Thinking About Ob/Gyn
A fresh and evidence-based perspective of all things related to obstetrics and gynecology. Follow us on Instagram @thinkingaboutobgyn or visit thinkingaboutobgyn.com for show notes and more.
Thinking About Ob/Gyn
Episode 9.11 Cervical Cancer with Stuart Winkler
Cervical cancer represents a success story in developed countries due to screening and vaccination, yet remains a significant global health problem with over 340,000 deaths annually worldwide. We explore the current state of cervical cancer prevention, screening, and treatment while discussing exciting advances that could eventually eliminate this disease.
• Different levels of prevention for cervical cancer: primordial, primary, secondary, tertiary, and quaternary
• HPV vaccination as the most effective primary prevention method, with Australia on track to make cervical cancer rare by 2035
• Evolution from Pap smears to primary HPV testing, with potential future urine-based screening options
• Less radical surgical approaches for early-stage disease, improving quality of life without compromising outcomes
• Immunotherapy advances showing 6-12 month survival benefits in metastatic disease
• Howard Kelly's pioneering work with radium in the early 1900s, establishing foundations for radiation therapy
• Importance of addressing healthcare disparities, as rural Americans are 25% more likely to develop cervical cancer and 42% more likely to die from it
Visit our website at thinkingaboutobgyn.com for more information and follow us on Instagram for updates.
00:00:00 Introduction to Cervical Cancer
00:08:10 Prevention Strategies Explained
00:18:02 HPV Screening Evolution
00:26:51Treatment of Early-Stage Disease
00:37:09Advances in Locally Advanced Disease
00:50:31 Radium and Howard Kelly's History
01:02:48 Final Thoughts on Prevention
Follow us on Instagram @thinkingaboutobgyn.
Welcome to Thinking About OB-GYN. Today's episode features Howard Harrell and Stuart Winkler discussing cervical cancer.
Stuart:Howard Stuart. What are we thinking about on today's episode? Cervical cancer oh man, you don't have to be so excited about it. I will say there. Actually I think there are some things to be excited about with cervical cancer, particularly in the more developed countries. Today we're going to talk a little about some of the improvements that we've seen for the people that can afford the treatment in the developing countries and unfortunately the disease burden is still a huge issue worldwide. So I thought we could talk today. We spoke a little bit because there was this New England Journal of Medicine paper that came out. It was just a review paper but it was by Chris Tawari, who's really well known in the field of cervical cancer and he did this good review on kind of the state of cervical cancer. So I thought we could talk about that today and maybe talk about some screening and prevention as well.
Howard:Yeah, this really is a great article and good for anybody residents or anybody who's studying for their boards or just anybody that wants to be up to date and, like a lot of these review articles, it's nicely written and concise and it does highlight, as you said, that worldwide cervical cancer still kills over 340,000 people. We don't see the burden of that in the United States because of a lot of things we're going to talk about, but we can still do a better job even here.
Stuart:So yeah, yeah, absolutely, and I was glad to see this article. We use articles like this when we teach our residents and they there had not been an update in a while, so we'll hit the highlight to this one. And then also I thought it'd be fun we could talk a little bit about the history of radium and discuss that a little bit for our history segment.
Howard:Yeah, that sounds great. We actually did the history of the pap smear not too long ago, so we've got that base covered. And maybe, before we get into the article, let me spend a couple of minutes talking about some of the public health ideas of prevention strategies, because cervical cancer is such a wonderful model to understand these for folks. Most of us in medical school, of course, learn about primary, secondary, tertiary and quaternary prevention, and so I want to illustrate those concepts as it relates to cervical cancer relates to cervical cancer and then, as we discuss the article and the current sort of state of play for cervical cancer, we can highlight how we're addressing these strategies. Essentially, that's what we're really talking about, but before I get into those, there's also the concept of primordial prevention, and I don't often hear that addressed when people talk about these levels of prevention.
Stuart:Yeah, yeah, you're right there. So I'm guessing, by primordial prevention you're not talking about the same as primary prevention, right?
Howard:This is something that goes before that population, or individual or individuals, to prevent the disease from ever occurring. So for cervical cancer, the most obvious and successful strategy for primary prevention is HPV vaccination which, of course, we're going to talk about in a little bit and this is intended to prevent a healthy population from ever getting the disease to begin with. So that makes sense. Primordial prevention, on the other hand, is an effort to reduce risk factors for a population that are more related to social and environmental conditions, usually through health policy and law. So we're not doing anything to the population explicitly, but we're changing the environment that they live in, if you will.
Stuart:Yeah, yeah, I can see how there's definitely some overlap between that, maybe thinking on a smaller versus a larger scale, when we compare and contrast those. I think primary prevention of cervical cancer includes things like smoking cessation, highlighting the unsafe sexual practices that can lead to HPV spreading and that sort of thing, and then maybe even in some instances, things like condom use and things like that could potentially help with HPV transmission. But all these things also have policy and legal implications as well.
Howard:Right, which would get more into primordial. So, from a macro level, we might look at the laws and policies that restrict, say, the availability of cigarettes. Rather than encouraging the person to not smoke. We might look at them and elude the primordial soup that's the way I remember this of those policies. So there are laws that affect the availability of cigarettes and what age you have to be to buy them, or the taxes that you might impose on them to discourage purchasing cigarettes. Them, or the taxes that you might impose on them to discourage purchasing cigarettes, or regulations around, let's say, advertising cigarettes, like we got rid of the Joe Camel ads when we were younger that used to target children, things like that that make that change people's desire to smoke in the population we're concerned about. So the sort of soup that people exist in. And how do you change that? Through policies and regs. Whereas don't smoke, get vaccinated, use a condom.
Stuart:That's something I'm directly telling you to do as a patient? Yeah, that makes sense. Yeah, I guess, historically, thinking about things like Virginia slums, which were targeted particularly in like older print ads and stuff which, by the way, you can see in old medical journals interestingly enough, you'll see these things and they're targeted towards young women and really smoking is presented as a form of empowerment and all these different things and that stuff really gets ingrained in a culture. I remember when I was a med student under you at East Tennessee we would do work in some of the rural counties there with smoking prevention and pregnancy and that sort of thing, and these are women who watch their mothers and grandmothers smoke and they were ingrained by this advertising. So that downstream effect of all of that really can take generations.
