Eye Toxicities: A Side Effect of Cancer Treatment

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 Shepherd, a medical oncologist here at Cleveland Clinic directing the Taussig Early Cancer Therapeutics program and co-directing the Cleveland Clinic Sarcoma program. Today I'm very happy to be joined by Dr. Shahzad Raza, a member of the Multiple Myeloma Group here at Taussig Cancer Institute. He is here today to talk to us about eye toxicities, a side effect of anti-cancer drugs. So welcome Shahzad.

Shahzad Raza, MD: Thank you, Dale, for having me here.

Dale Shepard, MD, PhD: Absolutely. Maybe just start out, kind of tell everyone what group you're with, but what do you do here at the Cleveland Clinic?

Shahzad Raza, MD: Yeah, I'm actually a disease, joined the Multiple Myeloma and AL Amyloidosis group last year, and my major area of research and what I like and what I'm passionate about, taking care of the patients who have plasma cells disorders, and I also do the bone marrow transplant, T-cell therapies. So, a lot of this stuff is related to plasma cell disorders here.

Dale Shepard, MD, PhD: Excellent. Well, we're not going to talk about treating those specifically today, but we're going to talk about eye toxicities. It is something that quite honestly is a great topic because I'm going to argue probably underappreciated. What do you think?

Shahzad Raza, MD: I 100 percent agree with you, and I didn't know how things evolve around it, but I can tell you that one of my first author of this paper, he was a medical student at my previous place, and he was very passionate about ophthalmology things, and he was asking my oncological perspective. That's how I came up with this topic. And as you know, one of our multiple myeloma drugs has very bad eye toxicities. That's a turning point for me to have this project and have this topic to be covered, because I see a significant knowledge gap knowing what toxicities can happen with these new types of drugs.

Dale Shepard, MD, PhD: Excellent. So, let's just take a big picture view first. What are the most common types of eye toxicities that we see?

Shahzad Raza, MD: Yeah, it's all over the place. You can see the problems with the anterior chamber of the eyes. You can see eyelid problems, you can see the pupils, back of the eye. Some people have excessive bleeding problems, sometimes excessive lacrimation problems. They have conjunctivitis, they have retinopathy. So, we see all types of problems, and it's really depending on the type of the drugs that patients are getting it, and what type of this drug can specifically cause particular side effect. So, I would say it's broad. It's almost a lot of manifestations can happen with this.

Dale Shepard, MD, PhD: And when we think about therapies, traditional chemotherapies, targeted drugs, immunotherapies, what do we find in terms of drugs that are most common to cause eye toxicities?

Shahzad Raza, MD: It's a very good question. I think it's, as you mentioned, it's an underappreciated thing and what I can tell you is that what we have seen in clinical trials in an actual world practice, is quite different. So, the toxicities with the traditional chemos, yes, it's been seen, it's been reported including a lot of alkylating therapies, a lot of light therapies. But then now we have this evolution of these new drugs that are coming out and we are using it. Patients are living longer, but little known about the side effects from these drugs. Some of them are class effects, like these drugs can cause skin and hair toxicities. They can also cause eye toxicities. So, we've been seeing a lot more with the new drugs which include these targeted therapies, checkpoint inhibitors, we see with immunotherapies. So, it's all over. And some of them are class effects, some of them are non-class effects. It's just like a sequel of having some other complications, leading to eye toxicities.

Dale Shepard, MD, PhD: So, when we think about the impact on quality of life, oftentimes we see patients in clinic and they'll say, oh, I have fatigue, I have diarrhea. They don't really talk about eye toxicities. Is that because we don't ask? They don't think to tell us. What do you think drives that?

Shahzad Raza, MD: I think it's both ways, I would say. It's underappreciated as you know. I think the problem is, the eye is our vital organ in the sense that it has a quality of life. You can't see it, but you live longer. I think you can make this as a statement to compare it.

I think I learned this lesson when I used one of the drugs in multiple myeloma called Belantamab, which has more than 50 percent eye toxicities, and a couple of my colleagues here, they have used it, and they have serious eye effects. Now the drug is withdrawn from the US market now, but it has great results in terms of treating multiple myeloma.

