Gynecologic oncologist Megan Swanson, MD, MPH, deciphers recent changes to cervical cancer screening guidelines and uses the data to illuminate the relative value of test options – Pap smears, detection of high-risk HPV strains, or both tests together. She explains next steps for patients with abnormal results, providing visual algorithms to depict paths to appropriate care.
I'm Megan. Uh one of five Joanne oncologists at UCSF and happy to be here with you guys today, we'll go through um screening. Uh really what is screening um and why cervical cancer is particularly suited for screening, which is secondary prevention. Um We'll talk about screening guidelines. The United States, specifically the United States preventative Services Task force and the american cancer society. A CS guidelines will talk about how they're similar, how they're different. We'll talk a little bit about data. Um I think a couple of the best studies that have compared some of the screening methods and the different sensitivities. We see we'll talk about barriers to primary HPV testing specifically in the United States. Um And if we get to it and if there's interest we can talk a little bit about management of abnormal screening. According to a CCP guidelines, we will not be talking about HPV vaccination, which is primary prevention, very important topic. But would be another talk. Uh We're not going to be talking about HIV immuno suppressed or other high risk populations guidelines are a little different. They're given different risk factors and prevalence of HPV um and increased risk of progression. Uh We're going to be focused on the US. So we're not going to be talking too much about low and middle income countries, although that is where my research and kind of passion is in this subject. Um And we're not going to be talking about vulvar or vaginal dysplasia. Not planning on talking about invasive cancer. But certainly if there are questions, I welcome them. Those are honestly the easiest questions for me to answer is a G. Y. N. Oncologist. But today we're focused on screening. So really what is the what is screening? Why do we do it really? We do it because it's secondary prevention. Somebody's already had the exposure in this case. HPV. We're trying to find and treat uh pre cancerous lesions to prevent progression to invasive cervical cancer. Um A pre cancerous lesion. There's some debate. Um And as you all probably know between what we consider a pre cancerous lesion. Specifically C. I. N. Two. This is it C. I. N. Two slash three or C. I. N. Three. Um And we'll look at some of the data about that. Different studies measure and report this a little bit differently. Um An area of contention, we'll talk about what tests we have to identify pre cancerous lesions, how to best stratify risk based on test results. And we'll talk about whether or not um triage testing is necessary and in what circumstances? So like I said, cervical cancer is particularly suited to a secondary prevention screening cascade because of this slow progression from HPV infection to this plastic lesions and then to cervical cancer. Um And so it's this pathogenesis and the slow progression um that makes it really amenable to screen. I'm gonna talk just briefly about HPV biology. Uh It's a. D. N. A virus. A double stranded DNA virus. Um There are over 30 types but really about 18 or so that are related to invasive cancer squamous or adenocarcinoma. Um and specifically the cervix for this talk. Um And it's really the E. Six and E. Seven genes that are responsible for this angiogenic potential. What they do. The virus has these um these areas in its genome codes for the E. Six and E. Seven proteins. And they inhibit our the host uh tumor suppressor genes like R. B. And P. 53. And what that means is ourselves can't do their normal checks and balances. They can't arrest growth, they can't do a pepto sis they can't do some essence. And so through this epigenetic programming we see a progression to this unregulated growth immortal cells and eventually cancer. So that's why that's why we see this progression. Different strains of HPV do have different risks. Um of of this progression and it's partially how they behave. Um You see on the right of the screen here HPV 16 and 18 specifically they integrate their viral DNA into the host viral D. N. A. Um and therefore can really accomplish this epigenetic programming better than the more like the 611 strains that are not associated with cancer. Um the viral uh material, the viral DNA states episode will um and so can't really accomplish that epigenetic reprogramming a little bit of background. I draw this cascade out for patients when I'm meeting them in clinic um and talk to them about how how this all happens, How we go from a normal service. two HPV infection. I do note that 80% of the time Infection clears uh about 20% can progress to pre cancerous lesions still possible to regress. I have some numbers on the next slide um for regression. Um And then some can progress to cancer. And I will kind of literally circle or draw star on that progression when I'm counseling a specific patient about where I think based on the available data we have usually