Howard:Yeah, yeah. So primordial prevention is a big part of how we change that through policy and policies about advertising or laws or things like that. So in some of it's even self-regulation. Television producers, movie producers they try not to portray smoking anymore in a glamorous or desirable way, and that has all these things together have led to decreased smoking in the target population that we're worried about young women for cervical cancer, and then in turn has led to decreased morbidity and mortality from cervical cancer and other cancers in the case of smoking obviously. So those sorts of things are good examples of primordial prevention, and primordial prevention might also include working on what we today call social determinants of health that are associated with an increased disease burden. So if you look at places where cervical cancers are more common, both in rural America Appalachian America is one of the hot zones, at least in this country or in countries with think sub-Saharan Africa, where a lot of this disease is still occurring that have less developed economic and healthcare systems, then you can see it becomes really obvious how much social determinants can impact the prevalence and the outcomes of cervical cancer. So there's actually a new research letter in JAMA Open Network we can put a link to that showed that cervical cancer was 25% more likely in rural versus urban America, and women in those areas were 42% more likely to die of cervical cancer, so both more common and more deadly. So primordial prevention would include things like in this case, like poverty reduction programs or improving socioeconomic risk factors, access to health care, promoting lifestyle elements associated with the reduced risk of cancer, and in this case that specifically might include sex education in early schools and promoting health literacy and promoting health in general through media campaigns and public messaging. So not just outlawing advertising that makes smoking seem more attractive to a vulnerable population, but also campaigns that specifically promote healthy diet and weight awareness and awareness of the disease and the importance of screening and promoting vaccination and all those things.
Howard:And then we mentioned primary prevention, and that would include, well, mostly the HPV vaccination, but also, as we said, health education for vulnerable patients. Now they're sitting in front of you, and so this is anybody with a cervix. What specific factors can you help them with? Then we get into secondary prevention. So secondary prevention is what we do with cervical cancer screening, where we're attempting to detect a hopefully pre-malignant, pre-cancerous lesion, an early stage, pre-invasive lesion, so that we can treat it before it becomes life-threatening or before it becomes morbid. And so of course we've used a lot of things over the years and most of us right now are still using liquid-based cytology to screen for cells from the cervix. And then, of course, HPV tests and lots of subtype testing that's going on now and lots of nuance in there that's changed over the last 20 years and we'll discuss some of that. Secondary prevention also would include the management of those pre-malignant lesions, so colposcopy, and then destructive or obliterative procedures, excisional procedures that we might do for dysplasia. All of that's part of secondary prevention.
Stuart:Yeah, so we think of cytology, pap smears as the main thing that we're doing, and certainly for screening it is. But really by that point we're already down that echelon of prevention where obviously, if we can nip that in the bud even before we get into those problems. That's the ideal time, which is why we recommend these HPV vaccine in pre-coital patients.
Howard:That's important Right and in boys and girls. And of course that gets in beyond just cervical cancer and head and neck cancers and things like that too. But yes, by the time you've discovered an abnormal pap smear in your office, you've already failed primordial and primary prevention and we've moved on to secondary prevention then to detect that lesion and try to take care of it, and then tertiary prevention is. Well, it's your line of work. So this is managing the patient's diagnosis of cervical cancer to prevent it from becoming worse or to reduce the morbidity and mortality associated with it and hopefully improve the quality and length of life and survival outlook for that patient. So this of course includes treating the cancer itself, managing the treatment side effects and the rehabilitative therapies that are part of that, and in some cases it includes palliation. So even though we haven't prevented the cancer at this stage, we're hopefully preventing the worst effects of the cancer. So it's still considered a level of prevention, yeah, yeah.
Stuart:You know this, but my wife is a preventive medicine doc and so we have kind of interesting conversations in our home about how we're both on the opposite ends the prevention and the treatment spectrum. From here on we really will discuss the corticosteroids, prevention or the treatment piece of things, and really almost I think about it as almost like damage control when you get to that point in some ways. And so once you've gone past the screening strategies, now you're like, okay, what can we do to treat this, to prevent mortality as best we can?
Howard:Right and quaternary prevention to finish that off part of that.
Howard:Well, what that is?
Howard:To prevent unnecessary or excessive medical interventions related to this whole pathway and particularly to cervical cancer.
Howard:So this includes strategies that avoid overtreatment of low-risk lesions, like doing an unnecessary leap or cone procedure for a patient, say, with CIN1 that might cause other problems like increased preterm labor, infertility, things like that. But it also includes a rigorous approach to our screening guidelines that help us not over-screen low-risk patients who then in turn might be harmed by over-diagnosis or misdiagnosis. And it includes promoting a shared decision-making model for patients. We might, for example, be more aggressive in the treatment of a high-grade lesion in a patient who we know is done with childbearing or has no intention for childbearing. Then we might be in a younger patient whose fertility is very important to her and still in the future, in some cases we might not even treat CIN2 in a patient under age 25, depending on her particular desires and risks, in order to minimize the harms from that treatment that might come along with a procedure. Then again, that includes not just anxiety and things like that related to it, but it includes potentially infertility or increased risk of preterm labor.
Stuart:Yeah, so I really think this is a great framework. I'm glad this has all worked together to talk about this framework of prevention and what we're about to discuss here with this article. And the article actually does start off with epidemiology but then it goes into some of the screening. I know you mentioned a little bit of the global problem at the beginning, but really to put those numbers on there, you mentioned the 340,000 cervical cancer deaths worldwide and that's really just compared to 4,000 here in the US, and so really you can see that there's a much disproportionate effect of this in the developing world and not outside of the US, Even here, given that cervical cancer is almost a completely preventable disease. Really one death is even a failure.
Howard:And overall it's still the fourth most common cancer worldwide for women. So less of a burden in the US. It's in the teens, I think, in the US for cancers, because we've done a great job with this but, as we'll discuss, we could do a lot better. A great job with this but, as we'll discuss, we could do a lot better. And, as a side, of course, you know that there are HPV-independent cervical cancers, but they make a small fraction, less than 5%, of diagnosed cervical cancers.
Stuart:Yeah, definitely. Yeah, that's good to mention that. Unfortunately, there's not really risk factors for those or precursor lesions and they really fall outside of the screening patterns and recommendations. Unfortunately, too, they tend to be very aggressive. They metastasize early and I've treated a handful of these and unfortunately the patients don't do very well with them. So it's an important thing to recognize. But for the remainder of the podcast, when we refer to cervical cancer we're really talking about the HPV-related disease.
