Leveraging Oncology Treatments for Vascular Anomalies

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals, exploring the latest innovative research and clinical advances in the field of oncology. Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale. Shepard, a medical oncologist and Director of International Programs for the Cancer Institute and Co-Director of the Sarcoma Program at Cleveland Clinic. Today, I'm happy to be joined by Dr. Michael Kelly, a pediatric hematologist and oncologist at Cleveland Clinic Children's, who is here today to talk to us about innovative care for vascular anomalies. So welcome.

Michael Kelly, MD, PhD: Thank you. I really appreciate the opportunity.

Dale Shepard, MD, PhD: Absolutely. So maybe before we start, give us a little idea, I gave kind of your title, but what do you do here?

Michael Kelly, MD, PhD: So basically I've been at Cleveland Clinic for about four years, and I was brought here really under the guise of being a non-malignant hematologist. And within that context, really wanted to pursue my interest in taking care of patients with vascular anomalies. And actually they have a very large program here that takes care of both pediatric and adult patients. So really, joining that program has been terrific as far as a learning experience and also bringing some aspects of care that have worked at past institutions to the Cleveland Clinic, which I hope has improved the care over that four-year period of time.

Dale Shepard, MD, PhD: Excellent. So a lot of different people with different backgrounds might be listening in. So let's kind of start basic. When we talk about vascular anomalies, I guess two things. How common are they and kind of what falls under that category? What are we talking about here?

Michael Kelly, MD, PhD: Yeah, that's a great question. So vascular anomalies is an umbrella term that basically encompasses both vascular malformations, which are developmental disorders of the arteries, veins, lymphatics or capillaries, or combinations thereof, and then a variety of vascular tumors. Mainly we take care of the vascular malformations. So again, largely sort of anatomic changes in veins, arteries, capillaries, and lymphatics. It's been estimated that there are approximately 3 million people in the U.S. that are affected by vascular malformations.

Dale Shepard, MD, PhD: When we think about these malformations, are these usually things you mention that maybe it's some sort of abnormality that was a structural abnormality that they were born with, for instance, how do most people come to know they have them? Are these things that they will develop a symptom or are finding, or are these sort of incidentally found on imaging, or what's the most common presentation?

Michael Kelly, MD, PhD: All of the above.

Dale Shepard, MD, PhD: All the above.

Michael Kelly, MD, PhD: Yeah. So basically, as you point out, they are developmental abnormalities. So they occur during development and can manifest at birth or even prior to birth. There are some patients with large lymphatic malformations that are noted on prenatal ultrasounds, but we also see patients that present in adolescence and later in adulthood with symptoms of vascular malformations. Most of the symptoms that we see are swelling and pain, or certainly the most common ones that we see. And again, depending upon the anatomic location or body part that's affected by the malformation, you can see other types of symptoms like bleeding, infections, and others.

Dale Shepard, MD, PhD: And so when we think about how we treat these, you mentioned there's a program. So tell us a little bit about the program. Who's involved, what kind of caregivers are involved? What does that look like?

Michael Kelly, MD, PhD: So the program, as I said, is one of the few programs in the country that actually takes care of both kids and adults with vascular malformations. And so we have several dermatologists as well as interventional radiologists, diagnostic radiologists, surgeons, including plastic surgery and general and other subspecialties. So there's a wide variety of disciplines that are actually a part of this. And most recently, over the last few years, we've really tapped into expertise within lymphedema clinic here at Cleveland Clinic and also the Vascular Medicine clinic. So again, I think that we are really utilizing each other's expertise in order to take care of a wide variety of both adult and pediatric patients.

Dale Shepard, MD, PhD: And I guess this is a shameless plug. I'll point out we've previously had an episode about lymphedema, so if somebody wants to go back and listen in. These are pediatric and adult patients. What about the psychosocial component?

Michael Kelly, MD, PhD: Psychosocial component is very real. And again, I think it's very important to address. One of the things that we've worked very hard in the Vascular Anomaly Program is developing and bringing in new disciplines in order to help support our patients in a more comprehensive way. For instance, we brought on geneticists who actually are incredibly important in making diagnoses and helping us with targeted therapies. But one of the keys over the next year to two is really bringing in the sort of psychosocial support, very similar to what we see in comprehensive cancer care here at Cleveland Clinic.

Dale Shepard, MD, PhD: And you mentioned genetics. So tell us a little bit about what we know about the basis of these malformations, the genomic abnormalities, and how that may or may not compare to cancers.

Michael Kelly, MD, PhD: Great question. I think that what we have found over the course of the last 20 years is that a majority of the patients with vascular malformations actually have somatic mutations in genes that are identical to those that cause cancer. So these genes occur after fertilization, so they're not inherited from mom or dad, but what happens is they occur in different cells and usually in the endothelial cells that line the vessels that they affect. And so what happens is that these genetic changes often activate growth pathways, and it's that activation that causes abnormal growth and abnormal function of these abnormal vessels.

Dale Shepard, MD, PhD: And I guess just for reassurance, what do you talk to patients about their risk for cancers? Is there a concern that one of these malformations may become a cancer, whether they're more susceptible to cancers? What are those discussions?

Michael Kelly, MD, PhD: Yeah, it's really a key point because many patients come to us after being cared for by a variety of different providers, and many providers will actually equate these to cancers. So it's unclear to patients when they come whether they have cancer and what their risk of cancer would be. So we reassure them that even though the genetic changes are identical to what we see in cancer, there's no increased risk of cancer in a majority of patients that have these malformations.

Dale Shepard, MD, PhD: And so from a treatment side, you mentioned people in the program, dermatology and interventional radiology, surgeons, benign hematology. I mean, what are the most common things we see in terms of how we treat these?