So, we learned with experience. So, I do feel that the experience actually teaches us quite a lot of these things and once you see these types of patients who have toxicities we discuss, and then you learn it and then you imply to other patients to improve the healthcare across us. So, I think there is a lot of room for improvement to understand these side effects, and physicians, especially the clinicians who are treating oncologists, should discuss these toxicities. If it's mentioned, it's been experienced personally and it's in the label, at least the patient should be aware that these toxicities can happen, and how best we can manage those toxicities.

Dale Shepard, MD, PhD: Makes sense. You mentioned before about, sort of a study that you looked at in the past. Tell us a little bit about that.

Shahzad Raza, MD: So, we do typically computational genomics with a team of doctors who are biostatisticians and also, they have a high level of data mining on genomics and vigilance. So, we look at particularly different types of the drugs and their therapeutic targets, and how those therapeutic targets can impact the patient's adverse events. A portion of that paper we have recently presented in an American Society of Clinical Oncology this year, but it was generally focused on all the side effects.

But when we specifically focus on the eye toxicities, I think for this particular paper what we have published, we actually look at two directions here. First, we say, okay, what are we seeing in the post-marketing effects for this? I think that's a really important one. And then we see how these patients were treated when they have those effects. So right now, we know, okay, this drug can cause this problem. Okay, what's the solution? We just blank here. We don't have answers, a lot of these things.

So I do feel that it has an impact, particularly this type of study where you really want to see how, actually, these patients were treated in the real world setting and learn from their experiences and educate your patients, educate the ophthalmologist, so that we can close the knowledge gap, what has been between the two specialties and help the patients in the end, so that they can live longer and live with healthy eyes. That's what the whole goal is.

Dale Shepard, MD, PhD: And tell me a little bit about this whole real-world experience. What kind of things did you find?

Shahzad Raza, MD: So, we saw a lot of these exciting results first. Okay, these are great, drug experiences are awesome. We actually did an extensive review of our literature through the published literature and saw in the last 30, 40 years how patients have published these papers. If somebody has an eye toxicity from cisplatin, which is a very commonly used drug in head and neck cancers and other cancers. So how the eye toxicities happen, how they treated, what drugs they used. Leukemia patients can get eye toxicities, increased lacrimations, increased conjunctivitis, how they treat, do they use anything prophylactically and how we can improve it.

I can personally tell you that one of the drugs that has been used for us was the Belantamab, which has more than 50 percent rate of eye toxicities. And we were actually, when we saw this is at such a high rate, we have advanced ophthalmology evaluation, ophthalmology clearance, then we were treating the patient.

I think that was a very good model where you see some toxicities are happening and you incorporate the eye physician's way early before the patients develop the toxicities and use some prophylactic on preventive measures.

Unfortunately, in the real-world setting, what we have seen it, we don't have these metrics, we only follow the ophthalmologist or refer the patients to ophthalmologist when they have toxicities happen. I think it's good, at least, we refer to them and address them. But I think what we are lacking is how we can prevent it from these effects and what patients should be watched for if these things are happening.

As an oncologist, once we see good results in one area, we also see sometimes side effects from that particular drug, and we really have to dig into that, and how we can prevent them. So, this review is actually helping oncologists, especially the journal oncologists who treat all the cancers. They have knowledge to improve among the oncologists, also the primary care physicians, and then the ophthalmologist as well. Because there are so many new drugs, there is no idea what these drugs do and people look at just UpToDate or some limited literature, but this review will help them to have an idea and kept them with them so that how we best we can help our patients.

Dale Shepard, MD, PhD: And I guess the good news/bad news, there's a lot more effort involved with doing trials these days, because a lot of our early phase trials, even later stage trials incorporate ophthalmology exams.

Shahzad Raza, MD: I love that. And as you know, the new drugs that are coming out, people are recognizing them. For example, we have FGFR inhibitors, which can cause eye toxicity, especially retinopathies. So, the question comes up, how do you treat? Do you hold the drug, retinopathy will improve, or do you have to do some other approaches. Macular edema with certain drugs, sometimes they have significant conjunctivitis that affects their quality of life. I think I would say it's a mini encyclopedia in terms of an eye for the reference guide for our ophthalmologist. And I would say that our students who really worked on that who have a passion to be an ophthalmologist, they are the ones who are the driving force for this particular article to help the eye doctors.