Howard:Yeah, and also when we talk about screening for any disease, but in this case for cervical cancer, and our sort of system and approach for doing that, as you said, we're just talking about the HPV cancers. If all that existed were the HPV-independent cervical cancers, we wouldn't screen for them Because, as you said, they're both rare and they don't have this well-defined pre-malignant finding where you have an opportunity to intervene. And the principles of a good screening test mean that you need a pre-invasive or pre-malignant or pre-morbid state of the disease that you can accurately detect with a low cost test and have an intervention available that prevents the burden of the subsequent burden of the disease and has pretty high, pretty reasonable sensitivity and specificity. And so cervical cancer again is like the greatest example of that I think anybody can think of.
Stuart:Yeah, there's a patient conversation that I have frequently, usually with my 18 year old patients who are begging for a pap smear. Right, they've listened to their friends and to the healthcare community and there's like, okay, paps are really important for preventing cervical cancer. I want a pap, and what I talk about there is kind of what you said about, about what is your, what is your probability of having cervical cancer at 18 and what a pap is going to detect. And so the thing I always use is you would never. If you had a male friend who was 25, you would never recommend that man go get a mammogram. But your risk of getting cervical cancer at 18 is about the risk. I looked at it one time but it's like about a male getting breast cancer at about age 30 is the same risk, right?
Howard:So we're talking about tiny risks, but sometimes that's a little bit of a way to get the patient to laugh and then realize, yeah, maybe I should think about this differently, and that's quaternary prevention, because by doing that you're saving the patient from the bigger risk, which might be, again, loss of fertility or things like that, that are associated with what might be an unnecessary screening test. So we have to think about that when when people question should we do yearly PAPs, for example? Why don't we? What's the harm of it? And that's where quaternary prevention comes in.
Howard:So we'll focus on HPV, and HPV is a relatively new concept. If you read books in the 1990s about cervical cancer, they were focusing on all sorts of other theories back then, before we really understood that HPV was the large player in all this. So I'll make a few points about HPV and the vaccine before you go into the cancer portion of the article. And first, infection with HPV virus is usually transient, at least in the tissues that we're examining. But persistence predicts progression. So the vast majority of HPV infections will clear and never lead to a high-grade lesion. But if the patient has detectable high-risk HPV for more than a couple of years, one in three of those patients will develop a high-grade lesion at some point. That'll need to be treated.
Stuart:Yeah, and this is really where that risk-based screening approach developed by the ASCCP it's really changed our management. It's almost impossible now to manage this without the app because a lot of inputs go into what the risk is to the next level of whether it be a colposcopy or, in some cases, direct to treatment. And the PAP has been incredibly important. It's now almost I think it was 41, I think was when it was first the first paper came out so we're talking about almost a century of pap smears and worldwide they've probably saved somewhere in the range of 7 million lives is the number I've seen more recently. But it is not as sensitive for detecting dysplasia as an HPV test.
Howard:Right, and that's again. That's something that a lot of people need a mind shift in, because we are moving rapidly away from cytology being the primary way we screen for things. And in a screening test, of course you want as sensitive a test as possible. You want to find all of the disease you possibly can, because you can always then take those patients and move on to a confirmatory test which is going to have higher specificity, and that's what we've always done right. Even if you have the abnormal PAP and the cytology from that, well, you're going to confirm that with colposcopy and biopsy In most cases.
Howard:Traditionally, that's what we've done, as you said. Now there's some opportunities where you might move more directly into treatment, but you're getting a highly sensitive test and then confirming it with a highly specific test, and so you want the most specific test and that's the HPV.
Stuart:And you can get around the sensitivity thing in some sense by frequency of testing. So that's why there's different recommendations for doing a pap with an HPV versus cytology alone. Right.
Howard:And all that goes into that.
Howard:Yeah, in the old days the pap wasn't and I just said most specific, but I meant to say most sensitive In the old days the pap wasn't very sensitive. The old pap, the pre-inquid-based cytology pap so you did it more frequently to get a rolling average of that over a course of three or four of them, had a good sensitivity and I think that one of the things that in the old days where we had yearly paps did, was it gave the implication that this was a rapid moving disease and that wasn't why we did them more frequently. We did it more frequently because we didn't have a very sensitive test. But unfortunately, I think both doctors and patients assumed I'm normal this year and abnormal next year. No, you just didn't have a great test. No, that's a great point yeah.
Howard:So we have to disabuse people of that concept. So today, an HPV test every five years is actually better than a yearly papinicolai smear, and it's not a rapidly progressing disease.
Stuart:Yeah, it takes about 13 to 20 years to make a cervical cancer, so it really does take quite a long time. So, yeah, that's a really great point. Though, about the frequency but kind of with the sensitivity of HPV, there has been this push to go towards primary HPV testing and this is a hot topic. This is one of the things we talk about at our conferences very frequently. It is actually FDA approved in a healthcare setting and that's been the case for about a year or so, and the article in the New England Journal does discuss a couple of the trials that went into that.
Stuart:So the Athena and the HPV focal trials, which you know support HP primary HPV testing. I will just note, like Athena is is completely funded by Roche, so you know which is the maker of the HPV tests. So you do need to take some of those things with a grain of salt, and there's a lot of a lot of the folks doing the pushing for primary HPV testing. If you run a sunshine act on them, they're definitely getting paid, which doesn't mean it's wrong, but I think it does.
Howard:It means it's wrong, but it's the way the world works Give yourself pause.
Stuart:Yeah, so I will say that if you're considering doing this in your practice, it's not something you should just up and do. I currently do not do primary HPV testing, but I'm considering it. But you got to talk to your pathologist because the whole testing system that runs the PCR and does the nucleic acid hybridization it has to be validated for self-collection and so it'd be part of the FDA approval.
Howard:So you need to make sure that your pathologists are keeping up with that and of course, acog and our professional societies are still recommending a cytology first screening program. But the American Cancer Society, for a couple of years now, has recommended HPV first and, like in Europe, it doesn't start till 25, which is another thing that people are going to have to get used to, and I think you gave a good example of that a second ago that you're screening for HPV in a young population of people who, vaccinated or not, they're still very likely to deal with that HPV effectively and it not progress. You've got plenty of time to do it and they're the population that you most want to prevent the harms of excess testing and cervical procedures from. So it's a mind shift for us here and this whole idea of how it's collected. So if you saw the headlines just this past week, the FDA approved in the US now a home collection HPV system. So this is a product called the Teal Wand and I think the way this product's going to work, at least for the rollout, is that you use this. It's an app in a company in California and you order the kit and somebody a doctor or a nurse practitioner, their orders that they send it to you. You collect the sample yourself at home and this device goes in the vagina, you send it back to them. They're starting to roll this out in California and they'll, of course they'll get payers on board and then you'll see this roll out all over the country and we'll see where this goes. And all of these devices still require that we're talking about now, still require a vaginal sample to test for the HPV.
