Intro: Welcome to UAB MedCast, a continuing education podcast for medical professionals, providing knowledge that is moving medicine forward. Here's Melanie Cole.

Melanie Cole, MS (Host): Welcome to UAB MedCast. I'm Melanie Cole. And we have a thought leader panel for you today with three UAB Medicine physicians here to highlight percutaneous hepatic perfusion, a new treatment for metastatic uveal melanoma. Joining me in this panel today, we have Dr. Venkatesh Krishnasamy, he's an Associate Professor in Radiology and the Director of Interventional oncology; Dr. Kristy Broman, she's a surgical oncologist and an Assistant Professor of Surgery in the Division of Surgical Oncology; and Dr. John Dubay, he's the Section Chief of Melanoma and an Associate Professor of Hematology-Oncology.

Doctors, thank you so much for joining us today. And Dr. Dubay, I'd like to start with you if you'd start by giving us a little working definition of uveal melanoma. What is the prevalence and the scope of what we're discussing here today?

John Dubay, MD: So, uveal melanoma is a little bit less common of a cancer than we typically talk about. There's approximately 3,000 to 5,000 cases a year of this. And it arises in the melanocytes in the eye. These are the same cells that provide pigment in the skin and also result in melanoma of the skin. So, the same process can happen in the eye and result in what we call uveal melanoma.

At this point, it's a little bit unclear what causes uveal melanoma, but there does appear to be certain factors such as fair skin, light-colored eyes, difficulty tanning, or some people just have too many melanocytes in their eye normally that put them at increased risk. It doesn't seem to be as associated with sunlight or ultraviolet light as cutaneous melanomas. You may also have heard of certain pockets of patients with uveal melanoma, such as Auburn University, where several students have been diagnosed with uveal melanoma. However, statistically, these don't appear to be unexpected.

Melanie Cole, MS: Well, thank you so much, Dr. Dubay. So Dr. Krishnasamy, we're talking about percutaneous hepatic perfusion as this newer treatment for metastatic uveal melanoma. Can you tell us a little bit about what this is and what it involves?

Venkatesh Krishnasamy, MD: Yeah, sure, Melanie. It's a great question because the intervention has only been around in the U.S. for a little over a year now since FDA approval. However, it's an intervention that's been available in Europe for about 15 years. So, there is a fair amount of worldwide experience for this. And it's kind of grouped into what we call liver-directed therapy or local radiational therapy of the liver. The nuance being here that instead of injecting things like radiation particles or chemotherapeutic particles directly into tumors within the liver, we're injecting just liquid melphalan, which is a chemotherapeutic agent in liquid form into the liver. And then, in the venous outflow of the liver, we're actually sucking out that blood that is full of melphalan, running it through a bypass circuit, filtering out the high dose chemotherapeutic agent, and then giving the clean blood back to the patient. So, it really allows us to effectively soak and saturate the liver that's full of tumoral deposits with this drug.

Melanie Cole, MS: That's fascinating. What an exciting time in your field. Dr. Broman, you represent three different specialties here today, all focused on treating uveal melanoma. Tell us about why this is relevant and what are you finding are the largest benefits integrating PHP into this multidisciplinary treatment approach.

Kristy Broman, MD: Patients who have metastatic uveal melanoma end up seeing many different disciplines along the course of their journey. Most of the time, they present with localized disease, and that's either treated with local plaque radiation therapy or surgery. And typically, that would be done by a surgeon and/or a radiation-oncologist. However, patients can develop metastases in the course of their follow-up, and it can often be several years down the road, even decades down the road. When patients develop metastatic disease, it is often isolated to the liver or liver-dominant. And typically, medical oncologists are the people who have been following these patients and identify the evidence of disease progression and bring patients for a discussion about management options.

Typically, when we have these patients, we review them at our multidisciplinary tumor board where we have representatives from all of the disciplines that treat uveal melanoma including Surgery, Medical Oncology, Radiation Oncology, and Interventional Radiology. And we really take these on a case-by-case basis, considering the patient, their own performance status, the extent of disease that they have, and any treatment options that they've already tried.

So, not everyone is a candidate for percutaneous hepatic perfusion. Patients are required to have less than 50% parenchymal replacement, meaning that they can't have more than half of their liver volume replaced by tumor, just to ensure adequate liver that is normal and able to function to help them carry on. And then, occasionally, we will do this procedure for patients that have limited disease outside the liver. In those cases, we need to have some sort of local treatment for that disease outside the liver, because PHP does only treat the liver.

