Cervical Cancer Screening Strategies: Evidence in Context
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Cervical Cancer Screening Strategies: Evidence in Context
Announcer Opening: You’re listening to ReachMD. Welcome to this medical industry feature sponsored by Hologic. The following program is intended for U.S. healthcare professionals only. Dr. Mennen: I am your host, Dr. Barry Mennen, and I would like to welcome Dr. Mark Spitzer to the program. Dr. Spitzer is Professor of Obstetrics and Gynecology at the Hofstra-Northshore-LIJ School of Medicine and past president of the ASCCP and founder and Medical Director of the Center for Colposcopy in New Hyde Park, Long Island, New York. Dr. Spitzer, thank you for being here to share your insights.
Host
Barnett (Barry) Mennen, MD Family Practice and Urgent Care BETHESDA, MD
Faculty
Mark Spitzer, MD Professor of Obstetrics and Gynecology, Hofstra North Shore-LIJ School of Medicine; Medical Director, Center for Colposcopy LAKE SUCCESS, NY
Dr. Spitzer: Thank you for having me. Dr. Mennen: Now, cervical cancer screening guidelines have been revised several times in the past decade. The changes can be confusing to patients and clinicians alike. Let’s begin our discussion today with how the cervical cancer screening guidelines were determined and how evidence-based studies influenced the screening strategy and screening intervals. Dr. Spitzer: Well, if you go back prior to 2012, there were many competing guidelines out there, and clinicians sort of had their way. They could choose anything they wanted and do anything they wanted to do. So, in 2012, both the American Cancer Society, the ASCCP (the American Society for Colposcopy and Cervical Pathology) and, independently, the US Preventive Services Task Force, decided that they were going to put out guidelines, and it turns out that those guidelines coincided with one another. They were virtually identical guidelines. They came out at the same time. I was involved in the development of the American Cancer Society guidelines. What we did was we did a literature review, looked at all the relevant data. There was mathematical modeling that was done based on the Million Woman Kaiser Permanente Northern California study. They took that data and projected outcomes based on mathematical modeling from that data. And the combination of that was put together. Some guidelines were developed. It was put online for commenting by the public, not only, obviously, patients but certainly other professional clinicians. We took their comments, put together guidelines which were then presented to a consensus conference of probably about 30 different organizations. It was voted on, and anything that had a super majority, 66%, was accepted. Anything that didn’t, we took back, reworked; we jiggered those guidelines until we did get a super majority to vote for it, and those were the guidelines that were posted. And, in fact, virtually identical guidelines came out between the American Cancer Society and the US Preventive Services Task Force, so now we have unanimity on the guidelines.
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Cervical Cancer Screening Strategies: Evidence in Context
Dr. Mennen: Now, cervical cancer screening is a screening test. Why is an evidence-based approach so important here?
“You’ll identify more disease. But what happens is when you screen more frequently or when you screen with a more sensitive test, you identify more of the benign viral infections that are, in fact, not precancerous.”