Howard:But in Europe, in France, belgium, germany and the UK specifically, there are a number of trials underway from different products, different companies, looking at the accuracy, sensitivity, efficacy of urine HPV testing, sensitivity efficacy of urine HPV screen testing. So these tests use PCR, they collect a first void urine sample and most of them are specifically just looking for the E6 or E7 oncoprotein. And there's a variety of these that are different protocols, different considerations. The question will be how well they compare to either a clinician-collected or self-collected vaginal or cervical sample. But many of them are looking at using urine sampling or perhaps using that in combination with a self-collected vaginal specimen.
Howard:I think what it may be that you see a yearly urine HPV sample and that outperforms a Q five-year self-collected or clinical, and of course this is just pee in a cup once a year or once every two years. So a lot to come on that and a lot of questions there, but this is definitely the direction that we're moving in. It's certainly not this isn't standard of care in Europe by any means and still being validated and researched but this is the future. And eliminating the invasiveness of the test altogether, even if it's done at home the future and eliminating the invasiveness of the test altogether, even if it's done at home, and so that stuff's a few years off, but I think we'll get there. Like I said, the frequencies may be different, things like that and the upside of that is you increase the number of people who get screened. If somebody can just pee in a cup every two years, you may see more sensitivity with more frequent urines and more uptake from some of the more vulnerable populations.
Stuart:So okay, I think, sorry. I think the vulnerable population thing is important too, because when we look at people with advanced cervical cancer in the United States, these are people who are scared of going to the doctor in many ways. Either they're in a situation where maybe their racial group has been mistreated by the medical community in the past, or they have a different complementary view of medicine or whatnot, or maybe they just can't get to the doctor because of their rural location. So, like you said, anything to lower that barrier is going to be huge.
Howard:Or anything to avoid a pelvic exam because of prior traumas or things like that, and so for many people the enemy of good is better here. This is comparable to like Cologuard or some of the stool tests for colon cancer versus a colonoscopy. So talk to your neighbor and they are way more likely to poop in a box and mail it back in than they are, and even do that more frequently, right, even if they have to do it every couple of years or whatever. They're way more likely to do that than go schedule a colonoscopy. So, okay, well, more to come on urine HPV testing, but that is coming at some point. So well, why detect something you can prevent? So maybe let's talk about the vaccine.
Stuart:So unfortunately, our vaccine rate in the US still isn't great.
Stuart:In 2023, only 57% of adolescents between 13 and 15 had received the HPV vaccine, and the US Department of Health and Human Services does have a long-term goal to get this to 80% by 2023. But unfortunately, for the time being, we're still going to have patients with these precancerous lesions who are going to need treatment with what we call a diagnostic excisional procedure. So either a LEAP or a cold knife conization in the OR or, in some patients, possibly a cryoablation could be appropriate as well. So, as we discussed with quaternary prevention above, selecting the right patients for these excisional procedures is important. So we know that patients with CIN1 have spontaneous regression in up to 75% of cases, and so these are ones that we can just watch. We don't want them to disappear on us, but these are ones that we can watch and not necessarily intervene immediately. But when it comes to CIN3, if that is left untreated, that will actually progress to cancer in about 30% of patients at the two-year mark. So that's something that we should make that differentiation there.
Howard:Now you mentioned cryoablative procedures, which I think younger gynecologists are probably not seeing that anymore. It used to be more common. Who do you think is still the appropriate candidate for a cryo?
Stuart:Yeah, so the big one for me is that they have a negative ECC, so it is difficult. There are some tips on the cryo gun that can get up into the cervix a little bit If they have H-cell on their ECC. I'm much more likely to do an excisional procedure on those patients. Cin2 with kind of a surface lesion, I think is your ideal candidate, maybe one who potentially would want future childbearing or for whatever reason. You don't want to deal with the bleeding and whatnot that could come from these excisional procedures.
Howard:And leap versus cone. I think a lot of big leap advocates would say a leap with it plus a top hat. I can do almost anything I could do with a cone. It's just people's comfort level at this point.
Stuart:The recommendations have changed now for top hat, definitely for AIS, but really for CIN as well, where that fragmentation can be really tough on your pathologist. So that's another one where, if the ECC is positive, I am more likely to do a cone because you can tailor it a little bit more. These are tough. When you look at retrospective data sets that look at preterm delivery, those tend to be higher in the cone group. But in the ones that look at how much of the cervix is removed, we think that may be a piece of it right. So if you have either multiple procedures or more of the cervix removed, that may increase your risk of preterm delivery more. So I say all that to say that if I have a patient who desires fertility and needs one of these procedures, I don't necessarily say that I would not do a cone, but I would probably do it in a more tailored fashion.
Howard:Yeah, you can control how much you take.
Stuart:Right, exactly.
Howard:And I think what you're saying is, if we're going to take a centimeter and a half and I do that with a cold blade versus I do that with a leap and a top hat the effect on preterm labor is probably the same, exactly, yeah, because it's the same length, and so I need to get the length I need to get.
Stuart:Yeah, and if I'm concerned, if the patient has a long history of HPV 18, for instance, I want to get my pathologist the best shot too. V18, for instance, I want to get my pathologist the best shot too, and I think these things. Sometimes we think pathology is just reading numbers off of a screen or something and it's not. There's a lot of art to it, and when we work with our pathologists to set them up for success, I think it helps too, absolutely Okay.
Howard:Well, I know we have a history segment coming up later the radium you mentioned but I did see this article recently about. I guess we've come up on the 100th anniversary of last year of Henselman's seminal colposcopy paper, and colposcopy now, of course, is an integral part of how we tie together the cytologic findings, or maybe evaluate in the future the HPV findings, to a histologic diagnosis from our pathologists that we can then use to inform our treatment. So this was developed really by a German named Henselman in the 1920s and colposcopy was, and it set the stage for identifying cervical cancer at its earliest stage. He didn't have all these ideas when he first started with it, but it afforded people the ability to think about how do we find dysplasia, pre-malignant, pre-invasive disease, before we see this tumor. So before Kolpowska, if you think about it, all you could really do if you read Kelly from 1900s all you could really do was just look at the cervix with your naked eye and if you're seeing something, you're seeing almost certainly an already invasive tumor. If you're seeing a cancerous growth or maybe you could palpate it with your finger, but again you're going to palpate almost certainly an already an advanced and invasive tumor and so, frankly, most of the patients who even present with symptoms like persistent bleeding or pain, they're going to already have advanced tumors.
