Melanie Cole, MS (Host): Welcome to the podcast series from the specialists at Penn Medicine. I'm Melanie Cole. And today our discussion focuses on SBRT for ventricular tachycardia. Joining me in this panel, I have Dr. Timothy Markman. He's an Assistant Professor of Medicine in Cardiovascular Medicine at the hospital of the University of Pennsylvania. And Dr. Keith Cengel, he's a Professor of Radiation Oncology at Penn Medicine. Doctors, thank you so much for joining us today, and Dr. Markman, I'd like to start with you. Can you please describe ventricular tachycardia, or VT, for us, and its place among the cardiac arrhythmias? How is VT different from AFib, for example?

Timothy Markman, MD: Well, unlike most cardiac arrhythmias, including AFib or atrial fibrillation, VT is a potentially life-threatening arrhythmia. Similar to other arrhythmias, it can cause a range of symptoms, from palpitations to worsening heart failure or syncope, but it's relatively unique in that it can result in sudden cardiac death.

Host: Well then, do we understand where VT comes from in the heart, and what causes it, Dr. Markman?

Timothy Markman, MD: Generally speaking, VT, or at least the VT that's most relevant for this discussion and poses a risk for sudden death, comes from regions of scar in the heart. Those regions of scar can be there because of a prior heart attack, prior myocarditis, or due to other pathologies such as cardiac sarcoidosis or hypertrophic cardiomyopathy. We unfortunately do not always know the underlying process that led to the development of scar and subsequent VT.

Host: This is a very interesting conversation that we're embarking on here today, and Dr. Markman, I'm going to stick with you for a minute. Standard of care treatments for VT include implantable cardioverter defibrillators, antiarrhythmic medications, catheter ablation. What are the various roles and limitations of these therapies as we've seen over the years?

Timothy Markman, MD: Well, the main role of ICDs, or implantable cardioverter defibrillators, is to prevent sudden death when VT happens. They don't actually do anything to prevent these arrhythmias from happening. We implant them both in patients who have had VT previously and in patients who are at a high risk for sudden cardiac death.

Antiarrhythmic medications and catheter ablation, on the other hand, are used in patients who have had VT in order to prevent VT from occurring again. Antiarrhythmic medications have the advantage of being non-invasive, although there are significant side effects and toxicities that are associated with their use, and their efficacy is overall disappointing.

Catheter ablation is more effective than any antiarrhythmic medication that we have available, but it is a minimally invasive procedure and it has inherent procedural risks as well as its own limitations in terms of efficacy. Patients with particularly weak hearts or significant comorbidities may have a harder time tolerating this procedure.

And additionally, VT can come from certain regions of the heart that are particularly challenging to reach with a catheter. And in those patients, there may be significant limitations in terms of the efficacy of ablation.

Host: Well, then based on that, Dr. Cengel, as we've mentioned, and as Dr. Markman just mentioned, the current therapies for VTach are often ineffective in the long term, and the search for enduring treatment has now led to the use of radiation therapy or cardiac radioablation for recurrent and refractory VT. Why radiation therapy and how did this treatment traditionally identified with oncology make that transition to cardiology?

Keith Cengel, MD, PhD: We started this with a main goal of essentially ablating the cardiac tissue in the same way that the electrophysiologists do. So they use things like thermal energy, heat energy, or radio frequency energy to attempt to divert the electrical circuit or interrupt the electrical circuit.

With radiation, we have been using this for almost 130 years now for treating cancer, and the idea there is that you use the radiation to ablate or kill the cancer cells, and so it's sort of a natural extension in that regard to use the radiation as a similar type of tool. At least that's what we thought we were doing when we got involved in this. So good news about this entire process is that we have spent the last 30 to 40 years increasing our technical capabilities in the chest to the point where now it is very routine for us to be able to target very small areas of say one or one and a half centimeters of lung tumor accurately throughout the breathing cycle and incorporating motion and all the other sorts of things that you need to incorporate to be able to do that on a regular basis.

So we can do that on a very accurate and dependable way of delivering radiation. So these techniques that were developed were for ablating cancer. And that's where we get this stereotactic body radiotherapy or SBRT. Essentially, what we've done in the cardiology space instead of aiming at a tumor in the lung or even a tumor in the heart, we're now aiming at an electrical circuit in the heart and trying to interrupt it with the radiation.