from co test where I think they are on that. Uh This has a little bit of numbers. Uh This is this is a paper from Mark Schiffman. It was published in the Lancet but the numbers I quote are actually a little different from this. But uh but these are also reasonable numbers. Um You see most uh C. I. N. One will regress on its own. I quote about 10% risk of progression. Um C. I. N. To actually has a higher likelihood of regression and CNN three obviously. But overall I think it's reasonable to talk about regression in the 30 to 40%. Uh for both C. I. N. Two and three. But there is some difference there. Um and progression and we're talking on the order of years to progress to cancer. The I. N. Three. Uh This was a study that had a bit of an unethical study was done in Australia. The data are decades and decades and decades old. But there was a group of Of patients of women who were with CNN three that were not treated and followed. Um And what this showed us with the natural history of C. I. N. Three that the cumulative risk of cervical cancer at 30 years over here was about 30% but for people with persistent disease at that 6 to 24 mark they had about a 50% chance of progressing to cancer. So especially persistent um or or recurrent um C. I. N. Three that we're seeing pretty high risk of progression to cancer and that's why definitively we think of C. I. N. Three as the pre cancerous lesion that really does warrant warrant treatment. There are some circumstances very young patients where we will sometimes consider observation for CN three but with incredibly tight follow up almost all the time, it's unacceptable not just be treating cm three. I thought I wasn't going to talk too much about low and middle income countries. Just I'll quickly say screening is context dependent it depends on where you are. It depends on the prevalence of both HPV and cervical cancer. When you're thinking about balancing risks and harms cryotherapy. So she's they're holding holding a cryo gun. The screening in the U. S. We have three main methods um as you all know we have cytology pap smears. We have primary high risk HPV testing and we have the hybrid strategy co testing which is of course Psychology and the high risk HPV testing. Now if we're doing a contest, you kind of have a triage step built in, you have two points of data that you can use to figure out who goes on for colonoscopy or not. Um If you're doing only cytology we know from the arts trial that adding a reflex HPV first for a psychology like ask is can be very helpful to triage. Um And then if you're doing primary HPV testing there's a complicated uh triage paradigm. We can talk a little bit about that later to figure out who would go on for colonoscopy. Um So I'm going to get into now talking about the United States preventative Services task Force recommendation. Then we'll talk about the american cancer society recommendations. Um and why I think they're both pretty reasonable method. Um I know there's been some confusion in the group about which you know which which which recommendations to to have. So we'll talk a little bit about the differences and and why they're both really probably fine ways ways to be screening people. Um this slide I took off of the main publication. Um it's curry is the scene is the first author of this was the published in Jama in 2018 this is the task force, the United States preventative services task force recommendations. So they recommend starting screening at 21 And for the 20 year old 22, because HPV is so prevalent, the task force does not recommend HPV testing outright. There's a little footnote But they recommend cytology alone every three years for the 20 year olds. There's a footnote um that ACOG Sugo and A F. C. C. P. Which are three professional societies that endorsed these guidelines, they do advise um and the task force notes this in a footnote on this table Uh that primary HPV testing which is FADA approved starting at age 25. And we'll see this when we look at the recommendations can be an alternative cytology for average risk patients 25 to 29. So there is an acknowledgement that there's primary HPV testing could be a consideration and we'll talk about the data that informed that FDA approval for the really the most people are falling in uh in the 30 to 65 age range and the task force basically has three um methods. They don't recommend one or the other one over the other but they say any of the following three are reasonable balance of benefits and harms um cytology alone every three years. Um FDA approved primary HPV testing which is really in this country. Just a cobalt test, we'll talk a little bit about that or co testing every five years because the sensitivity is different sensitivity is higher and I'll show you data for this but sensitivity is higher for HPV testing, you don't need to do it as often. Whereas psychology because sensitivities It's lower specificity is higher but sensitivities lower. You need to be repeating that more often. So any of these three strategies in the 30-65 year olds is thought to be reasonable. And then there last point the task force's last point is when can when can one exit screening? So 65 is thought to be