Irreversible Electroporation for Pancreatic Cancer

In this SIO Corner podcast, Elena Violari, MD, RPVI, discusses irreversible electroporation (IRE) for pancreatic cancer with Govindarajan Narayanan, MD, Miami Cancer Institute, Florida.

Transcript:

Elena Violari, MD, RPVI: Hello and welcome everybody. Thank you for joining us for this SIO podcast. My name is Elena Violari, and I'm an interventional radiologist in private practice in the Chicago area. I'm super excited because we have a great guest with us today, Dr Raj Narayanan.

Dr Narayanan is an interventional radiologist at Miami Cardiac and Vascular Institute, Chief of Interventional Oncology at Miami Cancer Institute, and Professor of Radiology at Florida International University (FIU) College of Medicine. Raj, welcome and thank you for joining us today. As an MCVI fellow, I'm fortunate to have worked and learned from you and I'm thankful for the great opportunity to continue learning from your awesome experience for this podcast today. Thank you so much.

Raj Narayanan, MD: Thank you, Elena. Honored to be here. I'm even more excited that you're doing the podcast, so thank you very much for having me as a guest.

Dr Violari: The main topic of our conversation will be to discuss [irreversible electroporation] IRE for pancreatic cancer and we will also discuss other applications of percutaneous IRE ablation. But before we dive into our topic, why don't you tell us a little bit about yourself, your career path, and background?

Dr Narayanan: Sure. I trained in diagnostic radiology and completed my residency in 2000, and then followed that with a fellowship in interventional radiology at the [Medical University of South Carolina] MUSC in Charleston, and then started my real career here in Miami back in 2005 as one of the junior attendings at the University of Miami and then 2008 I was promoted to the section chief and program director and then we continued to grow that program and by 2016 we established the first independent IR department in the country and I was honored to be the founding chair. In 2018, I moved from the University to the historic and legendary Miami Cardiac and Vascular Institute and have been at MCVI since then. It coincided with the start of the Miami Cancer Institute, which has grown tremendously since its inception and we're very proud and happy to be a part of this alliance.

Dr Violari: This is a fascinating journey. How did you get interested in interventional oncology specifically?

Dr Narayanan: The story is that back in 2005 at the University, we were also in charge of covering the Sylvester Cancer Center at that time. Interventional oncology had not yet become one of the main parts of IR as it is today. And I felt that there was the potential for us to develop that part of the service since we were affiliated with a cancer center and that we offer more minimally invasive treatment options that interventional oncology offer. But back ‘05 the only things we had were TASE and radiofrequency ablation, which is what we started with. And then over the years, that was a huge catalyst for the growth of the group and expansion and building more IO procedures like drug-eluting beads, Y90, and then evolving the ablation practice into microwave, cryo, and then finally IRE in 2010.

Dr Violari: Yeah, I know that at MCVI, you have a very busy interventional oncology practice with a robust ablation program. Would you mind telling us a little bit about your current status of your practice?

Dr Narayanan: Sure, it's been a very exciting journey since I started there in 2018 for me. Obviously, everyone at MCVI is well-known all over the interventional radiology world, although it is called MCVI for a specific reason because it's world renowned for its vascular interventional.

I was fortunate when I came there that my partner Dr [Ripal] Gandhi had already established a very robust Y90 practice and the ablation practice is what needed to supplement what he had already done with the Y 90, which is what I was tasked with. And fortunately, all the support we got both from MCI and MCVI has led us to build what I would say easily the busiest interventional oncology program in South Florida now. We not only have the entire gamut of ablation and transarterial tools, but we also use all of them. And in addition to just the clinical part of the project, we now also have a very active publishing and research part of our practice, where we now have 2 dedicated research associates who help us bring our practice out to the publication world, and recently we’ve had several of those. So overall, it has translated into a very fruitful combination and also collaboration. In addition to having a world-class vascular program, I think we also have a world-class oncology program now.

Dr Violari: This is wonderful, yeah. Going back a few years, you pioneered the use of percutaneous IRE ablation in the United States. You are the first to perform percutaneous IRE ablation for pancreatic cancer at the University of Miami in 2010. First of all, walk us through a little bit: what is IRE? How did you decide to start offering this treatment? And what were some of the main challenges you faced, and how did you overcome them?

Dr Narayanan: Sure, so back in 2010, we already had a well-rounded interventional oncology program: we had cryo, microwave, radio-frequency ablation, TASE and Y90. And IRE was actually being introduced to the interventional radiology world in 2009 at the CIO conference. And I happened to be in the audience listening to Professor Ken Thompson, who'd done the pioneering work with IRE. After his talk, I introduced myself. I've never met him before and asked him if he would be kind enough to come to our tumor board and give the same talk. And to my surprise, he agreed.

We picked him up the very next morning. He came to our tumor board, which had some of the biggest names in transplant and hepatology at that time —  Professor [Andreas] Tzakis, [MD,] who was trained by [Thomas E.] Starzl [MD, PhD]. Professor Gene Schiff, [MD] considered one of the biggest names in hepatology, they were all part of the tumor board. Everyone was very impressed with Professor Thompson's presentation. Not only did he give the presentation, he also offered any help if we wanted to start the program. And our tumor board was very excited to bring this technology. And I had the opportunity to visit him in Melbourne and stay with him for a couple of weeks to learn. He was very generous, he taught me all that they had learned in their early human experience. And we brought it back in 2010, January, is when we launched the IRE program.