Host: So Dr. Cengel, Penn's participating in the RADIATE VT clinical trial, which compares radioablation to radiofrequency for VT ablation. Can you tell us a little bit about the trial, its therapies, and the objectives?

Keith Cengel, MD, PhD: So when we started this, and we've now been doing the radio ablation at Penn for over five years now, where we began was in cases where the electrophysiologist felt they had no further opportunities to ablate that rhythm using conventionally available or even experimental electrophysiology techniques, and these patients were still experiencing VT, still experiencing pain and suffering, and the thought was that is an appropriate population to try this on, on an investigational basis.

So, the question becomes, in a patient for whom perhaps a second or a third attempt at ablation might be possible, where does radiation fit into that?

So, and I'm going to make this very clear, if you are a very healthy patient who is doing well otherwise, who has a relatively simple and ablatable VT circuit, these are not patients for which radiation is likely to become appropriate at any time. They are well served by ablation. We're talking about patients who've had at least one or maybe two attempts at ablation, and the electrophysiologist looks at their case and decides I think I might be able to ablate that with one more attempt.

And so those are the patients who are now trying to look at in this trial. And it's a very simple question, which is if you take those patients who are potentially eligible for ablation, who've had failed attempts at ablation before, so the high risk people, we randomize them, assign them to either cardiac radio ablation or a standard of care catheter ablation, and we want to see at the end of a year, what are the outcomes? What are the rates of VT? What are the side effects people experience? What's their quality of life? And we're even having a separate protocol that people can optionally enroll in that we'll be taking biological samples of blood and immune cells to try to look at what are the mechanisms by which this is working and can we identify patterns in them that suggest one therapy or another would be more effective. And so basically, this is a trial to figure out where does radiation ablation or radio ablation fit in the electrophysiologist toolkit.

Host: Well, then along those lines, Dr. Cengel, according to the trial description on clinicaltrials.gov, patients in the radio ablation arm of this study will receive 25 gray. How is the dose arrived for the treatment of the refractory VT? What's the intended effect of that?

Keith Cengel, MD, PhD: When we first started thinking about this, we did some radiation work in some animal models and came up with a dose that we thought might be effective at scarring the heart in a way that would interrupt a VT circuit. That 25 gray does seems to be fairly effective and reasonably well tolerated. As we've gone forward, it is not 100 percent clear that this is actually killing cells in the same way that the catheter ablation energies kill cells.

And so one of the other things that we're certainly studying is what are other potential doses? What are other potential effects? Are there specific circuits that might benefit from an increased or decreased dose? We're studying that in addition, in clinical trials and in animal models. So this is our best foot forward in the radiation arm to sort of see where we get. And in point of fact, it's also helpful; it's similar to the dose that we use for single fraction treatment of patients with lung cancer. So we've treated a very large number of those patients.

And so we have a pretty good idea of its safety and efficacy and treatment in the chest as well.

Host: As we get ready to wrap up, Dr. Markman, please give us the key takeaways for other providers, what you would like them to know about these studies and the work that you're doing for VT at Penn Medicine.

Timothy Markman, MD: We have a lot of experience with managing ventricular tachycardia, and we know that with antiarrhythmic medications and with catheter ablation, we're able to effectively treat these arrhythmias in the vast majority of patients. In the subset in whom these traditional therapies are ineffective; it is important for us to clarify exactly what the role of SBRT is, in whom it is effective, what patients are most likely to benefit and whether and how it can be done safely. This trial is critically important to get those answers. And so we're going to eagerly await data from the RADIATE VT study to figure out what role SBRT will have in managing patients with refractory VT.

Keith Cengel, MD, PhD: I would just like to add. This trial is all about figuring out where radioablation might fit in the electrophysiology toolkit. It is certainly, in my mind, not going to result in an either or situation, but rather a both and. And I think this is an opportunity for collaboration and I really look forward to working with Dr. Markman on this trial.

Host: Thank you both so much for joining us and sharing your expertise in the trial with us today. And to refer your patient, please call our 24/7 provider only line at 877-937-PENN. Or you can submit your referral via our secure online referral form by visiting our website at pennmedicine.org/referyourpatient.

Varian’s cardiac radioablation system is an investigational device and is limited by United States law to investigational use. It is exclusively for clinical investigation (EU, UK). Not available for sale in any market and no guarantee of future commercialization or feature availability.

That concludes this episode from the specialists at Penn Medicine. I'm Melanie Cole.