinical trial and three-year followup before considering a claim of primary screening,” he continues. “The question for other FDA-approved tests is whether they will perform in the same manner. The answer is maybe, but we don’t know for sure. Each manufacturer will have to prove its case.”

Primary HPV testing is unlikely to be adopted quickly in the United States. However, FDA endorsement of the test in a cervical cancer screening context may give a boost to those who use cotesting. Once they become comfortable with HPV test performance in that setting, eventually they may switch over for cost reasons.

“No matter how you analyze it,” Dr. Stoler says, “a good, clinically validated HPV-driven algorithm outperforms cytology and is about equal to cotesting with minor adjustments by interval.” For him, at least, it’s about “doing better for patients or even as good while taking out subjectivity, redundancy, and complexity.”

William Check is a writer in Ft. Lauderdale, Fla.

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Kaiser study: single negative HPV test is sufficient reassurance

Many of the conclusions from the ATHENA study were mirrored independently in an even larger study of a different kind published a few years earlier.

Kaiser Permanente Northern California in 2003 adopted a screening program for cervical cancer based on cotesting, with extended screening intervals for women with normal cytology who test negative for HPV. After the program had been in operation for several years, Kaiser physicians teamed up with epidemiologists from the National Cancer Institute to evaluate its efficacy. They assessed the five-year cumulative incidence of cervical cancer and CIN3 or worse among more than 330,000 women 30 and older who enrolled in the program (Katki HA, et al. Lancet Oncol. 2011;12: 663–672).

As they wrote in the introduction, they believed that the results would have wider application:

“The KPNC experience serves as a large-scale demonstration project of what could realistically be achieved in routine clinical practice, where providers receive no special training and do not need any special qualifications to participate and that no provider, provider group, patient, or group of patients is excluded.”

Here are the core findings from the assessment:

“In 315,061 women negative by HPV testing, the five-year cumulative incidence of cancer was 3.8 per 100,000 women per year, slightly higher than for the 306,969 who were both negative by HPV and Pap testing (3.2 per 100,000), and half the cancer risk of the 319,177 who were negative by Pap testing (7.5 per 100,000).”

While both HPV testing and cotesting were highly superior to Pap testing, the authors considered the cancer incidence among the HPV and cotesting groups to be equivalent and concluded that primary HPV screening as a single test was as effective as cotesting:
“A single negative test for HPV was sufficient to reassure a woman of extremely low risk of CIN3 or cancer for 5 years. We identified that negative cytology provided no extra reassurance against cancer beyond that conferred by a negative HPV test result.”

While performing a Pap test along with an HPV test identified an additional 27 (four percent) of the 747 cases of CIN3/AIS (adenocarcinoma in situ), over the longer term this made no practical difference. Doing 330,000 additional Pap tests to detect an additional 27 cases of CIN3/AIS would not be an effective use of health care resources. Therefore, they wrote:

“Our findings strongly suggest that primary HPV testing, with a positive test for HPV triaged by cytology (or other tests with high specificity), a strategy that might preserve nearly all the safety of co-testing while reducing the number of Pap tests by 95% in our population, could be more efficient than co-testing—as has been suggested by others.”

In the study’s discussion section, the authors reiterated their broader conclusion:
“[W]e believe that the KPNC experience serves as a large-scale demonstration project of what could realistically be achieved in real-life clinical practice.” —William Check, PhD