What were the challenges? Clearly one of the biggest challenges at that time is the workflow, to start with, because you need to have general anesthesia. And to touch a little bit on what is IRE, which you asked, it was a new technology in the ablation world  at that time, where compared to the thermal ablative techniques that we had, which were microwave, RFA and cryo, this was a non-thermal way of creating tumors with electricity and delivering up to 3000 volts of DC current to electrocute the tumor. Basically, the way it works is when you expose a cell to this level of DC current, it creates multiple pores in the cell membrane. This leads to cell death.

This technology was available even before 2010, it was called reversible electroporation. It was used at a lower voltage, up to 1000 volts, and the pores that were created in the cell membrane were reversible. This was used to introduce proteins, gene transfer, and also for something called electrochemotherapy for cutaneous tumors, where you would use that reversible phase to introduce stuff into the cell. The scientists at UC Berkeley under Boris Rubinsky, [PhD,] when they were working with the technology, they found that when they bumped the voltage to 3000, the cell death happened independent of chemotherapy and that's how irreversible electroporation was born.

AngioDynamics picked up this as a commercial product and early challenges which we had was A, getting anesthesia for every case because you cannot do this technology without anesthesia. B, the learning curve, there is a learning curve with this technology unlike microwave where you place a single needle or cryo where you place multiple but your geometry is not that critical, you can come at different angles, they don't have to be parallel. This one required a lot more of your planning and the needle placement had to be parallel at a certain distance. So those were some of the challenges from the technical side. And also back at that time, it was the most, more expensive of all the ablation technologies that were available.

So fortunately for us our administrators and the leadership of the cancer center believed that we should be able to offer cutting-edge solutions and we were able to bring it in. Even before we got into the pancreatic ablation realm, surgeons were already doing this in the open setting and they were treating pancreatic cancer in the open setting. Professor Rob Martin [MD, PhD], from Louisville and Professor Kevin Watkins [MD], at that time from Stony Brook, were one of the earliest ones to do open pancreatic IRE.

After 10 months of our experience with this, we thought that, you know, this could be a technology that could work in In pancreatic cancer, at that time, the only reason we thought that this would help was because we found that this technology was safe in your blood vessels. We found that the vasculature was preserved when used dyadic in very close proximity. Pancreatic tumors are in a very tough real estate, there's a lot of vasculature around it. We thought that if it's done in open setting, maybe we should approach this in a percutaneous setting.

This was supported by our Head of GI Oncology and the Chair of Surgery at that time, which then led to our first patient being treated in 2010 in November, who did extraordinarily well and was able to get down-staged to surgery. She ended up having an R0 resection and went on to live another 5 years. So that was the beginning of our journey in pancreatic cancer using IRV.

Dr Violari: Wow, that's a fascinating journey. Thank you. This is amazing. Thank you so much for sharing this story. I really appreciate how you walked us through, you know, the beginning since 2010. And I was wondering, you kind of touched a little bit on it, but a little bit about the benefits of IRE versus thermal ablation modalities. What are the ideal lesions to treat with percutaneous IRE ablation?

Dr Narayanan: Great question. IRE, as I've always said right from the beginning, from our early experience, I did not think that this is a technology that was going to replace cryo or microwave or even for that matter, RFA. It is a great supplemental tool, which helps expand your abilities as an interventional oncologist or somebody offering ablation treatment options for your patients. If you have a solid lesion in the liver —which is not close to critical structures: gallbladder, bile duct— or a kidney tumor that is exophytic —it's not central, you don't have to use hydrodissection— any of the thermal modalities would work fine there. You don't need IRE because, as a bare minimum, you need at least 2 needles with IRE to create a treatment zone, a positive and a negative. And depending on the size of the tumor, those number of needles can go up, adding to your costs and all those. When you are able to do cryo and microwave with some cases with conscious sedation, then you don't need the entire elaborate prep of IRE.

But when you have tumors which are close to critical structures, say next to gallbladder, bile ducts, or blood vessels, vasculature, and the liver, or you have the colon next to it, or central renal tumors, these are all critical locations where being a non-thermal technique, IRE works well and is shown to be a good alternative to treating tumors in these challenging locations. That’s typically where we would use IRE or where I suggest using IRE: when you have tumors which fit the size criteria, is in a location that you can get to with the caveat that while the technology is safe near blood vessels, it's still a very sharp 19 gauge diamond tip needle, so you can still cause vascular injury, placing the probe. It does not mean that because the technology say you're not going to have vascular complications, we can still have it. But if it's placed properly, and if it's done without any vascular injury, the irreversible electroporation process itself is not going to cause any serious injury to these critical structures.

Dr Violari: Now, what are some of the disadvantages of IRE versus a thermal ablation modality?

Dr Narayanan: So I would say instead of using the word disadvantage, I would say one of the either the…

Dr Violari: Limitations?

Dr Narayanan: Or requirements, which could be adding up to being a disadvantage for some practices. Because to use this technology, first of all, you need general anesthesia, which could be a luxury for many practices and something that they might have a few slots. It happened to me in my previous practice, you typically are not going to have dedicated anesthesia all the time. Also having dedicated access to a CT scanner, which we take for granted in some practices, but that could be a challenge for many practices to find the time slot.

To the time, a single needle microwave could take under a couple of hours to do it even on anesthesia, start to finish. Whereas with IRE, you have the induction general anesthesia, you have to then do the planning and then because things could change on the day of, so you cannot really plan all this before. You could but sometimes you'd still have to do it on the day of because then you have to match your plan. And then, of course, after the ablation is done, waking up the patient, getting them out of the room. Overall, it takes more time in the room. So that could be a limitation for other practices.

