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Data spark new directions in cervical cancer

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William Check, PhD

June 2014—When Mark Stoler, MD, stood up to speak at the 30th annual Clinical Virology Symposium on April 29, his topic was timely. Dr. Stoler was presenting three-year followup data from the ATHENA trial, in which a primary human papillomavirus screening algorithm based on the Roche Cobas HPV assay was compared with traditional cytology and a hybrid cotesting algorithm for their ability to prevent cervical cancer. On March 12, Dr. Stoler, a cytopathologist and professor emeritus of pathology and clinical gynecology at the University of Virginia, was part of the team that presented much of the same data to a 13-member FDA advisory committee, which unanimously recommended that the agency approve the primary HPV screening algorithm used in ATHENA. Six weeks later, on April 24, the FDA agreed with its committee.

Five days after the FDA approval, Dr. Stoler presented results from the trial of 40,901 women age 25 and older recruited at the time of undergoing routine screening for cervical cancer. Summarizing the conclusions from the ATHENA trial, Dr. Stoler said the data demonstrated that:

  • Primary HPV testing was significantly superior to cytology and cotesting for detecting CIN3 or worse. It not only found more disease but also found it earlier.
  • Specificity of HPV testing was at least equal to that of cytology when HPV genotyping and reflex cytology were added.
  • Positive predictive value (PPV) and positive likelihood ratio (PLR) of the primary HPV algorithm were twice that of cytology.
  • Negative predictive value (NPV) and negative likelihood ratio (NLR) of the primary HPV algorithm were improved over both cytology and cotesting.

Taken together, these findings showed that the HPV primary screening algorithm provides “a better balance of resource management,” Dr. Stoler said. Compared with cytology alone, it triggers more colposcopies but finds much more disease. Compared with hybrid cotesting, it triggers slightly more colposcopies but finds slightly more disease and requires far fewer total screening tests.

Dr. Stoler added that the reported positive and negative likelihood ratio values are important because these parameters are independent of prevalence, so the data can be applied to any population.

Primary HPV testing with genotyping and reflex cytology simplifies algorithms, says Dr. Mark Stoler, here with gynecologic oncologist Leigh Cantrell, MD, MSPH, of the University of Virginia.

At the March 12 FDA hearing, R. Marshall Austin, MD, PhD, had spoken in favor of FDA-approved cytology and HPV cotesting as the best cervical screening practice. In an interview with CAP TODAY, Dr. Austin, professor of pathology and director of cytopathology at the University of Pittsburgh Medical Center, said, “I think it is better to do cotesting. I talked to the medical staff about it this morning, and they were quite supportive.”

Dr. Austin’s primary reason for preferring cotesting: “You can get significantly more disease with cotesting than with just an HPV test alone.”

“I tell gynecologists and other clinicians, ‘What you could elect to do with primary HPV screening is still somewhat unproven. We will have a chance to see how this new test performs in the field. We will collect data to gauge protection from cervical cancer, which now we can only do by inference.’”

Barbara A. Crothers, DO, chair of the CAP Cytopathology Committee, also has reservations about the primary HPV algorithm. “At this point we need to be cautious about implementing this new algorithm on a widespread basis,” Dr. Crothers, who is pathology program director and director of cytopathology in the Department of Pathology and Area Laboratory Services at Walter Reed National Military Medical Center, said in an interview. (Dr. Crothers emphasized that she was representing the CAP Cytopathology Committee, not the military.) “We have some concerns about how it will be implemented in a clinical scale setting.”

Dr. Crothers

Dr. Crothers says there are “still unanswered issues and questions about the primary HPV screen for cervical cancer.” For example: “Will the results [from the ATHENA trial] apply in everyday clinical settings without the benefit of a controlled environment with patient recall and followup? And what effect will the subjectivity of colposcopy and cervical biopsy interpretation have on the correct identification of high-grade premalignant processes and followup for women?” These issues have not been sufficiently explored, she says.

Mona Saraiya, MD, MPH, was a member of the FDA advisory committee that recommended approval of the HPV assay and algorithm. As an associate director in the Office of International Cancer Control at the Centers for Disease Control and Prevention, Dr. Saraiya works on assessing major medical practices in the U.S. with regard to cervical cancer screening, monitoring them to ensure that guidelines from major medical groups are being followed.