Dr. Spitzer: Well, in anything that you do, and screening is no different, you have both risks and benefits. If you only think of the benefits, you would screen… Certainly, if we screen more often we’ll identify more disease, so instead of screening annually, screen every 6 months, screen every month, every week. You’ll identify more disease. But what happens is when you screen more frequently or when you screen with a more sensitive test, you identify more of the benign viral infections that are, in fact, not precancerous. And every time you identify a non-precancerous lesion that has you doing colposcopy, biopsy, and further evaluation and possible treatment, you are harming the patient. You are doing something that the patient doesn’t need. And whether you’re harming her physically by, for example, treating something that will go away by itself, or you’re harming her emotionally with anxiety and the like by making her afraid that she has cancer, you are harming the patient. So, what we need to do is we need to develop a screening paradigm that will balance both the benefits of preventing cancer and the risks of harming the patient from unnecessary treatment and evaluation. Dr. Mennen: So, when should cervical cancer screening begin, and what is the evidence for the designation? Dr. Spitzer: I’d like to start by describing the natural history of the disease. Cervical cancer is caused by a virus. Ninety-nine point nine percent of cervical cancer is caused by HPV, a sexually transmitted virus. 80% of all men and 80% of all women will have HPV at least once in their lifetime. Most HPV, however, goes away. It goes away by itself without treatment, so 50% in the first 6 months, two-thirds in a year, 80% in 2 years, 90% in 3 years, in some studies even faster than that. HPV is going to go away. Dr. Mennen: And this is due to normal immunological – Dr. Spitzer: Normal immunological – right. So, when you look at a patient and you realize that she has a sexually transmitted infection, you’re now going to start thinking: When is she more likely to have that sexually transmitted infection? And the answer is the younger she is, the more sexually active she is, the more she is changing partners, the more likely she is to have that infection. The more time between partners the more likely she is to have enough time to have resolved that infection. You remember we just said it resolves over time. And so you’re now going to have to realize what is the likelihood that she has that infection, and then what is the likelihood that she has a persistent infection that develops into a pre cancer or even a cancer? So, as you get older, the chances that you develop a precancer or cancer goes up, and the chances that you have a sexually transmitted infection as you become fewer partners, more monogamous with one partner, longer relationships that tends to happen as you get older, you’re less likely now to have these sexually transmitted infections because you’ve resolved the ones that you had. Take that understanding of the natural history of the disease and now translate that into guidelines and risks. So, in women under the age of 21, the chances that they have cervical cancer are literally one in a million, and that cancer is also probably not HPV-related and screening doesn’t help. So, screening a
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woman under the age of 21, very likely to find non-precancerous conditions, less likely to find precancerous conditions and “80% of all men and 80% of virtually never likely to find cancer, you don’t want to screen all women will have HPV at that woman at all. When you pass the age of 21, 21 to 29, now least once in their lifetime.” you’re more likely to find the precancerous conditions a little bit and slightly less likely to find a benign viral illness as they become slightly more monogamous, slightly less sexually active with multiple partners. And so, as you get older, fewer and fewer of those conditions, and therefore, still, because the risk of cancer is very low, you don’t want to screen with that super sensitive test. They are still likely to have it, but as you get older, it becomes more comfortable to screen with the more sensitive test. Dr. Mennen: So, what are the specifics in the screening of that age group, 21 to 29? Dr. Spitzer: So, in the 21- to 29-year-old age group, an HPV test is much too sensitive a test. These women still have a lot of HPV and a lot of these benign conditions. There’s harm with screening with a test that’s too sensitive, so you want to screen with a Pap test, and you can screen them every 3 years. It will give them a chance to resolve some of the benign conditions that we have spoken about. Remember, HPV goes away over a period of time, and once every 3 years is the paradigm with a Pap test only. Dr. Mennen: Now, guidelines change at 30 for women 30 to 65 years of age. What are they and why did they change? Dr. Spitzer: Well, again, to continue what we were saying before, as you get older, you’re less likely to have HPV, less likely to have some of these benign conditions that are not precancerous, more likely to have precancerous conditions and are at greater risk for cancer as you get older, so now we want to test with that most sensitive test. That most sensitive test is the combination of the Pap test and the HPV test and, therefore, that test is recommended as the best test. Now, question is: How often should you test? The more often you test, remember, the more likely you are to get these benign conditions that are only harming the patient when you identify them. The question is: Is it