OK. Hi, everybody. Thank you so much for having me. For those of you who joined late, I'm Rachel Masch. I am an obstetrician gynecologist working here in New York City. I also work with a nonprofit organization called Basic Health International with a mission to eliminate cervical cancer globally. So I've been working with IGCS for several years now and really appreciate the collaboration. And I'm really happy to be here today. The title of my talk is What's New in Thermal Ablation. New, I realize I should probably put in quotes because it's not so new. But we have new research that's kind of hot off the presses that I wanted to share with you. And then just clarify some issues that I think need to be addressed so that we can try and have more standardization in this treatment alternative. OK, so OK, let's see how I can advance. OK, so here are the learning objectives. I hope we're going to review some of the components of thermal ablation, which I am going to say TA. That will be thermal ablation. I will use that throughout this talk. And how it works and when to use it. And discuss the different protocols that are out there for performing TA. And cite some research supporting the use of it. And then talk a little bit later about future, what we can do in the future to help us maximize this really important treatment. These are my disclosures. OK, so let's get started. So thermal ablation, one of the first things we hope to standardize is what we call it. It has lots of other names, such as cold coagulation, thermoablation, thermocoagulation. But we're going to, we're trying to come to some consensus that we should call it thermal ablation, just so that we're all talking about the same thing. It was developed by Kurt Sem in the 60s and has been used in the United Kingdom since the 70s with a desktop device that's pictured here on the right hand side. It's called, they call it the mains unit, and it requires electricity. It needs to get plugged in. And whereas it's not so big nor so heavy, it is difficult to, more difficult to transport than some of the newer devices. And again, requires electricity. Just to review how thermal ablation works is it ablates tissue by using heat rather than cold, which is what cryotherapy does. And it blisters the superficial epithelium of the cervix and gets to the underlying stroma and glandular crypts that are there that are destroyed by the heat. And a meta-analysis shows that in high resource settings, cure rates can be as high as 94%. There's some more recent data that I'll get to in a few moments. But there are, because of the bulkiness of this machine, there are some new modified devices that are available that are safe and effective and seem particularly promising for LMIC. And I bet that many of you are perhaps using them in your clinical settings. These are the three that are currently available commercially. To be full disclosure, I've never used a Medgyne handheld device, but I have used the other two, the Wysap C3 and the Liger device. And they are pictured here. So similarly to cryo, TA does not require electricity. But different than cryo, it also does not have a consumable. So cryo, one of the big problems with cryo is getting the cryogen gas, which can be expensive, difficult to transport, even dangerous when transported in hot conditions and bumpy rides. So the TA is battery operated and has a battery. One of them has a battery that's integrated into the device, and one has a battery that's connected to the device. But both work really well on batteries for many, many treatments before needing to be recharged. It does not require anesthesia, and it weighs less than a kilo. So it's about the size of a curling iron and therefore can be stuck into a backpack and easily transported far distances without concern. It also can be performed by many different levels of providers. So it does not have to be a physician who performs that, unlike, for example, a LEAP in many places. The requirements are that a physician perform a LEAP. This is not the case for TA, similarly to cryo. Side effects are usually well tolerated. It's faster than cryo. It has good efficacy, which we'll discuss briefly, and complications are rare. So similarly to cryo, women who screen positive are eligible to get a thermal ablation treatment if you don't think that you have cancer, that the person has cancer. And that means that it doesn't extend onto the vaginal wall or far into the endocervix, which is a transformation zone type 3, which I'll show you in the next slide. So you need to think that you can see and treat the entire lesion. So the squamo-columnar junction needs to be identified completely, which is a transformation zone type 1 or 2. Also, TA is not recommended if a patient is pregnant or less than three months postpartum, nor in those who have active pelvic inflammatory disease. So these are the different transformation zones. You can see on the left, type 1 is a completely ectocervical lesion, and it's fully visible, whereas a type 2 has a small endocervical component, but also the lesion is fully visible, whereas a type 3 has a more significant endocervical component, and the higher parts of it are not visible, and that is something that needs to be referred in most settings. Here are some of the probe tips, but not all of these are currently available, but there are a wide range of shapes and sizes, and the probe tips are used at the clinician's discretion. So to the left are some of the probe tips used for the YSAPC3 device. The middle one there, I don't know where my pointer is, but the middle probe is not currently commercially available, and the larger probes are the ones to the right, and these three are what come with the device, these three, 16-millimeter flat, 19-millimeter flat, and this nipple probe, a 19-millimeter nipple probe. Those come when you order the LIGER device. So in 2019, the WHO actually published guidelines for thermal ablation, but there was not as much guidance in terms of exactly how to perform it specifically. So the most effective application method for these handheld devices has still not been determined. So people who have these devices vary their treatment duration. Some do 20 seconds, some do 30, 40, some do 60. I think we've all pretty much agreed on the 100 degrees Celsius, and