Looking Out for Rare Cancer: Uveal Melanoma

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals exploring the latest innovative research in 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 here at Cleveland Clinic overseeing our Taussig Phase One and Sarcoma programs. Today I'm happy to be joined by Dr. Arun Singh, director of the department of ophthalmic oncology. Dr. Singh is here today to talk to us about uveal melanoma. So welcome, Dr. Singh.

Arun Singh, MD: Well, thank you. It's a privilege to join this podcast. Uveal melanoma is a rare tumor relatively speaking. We say everyone has heard about skin melanomas all the time, but if you look at all the melanomas that happen, about 15% or so are actually uveal melanomas. So skin melanoma is 85% vast majority and a small component is uveal melanoma.

Dale Shepard, MD, PhD: All right.

Arun Singh, MD: And uvea is part of the eye that's inside the eye. That's if you think about the pupil and kind of think it goes backwards, lining the eye, that's a part called uvea and melanomas arise from that.

Dale Shepard, MD, PhD: And so uveal melanoma is a unique disease. It's a unique type of melanoma. How often do you see people that may come to you with a cutaneous melanoma that involves the eye and kind of sorting out issues related to that?

Arun Singh, MD: That's a rare situation. So there are two or three ways we can see a patient with cutaneous melanoma and uveal melanoma overlap. One is that somebody has a history of cutaneous melanoma and they see a brown spot inside the eye and they say, "Oh, could this be a metastasis?" That's very unlikely or unusual. And in general, metastasis happens in advanced stages of cutaneous melanoma, almost terminal stages, when the melanoma is all over the place and then they get it in the eye as part of that. So it's very obvious when they have well developed metastatic disease to have something in the eye.

The second scenario is that the patient actually has a nevus, or a mole or a freckle in general words. And that's an incidental finding. And because they have a cutaneous melanoma, they get alarmed and we say, "Oh, it's just a freckle."

Dale Shepard, MD, PhD: Gotcha.

Arun Singh, MD: Nothing else has to be done. And the third, and that's a rare one, where they could be some kind of genetic component to skin melanoma and uveal melanoma through a germline mutation, like a genetic predisposition. That's a rare disease but that, we see time to time.

Dale Shepard, MD, PhD: And so just to give us an idea of perspective. It's 15% of melanomas from a number standpoint. How many cases do we consider a year?

Arun Singh, MD: So in the United States, we expect about 2000, 2,500 new cases of uveal melanoma per year. We see about 150 of them in the Cole Eye. Yeah.

Dale Shepard, MD, PhD: Okay. So you're pretty busy seeing these.

Arun Singh, MD: Yeah. We do see them. They arise in the iris. They can arise in ciliary body. They can arise in choroidea. So we see that in many cases of uveal melanoma, new cases.

Dale Shepard, MD, PhD: So what would be... What are typical symptoms? How would people suspect they have a uveal melanoma?

Arun Singh, MD: There's no specific symptom of uveal melanoma. Symptoms are all very non-specific such as, oh, blurred vision, some floaters, some flashes, and do want to alert that there many thousand causes, more common causes of those conditions than uveal melanoma, but uveal melanoma could be causing any of those. And when they go for a checkup, they will find some kind of a growth or a tumor inside the eye that has brownish color typically and they say, "Oh, this could be melanoma." And that's how patients kind of get diagnosed or suspected. And then we diagnose them.

The other is they go for routine examination for glasses or when they are diabetic or something along that when they're 60, 65 years old and they get a dilated eye exam. And it, a dilated means the pupil has been dilated and somebody looked at the retina inside and finds a mass which is incidental. That's the other way of diagnosing melanoma. So it's suspecting. And then, of course, we diagnose them with imaging and biopsies really.

Dale Shepard, MD, PhD: And which is most common? Do you see more patients that are incidentally found to have them or do most people come in with symptoms?

Arun Singh, MD: Most of them come with symptoms, but more recently because of a wide availability of fundus cameras. So many optical services and opticians have bought these cameras where they can take a picture of the eye. And once they take a picture of the... It's a panoramic picture of the retina. And once they take a picture of this here brown spot, that can alert to you to that's melanoma, which may have been missed on examination but shows up on a picture. So we see several such cases, but still overall it's more symptom-related. Yeah.

Dale Shepard, MD, PhD: Excellent. I guess, to sort of temper people not being overly concerned with what might be common symptoms, but not be dismissive and miss something, when should someone get an exam? So if someone has symptoms, what should trigger them to go to see their ophthalmologist and have that exam to see?