Michael Kelly, MD, PhD: Traditionally, this has been a surgical and interventional approach to treatment. So surgical meaning cut it out. What you see, you cut out. Interventional, what has been developed is techniques where you go in and you enter the abnormal vessels and you can actually scar down those vessels with certain chemicals, and that's called sclerotherapy. And those were the hallmarks of therapy until very recently. The problem with those therapies, they have a place and they're good. However, they're limited in a sense that almost always these malformations come back. And so what we have learned based upon the genetic causes of these malformations is that we can repurpose medications that have been used to treat a number of different cancers to the treatment of vascular malformations.

Dale Shepard, MD, PhD: Which is good for patients, but also adds maybe to that confusion about links to cancer, right?

Michael Kelly, MD, PhD: Absolutely. Especially when you're sending them information about basically cancer treatment drugs. So absolutely.

Dale Shepard, MD, PhD: This drug is used to treat... So tell us a little bit about trial options for patients and things we might be doing here in a trial setting.

Michael Kelly, MD, PhD: Yeah, it's very exciting. Actually, one of the major pushes in the last year for me as far as program development has been the implementation of a research program centered around a very comprehensive care approach. And so what we are developing and bringing into Cleveland Clinic are clinical trials that actually objectively measure not only the effectiveness, but the safety of different medications. Prior to the clinical trial development over the last few years in this area, there were a lot of anecdotal experiences that then triggered sort of almost a standard of care approach. And so rather than working on those anecdotal experiences, we're now actually looking at appropriate patient populations under very stringent conditions in order to look at both effectiveness and safety.

Dale Shepard, MD, PhD: I guess one thing, kind of doubling back a little bit, because there are somatic mutations that cause some of these, and you mentioned about recurrence after surgical procedures, do most patients tend to have localized disease or does it tend to be more systemic disease? And it kind of comes to mind when we're talking about trials where we're giving sort of systemic therapies. Is this more of a localized disease usually, or is this more systemic?

Michael Kelly, MD, PhD: So the diseases can actually present both localized as well as regional and then more systemic. And the percentage of patients, the most common presentation is localized, and surgery and sclerotherapy are actually very beneficial to those patients. Patients with extensive regional involvement, like a whole leg, are less amenable to those localized therapies. And obviously people with systemic disease actually would benefit more from a systemic therapy than local or regional therapies.

Dale Shepard, MD, PhD: You mentioned that oftentimes patients have been seen by a number of different providers or types of providers. What would an ideal patient be that should come and be seen in the program here?

Michael Kelly, MD, PhD: I think that patients that have really unexplained swelling and pain associated with an extremity or part of their body, often these individuals will have changes on their skin, which suggests that there's something underneath that might be a problem, including abnormal vessels. And I think that any patient that has fluid collections in their chest, in their abdomen, or unexplained lymphedema, actually often will have vessel malformation as an underlying cause.

Dale Shepard, MD, PhD: If we think about the patients, you said that within the program here at the clinic we have pediatric patients, adult patients. What kind of things can we learn by being more comprehensive and seeing the adults and pediatric patients, even like maybe the same patient over a continuum of time? How do we benefit with our program by being inclusive?

Michael Kelly, MD, PhD: I think that the biggest advantage of seeing both adult and pediatric patients is having a much better understanding of the natural history of these diseases. Those that take care of just pediatric patients see a certain component of disease, but when they transition to adult care, what you see is honestly very different symptoms and manifestations of the same disease over time. The other piece of this is that most of the experts in the field are actually pediatric hematologists, oncologists, and pediatric providers. So again, finding providers that can take care of adult patients is very challenging. So having one of the few centers in the country that actually takes care of both pediatric and adult patients, we have a natural built-in system of transition for these patients for care.

Dale Shepard, MD, PhD: That's good. What sort of issues, and again, modeling off of traditional cancer programs, what sort of survivorship issues are there when you see these younger patients with these abnormalities and then as they grow older?

Michael Kelly, MD, PhD: Yeah, most of the time these are chronic problems and manageable problems, but clearly problems that affect quality of life. However, there are life-threatening complications that can occur with some of these disorders, particularly lymphatic disorders in which there's significant leakage of lymphatic fluid into body cavities like the chest and abdomen. And also the other kind of major problem area is a subset of patients with arterial venous malformations, or AVMs. Those actually can be very symptomatic and can grow very quickly and cause a lot of problems, including bleeding that can lead sometimes to death. So although most of what we're talking about is chronic and manageable, there are situations that require a much more comprehensive quick approach to therapy in order to save lives.

Dale Shepard, MD, PhD: What do you think's going to be sort of the next big break in terms of managing these patients? What are you looking forward to on the horizon? You mentioned clinical trials and maybe some new mechanisms. What excites you in the area right now?

Michael Kelly, MD, PhD: So what excites me is actually several things. Number one, I think that we're generating mutation-specific inhibitors that will actually, at least in theory, be more effective and safer than the current targeted therapies that we use. We're actually developing a lot of new surgical approaches, some of which are being developed here at Cleveland Clinic in the lymphedema clinic, that can be applied to the patients with vascular malformations and lymphatic leakage, wherever that can occur. And the other really exciting component is that we're better understanding the biology of these malformations in order to use not only targeted therapies, but use therapies directly inserted into the malformations rather than giving orally or systemically. So this actually will offer, again, opportunities to have more effective therapy and safer therapies moving forward.

Dale Shepard, MD, PhD: Well, it sounds like you're putting together a really comprehensive program and looks like there's a lot of exciting things in the future. So appreciate you being here for your insight today.

Michael Kelly, MD, PhD: I really appreciate it. And I will say I'm a member of a very large team and couldn't do this without their help and without their guidance.

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