Dale Shepard, MD, PhD: Yeah, I mean I guess incorporating that into clinical trials certainly will help get those side effects a little maybe more front and center and warnings, precautions, and let people know what to look for.

Shahzad Raza, MD: Absolutely. And it gives us a good idea how best we can treat them. So, I 100 percent agree, and we learned the lesson from one drug already that I mentioned to you, Belantamab, they incorporate having an eye exam before you treat, and I think that's what makes a difference. And then you really have a dose adjustment. So clinical trial is the way to go to understand the side effects and as you mentioned that they're using the ophthalmologist. Many of these trials, I like this idea because people are recognizing them, and I hope that there will be more recognition in this area and people will use a more comprehensive approach in this area as well.

Dale Shepard, MD, PhD: So, one thing we're sort of expanding upon here at Cleveland Clinic is, within novel therapeutics clinic, a pharmacovigilance sort of arm to that. Is ophthalmology included in these eye toxicities included in that effort?

Shahzad Raza, MD: I think it depends on the class effects on the class of the drug. If the drug has been shown to have some eye toxicities significantly seen, I would prefer that, yes, it should be included. I think it depends on each drug and its impact what has been seen in the clinical trial setting. But I would strongly advocate for any future trials just to make sure they do not have a side effect, which could be a class effect or that can cause eye toxicities. Our clinics are usually multidisciplinary, so we involve neurologists, ophthalmologists, audiometric, there are a lot of other doctors involved as well. So, I think the multidisciplinary approach is the key, get the input from everyone so that we can develop new safe drugs for the patients.

Dale Shepard, MD, PhD: When we think about that collaboration, quite honestly, ophthalmology isn't one of those disciplines, often you think of top of mind in terms of multidisciplinary. Any thoughts about how there's a wide range of people that might be listening in on how people might be able to most effectively engage an ophthalmologist to help them with the care of their patients?

Shahzad Raza, MD: I would say communication, communication, communication. That's the key. It comes from both sides, from the patients as well as the doctors. Early recognition of these symptoms and engaging the ophthalmologist way early into the care of these patients. I think that would help the patients a lot and improve their quality of life. Knowing these cases later, the stages will not help anyone. So, I think if we involve them early, we learn from eye doctors, they share our experiences, I think in the end the patients will benefit because we mutually make the decisions as a shared decision among eye doctors and the oncologist.

Dale Shepard, MD, PhD: Any sort of early thoughts in terms of, you have lots of patients, you've mentioned a couple of times 50 percent of patients might have a toxicity, which is really high. Oftentimes these are lower numbers. Do we have any heads-up on what are risk factors, what patient characteristics, for instance, that might lead to increased risk?

Shahzad Raza, MD: Yeah, it's a very good question. I think it also depends on the class effects of the drugs. What is the preexisting eye conditions present. I'll tell you that each drug has a different way of working, so we understand that part. But I think when there is a class effect, we already have an idea, they're at higher risk of keratitis or cataract or uveitis.

So, we always recommend if a patient has a higher risk of eye toxicities, they should have an exam before you start the treatment. At least you know what the baseline actually looks like. Anything that is preexisting present, there is a potential that things can get worse in the future. So, if the ophthalmologist was involved early, we can create a very good baseline. Sometimes, and if you look at it in our study, what we have seen, there are idiosyncratic reactions too, and sometimes the reactions are dose dependent. So, it's a wide variety, like, when you see the toxicities.

That's why if we know what these drugs can cause the problems, educate the patients and if they have an ophthalmologist, I think we should involve them early in the care because many people wear glasses, so they have an eye physician as well. At least they're aware. What treatment are you getting? What are the potential impacts on it? I think that would be a big help to the patients and it'll be a good service to them.

Dale Shepard, MD, PhD: I guess just in terms of, sort of putting in perspective, some of these wide range of toxicities, do most of them tend to be reversible or not.

Shahzad Raza, MD: So, our data, when we reviewed the whole literature, we did notice that stopping the drug, in some cases, these cases are reversible, but sometimes it's not reversible. I mean people can have low white platelet counts and they got hemorrhage in the eyes. That's different than somebody who has neurotoxicity from cisplatin causing the optic neuritis that you treat a little differently.