Arun Singh, MD: So melanoma is not going to cause pain. Melanoma isn't going to cause redness, is not going to cause irritation. Isn't going to cause mucus discharge from the eye. It all has to do with vision. So there's blurry vision, distorted vision, some flashing lights, some floaters, those things, but most of them would have a more common retinal cause like a vitreous detachment, retinal tear, diabetes, hypertension, those things affecting the retina. Melanoma will be way down in the list of it. Yeah.

Dale Shepard, MD, PhD: How do we make a diagnosis?

Arun Singh, MD: So diagnosis of melanoma is clinical in the sense that it's based on examination, based on imaging. Unlike other parts of the body, we can actually see the tumor directly. So once we dilate the pupil, we can examine all of retina and this tumor is not in the retina. It's under the retina, but we can see it directly. And it has characteristic features on examination, on photographs, on ultrasonography, on the fluorescein angiogram and ICGB have our own set of tests. And based on all that we can pretty much diagnose uveal melanoma with 99.4% accuracy. And so the misdiagnosis rate is very low.

Dale Shepard, MD, PhD: That's good.

Arun Singh, MD: And in cases where we can't make a diagnosis, then we have techniques of biopsy, so we can biopsy them.

Dale Shepard, MD, PhD: So usually it does not require biopsy.

Arun Singh, MD: Usually it does not. Yeah.

Dale Shepard, MD, PhD: Excellent. So a person has some symptoms. They come in, diagnosed. What are the treatment options?

Arun Singh, MD: A treatment option depends upon the size and the vision potential in the eye. But in general, we would say that... First of all, you say, "Well, is it really melanoma? Or is it just a big freckle inside the eye?" So cases that are going to borderline and we can't be very sure about the diagnosis, we'll observe them. So it's reasonable to observe smaller tumors where the diagnosis is not clear cut, for example.

And, but once the diagnosis is made based on history, growth or imaging, et cetera, then most common treatment is really a radiation treatment. When we say radiation, it's a brachytherapy where we take a radiation implant and stitch it to the eyeball where the tumor is, right at the base of the tumor. So the radiation is focused onto the tumor with least collateral damage. So that's the most common treatment.

Other treatments, if a tumor is large and if there is no vision potential in the eye, then we talk about removal of the eye and tumors that are located more towards the front of the eye, such as in the iris or ciliary body, which is just where the lens of the eye is, then those can be resected. So we can resect smaller tumors like that too.

Dale Shepard, MD, PhD: So what do you see as the drawbacks of our current therapies? Where do we fall short and where do we need to make progress?

Arun Singh, MD: Yeah. So the radiation has been around for uveal melanoma almost 100 years. And that's because we have a control rates almost 95, 99%. So our local control rate's very, very high. So it's very hard to come up with new treatments that are to suppress something that's highly effective.

Dale Shepard, MD, PhD: I'm just going to jump in and say, I'm exceedingly jealous.

Arun Singh, MD: Yeah. In all oncology, in all of radiation oncology, choroidal melanoma or uveal melanoma radiation has the highest control rate, 99%. In our series here that we published from Cleveland Clinic, overall 95.6%, smaller tumors 99% control rates over the last 15 years. So that's very high. Of course, there is a collateral damage from radiation and that's called radiation retinopathy, which affects vision. And there is a trial starting later this year, a multicenter trial, to figure out the treatments of radiation retinopathy, how to mitigate it, how to treat it once it happens and Cole is taking the lead on it because we are going to be the main center driving the trial.

Dale Shepard, MD, PhD: When we think about the treatment, most of the time we get local control. In those cases where it spreads outside of the eye, where does it go and how do we treat that?

Arun Singh, MD: So metastasis is not uncommon. Again, it depends upon the size and the genetic profile of the tumor. And there are ways to predict that using biopsies and other new genetic molecular techniques to prognosticate each case, and the most common site for metastasis is actually liver. So it does not go to the brain and doesn't go to the other eye. It doesn't go to any other place.

And so we deliver directed imaging in patients based upon their risk profile. And if it goes to liver, then there are ways to treat it. There is laser ablation, surgical resections. And just about last month, a new drug has been approved by the FDA called Kimmtrak of which is effective in prolonging survival in patients with uveal melanoma that's metastatic to liver. So there is an exciting things happening in this field.

Dale Shepard, MD, PhD: Yeah. What role is there for things like immunotherapies or genomic... Sort of analysis like you see with cutaneous melanoma?