that's what these typically go to, but different probes are used in both single and multiple applications, and there's not standardization thus far. So again, TA has shown to have a really good overall cure rate of up to, you know, in the high 90s, but it is lower in low- and middle-income countries and lower still, excuse me, if you only use a flat probe. So most articles talk about persistence of disease of about 4%, and that is in a non-HIV population with recurrence at six months to three years, roughly of about 13%. So our colleagues in Scotland, who have most experience using this desktop device and have been using thermal ablation, again, since the 70s, use a two-probe approach, use this desktop device in a two-probe approach. So the first probe is this endocervical probe, which is here. I don't know if you can see my arrow, but it's here on the right-hand side on the bottom picture. That is what they call, they call it, they don't call it an endocervical probe. That's another thing, our terminology differs, so we are trying to standardize terminology across the board for these things. But they put that into the distal endocervix and ablate the cervix at 100 degrees C for 20 seconds. They then remove that and switch to a flat probe, which is pictured there on the left, on the bottom picture. And then the flat probe is used in overlapping applications to ensure that the entire SCJ is ablated, and each application lasts for about 20 seconds. So in a paper that they published back in 2022, they have biopsy-confirmed cure rates for over 20 years, and you can see here that their cure rates are quite impressive. One thing to know about this area is that they had less than 10% of women who actually left the area, so they have a quite an insular population, which enabled them, both their national EMR and the fact that there was not migration out of the area, allowed them to follow these women for all of this time. So impressive. So at Basic Health, we thought, well, how do we do, how do we mimic that success in a portable handheld device? And so we wanted to just confirm first that the alternative devices, the non-gas-based cryotherapies, a device called the CryoPen, which is no longer available, and the thermal ablation are non-inferior to our standard, which is gas-based cryotherapy. So we did a three-arm randomized trial in three different countries, El Salvador, China, and Colombia, and we saw 1,152 women who had biopsy-proven CIN2+, and the study was powered to detect non-inferiority of the alternative treatments against the gas-based cryotherapy. And our primary endpoint was biopsy-proven cure rates at 12 months. This was a Cleveland Clinic project that Basic Health actually did in those three countries. So this is kind of hot off the presses. This was presented at IPBC in Scotland just in November. These are our cure rates with the different devices. So you can see the gas-based cryo versus the CryoPen versus the thermal ablation. All had 12-month cure rates of greater than 90% for CIN2+, and greater than 95% for CIN3+, that's listed there. So quite successful and good efficacy. So here's the non-inferiority margin, which you can see the red line all the way to the left here is the non-inferiority margin. And this indicates that the thermal ablation relative to cryotherapy is indeed non-inferior. In terms of side effects, the thermal ablation was seen to have slightly higher pain during the treatment, but then resolved to be the same as the others shortly after the treatment was over. In terms of cramping, discharge, and spotting, roughly similar in terms of all of those side effects. Patient satisfaction was high when we saw them back for their six-week visit. Overall, that 91% were satisfied specifically for thermal ablation. It was a little higher at almost 94%. And then at 12 months, the satisfaction actually increased to almost 97% for all of the different devices. We didn't have many adverse events. There was one patient hospitalized after cryo for PID, one patient who needed antibiotics after cryo for an infection, one patient who had, at their six-week visit, had some stenosis, which meant that a cytobrush could not be passed through their cervical os, and that was after a thermal ablation. That was one patient. But no one needed blood transfusion, and there was no one who died. This will be published relatively soon. We're sending it in. I think we're finishing the final draft and sending it in within the next week or two. So look for that. It should be coming soon. But after we got these results, we were like, okay, so we know that it's non-inferior, but can we mimic the two-probe desktop approach with a handheld device? Because we didn't have the same probes that the mains device, the desktop device, had. So another study that is just getting off the ground, we hope, is we are trying to modify this device that's up here on the upper right-hand side, the Iris device, which is a Liger device that is both a thermal ablator and a colposcope in one. And we are trying to make endocervical probes that are similar to the ones used in the desktop device that they've used in the UK, which had such great data. So we're trying to make, this is a prototype that you see here on the bottom picture. We're also making the probes longer. It's going to be, the probes themselves won't be longer, but there'll be an attachment that can make the probes longer if someone's body habitus is, if you're having difficulty reaching their cervix because of the long vagina or the body habitus makes it difficult. So we're trying to make it easier to see and to reach all different types of services and anatomies. We also are going to develop a smaller, a 10 millimeter flat probe for those who have very small cervices. In addition to the probe modifications and development, we're also going to, in this device, this Iris device, we're going to incorporate a deep learning algorithm that will give us what we call automated visual evaluation, which allows us to take an image to make sure that the image is clear and then there is a diagnostic classifier, which based on the image and some data from the patient, such as their HPV genotype, history, and some other demographic information, we'll be able to say whether or not this is, we'll assign it a number and that number