So for example, if they have mostly liver disease and one other site of disease, if there's an option to radiate or resect that area, then those patients can still be candidates. And then finally, as we're considering who can have this procedure, once we've decided from an oncologic standpoint that it's appropriate for a patient, we then have to verify that it's safe. So, patients have to have good cardiopulmonary status, and we do engage our anesthesia colleagues as well as our cardio-oncology specialists in evaluating these patients to make sure that it is safe for them to undergo the procedure.

Melanie Cole, MS: Dr. Dubay, how does PHP compare to systemic immunotherapies or targeted therapies in terms of efficacy, durability of response, given the isolated hepatic perfusion technique that Dr. Broman was just discussing? What are some of the main risks and how are they managed? Speak a little bit about comparison.

John Dubay, MD: Well, I think that's an important question. We do have other treatment options for patients with metastatic uveal melanoma. These typically revolve around immunotherapy. And unfortunately, these treatments don't work very well with typically a less than 10% response rate. So, the local therapies become a very important part of treatment of metastatic uveal melanoma in terms of toxicity. I think I will defer that to Dr. Krishnasamy.

Venkatesh Krishnasamy, MD: I think it's important to remember, I mean, this is coordination of teams with respect to just the intervention itself. It is a whole-day procedure. The patient is going to be under full general anesthesia. We're coordinating, Dr. Broman and myself, Surgical Oncology and Interventional Oncology, as well as Perfusion and Anesthesia or Cardiac Anesthesia, to safely care for the patients during the procedure. It is about a few hours to go through the whole process, to soak the liver and then extract the melphalan from the blood to safely give the blood back, incorporate it into that procedure or blood pressure changes, which Dr. Broman alluded to the importance of having good cardiopulmonary function and status. So, things that we're very keen on evaluating to ensure a patient can tolerate the procedure without some sort of poor outcome. These patients will wake up and then be admitted to the ICU overnight. That's standard protocol. So, we can monitor blood pressure and blood counts, and electrolytes specifically. By and large, these patients will go home the first day postoperatively. And then, the first weeks can be a little bit rocky. Most patients will very sluggish, but that does return to normal in a few weeks.

And more importantly, there are multiple clinical followups in those first few weeks so we can evaluate blood counts. One of the toxicities of melphalan specifically is to diminish blood counts. And so, we have to keep tabs on that, replace with blood products as needed, even giving potentially injections to stimulate the bone marrow to produce more blood cells, but this is all a normal part of the process and has been seen in 15 plus years in the European data.

On the positive side, melphalan is not as toxic to the liver as other liver-directed therapies. And so, that's one of the reasons why it has really come to the forefront of therapies for uveal melanoma, metastatic to the liver in particular, because a normal liver is not nearly as affected by melphalan as the tumor. And then, the normal liver is not nearly as affected as with other local regional therapies that we traditionally have offered to these patients.

Melanie Cole, MS: Well, thank you, Dr. Krishnasamy. And you got to my next question before I even asked it, so thank you for that. So Dr. Broman, kind of a similar question to you. How does this compare to surgical options like hepatic resection or transplant for metastatic uveal melanoma? And given that the metastasis is predominantly to the liver, as you've said, how does it change your approach to managing these patients surgically?

Kristy Broman, MD: It's important to note first that a patient with metastatic uveal melanoma would not typically be considered a candidate for a liver transplant. There is intermittently some discussion about that, but it has not been evaluated or tested and would not be considered standard of care at this point. There are some limited circumstances in which we would consider surgery over percutaneous hepatic perfusion. But I would say that for the majority of patients, PHP is going to be the preferred approach. And the reason for that is the biology and anatomy of the tumors. Typically, the disease presents as multifocal bilobar miliary disease. So, the patient will have many tiny spots throughout the liver, and it really isn't amenable to any form of surgical resection for that reason.

Now, there are select cases where a patient might have a single isolated lesion. And in those cases, we might consider surgery over percutaneous hepatic perfusion. But in general, because of the pattern of disease, most people will likely get better local therapy with an approach that perfuses the entire liver. And that is one of the benefits of discussing these cases in a multidisciplinary fashion, is that we can have those nuanced discussions about what option is best for a given patient given their disease.