the time to exit but One has to have in the last 10 years completed either three negative psychologies or five or two every five years um HPV test. So they have to be up to date in the last 10 years with some reassuring negative testing to exit at 65. Those are the task force recommendations. The ACS recommendations are a little bit different. This is um copied off of their main paper which was published in 2020 and their journal which is cancer. Um their recommendation is a little bit different and also a little bit the same. They recommend starting screening at 25 And they recommend primary HPV testing. So not like the task force which does really any of the three strategies for the 30-65 year old. They come out and actually say because of the improved sensitivity. Um and I'll show you some more data to to uh to suggest that there there might be a benefit to primary HPV testing. That is the recommended test by the by the they acknowledge however that because availability of the FDA approved tests for primary screening which are different than the FDA approved tests for protesting because there's there just aren't many of those they're hard to access. Um They acknowledge that co testing or cytology are acceptable um Is the word? They use acceptable alternatives for cervical cancer screening. Um and and so there's there a little bit different and a little bit the same. Um and then they also recommend stopping at 65 with adequate screening in the ten-year period just prior. So I think there's there's more similar than different. The main difference really is when to start screaming and that a CS really takes the stand and does recommend primary HPV HPV testing. Now. What about these poor 20-24 year olds? Are we giving up on them if we're not screening them? Um in their paper their main paper that they write on this the American cancer society talks about really the reason why they moved that age up is because there's such a higher prevalence of high risk HPV in women, less than 25 using um HPV testing. You're gonna catch a lot more people require a lot more cold pasta piece. And really they asked for what benefit? It's really the cervical cancers really only 250.8 Percent of the uh, the sorry the incident is at .8% in the 20-24 year olds which is you know much different than um than the rest of the rest of the age groups. So it's really a very small proportion of cervical cancer is found in these in these younger women and there's a lot more HPV. So and they also um they also say talk about in their discussion um that they're kind of postulating that with increasing vaccination uptake um they do think that these younger women coming of screening age are going to be at lower risk for HPV infection. So that was another point in their discussion. So this is a busy slide but you can come back to it, take a look at it if there is one study that you want to take a look at and and no or or or have some reference to inform some of this. I think the Athena trial is the trial to know. Uh This is a trial. It was published a few years ago, I believe in it looks like I cut the date off but I believe it was Are there 2016 or right around there? Um thomas Wright is the first author on it. It was a huge study, 40 some odd 1000 women. It was a bit of a validation study and that every one of these 40,000 women in the trial got screened with psychology with kobus uh primary but it's not exactly primary HPV screening cause everybody got all the methods but they were screen with cytology, Cobus HPV testing. Um And it was a complicated algorithm but people were followed even a proportion of normal people were followed with cold pasta P and even biopsies. So they did have some normal people um to try to assess the sensitivity. Um And basically their main finding um was that primary HPV testing did detect more cases of C. I. N. Three. Um Then either the cytology or the hybrid strategy the Co test strategy um but did require a lot more culpas copies this this table. I I chose to highlight the sensitivities um in this table so that you could see. But um basically you see the sensitivity at year 33 years after starting screening with Um if if everybody had all three different all right everybody had cytology and HPV testing. But for the sake of analysis the authors were able to to show if they had only had cytology this is what the sensitivity would have been if they'd only had Cobus HPV this is what the sensitivity would have been. And if they'd had both according to the triage algorithms you can reference the paper to see the very complicated diagram But the the the end of it was at three years sensitivity was best 76% for C. I. N. Three for the HPV Primary strategy Cobus test Feel good 61 for the co test and sensitivity not as good for psychology and that's why psychology has to be done more often takes as as you saw before decades for progression to cancer. So even though sensitivity not as great for cytology, if you do it more frequently the end result um will be okay. This is the other trial. This is this was a randomized trial Canadian trial called the focal trial gina ogilvie with the with the primary author on it. They also have a very complicated consort