safe to extend the screening interval all the way out – in the case of this recommendation, the recommendation is 5 years – is it safe to increase that screening interval to 5 years? So, in order to answer that question, you need to have a paradigm. What is the accepted risk? In other words, we screen certain tests done at certain intervals. We know that no matter what the interval is and what the screening test is, some people will slip through the cracks, but we say, do you know what, that’s acceptable, that we can’t be perfect. We can’t be perfect. That’s acceptable. If you ask most patients and if you ask most clinicians, that paradigm is the annual Pap test. So, if we know what the risk is for an annual Pap test, you can then say if I can achieve that risk with an extended screening interval – because remember, since the HPV test is earlier in the process, it will pick up the disease earlier. If we can achieve that level of risk with an extended interval, then we should do that. That extended interval works out to be 5 years. So, an annual Pap test carries the same amount of risk as a 5-year co-test, Pap plus HPV co-test. You say, “Okay, if it carries the same risk, I’ll do annual Paps. What’s the problem?” And the answer is, when you do annual Paps, you’re identifying more of those benign conditions, and every time you identify the benign condition, you’re harming the patient. So, let’s take the following paradigm. You have a woman; she has a negative Pap and a negative co-test. She then meets a new partner, and wouldn’t you know it, she gets HPV. That HPV over a period of years – 50% the first 6 months, two-thirds in a year, 80% in 2 years, 90% in 3 years – is going to go away. The next time she
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Cervical Cancer Screening Strategies: Evidence in Context
comes to be screened 5 years later she has a negative Pap test and a negative HPV test. She’s fine. Her risk of cancer is the same as if she would have had annual Pap tests, discovered the benign lesions, followed the lesions with biopsies and treatments and blah, blah, blah, all those things. She would have the same ultimate risk and her Pap test would eventually have gone to normal, but she’s avoided all the harms, and that’s why that’s the preferred approach. It’s still acceptable to do Pap tests every 3 years, but the preferred approach is the Pap plus HPV co-test every 5 years. Dr. Mennen: Now, what about guidelines on when to stop doing cervical cancer screening? Dr. Spitzer: So, again, it all boils down to risks and benefits – harms, benefits and harms. So, we know that it takes a certain “You have to find an age where amount of time for a woman who does not have disease you’re comfortable to stop to develop cervical cancer. It takes 10, 15, 20 years. When [screening]. The guidelines you have a woman who’s negative – and we’re going to say 65... I think everyone agrees define negative either as having a negative Pap test on three consecutive occasions within 10 years with at least one of at some point or another you them within the last 5 years or having a negative Pap plus need to stop.” HPV co-test at least two in the last 10 years with at least one in the last 5 years and not having a history of CIN2 or 3 or cancer in the past 20 years – you take that patient, she’s at extremely low risk. Now, the question is: Are we concerned she’s going to get HPV now and develop cervical cancer? Well, if it’s going to take 10, 15, 20 years, the question is: What’s her life expectancy? And if she’s going to die of something else before she develops cervical cancer, the fact that she has CIN3 doesn’t bother us. Nothing happened from her CIN3. So, we now need to look at life expectancy. And so, when we developed – and that was the subcommittee that I chaired – when we developed these guidelines, we looked at what age would seem acceptable, because we wanted to get the confusion out of it. We didn’t want different organizations to have different ages. And the US Preventive Services Task Force had the age of 65, so it was sort of arbitrary that we chose the age of 65 to stop screening. Now, I can understand – and this is from somebody who actually was the chair of that subcommittee – if you have a particularly vigorous woman, she’s healthy, she has no other health risks, and she’s 70 years old, and you can expect that her life expectancy, in fact, might be 90 or 95, and you want to continue to screen her for a period of time, I think that’s reasonable. It makes sense. It fits with the science. But I think everybody can agree that by the time she’s 85 and 90, all you’re picking up is harms. You’re not giving her any benefit at all. So, you have to find an age where you’re comfortable to stop. The guidelines say 65. I can certainly support if somebody said 70, but I think everyone agrees at some point or another you need to stop. Now, the other group where you need to stop is somebody who’s had a hysterectomy for benign disease. She hasn’t had any CIN2 or 3 in the past, and now she had a hysterectomy for fibroids, for prolapse, or for something like that. Those women you’re screening for vaginal cancer, and the risk of vaginal cancer in such a woman is roughly comparable to the risk that a man will get breast cancer, and I don’t see you or I or any other man lining up to get their mammographies; nor should women in this construct go and have their Pap test. They’re going to pick up harms with little to no benefits. Dr. Mennen: Well, Dr. Spitzer, that was a great discussion of the current guidelines. What can you tell us how they might evolve in the future?
