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>> From the JAMA Network, this is JAMA author interviews. Conversations with authors exploring the latest clinical research reviews and opinion featured in JAMA.

>> Hello, and welcome to this author interview. This is Howard Bauchner, Editor-In-Chief of JAMA, and I'm here with Carol Mangione from the Ronald Reagan UCLA Medical Center. Welcome, Carol.

>> Thank you very much.

>> Carol holds the Barbara A. Levey and Gerald S. Levey, MD, endowed chair in medicine at the David Geffen School of Medicine at UCLA. Carol, how long have you been on the U.S. Preventive Services Task Force?

>> About two and a half years.

>> And what's it like?

>> It's been really interesting, Howard. The other task force members are all primary care providers of different types, and they all have tremendous expertise in evaluating for literature. So it's just been a really great opportunity to learn a lot and to collaborate with really wonderful people.

>> Well, people have heard me say it in every podcast with task force members. I love the task force. I loved it before it was published in JAMA, but I love it a little more now that we publish it. So we're going to discuss one of the more important, but slightly more confusing, task force recommendation statements. It's entitled screening for cervical cancer, U.S. Preventive Services Task Force recommendation statement. I want to point out that it's accompanied by two other reports, but they will not be the focus of this conversation. The first is entitled Screening for Cervical Cancer with High-Risk Human Papillomavirus Testing Updated Evidence Report and Systematic Review for the U.S. Preventive Services Task Force by Melankow [phonetic] and colleagues. And the second accompanying paper is entitled Screening for Cervical Cancer and Primary Care: A Decision Analysis for the U.S. Preventive Services Task Force Cervical Cancer Screening by Kim and colleagues. So Carol, in a lot of different detailed recommendations in the statement with different types of screening tests available. So do you think we could start by just summarizing the recommendation statements? We'll return to them more than once. And then after we summarize the precise recommendation statements, we'll talk about the different approaches to screening, because I think it will be important for the listeners to understand evolving and new approaches. But why don't we start with the recommendation statements?

>> Sure, I'd be happy to do that. So our current final recommendation states that the USPSTF recommends screening for cervical cancer every three years with cervical cytology alone in women ages 21 to 29 years. And the USPSTF recommends screening every three years with cervical cytology alone, every five years with high-risk HPV testing alone, or every five years with high-risk HPV in combination with cytology, also known as co-testing, in women age 30 to 65 years. And that's an A level recommendation.

>> So let me stop you there, because there's more recommendations. And I just want to make sure that people are very clear about how they vary with age. So the recommendation for women 21 to 29 is?

>> Is to screen with cytology every three years.

>> And for women 30 to 65?

>> For women 30 to 65, there are three screening options. One would be to continue to screen every three years with cervical cytology, or to screen every five years with high-risk HPV testing alone, or every five years with high-risk HPV testing in combination with cytology, which is also called co-testing.

>> Thank you. So that's the 21 to 29, 30 to 65. And what is the recommendation for women older than 65?

>> So the USPSTF recommends against screening for cervical cancer in women older than 65 years who have had adequate prior screening and are not otherwise at high risk for cervical cancer. And that's a D level recommendation.

>> And for women under 21?

>> The task force recommends against screening for cervical cancer in women younger than age 21.

>> Thanks, Carol. I had to read them a few times. It's 21 to 29, 30 to 65, various recommendations for types of screening. And then for women who have been adequately screened who are older than 65, no screening. And for women who are under 21, no recommendation for screening.

>> Right.

>> The types of screening that's possible, could you explain cytology, how it's done, and what the test is? And then testing for hrHPV.

>> So essentially, there are two ways to do cytology. One way is called the good cytology, and the other is where the cells from the cervix during a Pap smear are put on a slide. And both methods are equally effective. So patients don't have to really ask or pay attention to which cytology test is being used because they seem to be equally effectively. In terms of the testing for high-risk HPV, there are a couple of methods, but most either use signal or nucleic acid amplification methods. So this is a situation where there would be insight to hybridization and polymerase chain reactions to be able to detect those high-risk strains that are almost always associated with patients who have had cervical cancer.

>> How does a physician obtain an adequate sample to test for hrHPV?

>> So the sampling technique for these two approaches, they use cytology or the hrHPV, from the patient's perspective is essentially the same. So either cells are scraped off the cervix gently for the cytology, or some fluid is removed from that same area and put in a container and sent to the lab for the appropriate test.

>> And what's co-testing?