diagram. I I put it in here just so you can see kind of how complicated it was. But essentially women were randomized in this trial to either cytology or primary HPV. So there was no um co test in here but their main finding was that HPV based screening resulted in a lower likelihood and you can see the separation of the curves here at two years of C A. N. Three associated with primary HPV testing. They used hybrid capture to not kobus a little different. Um as Canadian trial. Uh then psychology and the uh incident is reported here. You can see their risk ratio and a significant confidence interval comparing the intervention group being HPV primary testing compared to cytology which was the control group. So this trial as well as the Athena trial, I think these are the two best trials. This was in the U. S. And the focal trial in Canada um supporting moving towards um primary primary HPV testing um given the better sensitivity. So why haven't we done this yet? Why haven't we in the United States move toward moved to Primary HPV testing? Well, there aren't very many FDA approved tests that are specific for primary HPV. I have a table um that I took from up to date but I have a table of what all the different tests are in a in a coming side and flight and I'll show you it's really the Cobus test is the one that is most frequently used for primary HPV but it's um it just aren't very many tests and it's harder to get access to. Um all sorts of side of pathologists out there um are busy looking at perhaps mirrors and our hospital systems and our laboratory structures have a significantly invested and set up the infrastructure for either pat smear based or co testing based screening. So significant infrastructure changes are necessary. Um and it's been noted in many, many uh papers that have been written um modeling papers and um and critiques that have looked at the strategy have noted that the limited access to primary um high risk HPV testing is a particularly up particular concern in historically and contemporaneously marginalized people living in rural areas under resourced community um individuals of color who have disproportionately higher incidence of cervical cancer and morbidity and mortality. So we're not yet ready uh to make that jump and that's acknowledged in all the in all of the in all of the guidelines that um psychology has been the backbone for so long of our screening. All of the guidelines have worked in ways to triage tests. Uh This is the table that looks at the different types of um HPV test. The one we use um in in our clinic is the Optima um HPV 16 18 45 with a co test with cytology. It specifically reports out 16 and 45 then gives you an other category. And then of course we have our cytology results as well because these are the tests FDA approved um for protesting um for primary HPV testing kobus um is FDA approved? You can see the FDA approved ones have this little, they don't even know what symbol that is but have this little symbol here. So it's just a Cobus and Bt on clarity. Um I don't think I've seen this test. That is another one which is FDA approved. The Chef EOD Expert. The gene expert. Um HPV test is really exciting especially for use in low and middle income countries. Um It's a there's a one hour turnaround time on that test um and you get a report out of high risk HPV uh 16 18 45 or other. Um And the really exciting thing about this test is that it can almost be done as a point of care test. It's not FDA approved, it is W. H. O. Pre qualified um and it's been used more in more in international settings specifically in low and middle income countries that don't have the resources to do cytology. Um So yeah kind of a different application but you see there aren't many tests um and the availability of tests with cytology are the ones that I've seen more commonly in our clinics. The hybrid capture two is also FADA approved. That is the test that the Canadian study used for primary testing in the focal trial. So I mean potentially that one in the future you know hopefully the FDA will consider the data and think about that. But for right now we have some limited availability of FDA approved tests. Um So we're all pretty used to I think the triage from pap using the HPV testing and the genotype testing for triage to figure out who goes to corpus copy or not. But for primary HPV screening I feel like people are a little bit less familiar with what the triage step should be before going for corpus copy. And so this is a Warner ha who's the U. N. Oncologist at University of Alabama um wrote this paper in the this is the SCP journal. Um and just highlighted this algorithm um to show who who screens positive for primary HPV would go to cool apostrophe. So you see there's a way that one could get to colonoscopy without ever having a pap smear If they were 1618 positive you know from the jump versus um you know being in the other other high risk group and then meeting a cytology to to figure out if they go to corpus copy versus versus close follow up from here. I'll just introduce a little bit about the A. F C C. P. Um principles the CCP. Also there are governing body that gives recommendations for not for screening