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Cervical Cancer Screening Strategies: Evidence in Context
Dr. Spitzer: Well, there are a couple of things and two that come immediately to mind. The first is that since the guidelines were developed in 2012, in 2014 the FDA approved primary HPV testing. Now, when the guidelines were originally written in 2012, they addressed the issue of primary screening with HPV and said there is insufficient evidence to justify that, but subsequently, the FDA came out and approved primary screening with HPV and they developed an algorithm. The algorithm has if you are positive for 12 HPV types other than 16 or 18, then you’re going to have a reflex Pap test, which means you’re going to have a Pap plus HPV co-test, which we already know how to manage. If you are HPV positive for HPV 16 or 18, you’re going to have immediate colposcopy. And it’s really, also, when you think about it, part of the already existent guidelines. And if you have a negative HPV, then you don’t need any testing at all. You’ve had a negative screen, and the recommendation at that point and the current guidance – not guidelines but guidance – by the ASCCP and the SGO is that those patients should be rescreened in 3 years. Now, there are some problems with that because there are a few gaps that weren’t addressed. What do you do with that patient who’s had an HPV 16 or 18, no Pap test, not necessary, but if she would have had a Pap test, what would it have been? Because, yes, you’re going to do a colposcopy, but are you going to do an ECC? Because if her Pap test was atypical glandular cells, if her Pap test was atypical glandular cells favoring neoplasia, if her Pap test was adenocarcinoma in situ, if her Pap test was high-grade SIL or cancer, those patients need something else. They might need an ECC. They might need a LEEP or a cone biopsy. And if you don’t have that information – you do a colposcopy, you don’t see anything – colposcopy is not anything but perfect. We only identify high-grade disease, squamous disease, 60% of the time, maybe even less with the first colposcopy, and with glandular disease we do a horrible job. So, what are you going to do with that unknown colposcopy? And again, if you’re waiting, if your Pap test is negative, then you’re not going to rescreen for 3 years. If there’s a missed cancer, you have a problem. And in actual fact, when you’re talking about cancer, a rare event admittedly, it’s a rare event, but it does happen, and those are the most serious, life-threatening issues that we have to worry about. It turns out that while HPV testing is very good, better than a Pap test, in detecting precancer early on, when you get to cancer, the viral loads of HPV go down. With adenocarcinoma the viral loads go down. With age the viral loads go down. And the lower viral loads may be below the threshold. And so you have studies – the Blatt study; there’s a Julia Gage study; there’s a Katki study; a variety of different studies, at least 10 different studies that come to mind – all of which showed that Pap plus HPV co-testing is more sensitive for the detection of cancer, and for that matter for precancerous conditions, than the HPV test alone. So, I have a few concerns about the HPV test. It’s a good step forward if what you’re doing is comparing it to the Pap test, but it’s not as good as the Pap plus HPV co-test. The second issue is intervals. The screening interval of 5 years is something new for the United States and, for clinicians, many clinicians, and for many patients it is really a bridge too far. They are very uncomfortable in going for 5 years. And in the United States, we have an opportunistic screening program. So, a patient comes in for a Pap test, great; we do a Pap test. We’re going to see her again in 5 years. Where is she going to be in 5 years? Is she going to be in your practice still in 5 years? Is she even going to be in your city? Is she even going to be in your country in 5 years? Who’s going to remember to redo that Pap test and HPV test, that co-test, in 5 years? We have no such evidence on screening every 6 years, 7 years or 8 years, and if somebody slips through the cracks, we’re not exactly… Dr. Mennen: We’re in trouble. Dr. Spitzer: … we’re in trouble. So, I think that many clinicians – and actually, studies have shown it – that patients and clinicians are actually more comfortable with 3-year testing. And we should be looking at the fourth and fifth year
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as our safety valve to, if you didn’t catch her at 3, you’ll catch her at 4 or you’ll catch her at 5, rather than saying that I’m going to do it at 5 and I have no safety valve. So, again, I think that we may, moving forward, rethink that paradigm. And if you do everything at 3 years, cytology every 3 years, HPV testing if that’s what you’re going to do every 3 years, or co-testing every 3 years, it gives you a consistency, a consistent message, which makes it very easy, much easier for both patients and their clinicians to understand and follow a set of guidelines, and that’s, I think, where we will be going. Dr. Mennen: Sounds quite reasonable. Dr. Mark Spitzer, thank you so much for speaking with us today. Terrific. Dr. Spitzer: Thank you very much. Announcer Closing: You’ve been listening to ReachMD. The preceding program was sponsored by Hologic. If you have missed any part of this discussion, visit ReachMD.com/ScreeningStrategies. Thank you.
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