Howard:So prior to the colposcope we didn't have pap smears. At that time we didn't really have anything but physical exam and history. So Henselman worked at the University of Bonn and developed the colposcope and it had a 10 to 20x magnification view and it had better light source and then it could help direct biopsies and understand what we were looking at and give the opportunity to develop Lugol's and acetic acid and play around with a lot of other things over the years to try to enhance what we were looking at. And at the time, as I said, back then, we didn't have cytologic screening. That came later, what we call the pap smear. That, as you mentioned, came in a few decades later, really with George Papanikolae in the United States. So when Henselman first had this colposcope, I think the idea was to use it as a primary tool to look at the cervix. There was no pap and again, it took a while to learn what we were looking for, what the different lesions represented, what to biopsy, what not to biopsy. But it was introduced first in March of 1924, so the 100th anniversary was last year Now.
Howard:Unfortunately, most of the advances of understanding about these lesions and what we were looking at and the clinical correlations and implications, unfortunately a lot of that came out of experimentation on patients at Auschwitz.
Howard:So there's this huge dark side to Henselman and a lot of science that was happening pre-World War II and a lot of people took advantage of what the Nazis were doing and they continued their research in some pretty dark areas. So he did supervise experiments on colposcopy that were conducted by Dr Edward Wirth at Auschwitz and he also participated, before the war started, in the forced sterilization of at least six gypsy women, which is something that was very common and in vogue in the late 30s in Germany, and he was sentenced to three years imprisonment and convicted of war crimes. He continued his work after that. He continued to do things after the war. This happened to a lot of people. But he's also infamous for never having in his career accepted the idea that leukoplakia was an important thing when we did the eponym episode a while back and he was one of our examples of doctors who go beyond the Sims line.
Howard:Right, yeah, so a clear example of someone beyond the Sims line. So well, let me just add one thing about vaccination against HPV. Australia may be the first country to eliminate cervical cancer, and I will say it's not that the US is horrible, but Australia leads the world and compared to other countries in the world, the US is actually doing really well, but Australia is the gold standard. So we define a rare disease in epidemiology as something that occurs with fewer than four cases per 100,000 women in this case. And Australia is on the way to making cervical cancer a rare disease, which is where we define it as doing as much as we can.
Howard:So, just like in the United States, they started there with the quadrivalent vaccine and now for several years, of course, they've been using a non-availant vaccine, which expands the number of cancers that should be prevented. We think that the non-availant vaccine prevents a little bit better than 90% of all cervical cancers and of course, it also will prevent other HPV related malignancies as well. Think all those head and neck cancers and even penile cancers and some things like that. So the estimate is that there will be 5.7 cases of cervical cancer per 100,000 women in Australia when the final 2024 data is available and that's half of the rate that they had just 20 years ago and that's basically exclusively from vaccination. And the plan in Australia is to virtually eliminate it, at least have it well below that rare disease marker with improved non-availant vaccination by 2035. And the difference, of course, is you mentioned that we're not doing quite so hot on uptake of the HP vaccine. They're doing fantastic and it's culturally widely accepted.
Stuart:Yeah, that's really impressive and I do think there's such a great example for that. So, but I think we probably should move beyond prevention and maybe talk a little bit about cervical cancer. Now what do you?
Howard:think, yeah, screening can only do so much. Prevention is the real cure, and for every case of cancer you've also prevented all those comorbidities that the screening and treatment process entails, like the procedures to the cervix and the leaps and the colposcopies and the cones and the infertility and the preterm birth and all those things that we thought about beyond that. And prevention with vaccination eliminates all those things. But at some point some people are still going to have cervical cancer and so this is how you, this is one of the ways you make your living, so I guess we have to talk about it, that's right.
Stuart:That's right, so. So the article goes a little bit into staging and I realized recently I keep referring to it as the new staging and it came out in 2018.
Howard:So when I was in what we learned it was so different.
Stuart:It really we went from being a completely clinical diagnosis to one where you can use imaging and you can use pathology and you really can use all of your techniques to to arrive at a staging. When I teach my med students I sound like the old fogey when I keep saying the new cervical cancer staging. So now we do use these imaging modalities. We use PET scans, mris. A lot of times we'll use both of those, especially with early stage disease where we're trying to determine the spread, or in locally advanced disease when we're trying to determine our planning for radiation.
Stuart:The cervical cancer spreads in a couple of ways. One is by direct extension into the parametria, and that's why our pelvic exams are so important when we do these for cervical exams, to do a rectovaginal exam to feel the parametria, because anything in that area it really just bumps the stage up. And then also it spreads by lymphovascular space invasion as well or lymphovascular dissemination. And lymphovascular space invasion is a precursor of that. And before the lymph nodes were incorporated into the new staging we actually recognized that lymph node involvement was the most important prognostic finding and so it actually makes sense that now that's a part of the staging, but at the time previously we would just put in a little addendum that the lymph nodes were involved.
Howard:Yeah, and the FIGO previously didn't use those advanced technologies for staging because this was predominantly and is predominantly a disease that affects countries that don't have the ability financially to offer PET scans and MRIs, and so they tried to make something that fit the capabilities of most of the countries that were affected by it.
Howard:But they also, when they changed this, recognized that if you have the information available you can do something with it. So I think it took a while to embrace a staging system that took more resources to properly stage the patient. Essentially, when I think about staging, I think of the three big categories of essentially not an oncologist, of early stage, locally advanced and, of course, metastatic disease. So in early stage disease the tumor is going to be relatively small, the diameter is less than four centimeters, there's no parametral involvement. And then for locally advanced cervical cancer, the tumor has spread by extension into the surrounding parametria or other pelvic structures. And then, of course, metastatic disease has traveled via lymphatic spread and includes nodes or other distant meds outside of the pelvis or deeply into the bowel or bladder, things like that.
Stuart:Yeah, exactly, and the treatment for these three different categories really differs a lot and really update that. We see in this article and if you haven't followed this stuff as closely as of late, there really are some changes in the last four to five years that I think are worth drawing out. The biggest treatment changes are just to summarize them and we'll talk about them more specifically, but I would say, less radical surgery for early stage disease and then the addition of immunotherapy, both in locally advanced and metastatic disease. So those are the big categories of changes. For early stage disease, surgery is the mainstay of treatment and the earliest stage of surgical cancer is actually microscopic. So if you can see a tumor, you're actually already stage 1B.