but for management of abnormal screening. Um and they have endorsed the United States preventative services task force but have also had that asterisk footnote where they support the 20 5-29 year old primary HPV screening as well. So seems like they're actually in support of both strategies honestly anyway. But this is the group that gives guidelines for management of abnormal screening and they're the ones that have the app that you may or may not be using on your phone. Um They redid all of their algorithms in 2019 and I just want to go um just just want to explain a couple a small um points with that. The main thing is that the in the new consensus guidelines they based all of their recommendation for who goes to Kapus copy based on risk estimates from real world data. They used a Kaiser permanente northern California cohort in order to figure out what the immediate risk of C. I. N. Three was based on a I'll show you a table in just a moment but the SAN a whole the flow of data about the psychology and the HPV. Test. Um And so it's all based on real world data and they also validated um their recommendations from the Athena trial cohort that we looked at before. And then this is also the national breast and cervical cancer um uh insurance program that so you have uh you have a managed group setting. The Kaiser group which is kind of a working class group. The national breast and cervical cancer group which tends to be um tends to be uh the group that otherwise qualify qualifying for Medicaid or MeDI cal and the Athena trial which is a clinical trial setting. So pretty good concordance. Um And they decided that the threshold would be a 4% risk. So if whatever the screening test is if there's a 4% risk or greater of immediately having C. I. N. Three. Those are the people that are recommended for colonoscopy. That's that's what I wanted to really highlight. Um This just kind of lists what the changes are from prior really based on risk not necessarily results. Um Although they're related. Um colonoscopy can be deferred for certain patients. Um There there are some situations where by co po may not be recommended an expedited treatment might be recommended based on those risk estimates. Um There are some interesting changes for A. I. S. Um that we'll talk about and and they do ablation there there they weren't as strongly in favor of ablation a blade of therapy um for H. L. C. I. N. 23 and do recommend excision. We can talk a little bit about ablation versus excision if people want. Um But a CCP is leaning towards recommending diagnostic exceptional procedures leap. Um But does still give a blade of therapies. Um An acceptable uh note especially for people with pregnancy plans for the future. A little bit of history, pathology reporting differences. Um Does surveillance changed a little bit after high risk? Um And surveillance of psychology alone is not recommended at this point. Um This is the last thing I'll show you and then I have a bunch of the algorithms that use TCP algorithms and We can talk about them if people have specific questions. But this is the the Linus cheung paper um that the 2019 recommendations are based on, it's based on these this risk table basically. So if you go to the S. E. C. P. Website all of these articles are freely available that the 2019 guidelines are based on their Perkins wrote the main one with with all the algorithms and the Linus Cheung paper um has the risk table in it. And so you see here it's these are the different combinations of HPV results and high risk HPV results um and Cytology results and these are the immediate risk of c. a. n. three that are above that 4% threshold. So it's any combination of this screening would then triage somebody to immediate capaz copy um The rest, the rest of my slides are mostly um the different a sec. P algorithms. I'll stop for a moment on the A. I. S. One because this one was a change. Um I'll go through this one with you guys and then I'll just kind of stop for questions. Um But this this was a change and I think for I think for the better it gives it gives people um a way out of needing a hysterectomy. Uh If all close follow up screening um is normal. So for for A. I. S. We would we would never do an ablation um for for a I. S. Adenocarcinoma inside too. We would want a diagnostic exceptional procedure. And you see they don't recommend that it's not saying cold knife count, it's saying diagnostic exceptional procedure. A leap is acceptable, cone is preferred for for margin evaluation but we've also acceptable. Um And if negative margins if one is considering future fertility or um or for whatever reason does not want to have a hysterectomy, poor surgical candidate something like that. You can consider every six months for for three years. Um doing a co test, pAP HPV testing and an end a surgical curettage um If normal every six months for for three years. Um And then annually for a couple years it does give a pathway To continuing close screening every three years HPV based Um for at least 25 years. So there is a pathway that doesn't necessarily end in a hysterectomy um for for women um or individuals with a. i.s. That was kind of a big difference for us.