Typically, whenever I talk about this topic, I say that practices which have already established themselves in the ablation realm and want to expand it to offer more, bigger practices in academic settings and also big private settings where you have access to CT and ultrasound and also anesthesia, this would help you expand into offering treatments, innovative treatments in the pancreas or tumors next to critical structures. Those are some of the challenges.

And, unrelated to this, like some of the other IO procedures that we do, this is also considered a 510K procedure. Therefore it was approved by the FDA on a 510K basis, so it's approved for soft tissue ablation and when you go specific to tumors, some of the insurance companies can call this “experimental” and deny the treatment to the patients, which then sets up the peer-to-peer and all these processes which we go through. So those are some of the challenges I feel that, you know, you would face in trying to build this program.

Dr Violari: Yeah. And what equipment, speaking about building a practice, someone who wants to build a practice, is there a specific equipment that this needs? And are there different systems, what about the cost and everything?

Dr Narayanan: Currently, there's only one manufacturer in the United States which is AngoDynamics, and they call it NanoKnife, even though it’s nothing to do with a knife, and there’s no cutting involved, but it’s still called the NanoKnife. There is another company which brought the same technology but has not come to the US yet —it’s available in China and some parts of Europe— they’re not here. It's a company called Search Nova. We've not used it, so I don't know how that device performs. As of now, we have one device.

As far as cost, I think that's something to be discussed with the manufacturer. Every practice would have to figure that out. And as far as the disposables, you're going to need probes for every case, just like how you would use probes for microwave or cryo. As far as support goes, the company has always been very supportive they have medical science liaisons who will support it so I don't think that would be an issue. Those are the disposable costs, other than that the time in the room, CT anesthesia, and one unique thing for this procedure is also you need to have defib[rillation] pads on the patient just in case there's a cardiac issue, so that's a little different.

Dr Violari: And that was my next question, which patients are the ideal candidates for percutaneous IRE ablation? Are there any absolute contraindications of doing the procedure?

Dr Narayanan: Sure. Patients who have a history of cardiac arrhythmias, who are prone to arrhythmias would not be the ideal candidates. Those who have pacemakers which cannot be turned off are also not candidates for this procedure. Patients with abnormal liver functions, like the other ablative tools that we use, when they have AST, ALT elevations, when they have alk phos [alkaline phosphate], bilirubin. Those are all in the same criteria which we use for microwave, it’s what we use for IRE.

In addition to that, I would think obviously patients who, in the pancreatic area, obviously we use this technology only for patients with stage 3 pancreatic cancer, so those who have metastatic disease would not the ideal candidates for this. And importantly, the performance status of the patient is also important. Anyone with an ECOG of 0 to 1 would be an ideal patient for the technology. If their ECOG is worse, then they would not be a good candidate for this procedure. Any other contraindications for general anesthesia would exclude them from being a candidate for the procedure.

Dr Violari: Can you walk us through a procedure and a technical approach, for example, for a pancreatic cancer patient. And can you briefly describe your technique, needle placement, and how many probes based on the size and so forth?

Dr Narayanan: Your whole journey with the patient starts from the multidisciplinary tumor board, which is critical for any IO practice. So you want to be part of a multidisciplinary tumor board, establish your relationships there. We have a very well organized multidisciplinary tumor board. And once you get a patient who you think is an ideal patient for pancreatic IRE, somebody with a good performance status, I typically don't pick patients with over 3.5 cm tumor size, although there are centers that that offer it for patients with bigger tumor cells. I'll come to the reason as to why in a few minutes. After we think that this is a good candidate in the tumor board, we see the patient consultation in our clinic and then they also meet with anesthesia. They finish all their pre -procedure clearance, get their cardiology clearance and get the authorizations and all of that done. The pre-procedure labs, we typically look at the coagulation profile and their liver functions and the routine tests that we do.

On the day of, they’re [nothing by mouth] NPO from midnight the previous day. When they come in the morning, we tried to get these done in the morning, get ready in the pre-op area, and then they brought into the CT scanner, where the anesthesia team would induce the general anesthesia. From a technical standpoint, what we've done is we've avoided extending the patient's arms above their head or by the side of their head, which I think could be potential for brachial plexus injury if their hands extended for an extended period of time. We at our center have their arms crossed across their chest with the stack of towels and the hands are taped.

And once that's done, we do a quick pre-scan, especially with pancreatic cancer, you wanna make sure that their colon or any other critical structures, not in the way. Before they get to the day off procedure, we also give them a colon prep for the pancreatic cancer patients. And if they have a biliary stint, we put them on prophylactic antibiotics before and continued after. After we do the quick non-contrast scan before the patient intubated, we want to make sure that we still have a proper path, patient is intubated, then we do a contrast-enhanced scan to make sure we see all the critical structures and vasculature and arterial and the venous phase. You use them on a dual monitor setup side-by-side, and then you plan your path.

I've always gone anterior to posterior. With the surgeons with an open approach, they can come from a tangential approach, because it's open, the pancreas is exposed and they use fingertip ultrasound to guide their needles. For us in IO we come anterior to posterior. We a lot of times have to transgress the stomach or small bowel to get to the pancreas, which we've done multiple times. And so you want to have the active tip of your needle no more than 1.5 cm. So when you're coming from anterior to posterior, depending on the depth of the tumor, you might have to do a pullback. Just to go a little bit on that, if the depth of the tumor is 3 cm, you would expose the active tip to 1.5 centimeters, then pull all of them back another 1 cm to cover the second half of the tumor. The reason we do not expose the active tip more than 1.5 cm in the pancreas is because that tissue draws a lot of current, so you don't want the amperage to be very high because it could cause the machine to shut off on its own.