Stuart:But 1A is the microscopic version and for these small tumors, most of these can be cured with either a conization with negative margins or an extrafacial hysterectomy. And that's been true for a long time, especially for 1A1 disease where the depth of invasion is less than three millimeters. But once you get into visible tumor the patient does need a little bit more surgery. The patient does need a little bit more surgery, but it used to be that patient needed a radical hysterectomy, so a removal of really the parametria around the cervix not just the cervix but the parametria, the uterine arteries, sometimes all the way out to the origin, the uterus, sacral ligaments, the upper third of the vagina.
Stuart:Really a large surgery that unfortunately had a lot of effects on the nerves around the pelvis and of the vagina really a large surgery that unfortunately had a lot of effects on the nerves around the pelvis and to the bladder and to the bowel, as well as higher rates of fistula and that sort of thing and sexual dysfunction that would come from a shortened vagina. So a lot of those things were standard for a long time and that's really changed, particularly for these smaller tumors now, and these changes are based on phase three data. So a couple of large studies and now actually the NCCN guidelines allow for a type A or a simple extrafacial hysterectomy for treatment. The difference and the reason that an oncologist still performs these simple hysterectomies is that you still need a lymph node assessment for these, and so when I do these cases I will do a simple hysterectomy, but then we'll usually do a sentinel lymph node assessment with that as well. But really it's really changed the way that we help to treat these early stage diseases.
Howard:Yeah, and we talked about some of these concepts before we remember. We talked about the history of radical surgery in general and how we've we started out and we've started to be more fine-tuned with our scalpels over the decades. But but it also highlights, I think, this idea about the levels of prevention again, because the earlier the diagnosis, well you're doing tertiary and perhaps quaternary prevention, but you're preventing some of the morbidities of a radical hysterectomy and some of the consequences by affording them a much more simple cure.
Stuart:Yeah, and I think this is really good news for patients who really used to be very affected by these surgeries. So the quality of life improvement is really a huge thing. There was actually one of those phase three trials. Quality of life was actually the primary outcome, which is not very common, but that was one of the big GOG studies. Okay, so that's big update number one. The other big update is both in locally advanced and in metastatic. But for locally advanced, the core of the treatment really hasn't changed that much.
Stuart:We still manage these not with surgery, but with primary radiation, with sensitizing chemotherapy. So we give them like a whiff of cisplatin with that to make the radiation work better. And that's the standard of care and it's been so for a long time, over two decades. And we've also known for a long time maybe counterintuitively that you don't have to remove the uterus if you have a complete response from radiation and in fact a post-treatment hysterectomy just increases the risk of fistula and a lot of the morbidity. So there's no changes. This is all stuff that's been around for 20 plus years. The difference is a couple. One is that for the radiation oncologist the radiation has changed a little bit, particularly the external beam portion, and so that has changed. It used to be this sort of nonspecific kind of box where they would just try to eyeball it in the field or they would use actually bony structures to help orient the field for the linear accelerator to deliver the radiation. Now they use what's called a conformal radiation, which is all done by computers and the goal there is to minimize off-target effects. So it lets you basically deliver higher dose to the tumor without affecting the bowel and the bladder as much. So that's a big difference. The brachytherapy piece, which is where we actually use the radioactive source and that goes next to the tumor, so usually a tandem that goes into the uterus and ovoids that treat the parametria All that has still been the same this Tawari article does discuss. I really like in this article that it doesn't just focus on the US and it looks at the approach in the developing world. And this article does discuss some alternative approaches where brachytherapy isn't available because it is a specialized thing and we know that survival is better when brachytherapy is used. But there are some ways to use chemotherapy and some other techniques to improve survival as best you can for patients who may not otherwise be able to do that One.
Stuart:Negative trials we don't like to. They're disappointing in some ways, but they are important to point out. And a big negative trial did come out it's now, I guess, about two years ago. It was published in May of 2023. It's called the Outback Trial and what that trial showed is that the addition of chemotherapy full course of chemotherapy to these patients did not improve outcomes and unfortunately, a lot of oncologists were assuming that it would. Based on kind of small retrospective things that seemed to show that people who got some more extensive chemotherapy did better, and so a lot of people actually change their practice and we give full dose chemotherapy in addition to radiation. But this very well-designed trial that had almost a thousand patients in it showed no overall survival benefit. So we need these big, even though they're disappointing. We need these big trials to help guide our coronary prevention right, so picking what is the thing that the patient actually needs and not over-treating the disease. So I will say that probably the biggest practice changer for me has been the addition of immunotherapy to radiation, and that's something that makes a lot of sense when you think about how immunogenic cervical cancer is, how the body's immune system handles the dysplasia from the virus and how immunocompromised people like patients with HIV are much more likely to get cervical cancer. All of these things make sense. So immunotherapy has a theoretic basis and then also it's, for the most part, has fleshed out on the trials that we're seeing some benefit from that.
Stuart:There was an interesting kind of disagreement with this, because there were two parallel trials that used different immunotherapy options and had different results, and they were very similar trials. The only difference was the drug, but the mechanism of action was the same, and so there was a lot of thought. Okay, they were trying to parse out what exactly is the difference in these trials? Why was this a positive trial? Why was this a negative trial? So what do I do as an oncologist? I treat with the drug that was in the positive trial, because that's what's made it to the recommendations, that's what's in the NCCN, but I do think it's a good discussion. What do we do with trials sometimes where maybe the only difference is this one thing?
Howard:Yeah, we make these mistakes all the time and over time who knows what will pan out?
Howard:This won't be the only two studies, and immunotherapy and things like this is the future of a lot of medicine.
Howard:This is going to accelerate rapidly and happen during our careers. So who knows what the next trial will show or if we move on to different agents and things like that. But I do think it's possible that a third trial will it'll agree with one of the two and it'll, and then we'll change again. And I do think that when you're dealing with cancer and things like that, you have a more of a liberty to take positive results and, as long as there's no huge negative and the patient wants that, you have the liberty to be more aggressive, to maybe expose someone to a treatment that might have some downsides but could have a big upside. I think the standard of evidence and the timeline for establishing that is lower and shorter, because you have patients who could potentially suffer just tremendous morbidity that might have been prevented. So err on the side of giving and then if the third and fourth trials show that it didn't work, then we'll talk about that in five years.
Stuart:Yeah, absolutely, and unfortunately with oncology trials overall survival is the standard, but there's a lot of inputs to overall survival and it's particularly in this was in primary treatment, but particularly in the ones where maybe it's like third line treatment. There's a lot ones where maybe it's like third line treatment. There's a lot of things that go into that overall survival picture. So we do tend to use surrogate endpoints like progression-free survival and those sort of things sometimes. But anyway, I'll give the kind of the final update for treatment and that's for metastatic disease and usually these trials include both metastatic and recurrent, so it's typically disease outside the pelvis or recurrent disease. Just because there aren't a ton of these patients and to get the trial numbers, they tend to be combined. Tawari put a really good figure in figure three. I thought was a great visual of how overall survival has really improved over time.