>> Co-testing is a kit that allows you to simultaneously do cytology and also sample for high-risk HPV.

>> And that's become more popular over the last say five years, ten years?

>> Well, if we take the look back on the task force recommendation in 2012, that was our previous recommendation for cervical cancer screening, that recommendation basically stated that for women between the ages of 30 and 65, we wanted to lengthen the screening interval from doing cytology every three years to a five-year interval that we recommended co-testing every five years. So over the last five years, since that has been the recommended strategy for women who want to stretch out that interval between tests to every five years, if they are between the ages of 30 and 65, they would be using co-testing as the approach of the

>> So detection and treatment of cervical cancer is one of the great success stories. What's happened over the last few decades in terms of the number of deaths from cervical cancer?

>> So Howard, you're absolutely right. This is one of the reasons why this is a level A recommendation. Rates of incidents and death from cervical cancer have decreased dramatically from the time that cervical cancer screening was first recommended. To get some sense of the decrease, if we think about cytology, which was the earliest test used, cytology every three years with the appropriate follow-up can reduce cervical cancer deaths from 8.3 people per 100,000 to less than 1 person per 100,000. So this is a dramatic reduction in death from a cancerous condition by a very simple test.

>> And number of women diagnosed with cervical cancer each year also declined?

>> Absolutely. But I think that the important thing to realize is that when we look at who today presents and has cervical cancer, it is much, much more likely to happen if women who have not been regularly screened or who have not received the appropriate follow-up in treatment after the screening, and these women are much more likely to be underrepresented minorities in the United States like African-Americans, Hispanics, Native Americans, and they also are much more likely to be women without health insurance and women who have other barriers to access to care.

>> Thanks so much for discussing some of the clinical issues about who gets screened and who doesn't get screened. I think it's always important to alert clinicians around those issues so they can do a better job with respect to outreach to high-risk groups who may not be screened. I wanted to go over some of the recommendations for various women of different ages. So the timing of screening for women younger than 21 years.

>> In terms of women younger than 21 years, we currently do not recommend screening. And the reason why is because if women are sexually active under the age of 21, and if they develop an infection with HPV, it's very likely to resolve on its own. And if there are any early changes in their cervical cells, those are also very likely to get better on their own or to regress. And so you wouldn't want to use a diagnostic test that might make you find an abnormality that's going to get better on its own. And the reason why you wouldn't want to do that is because that diagnostic test might trigger a more invasive test like a cervical biopsy, and we know that the second level diagnostic test sometimes have complications and could cause problems for patients. So we only want to do those when we feel that the benefits from doing the test outweighs the harms.

>> Women older than 65.

>> So for women older than 65, who have been adequately screened, there is very low likelihood that they would be having new cases of cervical cancer. And so the benefits of screening in that age group do not outweigh the harms.

>> And I believe the task force or some other groups define adequate prior screening as three consecutive negative cytology results or two consecutive negative co-testing results within the previous ten years.

>> Yes, that's correct. And, you know, a couple of other nuances. That recommendation also comes from three societies; the American Cancer Society, the American Society for Colposcopy and Cervical Pathology, and the American Society for Clinical Pathology. And a nuance on that recommendation that I think is important is if a patient had a pre-cancerous lesion, let's say they had a pre-cancerous lesion detected when they were 52 or 55, that recommendation does say that you do want to keep testing for at least 20 years after that pre-cancerous lesion has resolved. And so there will be some women over 65 who might need adequate screening, but still need to keep getting some kind of cervical cancer screening. And then when we think about our populations where there's been poor access to care, it's very possible that some of those women might still need to be screened after the age of 65.

>> The task force actually calls out a specific group, women older than 65 years who have not been adequately screened.

>> Right.

>> And the recommendation for those women?

>> The recommendation for those women would really be a decision with their doctor. We do not have a specific recommendation for women without screening older than 65. So they would want to discuss with their daughter which test they would like to have and which test is most available possibly in their setting.

>> Before we move on to some more of the detailed information about the results of research studies that have driven the task force recommendation, I, as a pediatrician, have to ask you about additional approaches to prevention. And so do you mind discussing HPV vaccination, which unfortunately in the U.S. remains embarrassingly low?

>> Sure, I would be happy to discuss that. So in terms of our current recommendation, we don't talk about whether women are vaccinated or not because at this point, we do not have much in the way of any randomized trial test of screening strategies in vaccinated women. So there is not really an adequate evidence base to support giving a specific recommendation among women who have been vaccinated. So, you know, I think that in terms of the call for further research, this is a group that definitely will need to be studied. But I would agree with you in your assessment that many young women and young men who are eligible for the HPV vaccine haven't gotten it yet.