The patient is also connected to something called the AccuSync device, which is gated to their EKG. The role of the AccuSync device is to detect the rising slope of the R wave in the patient's cardiac cycle, and then it sends a signal to the NanoKnife machine, there's a very short delay of .05 seconds and then the pulse is delivered during the refractory phase of the cardiac cycle. This is to prevent any cardiac arrhythmia risks and you need 70 pulses between a pair to complete the treatment. So if you're using only two needles to treat a tumor, you only need 70 pulses. If you're adding more needles, then you just keep adding more pairs and you can add or subtract as much as you want. At any given time, the energy is only begin delivered between 2 needles. So you can use an odd number of needles, or an even number of needles. Regarding the number of needles, as pertaining to the size of the tumor. A simple rule of thumb would be 1 needle per cm. So if you have a 3 cm tumor, you could get it with 3, but again, depending on the location and the margin that you're looking for you may have to add 1 more.

The pancreas is kind of different in that aspect, unlike the liver, where you are able to get— if you want a margin, we want to 1 cm a margin all around. It may be difficult for you to do that in pancreatic cancer because of all the critical structures next to it. A lot of times you're just getting the tumor up to the edge of it, maybe a touch, a little bit more, but it's not easy to get a big margin the way you would do in the liver.

Once you place your needles, you do a 3D reconstruction, so to make sure you're spacing between the needles is not more than 2.2 cm. You want it between 1.8 cm to 2.2 cm. Again, another quirk of the technologies, because you could go less than that, but you would get a smaller ablation zone. And if you go more than that, you could have some skip areas. So it's good to keep it at 2.2 cm. And then the 3D reconstruction gives you the distance between the probes accurately. And then once you've confirmed that, you turn on the machine and you watch as the energy is being delivered. You want to make sure there's complete muscle relaxation before you deliver the energy, you check with your anesthesiologist, ask them to check for the number of twitches. Usually, you want it between 0 and 1. If not, they would have to give some muscle relaxation and then you start delivering the energy.

If you're using about 4 probes, that's 4 times 70 seconds. And if you're doing a pullback another 4 times you're gonna have. The advantage of a quick treatment would be lost if you are having multiple needles and if you're doing a pullback, now your treatment time could be similar to a cryoablation.

Then once you're done with the treatment, one of the practical things is you cannot do a track ablation with IRE like you do with microwave, RFA or with one of the cryo devices. What I've done since the beginning of using this technology is to close the active tip and then removing it to reduce or not have the problem of track seeding. This has been reported in the literature, in one of the papers from Germany, where they had track seeding in their cases. So I'm not sure whether they've done, closing the active tip or not, but we've not had issues with track seeding. So that's something which is more of a practical pointer.

And the other practical thing with IRE is the needle is the 19 gauge, it's a very flexible needle. So unlike microwave or cryo, where the probes are rigid, you really don't have to bring the needle back every time to readjust your trajectory. You make minor adjustments by moving it medial, lateral, anterior, posterior and get to your destination.

After you're done, you get wake up the patient, then they get extubated, go to recovery. Typically, the pain associated with the procedure is less than other ablative technologies. And then they might have some nausea, they might have some discomfort in the throat, mild pain. We always have a PCA pump for all our patients, which is provided to them as soon as they get to the recovery area, so they can use it if they have any pain. We also admit the patients overnight for observation. We round on them in the evening, make sure they're doing fine, and then in the morning we get a set of labs, and if everything looks good, typically we discharge them the next day.

With pancreatic cancer, one unique thing is to keep the NG tube in place. That's something which is part of the protocol, they all get an NG tube. And the use of that is two-fold: A, it helps us give oral contrast to visualize the small bowel in the stomach because the pancreas is in a critical location, not only do you have vessels, you also have these structures. And sometimes you cannot see the margins of the tumor very clearly, it kind of blends with the small bowel. So when you have oral contrast, that helps you. It also, we use the NG tube, we put it to suction immediately after the ablation for the first 24 hours. Just in case after the ablation, say in the head of the pancreas, you have swelling and edema, that could potentially cause outer obstruction. So the NG tube helps prevent that. And in the morning, we get their amylase and lipase. If it looks normal, then we remove the NG tube, we start them on clear liquids. They can start with something easy and then that they tolerate, that we go to soft solids, and then they have a full meal by the evening, and if everything looks good, then they go home. If necessary, we keep them overnight. If they do have elevation of the amylase and lipase, we keep them NPO, we let them have ice chips, but we watch for it to trend down, typically in 24 to 48 hours, it'll be back to normal, and then they go home.

Our average length of stay for our pancreatic patients has been about 1.5 days, much less than compared to the open procedure, but little more than what we would do with all the other organs because most of them go very next morning after the procedure. That's pretty much about the procedure. And as far as follow-up goes, we see them in 1 month in clinic. And typically we get an MRI with contrast and diffusion-weighted sequences. And then also combine that with their markers, tumor markers, and their other lab values to see how they’re doing. And then if necessary, we repeat the PET scan in 3 months after the ablation to get a better idea. Obviously, we always correlate things with the oncologist in these patients, seeing us and the oncologist together.

Dr Violari: Wonderful. You mentioned earlier, how with the thermal ablations, we have the margin after the ablation as a way of assessing the technical success of the procedure. We have the 10 mm margin that we see on our post-ablation, the contrast-enhanced CT. What's your best predictor of technical success with pancreatic cancer percutaneous IRE.