Melanie Cole, MS: Dr. Krishnasamy, as you mentioned before a little bit what recovery was like, take us further on down the line for these patients, and what can they expect as far as quality of life?

Venkatesh Krishnasamy, MD: Yeah, absolutely. It's a great question because there are a couple of quality of life studies that have been published out of Europe that show improvement in overall quality of life down the line. Once recovered from the initial intervention, there is another aspect to this because this is called percutaneous hepatic perfusion, and the intervention is strictly percutaneous. It is repeatable. And so, it's very common for patients about every two months to have the procedure repeated, depending on their response to the treatment, and then to go through these cycles of treatment. And obviously, I think when patients kind of know what to expect, it's a little bit easier potentially in the second and third treatment and so on. But the goal is to get disease control and limit progression of that disease, and then improve survival and time for these patients and their families.

Melanie Cole, MS: Such an important point. And I really want to give you each a chance for a final thought here. Dr. Dubay, other treatment options for this condition, how they compare. And when you're thinking about looking to the horizon, can you give us a blueprint for future research and what you see happening in the world of uveal melanoma and metastatic uveal melanoma?

John Dubay, MD: Yes, this remains a very challenging area for us. We do have new treatments coming down the road, such as the one we're talking about today. We also have available tumor-infiltrating lymphocyte therapy, that may play a role in the treatment of uveal melanoma down the road. So overall, we have a lot of treatment options, but are still left with unsatisfactory treatment most of the time. So, we are hoping that our treatments will improve as further research helps us understand the biology of uveal melanoma and how that's different from our cutaneous melanomas.

Melanie Cole, MS: It's such an interesting conversation we're having. And Dr. Krishnasamy, similar question to what Dr. Dubay just answered as far as typical treatment outcomes and survival rates with these liver-directed therapies, what would you like to see?

Venkatesh Krishnasamy, MD: That's a great question. And I'll add to that a little bit also, because we're in an era where collaboration between specialties is extremely beneficial for the patient. And so, this concept of multimodal therapies and improving upon outcomes for each individual therapy by combining therapies is real and relevant. And as Dr. Broman and Dr. Dubay both know, there's emerging data combining systemic immunotherapy with PHP coming out of Europe as well, that you were looking at disease control rates much higher than just PHP alone, which is very, very exciting.

So, the future is really bright, and I think when we talk about collaborative efforts and what I like to call multimodal therapy, there's a tremendous amount of potential for these patients and controlling their disease processes.

Melanie Cole, MS: Well, the future is certainly bright with experts and specialists such as yourselves. It's a really exciting time for you all, and looking to the future for these patients is really a very positive-looking future. So, Dr. Broman, last word to you, key takeaways, what you want other providers listening to know about this multidisciplinary approach that you're doing for patients with uveal melanoma, what you would like them to know about the work you're doing at UAB, but also why it's so important that you're all working together.

Kristy Broman, MD: Thanks for your question, Melanie. I feel very fortunate to be in a center where I have true experts in every area who enjoy collaborating. We really like working together. And I think that is what sort of drives us to keep working to identify new treatment strategies and to bring them forward as options for our patients. So, we are very lucky to be in this environment. And it does enable us to have unique treatment offerings.

The only other takeaway that I think is important is the importance of surveillance. For people who have initially been diagnosed and treated with localized uveal melanoma, it is important that these patients remain in long-term follow-up and understand that despite having a successful initial outcome, that they're still at risk for developing disease down the road. And so, it's important for them to maintain themselves in care with routine clinical assessments. So that if they do develop metastatic disease, we will have a window of opportunity to initiate these excellent therapies that we've been discussing. So, that's part of our multidisciplinary approach, is making sure that we maintain these patients in follow-up and that they're getting careful monitoring in case they do need these treatments down the road.

But again, just to reiterate, really grateful to be at UAB and to be working with Doctors Krishnasamy and Dubay, as well as our other colleagues to be able to bring this technology.

Melanie Cole, MS: Thank you all so much for joining us today and sharing your incredible expertise for other providers. And thank you again. This was very enlightening. And for more information, you can always visit our website at uabmedicine.org/physician. That concludes this episode of UAB MedCast. I'm Melanie Cole. Thanks so much for tuning in today.