Dr. Saraiya

“Data from the three-year followup of ATHENA opens up an opportunity for and opens the door” to a primary HPV screening algorithm, Dr. Saraiya tells CAP TODAY. “The next step is for professional groups to evaluate the data.” Dr. Saraiya believes that guidelines should be based not just on ATHENA data, but that “ATHENA in conjunction with randomized clinical trials from Europe and other relevant data should be used to make decisions about the best way forward.” Even before ATHENA, she says, in the U.S. and Europe there was fairly strong evidence about the negative predictive value of primary HPV testing—“just some concern about how to manage the HPV positives.”

To Dr. Saraiya, the issue is the negative predictive value of HPV testing and what it means in terms of extending screening intervals in practice. Because of the high sensitivity of an HPV test, a woman with a negative test has a very low risk of developing cervical cancer in the next three to five years, raising the possibility of safely extending the recommended screening interval. Dr. Saraiya sees “a lot of promise with primary HPV testing,” saying, “We need to examine whether primary HPV testing with extended screening intervals can really play that role in the United States, a largely annual Pap-based opportunistic country.”

Dr. Massad

L. Stewart Massad Jr., MD, another member of the FDA advisory committee, says the three-year followup data demonstrated that HPV-based screening using the Cobas HPV test and the algorithm Roche proposed had good sensitivity and specificity, “with reassuringly low risk for CIN3+ out to the end of the three-year followup.”

“The vote of the FDA expert panel was strictly on the question of safety and effectiveness. Cost-effectiveness and comparative effectiveness are not part of the FDA review process and weren’t assessed,” says Dr. Massad, a professor of obstetrics and gynecology in the Division of Gynecologic Oncology at Washington University School of Medicine. Professional societies and the American Cancer Society will need to review those issues, he adds.

Dr. Stoler began his presentation at the Clinical Virology Symposium with a respectful but clear-eyed nod to cytology, which has accomplished so much in the past 60 years despite its limitations. “Cytology has been quite successful,” Dr. Stoler said, and screening with cytology at three-year intervals is still recommended for cervical cancer protection. More than half of the 12,000 cervical cancer cases each year in the U.S. occur in women who haven’t had a Pap test in five years or haven’t been screened at all.

Pap screening has reduced cervical cancer incidence despite the fact that cervical cytology is relatively insensitive for detecting high-grade cervical cancer precursors, Dr. Stoler continued. A 1999 review estimated the sensitivity of the conventional Pap test at about 50 percent. In the four laboratories doing Pap reading in ATHENA, sensitivity for CIN3 or worse ranged from 42 percent to 73 percent, the same range found in six studies from around the world—44 percent to 74 percent. These figures document that Pap testing has not only low sensitivity but also low reproducibility, he said. Sensitivity in the ATHENA laboratories correlated directly with the rate of slides called ≥ ASC-US and inversely with specificity, underscoring the tradeoff inherent in reading Pap tests.

In contrast, sensitivity of HPV in ATHENA was higher and confined in a much narrower band—88 percent to 90 percent. So the HPV assay is much more sensitive and much more consistent than cytology. This finding is consistent with a review that found that HPV testing had an average 35.7 percent increase in sensitivity for ≥ CIN2 over cytology in six published studies (Whitlock EP, et al. Ann Intern Med. 2011;155:687–697). Based on this concept as part of the systematic literature review performed to inform the guidelines, screening recommendations were augmented in March 2012 to include cotesting every five years for women ages 30 to 65 as the “preferred” algorithm, with cytology becoming an “acceptable” method.

Dr. Stoler noted problems with cotesting: “It is expensive,” he said, and “it isn’t logical. It combines a relatively insensitive test with a highly sensitive test.” Moreover, he added, it leads to “an incredibly complex set of algorithms” for managing abnormalities (one guideline has 18 algorithms), and complexity can lead to mismanagement. Perhaps this is why cotesting hasn’t been widely adopted. “More than half of the women in this country who are screened are still only getting Pap smears,” Dr. Stoler said.

In contrast, primary HPV testing with genotyping and reflex cytology dramatically simplifies algorithms relative to hybrid cotesting, he said. If a woman has genotypes 16/18, she is referred for colposcopy; if she is positive for any of the 12 other high-risk genotypes contained in the HPV assay, she has reflex cytology. If the Pap test is ≥ ASC-US, the woman is referred to colposcopy. Women negative on the initial HPV test continue routine triennial screening.

In a process called verification bias adjustment, or VBA, about 900 women in ATHENA who were HPV negative and negative for intraepithelial lesion or malignancy were also referred to colposcopy. The results were used to correct the raw sensitivities. “No test is perfect,” Dr. Stoler explained. “All miss some disease. This is a process for finding how much disease is still in people who you think test negative or normal.”