Dr Narayanan: Another great question. I think with pancreatic cancer, the difference is unlike other organs when you use IRE, especially in the liver, you will notice a significant decrease in the size of the tumor zone, the ablated zone. And in many cases you would kind of see that kind of blends with the background, like it was nothing there. We've seen that time and time again when we treat tumors in the liver. With pancreas, which stage 3 locally advanced pancreatic cancers, you have encasement of the blood vessels and therefore they're not considered surgical candidates. After IRE, it's not like they kind of fall off the vessels. The encasement continues and the key is not to just use anatomic imaging such as CT to assess the response of this particular treatment in pancreatic cancer. Because your best outcome is going to be stable disease. Your CT alone never gives you the picture, but when you use MR and your diffusion-weighted sequences and a PET scan along with the tumor markers, that gives you a more comprehensive picture as far as response, than just using enhancement or even RECIST criteria, which medical oncologists typically use for their treatment. You're never going to see the tumor disappear or the treatment area completely vanish.

We have seen size decreases that we've seen in many patients, but the response, the ablated zone changes are not as dramatic as you would see in the liver. So we correlated with all the imaging tools and the markers as I mentioned.

Dr Violari: A couple times you’ve mentioned the significant real estate around the pancreas. What are some potential complications you encounter? What is your complication rate from IRE? And how do we avoid those potential complications?

Dr Narayanan: Your patient selection is critical. A lot of times as IRs, we might get patients who nobody wants to touch. And I mentioned about the size. When we started, we did treat patients who were over 3.5. When we published our second experience in 2017 in JVIR, we looked at 50 patients. We also did individual multivariate analysis, and we found that tumor size played a critical role. So if the tumor was less than 3.5 cm, they did much better than those who the tumor was bigger than 3 cm actually. So the difference was, say, as much as 33 or 34 months to 23 months if the tumor was bigger than 3 cm. So we concluded that this is a technology that ideally is best suited for those who have a tumor size. So your patient selection is very important from the size, the ECOG status, and also the path for you to place the needle from the skin to the target. You want to pick a patient where you feel that you have reasonable access to go from skin to target. And I would not recommend somebody to start with IRE of the pancreas. When they build their program, ideally, you want to do some liver cases and kidney before you move into into pancreas. Of course, if somebody is a skilled an experienced interventionist, ablationist, then that caveat may not apply.

What can you do to avoid or minimize the risk of complications? Nothing is 100%. Anybody can have complications. The most common ones which we have seen is pancreatitis, especially in patients who have not had radiation before. We typically don't see it in patients who already had radiation. Those who have not had radiation, there's a potential for pancreatitis, which is something we talk to our patients. Abdominal pain/discomfort is the most common one, which was also documented in our study. About 10%, you can expect these complications, about 10%, at least in our series, it's been about 10%. There are some which were higher than that, but most of them are in that ballpark. Usually they're minor complications.

Major complications obviously would involve sepsis, bleeding, death, which is possible. And so those are some of the things which the patient should be made aware of. The risks of this procedure should not be minimized because it's possible for them to bleed and you might have to move them from the CT suite to angio to do an embolization or even to the OR. So, those have been reported in centers where they've had patients with bleeding complications.

How to minimize them, would be to have a good pre-procedural assessment, a more realistic assessment of how your needle is going to go and what path you're going to take. You want to make sure that you're not in the path of any major vasculature. One of the practical tips or pointers which could help if you find something that's inevitable is, with IRE you can go blunt. If you are near a critical structure in other words you advance the needle but you're able to cover the active tip and make the tip blunt if you want to just immediately cross something which you think might be hurt, and then open it the active tip to make it sharp. You can use ultrasound in combination with CT. So you have Doppler ultrasound, you put color, you see where you are with reference to the vessel. So that is another tool you can use in the CT suite to minimize your complications. But more importantly, I think it all comes down to finally being realistic, getting an ideal patient where you do think you have a good path to get the needle from skin to target.

In spite of being doing this for more than a decade now, I still think it's one of the most demanding ablations. So following the pre-procedure protocol, the prep, the antibiotics, the NG tube, planning your path, keeping them NPO after the procedure, NG tube to suction, all of these play a role because any one of these goes off, it can impact the outcome of your procedure. So it's important to look at everything as a whole. But these are the potential pointers that I have to share to minimize complications.

Dr Violari: Is there any thermal zone with IRE ablation? And is there any risk of, nerve injury, adjacent to late nerves and so forth.

Dr Narayanan: I call IRE predominantly non-thermal, because that is potential for you to have a thermal injury if you keep repeating the treatment over and over again, but the good part of the technology is it releases the energy in packets of 10 pulses. So, there's always a dip and then a rise again. You don't have a real thermal effect as you would have with microwave. The other thing is, based on bench studies in the Netherlands, they found that, among the positive and the negative probes, the negative one has a little bit more thermal effect than the positive. So your medical science liaison would be able to adjust the polarity of the needles, if you feel that one needle is very close to a critical structure, you can reverse the polarity and make that positive, and the one that's away from it could be the negative one. So that's another way of helping to avoid any potential thermal injury. But realistically, the technology is not something where you should expect injury that you could have with thermal devices.