So, I think some of them are reversible as long as you know what you are doing, what you're treating. But I'm afraid that there are sometimes that damage can happen far substantial, and we just don't have a guideline. We don't have any recommendations on how best we can treat it, sometimes they use prophylactic steroids, prophylactic teardrops, and antibiotics. But I feel that our focus should be on, somehow if we can prevent those toxicities before happening, that would be a huge help. And I'm afraid that not all toxicities are reversible.

Dale Shepard, MD, PhD: And I guess in terms of, sort of not letting things get too carried away, what kind of insights do we have in terms of minimizing risk? Are there things that a class of drug might lead to high risk? We don't really know necessarily who's at risk. Are there things that could be done other than just being really vigilant?

Shahzad Raza, MD: I think that's one way of looking into the picture, but vigilant is some sort of thing that it depends on the doctor making those decisions, which I think makes sense in some centers. But I think the best way to deal the situations, if we are seeing on the package label insert that there are eye toxicities are seen with this particular drug, I would incorporate eye physicians earlier in the course of the treatment, at least the person has a baseline exam, and the eye physician is aware.

Unfortunately, the irony of the health systems is, across the US what we have seen, that if you see the eye toxicities then the eye ophthalmologist will see them in three weeks and four weeks. I think there's a lot of delay happening. So, I always feel that if the package inserts, after the clinical trial publications, we do see we should always incorporate eye physicians. If we are using a lot of cisplatin in higher doses, we should involve them because then it can increase the risk of ocular toxicities. If we are using a novel class of agents which are known to cause retinopathies or keratitis, conjunctivitis, I will involve the eye physicians way early, and now we are learning more and more about these effects and I think the eye physicians are a part of our team and they should be involved if there is undocumented eye toxicity occurring with these agents.

Dale Shepard, MD, PhD: You mentioned some things before about possible treatments for some conditions. Again, there is a wide range of different things, but is there much that's known about? You have this sort of conflict, you want to treat disease and you want to treat symptoms, and you want to make people live longer. But in a situation where you have an eye toxicity that's maybe limiting use of a drug that works, and you mentioned that. Do we know much about challenges and being able to mitigate those?

Shahzad Raza, MD: Yeah, so actually in this paper we actually have looked into how they have treated. So, in some cases of the class effect, there was rechallenge done. The toxicities still happen in some cases, and in some cases, we don't get the toxicity at the lower doses. I think it's a lot, depends on that awareness and how best we can mitigate them. Even if we challenge them. What one cancer drug which we were using that I give you the reference for that particular drug that can cause blindness, the blindness was irreversible. But people can have eye toxicity that was reversible in those cases because you can lower the dose, rechallenge them, give it a treatment holiday and you were able to successfully improve the overall outcome. A lot is unknown in this area, how we can manage them. And I think that's why I think this is a good review, so that we can have our eye physicians to be aware and then we can have some sheer decision making in terms of understanding how best we can help these patients with the toxicities.

Dale Shepard, MD, PhD: Unfortunately, it's a really important toxicity, underappreciated. How do we make that leap to answer some of these important questions.

Shahzad Raza, MD: I think we should involve eye physicians in clinical trials, and whenever we do those trials, if they've been involved, we should get their input if we know these drugs can cause. I think patients' education is very important that they should be aware these toxicities can happen and what they should do if these toxicities occur.

Close follow up with an ophthalmologist, same thing with an oncologist. And I think if we have an education and the well communication, I think patients will be well aware of the toxicities. Physicians will be well aware of how they can manage them and at least we have some challenges here with how to treat them. But at least some ways we can help them are by holding the drug, rechallenging it again when we can and we understand them, because a lot of things are unknown how we do it, and a lot of things based on experiences. That is the whole reason for publishing this paper, that people learn from other people's experiences, what happened, how they did it, if somebody else has a thing so they can learn from those particular experiences. But unfortunately, it's a lot of unknown we are dealing with, how to manage those toxicities.

Dale Shepard, MD, PhD: Well, Shahzad, I think if you don't watch out, you're going to be an honorary ophthalmologist here.

Shahzad Raza, MD: My pleasure.

Dale Shepard, MD, PhD: Appreciate you being with us for insights on this really important toxicity.

Shahzad Raza, MD: Thank you, Dr. Shepard. Thanks a lot.

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