Stuart:For first-line therapy for metastatic disease Back in 2013, the standard of care was chemotherapy plus bevacizumab, which is an anti-angiogenesis drug, and that's really been the standard for a long time. But overall survival was only 17 months, so only half of the patients were alive at 17 months. And then by adding immunotherapy, we're now seeing these median survivals six to 12 months longer than that, so well over two years. So I know that sounds. Sometimes we jump up and down and get excited about things like four or six months of survival, but what we're talking about is a really bad disease where there are essentially no cures. A cure is very rare for metastatic disease, and so we do get excited about what might seem like marginal improvement, but it's yeah.
Howard:Well, it just shows the importance of prevention. Yeah, absolutely, an ounce of prevention is worth a pound of cure. If that was Ben Franklin, whoever, that was Okay. So on this subject, you talked about some of the results earlier of the SHAPE trial. Yes, that changed some of the radicality of the surgeries I think a bit. But there's a new trial this past week in JAMA Open Network, I think partly out of the group at Walter Reed, and they looked at over 2,600 patients who had either a 1B1 or a 1A2 cervical cancer I think all of them are one of those two and they found that they had similar three-year, five-year, seven-year and 10-year survival rates, with similar rates of positive margins, lymphovascular space invasion, pathologic node mets, 30-day hospital remission rates of adjuvant treatment. All the things they looked at were the same among these patients who either had a simple hysterectomy versus a modified radical hysterectomy or a radical hysterectomy. Now I think the SHAPE trial had a lot of foreign patients in it, for sure, yeah.
Howard:This was primarily US patients, but is this going to change anything else? Does this add anything to SHAPE, or are we waiting on a different trial now? Does this inform another trial? Is this the same findings of SHAPE or something more?
Stuart:I think actually what's interesting about it is it looked back for several years.
Announcer:What's interesting is people were doing what we showed in shape before, before the shape trial actually came out.
Stuart:So I think this would be my and I know that the lead author of this he was one of my former attendings. I actually want to ask him this question. But what does that say about the people who were doing not the standard of care beforehand, but so?
Howard:so then, even people who weren't doing the standard of care beforehand.
Stuart:But so then, even people who weren't doing the standard of care beforehand, they still turned out pretty good. So I think a lot of people think that early stage cervix is going to end up like endometrial right, like we cure endometrial cancer 85% of the time with a hysterectomy. Simple hysterectomy, simple hysterectomy. Yeah, simple hysterectomy. And so I think that people are hopeful that maybe we'll see something similar for cervical cancer.
Announcer:Yeah, yeah, I was going to say everybody's hopeful, except the fellows, because this means pure and pure, radical hysterectomy.
Howard:Pure radical hysterectomy, but it confirms the direction that shape has taken. Things with a US-based population, absolutely yeah.
Stuart:I think we have to look at these things together and I think this is a great, I do think it's a great paper to kind of to dovetail into this conversation. Yeah.
Howard:Well, I know that you've long had an interest in Howard Kelly. For the listeners that don't know, stuart and I nerd out on OBGYN history. We have competing Howard Kelly collections. Together we might have the finest private holdings of Howard Kelly in the world. But you've also had some research on your own about his work with radium, which is not super well published. In his own writings he does talk about it and so you might be one of the most knowledgeable people on this in the world, but I'm excited to hear a little bit about his use of radium and obviously it relates to cervical cancer and other malignancies.
Howard:Radium was discovered originally, of course, in 1898 by Marie and Pierre Curie and in the early days it was a panacea right. They thought this was everything, it was going to cure everything and, like a lot of things, the original adopters were over-exuberant and they overestimated the benefits of radium and way underestimated, of course, marie Curie did, the potential risks. But people did realize that it had the ability to shrink cancer tumors and in particular, cervical cancer became an early target for it. I think another thing I always think about with history of surgery and history of gynecology if you look at the development of surgeries and even like vaginal hysterectomy in the early 19th century.
Howard:Well, if you're in 1840, when surgery is so dangerous and you want to actually risk operating on somebody, one of the few things that you could diagnose with the tools available at the time no CT scans, no blood work, nothing like that that involved an intra-abdominal organ with cervical cancer or maybe uterine cancer, because you could look in the vagina, you could see the lesion. The patient was bleeding, was going to bleed to death. You knew she was going to die. The risk-benefit ratio made a lot of sense. So a lot of early gynecologic surgery focused on either massive ovarian cysts that were causing obstruction and you knew the patient was going to die, or they focused on cervical cancer. And so by the time you get, the field grew up with that and Howard Kelly today if he were alive today we'd call him a gynecologic oncologist and he practiced in that era when radium before and after radium was discovered. And so tell us a little bit about that.
Stuart:Yeah, thanks. Yeah, this is a really fascinating subject. I think Kelly in general is just a fascinating human, but particularly with radium, particularly with kind of the zeitgeist of what people were looking for as far as cures and things like that. This is the era shortly after the World's Fairs and those sort of things. People are very knowledge hungry and are very interested in these sort of things.
Stuart:But yeah, I actually got to go to the Chesney archives up at Johns Hopkins and read some of his letters and a lot of them actually had to do with his acquisition of radium and his use of it. He wasn't actually the first to medically use radium in the United States, so that honorific belongs to Robert Abbey, who was a physician at the New York Cancer Hospital and there's some letters between Abbey and Kelly in that collection. Abbey got radium bromide directly from the Curies in 1903 and specialization was different than you would consider him a surgeon. But he also did a lot of skin tumors and things like that. So he tended to use it for like skin cancers and but he also treated like tonsillar cancer and then erectile cancer as well, also things you can see without fancy equipment.
Stuart:Yeah, you're right, that's a great point. So Kelly got his hands on radium the next year, in 1904, but he didn't really start using it until its true potential or until about 1909 or so. That's when he starts publishing more monographs and basically you'd say, kind of collections of case reports, which is the way that people publish things. Back in the day, howard Kelly was passionate, opinionated and actually lost a lot of friends through his maniacal pursuit of many things, but one of them being this treatment. But one of them being this treatment. There is a great quote from a colleague in the in those that archives that says he said of Kelly I'm aware that he becomes ultra enthusiastic on certain things and is likely to get let his enthusiasm get away with his good judgment, and so I felt like a good descriptor for him. So from all my readings with Kelly, I really I think he had a good heart, but he tended to go a little bit crazy when it came to these things.