will give us whether it's negative and intermediate or a high risk for advanced pre-cancer. So we're going to then, once we validate these probes and put that AVE algorithm into the Iris, we're going to test this out in 5,000 HPV positive women in El Salvador who will all have, so any HPV positive woman in El Salvador is treated, that's a Salvadoran guideline, but these women will have a VIA, a screen fired genotyping HPV test and a culpo biopsy and an ECC. And there will be a picture, an image taken, two pictures, two images actually, with this Iris device, with the AVE. Importantly, no clinical decisions will be made on the AVE. That's going to be aim three where we retrospectively evaluate that. But for this specific aim two, the primary endpoint is going to be the cure rate of CIN2 plus at one year. So here's the retrospective validation of the AVE algorithm. So with these images, we'll have two per patient, we hope, and it will be assigned a number which will then be put into a category of normal, intermediate or high-grade pre-cancer. And then we will take that diagnosis from the AVE classifier and see what the histopathologic diagnosis, which we will consider ground truth, that's the gold standard. So the AVE will be evaluated against the pathology. Again, we're not going to make any decisions using the AVE. We just want to see retrospectively how well the algorithm did in identifying higher-grade negatives and higher-grade disease. And possibly we can, based on the information we get from this, we can present a risk stratification system to the Ministry of Health of El Salvador to see if we can be more efficient in our triage and make sure that we get the women at highest risk treated first. I also want to talk about women living with HIV and how to address the persistence of CIN2-3 in these women who are treated with thermoablation. Some of the evidence, the 2019 meta-analysis that was available for TA efficacy showed evidence from 23 different studies, and the cure rate, again, was high for CIN2-3, was 94%. But only five of those 23 studies actually included women living with HIV, and only two of those studies were done in sub-Saharan Africa. Neither of the two studies that were done in Africa used biopsy-confirmed disease, which is considered gold standard, to define either the cervical pre-cancer cases or to evaluate the cure. What they did use was VIA, which we know tends to be much more subjective and nonspecific. A 2023 study out of India showed three-and-a-half-year treatment outcomes in a cohort of women living with HIV, and 32 of the HIV-positive women with biopsy-confirmed CIN2-3 who received thermoablation actually had follow-up, and nine of those 32, or 28%, had persistent, so almost a third, had persistent CIN2-plus at follow-up. Additionally, in Zambia, a 2020 pilot was presented looking at treatment success following a thermoablation, which they defined as type-specific HIV clearance at six months. In women living with HIV, treatment success was only 44%, as opposed to 83% in HIV-negative women. Our colleague, Chemtai Mango, who also did a study, groundbreaking study in Kenya, looking at CARE HIV-positive women who were offered colposcopy and biopsy, and if eligible, they then were treated with thermoablation. What was used for this study was, if it was a type 1 transformation zone, it was just one single flat probe, and if it was a type 2, it was a nipple-shaped probe, so not the endocervical probe, but a nipple-shaped probe, similarly to the one that I showed you with the Liger TA device. The device was heated to 100 degrees Celsius, and each of the treatment applications were for 20 seconds, and multiple applications were used to make sure they covered the entire lesion. Of note in this study, all of the participants had mean CD4 cell counts that were not different and were all above 400, and both groups had about 97% viral suppression at baseline. What was found in this study is that women living with HIV at baseline had 20.5% CIN2-3 at baseline, and at the 12-month follow-up after a thermoablation treatment, about 34% had persistence of CIN2 or worse, biopsy-confirmed persistence. So, treatment failure by baseline diagnosis, if women had a baseline diagnosis of CIN2, their treatment failure was about 23%, and if they had a baseline diagnosis of CIN3, they had an almost 40% treatment failure. So, HIV-positive women with CIN2-3 have high rates of treatment failure at one year following thermoablation, and the question is, why is that? And we hope to discover that. So, I just want to sum this up with some conclusions based on some of these newer studies, and what we found with the UH3 study that we did was that TA is non-inferior to standard gas-based cryotherapy, so I feel like we have good data on that now. We think that TA side effects are mild and self-limiting, and patients tend to be very satisfied with the treatment. However, we continue not to have any standard protocols on how to perform TA, what length of time, how many probes, which probes. So, we need to figure that out, and we do have good data on the two-probe approach in Scotland, and one of the studies we're undertaking now is to try and see if we can mimic that two-probe approach and see if we can come to some of those high-success treatment, good efficacy with that two-probe approach using a handheld device versus the desktop device. We also know that women living with HIV have high failure rates following thermal ablation treatment, so we need to explore the two-probe approach in this population because perhaps we're not getting to the entire SCJ, to the entire area that needs treatment, and perhaps the endocervical probe would allow us to do so. So, some future directions, looking at the two-probe approach, as I mentioned, in women living with HIV, establishing a standard protocol for the highest-efficacy TA treatment in both HIV-positive and HIV-negative populations, and then to think about perhaps where AI fits into all of this and how we can perhaps incorporate an automated visual evaluation into a triage protocol that can help to identify those women at highest risk. That's what here are my references, and I'm happy to take any questions.

thermal ablation

cervical cancer

Dr. Rachel Masch

portable devices

treatment protocols

AI integration