Nerve injury. So in the pancreatic area, usually the tumor involves, pancreatic cancer does spread through the nerves, so the nerve involvement is already there. We have seen some patients with improvement in pain, but we've also seen patients without changing their pain. But if you're looking at other structures where you have a major nerve that runs in very close proximity to the ablation zone, I would still not use— Even though technically it’s considered not as dangerous, I typically do not get those patients to an ablation technique, unless we have nerve monitoring, we’re able to push the nerve away. I would follow the same precautions that I would do with thermal ablation. With blood vessels, bile ducts, other structures are more comfortable using the technology, but if there's a major nerve, I would still use all the protection that typically you would need.

Dr Violari: I know these patients are usually stage 3 pancreatic cancer, but do you still approach each case with a curative intent?

Dr Narayanan: Realistically, in these patients, I don't consider pancreatic cancer something which is curative. A lot of places look at stage 3 or stage 4, which is not yet, you know, kind of identified itself or it hasn't progressed to that point. Our goal is to help patients in 2 ways. The smaller percentage of patients are those who we have down-staged to surgery. They are stage 3, locally advanced cases which are considered non-surgical. We have done the procedure and got them to surgery and the surgeon has been able to get an R0 margin. That number is much smaller.

The vast majority of the patients that refer to us are those with locally advanced pancreatic cancer who either had chemotherapy or chemoradiation and now even though they do have a reasonable good performance status, are showing signs of recurrence of disease either local recurrence most of the time or with their markers climbing up so those are the kinds of patients that we see more. When we talk to them it's very important to have a realistic conversation and make sure I tell them that we're not curing you, but our goal is to provide a better quality of life and to add to potentially your survival instead of just having just chemo or chemo radiation. So that is the goal.

We’ve shown that in our studies and also studies around the world where, when IRE is added in the treatment mix, in our series, patients survived about 14.2 months from the date of IRE and about 27 months overall survival, which is typically much better than what you would get with conventional treatment alone. There are other studies, there was one in JVIR, which showed that when you add [leucovorin, fluorouracil, irinotecan, and oxaliplatin] FOLFIRINOX plus IRE, it was a postop comparison study and they found that those who just got chemo alone did not do as well as the combination group.

The goal is to help with their survival, but with the good quality of life: you don't have the major side effects you would get with systemic chemo. As you know, FOLFIRINOX is not something that is usually well tolerated by most patients, especially older patients. You only have 2 or 3 lines of chemotherapy for these patients, so they run out of those quickly and then now they're looking at trials, clinical trials. If we add a local treatment to systemic, we can help them prolong their lives. That's our goal and that's typically what we talk to our patients before we offer them the treatment.

Dr Violari: You just mentioned some studies comparing chemotherapy plus IRE ablation versus chemotherapy alone. Have we ever seen an IRE ablation be combined with immunotherapy?

Dr Narayanan: Yes, there's one study that is from the Netherlands in which they have done called the PANFIRE-III study. And it was a small, small study. And in that group, they found that the role IRE does help augment the immune effects to the treatment of pancreatic cancer. I think it's very early, but there are also signals from animal studies, one from MD Anderson that showed that IRE reversed the resistance of immune checkpoint inhibitors in pancreatic cancer. There are some early studies which potentially show a benefit of combining IRE with immunotherapy. But I think that is a space that needs more work and we might hear more in the near future.

Dr Violari: That's fascinating. You mentioned earlier about participating in multidisciplinary tumor boards to help build the practice. What are other collaborators that are necessary to build the IRE practice?

Dr Narayanan: I think being a part of the multidisciplinary tumor board, and being aware of not just our literature, but also what other services can offer. I think it's critical, especially in pancreatic cancer, it's important to know about radiation, which is commonly used in this cancer. The role of radiation is sometimes argued, depending on which part of the world you're in. In the United States, radiation is still very commonly used in pancreatic cancer, but it's important to know some of their main studies that have been used in pancreatic cancer.

But more importantly, I think, understanding where this particular technology could help these patients and articulating that not just in the tumor board, but also with your outcomes. I think that builds a strong collaboration between your services. A lot of times, it's more the fear of the unknown for medical oncologists or their surgical colleagues, because they want to make sure that their patients are being helped and we're not just doing something because we can do it. Building that relationship, showing the outcomes, going back and presenting it and volunteering your time to actually educate support staff such as the nurse practitioners and PAs, I think it's critical to spend some time, to give them a lecture and educate them. Also the trainees in the hospital, if you're in academic practice, not just the interventional radiology residents, but also residents from the other service, because these are all people who see these patients. Talking to them, talking to GI, and educating that this is an option that exists which can work with all the other technologies.

The good part is this does not have to replace anything else and this does not take away any other option for the patient. Just because somebody had IRE doesn't mean that they won't get radiation, but if they had radiation doesn't mean that they cannot get IRE. It would be a little bit more technically challenging for the IR when you deal with the radiated pancreas, but you can still do it.

By combining the strengths of local treatments, we're able to help our patients more. If you bring that kind of a collaborative approach to the tumor board, I think that really helps. Sometimes we have to be patient and wait our turn. All politics is local, so it depends on how the tumor board is run. I've been fortunate both in my previous practice and here, we've had a very, very collaborative tumor board. I think that's critical.

Also being a clinical service and taking responsibility something that MCVA has done for decades, where you own your patient, not just to do the procedure and not take care of them after that, which many, many IO practices are now doing in the country and across the world. Where the patients are admitted under us, we round on them, we manage them, you know, take care of all that, which was not the case when I trained. But, you know, it's changed and it's a very healthy and positive change.

Owning the patients, seeing them and follow up, documenting your outcomes and then going back and presenting them, these are all things I think, which helped us. And I'm hopeful that it would help others if they want to follow that.