>> Thanks, Carol. I'd like to now turn to actually some of the evidence that supports the recommendation statements. And there's two groups of data that I thought would be interesting for you to summarize. The first is hrHPV testing alone versus conventional cytology alone. And then the second will be co-testing versus cytology alone. Can you just summarize the HPV alone versus cytology alone data?

>> Yes, I can. First of all, we have, you know, four very large clinical trials of high-risk HPV testing versus cytology, and those trials included over 250,000 women, so just to give you some sense of the scale. And with these trials, they were worked on exactly the same, they had slightly different screening intervals and slightly different follow-up procedures after a positive test. But what we can say is that the high-risk HPV testing has adequate sensitivity, and that our modeling, in addition to the clinical trials, suggest that it's safe to move to this five-year interval. We also know that the high-risk HPV testing has a slightly greater probability of finding pre-cancerous lesions, also called the CIN 2 and CIN 3 lesions, than cytology alone. But with that benefit also comes a few more diagnostic tests after the high-risk HPV testing when compared to just cytology alone.

>> And the co-testing versus cytology alone.

>> Right, so that we also have fourth randomized clinical trials with many women in them that have compared co-testing to cytology alone. And in those trials, we see really a similar pattern. There's more cases of the pre-cancerous lesions detected, but there also is a significant increase in the number of subsequent tests and procedures. So, you know, it's really a pretty similar story to what we see when high-risk HPV is compared to cytology.

>> The task force always does an excellent job about harms and benefits. So issues of harms and benefits with respect to cytology, hrHPV, or co-testing?

>> So in terms of, we could talk about harms first. And the task force determined, after doing its review of the scientific literature, that the harms from testing are what we call in the moderate range. And really when you think about the harms, whether you screen with cervical cytology, or whether you screen with high-risk HPV testing, the harms are mainly related to the subsequent diagnostic procedures, which are usually colonoscopy or cervical biopsy. And, of course, there are always harms associated with some unnecessary treatment in women with false positives. So, you know, what we know is that the main harms are things like vaginal bleeding, pain, or failure to diagnose cervical cancer. And when we think about the harms and benefits of the two strategies, those harms are slightly lower when you use cytology than when you use the HPV testing. But on the benefit side, we have high levels of benefits for both strategies and slightly higher rates of detection of the CIN 2 or 3 if you're using high-risk HPV testing as compared to cytology. And that would go for whether you were using a co-testing kit too, because obviously in the co-testing kit, you have the high-risk HPV test in there.

>> Thank you. Before we go back to reiterate the various options in women 21 to 29 and 30 to 65, can you just articulate what the recommendations are of the numerous other groups that have made statements about screening for cervical cancer?

>> Sure, I'd be happy to do that. You know, I think that the good news here is that most of the other major organizations, such as the American Cancer Society, the American Society of Clinical Pathologists, have recommendations that are quite similar to what the USPSTF is recommending. And, you know, I think the really important thing about this recommendation that I can't emphasize enough is that cervical cancer screening saves lives. And it's very important that we don't get tangled up in which test specifically, because all three of these tests; cytology, co-testing, and high-risk HPV testing, are highly effective at reducing the chance of getting cervical cancer. And so, you know, I think one of the challenges with this recommendation is there is this complexity with the various options. But the take-home message really has to be to screen people, and to screen people for the test that is available in the setting that they're in so that we don't create an access problem by saying one test is slightly better than another.

>> So let's wrap it up with once again focusing on the very precise recommendations for women 21 to 29 and 30 to 65. So let's take the group 21 to 29.

>> For the group of women between the ages of 21 and 29, the U.S. Preventative Task Force recommends cervical cancer screening with cytology every three years. And for women between the ages of 30 and 65, they can choose between three options, depending on their preferences and test availability and their settings. They can have a Pap smear or cervical cytology every three years. They can have a high-risk HPV test every five years. But they could have a combination of a Pap test and an HPV test every five years, which is also called co-testing.

>> Thanks so much. This is Howard Bauchner, Editor-In-Chief of JAMA, and I've been speaking with Carol Mangione, who is the Division Chief of General Internal Medicine and Health Services Research at UCLA, a professor of medicine, and she holds the Barbara A. Levey and Gerald S. Levey endowed chair in medicine at the David Geffen School of Medicine. Thanks, Carol.

>> Thank you, Howard.