Arun Singh, MD: So we do all those things in uveal melanoma too. We have a genetic markers for prognostication. We can say, "Well, if you have this kind of mutations, you are likely to have metastasis. And if you have this kind of mutational profile, then you're less likely to metastasize." So there are gene markers or mutational markers for metastasis that commercially available. Before that we were doing in-house kind of research work and now there are commercial tests available. We use them all the time. And regarding the treatment for metastatic melanoma is an immune therapy, CD3 T-cell Engager, as a new mechanism. But the immune therapies that are effective for cutaneous melanoma that do not work for uveal melanoma. That I do want to point out. Yeah.

Dale Shepard, MD, PhD: Right. Right. Yeah. I guess it's what I wanted to clarify as well. Just, people automatically think of checkpoint inhibitors and things for cutaneous melanoma.

Arun Singh, MD: Yeah. No. So the genetic mechanisms are very different in uveal melanoma. So melanoma is the common word within cutaneous in uveal, but they are basically different diseases. And so what works for cutaneous melanoma doesn't work for uveal melanoma at all.

Dale Shepard, MD, PhD: And I guess that brings me to the question of who should see you or someone at Cole for uveal melanomas? These are rare tumors. These are things that... Of course, people might be in a metastatic setting, be a bit fooled by the fact it's melanoma in the name. Who should be seen here?

Arun Singh, MD: So for primary uveal melanoma, treatment of the eye or anything related to the eye or side effects of immune therapy or any aspects of that, they should certainly see me for that. Again, these are rare diseases. So not at any institution you're going to have people who know about uveal melanoma. You're not going to have five people dealing with melanoma because you only have only so many cases in a year. So only big institutions can run a service like what we have here that started almost 20 years ago.

So if they have anything related to uveal melanoma, they should come and see me. If they have something related to metastatic disease of uveal melanoma, then we have two main oncologists that we have identified or we partner with. One is Dr. Kennedy. Another one is Dr. Funchain. So we kind of work with them in trying to establish their treatment protocols for metastatic disease.

Dale Shepard, MD, PhD: And of course, we also have a strong liver group and can do liver. Yeah.

Arun Singh, MD: So we have people who doing... So Dr. Berber did our liver ablations. We have people doing immuno radiation as infusions of liver, people in radiation oncology, but we start with Dr. Funchain and Kennedy and based upon the tumor location and tumor burden, tumor size, et cetera, there, which organs are affected, they will figure out the best treatment and they will direct the patients.

Dale Shepard, MD, PhD: You're doing really well with local control. We have a new drug for metastatic disease. What's the biggest gap? What do we need to be focusing on next in uveal melanoma?

Arun Singh, MD: One is, like I said, the efficacy is high. So we are looking for treatments that are not radiation-dependent. So we say, "Well, radiation retinopathy happens. And as of now it's not treatable. Can we develop new treatments that replace radiation?" So there is a trial starting in that field. There has some preliminary work already done. There would be a phase three trial randomized study coming up, I think later this year or next year, talking about laser-directed, the viral-loaded particles and laser energy being delivered to the tumors. So that's a trial coming up. It's promising for smaller tumors. So that's one. So you're trying to move away from radiation, so you don't have any radiation retinopathy at all.

And second is to say, "Can we reduce the dose of the radiation? Because the radiation complications are dose-dependent." So we're coming up with scenarios of how much dose can be reduced and still have good control. So we are starting to kind of come down on the dosing that's given.

The third is about the newer implant designs so that the radiation is more focused and less collateral damage. Just the way the radiation physics is, so we have some new designs that we are using now. And the last is one mentioned about the trial, where we have a prospective study where we are going to look at the natural history of the disease, of radiation, retinopathy and drugs, et cetera.

I want to point out that we are an orphan disease and it's very difficult to get funding to do major trials. So that's why it's taken so long and so difficult to make huge advances in this field of rare diseases and you, I'm sure, realize in other rare diseases as well.

Dale Shepard, MD, PhD: Yeah. Absolutely. I guess, from a radiation standpoint, this is being done by brachytherapy where you're applying radiation and you mentioned trying to make that more focused. Has there been work done on other ways to do focal radiation, like proton-

Arun Singh, MD: Yes.

Dale Shepard, MD, PhD: ... radiation?

Arun Singh, MD: Yeah. So proton beam radiation has also been used for some years now and it's again limited by the availability of proton. So there are proton centers in Boston, some place in San Francisco. The one in Cleveland hasn't been adapted for use of ice, because it needs special modules and special ways of delivering it. So again, it's limited by the cost. Proton, as you know, is very, very expensive. And to have it only for the eye is just not viable. So unless it's been used for some other tumors, brain tumors and children, et cetera, and there's a wider acceptance of proton or data to say that it's superior than radiation, normal radiation... It hasn't really caught on so widely. Yeah.