Dr Violari: Yeah. And do you think this is something that can be performed in smaller community hospitals? And, as you mentioned, pancreatic, percutaneous IRE ablation can be more technically challenging, but it's something that can be done, for example, and the liver and the kidney, lung, you recently published about IRE for lymph nodes as well at CVIR. What are your thoughts about applications of percutaneous IRE in different organs besides pancreas?

Dr Narayanan: Starting off with smaller, community hospitals. Again, depends on the resources, depending on the person doing these procedures. If they do have the appetite to expand their practice and want to offer more solutions, then definitely it would help. But of course, it comes with all the challenges we talked about. And the most important ingredient in building a practice of this type is that physician who's taking on the responsibility. Given all the other challenges, there's one main challenge: are you willing to take on something? But if you are, it is very rewarding, which I've seen, and many of our trainees have gone on to incorporate that into their practices and started it, and they've found results. I think that's critical. Can it be done in smaller community hospitals? Yes, I definitely think it can be, and it is being done.

A lot of times in those hospitals, you see a stronger collaboration between surgery and interventional radiology, and now urology, there's been a huge explosion of this technology in pancreatic cancer, I'm sorry, prostate cancer. Radiologists are using it very frequently as a treatment, a local option in prostate cancer. When you can potentially collaborate with other services and use the same technology, then it becomes a more viable proposition for smaller practices and smaller hospitals. Now it's not just something tied to one specialty. Establishing that kind of collaboration will also help.

For other organs, like I said, it has expanded where we as IRs or IOs play a role using ablation. We are now close to publishing or sending a series of tumors right on the colon or on small bowel where we treated metastatic deposits, which is something that IRs typically would not deal with. And, uh, radiation is also a problem in those areas. Most of these patients will have to go for a surgical approach or are stuck with whatever chemotherapy option that they have. There are some unique niche applications of this technology, plus, like I said, if you are dealing with the kidney, if you have an exophytic tumor, you don't need this, but if you have something more central or if you have a colon drape and you don't have to do hydrodissection with this technology, if you can get the needles in place appropriately. It expands your ability and expands your practice. For that matter, if a practice is interested in that or if a physician is interested and wants to do it, yes, it's going to help.

Dr Violari: That's awesome. Thank you so much. You also recently published the paper at CVIR about treatment of IRE ablation for hepatic epithelioid hemangioendothelioma (EHE). Actually, I had a patient who was just diagnosed with this this week. I did the biopsy of the liver. This is an international multidisciplinary experience. Why does IRE works better for this in comparison to other tumor ablations?

Dr Narayanan: Hepatic epithelioid hemangioendothelioma, as a pathologist, is dear to me, mainly because A, it's considered a very rare tumor, like one in a million, but you'll be surprised if you get into their foundation and realize the number of patients who are looking for options. Being kind of an orphan tumor, this pathology really does not have too many treatment options. Most of them either get a resection if it's in the liver, and then it shows up again. Liver transplant is an option, but many of these patients are young, and many of them also have disease outside the liver. So yes, they could get a new liver, but it I've seen it come back even in a transplanted liver. There's no real standard or established algorithm for these patients. It depends on where they are, they would find whatever is the local expertise and they could be put on system chemo and then see how it goes. And also it's very unique to each patient and how it progresses.

I would say eight or nine years ago, I treated the first patient who had a multifocal hepatic epithelioid hemangioendothelioma, based on one patient that was treated by Professor Ken Thompson in his series, which had shown a good response. So why is it different compared to other modalities or can you use other modalities? Yes, there is a series that was recently published using ablation, a thermal ablation. Anytime you use thermal ablation, and if it's a appropriate location, and tumor, it is going to die. But the difference between IRE and microwave is the healing mechanism. When you use microwave ablation, that area is going to undergo coagulated necrosis, fibrosis, and scarring. Whereas when you use IRE, the mechanism of healing is supposed to be apoptosis. And therefore, that's why we have the healing, which we've seen time and time again in many of these EHE patients, where we do see a significant decrease in their volume of the treatment zone compared to when we first started.

So we started with one patient with multifocal disease who I'm excited and proud to say at our very first patient, I think it was 2007 when we first treated them, is still doing well with multifocal disease and all of the lesions have responded well. And over time, since this is a rare tumor, the numbers that in our series was less, but still the biggest number for an ablation series. We had about 14 patients in that series, but many of them have multifocal disease in the liver. The reason I prefer to use IRE over thermal or any transarterial technique is A, from a transarterial technique standpoint, again, the experience is very limited. Some sites have used Y90, some of them have used TACE. So the experience is kind of all over the place. But since we have a good number of patients and even higher number of lesions that we've treated and we had good outcomes with them, we've stuck to what we feel works. In multifocal disease in these patients, I tend to treat about 3 to 4 tumors in one sitting. Can be time consuming, but like I said, it's something that's rewarding and has shown to be good in these patients. And we continue to offer this. and I'm actually seeing a patient this week in clinic. So far it's been working out, hopefully the series will expand. There are other sites which have also offered, started offering the, an option of IRE. So hopefully we will build this as a viable treatment option. The limitation is obviously the number of patients and it's very hard to do a randomized control trial or compare it to a standard because there is no standard.

Interestingly, the paper we did was in collaboration with one of the leading sarcoma specialists in the country and a transplant surgeon. All of them feel like, if there is a local option to prolong somebody from getting a transplant that should be, that's the school of thought. And also to help with a getting rid of disease with a local treatment so that they don't suffer from using systemic treatment as the only option.