Stuart:There was also some academic drama too. Kelly was one of the big four who, along with Osler and Halstead and Welch, helped to found Johns Hopkins. But Hopkins, the board made a rule that prohibited professors from billing for private patients, and Kelly was like the Robin Hood of medicine. He would charge these astronomical fees for rich patients and rich patients would come from all over to be treated by him. But then he would turn around and treat poor patients for free and sometimes as was probably more common back in the day before IRBs and such he would try out some of his new treatments on some of these patients who couldn't pay. But he also did do a lot of charitable work with the poor.
Howard:People are complicated.
Stuart:People are complicated.
Howard:For sure, a lot of things that happened back then were not weird at the time, but we view things through a different lens and you have to be careful about that, yeah, you're absolutely right.
Stuart:Yeah, and I feel like for my study of him, like I know, I feel like I know him as a person I've read so much of what he's written Like I really do think he was a good person like, who cared about people. I think he just lived in his time. So, anyway, he ended up opening his own hospital and resigned his Hopkins professorship when they made him choose between his hospital and remaining on the faculty. But at that point Kelly actually had a monopoly on radium and this gave him a lot of leverage. But it also led to a lot of strife because Hopkins had to send their patients over to him to be treated and he got really obsessed with controlling radium. He actually even testified before Congress to try to keep the mining of radium private and he founded the National Radium Institute. That was basically a lobby organization to work with that as well. And by 1917, really because of kind of his political wrangling he had five grams of Pyridium, which was the largest quantity anywhere in the world at the time.
Stuart:On the medicine side of things, he kind of started off treating maybe superficial things here and there. It definitely wasn't only GYN issues, but he would zone in on inoperable cervical cancers, vaginal cancers, and would use them for that treatment. The way he would do it was a little bit more akin to like low-dose radiation what we would consider low-dose radiation today, which has fallen out of favor for GYN use but essentially these were like applying the radium to the tumor for hours at a time. He actually understood a fair amount, things like the inverse square law and things like that that govern the distance of the source to the tumor and the amount of radiation that the tumor would see. And eventually he was getting he was publishing response rates of 30 to 40%, which was certainly better than the surgical response rates at the time.
Stuart:He also branched into treating things like fibroids and stuff like that, which kind of sounds crazy, but remember, this is the pre-antibiotic era. Myomectomies were basically you didn't do them unless the fibroid was prolapsing out of the vagina, and so he would be creative with these sort of things. So there was a high profile patient that he treated actually for a tumor up in his shoulder and that patient ended up dying and there was an investigation. It's hard to know whether this investigation was really medically driven or driven by jealousy, but anyway he ended up being censored by the Maryland Medical Society for what they consider to be medical ethics violations, which is really conflict of interest, is what we would see it as and behaving in kind of this overtly competitive manner.
Howard:A lot of pioneers face this. That reminds me of Carmen Nejat, who is the pioneer of video laparoscopy in the 1970s in this country, who had all sorts of problems because people thought he was a cowboy and a derelict and all he actually did was invent minimally invasive surgery and save thousands of people's lives. But he had issues just like that with some of the governing bodies. But when you talk about the big Fort Hopkins, I always remember, though, that Howard Kelly also gave us Whitridge Williams, the author of Williams Obstetrics.
Howard:Williams was a Baltimore native. He had gone to medical school in Maryland, he'd gone to study, actually, pathology and microbiology in Europe and then came back to Baltimore, started work at Hopkins and was, I think, really interested in pathology, and in fact it seems like he was great friends with Welch. In fact he dedicated, I think, the second edition and maybe the third or fourth of Williams Obstetrics to Welch the pathologist one of the big four. But anyway, by the late 1880s he had gotten down the obstetrics pathway and Kelly was all too happy to give obstetrics to Williams so he could just focus on gynecology, and Williams eventually became the chair of that department and wrote Williams Obstetrics, the first edition in 1903. And it actually was dean of the medical school from 1911 to 1923. So I always think of him as number five of the big four. He wasn't there at the founding but his influence over modern medicine is profound, so he's number five.
Stuart:Yeah, it's a Stuart Sutcliffe or maybe Pete Best kind of figure yeah Right, yeah, the fifth Beatle.
Howard:Yeah Well, listeners will have comments on that, because everybody has their own fifth Beatle. So if you think it's Sutcliffe or Best. It was a fifth Beatle, but you got to throw in George Martin and Brian Epstein and I think there's probably 10 other people. So we don't want to get the Beatle fans riled up. We've got a whole real problem if they start emailing us. But yeah, some other time we'll do an episode on which Beatle which of the big four matches up with best. But we'll have to make Kelly Paul McCartney.
Stuart:That's what I'm going with I think you're right. Yeah. He was young, very young. He was like 29 when he became full professor. So I've got a little bit of a denouement to that story. So you might wonder what happened to the Kelly Hospital.
Howard:His private hospital, his private hospital.
Stuart:Yeah, so it was right down the street from his private apartment, which actually is still there. It's 1408 Utah Street. If you ever want to go see it, there's somebody renting it now. But anyway, the hospital was just on the road from there and in the 50s it was nearly burned to the ground by a six alarm fire and it was just left there. The radium had been disposed of, but I guess eventually a US public health inspector came around and found what was like quote astronomical levels of radiation throughout the complex, and so they made the building stay vacant for a long time. Eventually it was cleared for a public park and you'll go there now and there's like all these mounds all over and supposedly I'm still looking for the records on this but supposedly they buried the stuff deep, deep underneath there, but now there's no surface radiation, so inverse square law in effect. That's far enough away, yeah.
Howard:But the half-life is long.
Stuart:It is. Yeah, iridium's half-life is like 1600 years, so we don't use it anymore, partly for that reason. It's also not as easy to use, like Iridium is a thing we use now which has about a three-month half-life. So it makes a lot more sense, a lot more sense.
Howard:A lot more pragmatic. Yeah, yeah exactly All right. Well, we'll have you back on again next season and some more history stuff to go. If people nerd out on history. You can ask us some history questions, because this is the stuff we really like For sure. And Tony and I will see you guys in a couple of weeks. Thanks for being on, Stuart.
Stuart:Great, thank you.
Announcer:Thanks for listening. Be sure to check out thinkingaboutobgyncom for more information and be sure to follow us on Instagram. We'll be back in two weeks.