Dale Shepard, MD, PhD: Got it. You mentioned the laser, the viral particles. Certainly an important part again of cutaneous melanoma would be injection of tumors with a virus that then elicits an immune response. Things like TBEC. Similar things being considered for... Realizing that some of the things that work in cutaneous melanoma don't work in uveal, but are there similar mechanisms to do sort of viral injections into uveal melanoma?

Arun Singh, MD: So this viral injection is virally just a capsid. It's a human papilloma virus capsid. So there's no DNA, RNA, nothing in it. Just a capsid. And it's loaded with a dye and that's injected into the eye. And the particles bind to the melanoma cells preferentially than normal retina or the rest of the eye. And then when you shine the laser, that picks up only the dye. So the laser is delivered specifically or preferentially or exclusively to the melanoma that's been targeted.

Dale Shepard, MD, PhD: Pretty clever.

Arun Singh, MD: That's the mechanism. Yeah. It's a new company that's been now trading and all that. It's a publicly traded company. Yeah.

Dale Shepard, MD, PhD: And I guess I'll, in terms of mechanisms, of course, as an ophthalmologist and a surgeon, I save that one for last, any...? You mentioned about surgery being a component of things in the front part of the eye. Oftentimes in any given thing more minimal surgery has, of course, been the key. Has there been any consideration of surgeries in that back part of the eye to remove...?

Arun Singh, MD: Maybe somebody gave you a tip? Yeah. We did come up with a minimally invasive surgery for iris resections almost 15 years ago. And we have done almost 70 cases or so. We published our first 22, 25 cases some years ago. Yeah. So just think about gallbladder surgery and you're doing laparoscopic approach with multiple holes and you go in there and you're able to remove and patient recovers very well. Imagine same way, you're making tiny one millimeter incisions in the cornea and entering the anterior chamber of the eye and cutting the iris, removing the tumor and suturing it through those tiny holes and having good margin controls, good controls and very good recovery. 20/20 vision. Yeah.

Dale Shepard, MD, PhD: Considering the anatomy of the eye and the lens and things, is there any consideration of being able to do similar things in the retinal area of the eye as well?

Arun Singh, MD: Yeah. So that surgery is called endoresection. The issue is that we really do not want to disseminate cells as we are cutting them. And it's difficult to get wide margins. So in cutaneous melanoma, say I want two centimeter margin, well, you have so much skin you can cut it. Well, two centimeter is most of the eye. So there you go. So you can't have a high margins and therefore it's a little more challenging. So, and the uvea is the most vascular tissue of the body. And so the moment you attach it, it bleeds. So you have this bleeding risk, margin risk and risk of tumor dissemination. So all that has hampered the role of or popularity of endoresection.

Dale Shepard, MD, PhD: Gotcha.

Arun Singh, MD: You really don't want to cut through melanoma inside the eye. Just going to spread all over.

Dale Shepard, MD, PhD: Very good. Any other new advances you're particularly excited at this point?

Arun Singh, MD: So one is radiation retinopathy. So really the control rate is no problem. We have 99% control and this treatment has been around for 100 years. So there are people in my business who are very familiar with it and very comfortable doing it. So don't have to learn new techniques. It's all there. All we have to do is find a way to reduce the complication. So I think I'm really excited about that. I'm the PI for this trial that's going to start out and it's a 600 patient trial supported by the DRCR network, NEI. It's almost a 12, 15 million dollar study and it's fully funded.

Dale Shepard, MD, PhD: Wow. That's impressive. That's a lot of patients for a rare disease.

Arun Singh, MD: Yeah. But we're going to have... It's a multicenter, so we'll have approximately 10, 15 centers contributing cases to it over three year period. So I'm excited. So finally there is some money coming through some different mechanisms-

Dale Shepard, MD, PhD: Very good.

Arun Singh, MD: ... and we need all that to do the trials.

Dale Shepard, MD, PhD: Wow. That's impressive. Well, I certainly appreciate all of your insight. This is an area that a lot of people don't know a lot about. And anytime people think cutaneous melanomas, it's always kind of a scary thing, but great to hear that you have new therapies and good control with uveal melanomas locally. Good luck with your trial.

Arun Singh, MD: Thank you very much. Thanks for having me.

Dale Shepard, MD, PhD: To make a direct online referral to our Taussig Cancer Institute, complete our online cancer patient referral form by visiting clevelandclinic.org/cancerpatientreferrals. You will receive confirmation once the appointment is scheduled.

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