Working with a collaborative sarcoma group, I think it's important. But it's it's I think kind of forgotten or I would not say forgotten. It's not in the mainstream as much as HCC or metastases in the liver, yet you will be surprised to see there's a huge number of patients who are affected by this, looking for answers. We're hoping with these 2 papers that came out back-to-back, we are making an impact with minimally invasive ablative techniques. Hopefully that would expand the access to these patients around the world and they can benefit from that.

Dr Violari: Hopefully this podcast will help too. Now are you currently involved in any research trials?

Dr Narayanan: Yes, that's something which we are very involved at MCVI. We were part of the #HOPE4LIVER study which brought histotripsy to fruition. We were one of the sites, I think there were 8 sites in it. Histotripsy, we're excited to offer that to our patients. We've treated our first patient last week. And that was one, and then we were part of other studies for Y90. The DOORwaY90 study, we're part of the RESiN registry before that. And also, we now have a trial open for a combination of immunotherapy plus radiofrequency ablation with Immunophotonics. We are also going to be part of the registry of the histotripsy cases. So those are some of the current offerings. Hopefully there'll be some more to go, but we're also active in publishing our experience in a retrospective fashion, a lot of times that's the way to at least get our experiences out to the rest of the world.

Dr Violari: That's fantastic and congrats. That's awesome. And through the years, Raj, we've witnessed the evolution of ablation treatments from palliative treatment, sometimes to curative treatments. Now, what are your thoughts about the future of percutaneous IRE ablation for pancreatic cancer specifically as a primary treatment earlier in the course of disease for a patient.

Dr Narayanan: We did have a positive trial from the Netherlands, the PANFIRE-2 trial, which was published in Radiology, which met its end point. The difficulty with comparing IRE with the current standard of care is the challenges with the randomized control trial (RCT). You asked about bringing it earlier in the treatment algorithm, which is why I'm bringing up the challenge. We did open a study, an FDA-approved study for randomized control trial with the registry using IRE and unfortunately the RCT arm did not recruit patients because of the challenge when patients come to a center offering IRE they don't want to be randomized they want to have that treatment, because they read about it and they know it. It definitely produces a challenge but well thought out well-planned registries getting more global collaboration and data and showing, say, synchronous effect with immunotherapy, these are all things which could potentially change, bringing this technology in collaboration with existing standard of care or even sooner in the algorithm. I'm hopeful that that would happen in the near future, but definitely having a randomized control trial has been challenging.

Having said, how things have evolved, yes, we have definitely gone from being anecdotal case reports, retrospective, to now having level 1 evidence and being part of NCCN guidelines for kidney, for colorectal, NACC of course, in the ideal selected patients. But the technology also, the techniques have also improved.

And now more and more, and you're going to see an explosion in the next few years, where we're going to see assisting devices helping with ablations, meaning you use navigation tools. There's been several of them commercially available now, and then also robotic assistance. We were fortunate to be the first in the country to introduce robotic assistive ablations last year. We're well over 140 patients now. That's an exciting area in the technical space, where it takes something as challenging as IRE and kind of democratizes the needle placement. It basically sets you up to get your needle from skin to target with a single push. We present our early data at SIR with a very high level of accuracy. That is also evolving, with more centers on board, as they are now, and more data, we will see how that impacts our day-to-day ablations. In our practice, of course, it’s now become part of every procedure, all the partners who do ablations use it. It helps you get off-plane placements with a single push, something which trainees are able to do without a significant experience. It also helps you assess the ablation zone with pre- and post- volumetric assessments. It has fusion capabilities of bringing MR into the picture. There's other third party companies that offer segmentation software.

It's moving to make this more safer and better, which will improve outcomes. When with improved outcomes, we're going to see that ablation is going to become more and more mainstream.

And in the trials, I forgot to mention a very important one, which is the ACCLAIM trial. And we're part of that too, where the reason I'm saying that is once upon a time, radiofrequency ablation in colorectal metastases was not able to compete because of local recurrences, and we were not getting the appropriate margins. And so that's a big focus now for interventional oncologists. And the recently concluded trial presented at ASCO, the COLLISION trial, where Professor [Martijn] Meijerink, [MD, PhD] presented the data showing that we were not inferior to resection in colorectal metastasis, which is huge. Things like this have taken ablation from just being another procedure to being something mainstream.

One last thing I would like to highlight on is the education of the patients. And I'm hoping podcasts like these would help get the message out to patients. We still are one of the best kept secrets in medicine and most of our patients have never heard about us. And once they get the treatment and have a good outcome, they cannot stop talking about us. I think educating the public is important. The more and more people know about a minimally invasive option or even a non-invasive option, they're going to go for that. I feel the future of ablation is very bright and we’re just getting started and we’re going to see more innovations, combinations, technical improvements, spectral CT for guidance. All of this is happening and it’s an exciting time to be in this space.

Dr Violari: I couldn’t agree with you more, Raj. I'm so, so excited to hear about all the amazing, fascinating, exciting things that you're doing at MCBI. Maybe I should come back as a fellow and I'm with you more. I really enjoyed our discussion and all the fascinating things you've been doing and continue to do. This has been very helpful. I feel that I've learned a lot, and as always, it's been a pleasure speaking with you. Thank you so much for spending your time and sharing with us your knowledge and your expertise. And really appreciate it.

Dr Narayanan: Elena, first of all, thanks a lot to you. I appreciate the opportunity. I really enjoyed the discussion conversation as much as you did. And I also want to thank SIO for this opportunity. So thanks again.