In the three-year followup ATHENA results, VBA sensitivities and specificities, respectively, looked like this:

  • Primary HPV algorithm: 58.26 percent, 95.91 percent.
  • Cytology alone: 41.71 percent, 96.88 percent.
  • Hybrid cotesting: 53.22 percent, 95.80 percent.

It is from these numbers that NPV and PPV and the ratios—PLR and NLR—were calculated, showing that the HPV algorithm had significantly improved effectiveness and safety over cytology and behaved similar to or even better than cotesting.
Based on these performance characteristics, the following cross-sectional measures of clinical disease management were reported at the FDA:

  • Primary HPV screening detects 232 ≥ CIN3 using 44,057 screening tests and 1,890 colposcopies, for an 8.1 colposcopy/CIN3+ ratio.
  • Hybrid cotesting detects 211 ≥ CIN3 using 75,574 screening tests and 1,916 colposcopies, for a 9.1 colposcopy/CIN3+ ratio.

“The primary HPV algorithm with a three-year interval is better than cotesting at a five-year interval, which is the current guideline,” Dr. Stoler said. “The primary HPV algorithm with a three-year interval is about equivalent to cotesting at a three-year interval, which is not in the guideline.”

Dr. Stoler added one more idea, which he believes to be critical. “It is increasingly apparent that there is one key educational message that must be driven home, and it is one we have been trying to get out there forever,” he said. “Clinically valid HPV testing does not just detect the virus. That is the No. 1 misperception in the entire field. It detects the virus at a clinically valid cutoff that optimizes the detection of cancer and precancer while providing maximal reassurance to the people who are not at risk and can be followed at long intervals.”

Dr. Austin disagrees with the basic data and the main conclusion Dr. Stoler presented. “From ATHENA data on the FDA website, we can see that more disease was detected with cotesting,” he tells CAP TODAY. Dr. Austin was referring to a table in the summary of the advisory committee meeting, http://j.mp/fda-cobas, which provides the following figures for VBA sensitivity:

  • 58.26 percent for the HPV algorithm (page 3).
  • 61.16 percent for a cotesting algorithm (page 66, Table A8.2).

The figure for the primary HPV algorithm agrees with what Dr. Stoler presented, but for cotesting Dr. Austin’s VBA sensitivity, 61.16 percent, is much higher than the figure that Dr. Stoler cited, 53.22 percent. Can both numbers be describing the same measurement? As it happens, the answer is no. Here is the FDA’s explanation (pages 11–12) of the algorithm that gave rise to the figure for cotesting in Table A8.2:

“In Appendix 8 of this submission, this same algorithm [the standard cotesting algorithm] is presented with co-test results for everyone 25 and older. This is not a candidate algorithm as it does not represent a primary HPV screening claim, nor is it a comparator algorithm since it is not a current acceptable screening paradigm. It is provided simply to illustrate the impact of including the entire proposed screening population (≥ 25 year old women) under the ASC-US Triage and NILM HPV 16/18 positive genotyping paradigm, which may help in evaluating the appropriateness of the proposed age range for the new indication.”

On page 3 of the FDA document, the agency makes the same conclusion about primary HPV screening (“Candidate algorithm”) relative to cotesting (“Additional Comparator”) that Dr. Stoler drew: “The Candidate algorithm is better than the Additional Comparator for women ≥ 25 years of age in the major performance characteristics (PPV, NPV, PLR and NLR) for both ≥ CIN2 and ≥ CIN3, and these improvements are statistically significant at the 95% confidence level.”

Dr. Austin posed other arguments for the superiority of FDA-approved cotesting of women 30 and older. In a Kaiser Permanente Northern California study published in 2011, cytology, cotesting, and primary HPV screening were evaluated in more than 330,000 actual patients followed for five years (see “Kaiser study” at right). “In this paper they estimated the amount of invasive cancer there would have been if they had acted on Pap alone or HPV alone versus cotesting,” Dr. Austin said in an interview. “The lowest estimated cancer rate was with cotesting. It was 10 percent to 15 percent lower than if they had just relied on HPV results.”

Not surprisingly, Dr. Stoler has a different view. “The purpose of screening is not to find cancers,” he told CAP TODAY. “With screening we are trying to find precancers, CIN3 or worse, and treat them. That is why invasive cancer decreased with cytology: We find precancer and treat it before it develops into cancer.” In both ATHENA and the Kaiser study, detection of precancer with HPV screening was equal to or better than with cotesting. That may be why the Kaiser investigators concluded:

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