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Dr. Corinn Cross (Host): This is Pediatric Insights, advances in Innovation with Children's Health, where we explore the latest in pediatric care and research. I'm your host, Dr. Cori Cross. Today, we're discussing how intra-arterial chemotherapy is shifting the treatment paradigm for retinoblastoma and improving survival while preserving vision.

We're joined by Dr. J. William Harbour, ocular oncologist at Children's Health, and Professor and Chair of Ophthalmology at UT Southwestern. Children's Health offers one of the few intra-arterial chemotherapy programs in the nation, and the only one in North Texas. Dr. Harbour, thank you for joining us today.

Dr. Bill Harbour: Thank you so much for having me.

Host: So, Dr. Harbor, can you briefly explain retinoblastoma and how the standard of care has evolved over the last decade?

Dr. Bill Harbour: Yeah. So, retinoblastoma is a cancer of the eye, specifically of the retina within the eye, which occurs in early childhood, often before the age of one. And most of the time, by the age of two years old, about 40% of the time, it affects both eyes. So, it can be a very serious threat, not only to life, but to vision and function.

Host: So in the past, we only had systemic chemotherapy, but that's changed. Can you explain to us what intra-arterial chemotherapy is and how this affects side effects and toxicity?

Dr. Bill Harbour: Yeah. So, systemic chemotherapy is what most people think of with chemotherapy, where a port is placed into a vein and chemotherapy is delivered throughout the whole body. And this was the way that chemotherapy was delivered for retinoblastoma exclusively, up until a few years ago. And while it can be effective, up until a certain severity of retinoblastoma, it was not as effective in more advanced stages. And it had a number of side effects associated with it.

Host: So, I remember from residency having quite a few patients with retinoblastoma. And sometimes you would see because of the chemotherapy, they would actually develop other issues in their bodies later. I'm assuming that that's not something you're seeing with the intra-arterial chemotherapy.

Dr. Bill Harbour: Not nearly as much. So with systemic chemotherapy, you can get a reduction in your blood counts, be susceptible to infections. One of the chemotherapy agents we were using can cause hearing loss. One of them can even lead to leukemias later in life. And we're not seeing that with intra-arterial chemotherapy nearly to the extent that we did with systemic chemotherapy.

Host: Now, when you're giving the chemotherapy directly to the area, how does that change the salvage of the eye and the vision? Is that more toxic because you're delivering it right there? Or is it less toxic because you're able to give a lower dose?

Dr. Bill Harbour: So when we deliver it locally, it does two things. Number one, it minimizes exposure to the body so we can actually give a higher dose while minimizing the side effects to the body. And then, obviously, with a higher dose, we can be more effective. So, we can successfully treat higher stages of retinoblastoma, meaning more advanced cases with intra-arterial chemotherapy than we can with systemic chemotherapy with much less systemic toxicity.

Now, the toxicity within the eye can be an issue with the intra-arterial chemotherapy, particularly with the initial agent that was used to treat this, which is called melphalan, which is a very strong chemotherapy. But what we're learning is that we can often avoid melphalan and use other milder chemotherapies within the eye, particularly topotecan and carboplatin, which have very low toxicity when delivered within the eye.

Host: So, are some of these children able to maintain their vision then?

Dr. Bill Harbour: Absolutely. Yeah. Many of them are able to maintain their vision. Just to give you an idea, when I came out of residency, over 60% of children with retinoblastoma were treated with removal of the eye. Today, that's less than 5% in my practice. So, it's been a dramatic change in just maintaining the eye and then the vision itself in those eyes that we can retain has improved considerably with the advent of intra-arterial chemotherapy.

Host: Now, just because I'm curious, how has it changed for the course of treatment? Like, are you treating for a longer period of time, a shorter period of time? How does treatment actually look for these patients?

Dr. Bill Harbour: It's usually a shorter period of time. So with systemic chemotherapy, it was a minimum of six cycles, monthly cycles. And then, many kids got nine cycles or even more if the tumor was not under control. With intra-arterial chemotherapy, it varies by patient. But my average and in our practice here is three sessions of intra-arterial chemotherapy at monthly intervals.

Host: That's a big difference.

Dr. Bill Harbour: Yeah. It's a big difference.

Host: So, I mean, this is obviously highly complex. I'm assuming, it requires a very multidisciplinary approach. Can you explain that team-based approach and how you guys deal with that in your department?

Dr. Bill Harbour: Yes, that is really the heart of the intra-arterial chemotherapy approach as a multidisciplinary method. And that's why it's not available more widely, because it requires a very skilled team that includes the ophthalmology team, the ocular oncologist, such as myself. It requires a pediatric oncologist who is familiar with retinoblastoma, who can manage not only the complications of chemotherapy, but understands the underlying genetics of retinoblastoma. You know, 40% of them will have a genetic form of the disease, which can lead to other cancers.

And then, the other key component is the pediatric neurosurgeon, who is especially trained in something called endovascular neurosurgery, which means that they do procedures where they are going inside of a blood vessel, like inside of an artery to deliver therapy. So, the pediatric neurosurgeon that I work with here, Dr. Rafael Sillero, is one of the few in the country who's fellowship-trained in both pediatric surgery and endovascular neurosurgery. And he's absolutely superb at doing this technique with a very, very low complication rate. As you could imagine, some of these children are three or four months old when they're first treated, and trying to thread of catheter into the ophthalmic artery is really, really, challenging. So, there's really a small handful of places that have this expertise available.

Host: So as a pediatrician myself, I mean, one of the worst things is when you're doing one of those newborn exams or the early exams at like the two or four-month visit, and you realize that, you know, you're shining that light and you're looking at their eyes, and it's not correct, something's off.

For your referring pediatricians, you're community ophthalmologists, what are the early warning signs of retinoblastoma? How urgent is that referral? And really, what should they be thinking at that moment?

Dr. Bill Harbour: So, first of all, just eliciting a family history of any kind of hereditary genetic condition such as retinoblastoma, I think is important. Because about 5% or 10% of kids will have a positive family history. But when you're examining the child, an important thing to do is actually turn off the room lights for a moment to allow the child's pupils to dilate a little bit before shining that light in the pupil. Because with the lights on, the pupils are so constricted that it's very hard to see any kind of abnormal reflex. But the most common initial sign by far, about 80% of the time is what we call leukocoria, which is white pupil. Usually, it's actually found by the family at home, when they're taking pictures. And they get just the right angle. And instead of getting that red reflex out of the pupil, they see the white reflex. But I think, a lot of times, it is missed in the office just because, you know, with the lights on, the pupils are so constricted that you can't see the pupil.

The second most common sign is a deviated eye, either turned in or turned out, wandering eye or a lazy eye as parents will often describe it. And as you well know, the cause of that is usually not retinoblastoma. There are much more common causes for a lazy eye. However, any child with a lazy eye needs to have that evaluated by a pediatric, ophthalmologist. And most of the time, it will not be retinoblastoma, but sometimes it can be, or some other condition that is compromising the vision.

Host: And you don't want to wait. And that's the thing, because every month that you wait, like if you are trying to refer and there's a six-month waiting period to get to a pediatric ophthalmologist, that's too long, obviously. Time is of the essence. So, you really do need to make those referrals quickly.

Dr. Bill Harbour: That's right. And the other thing that, you know, just from my experience, when mom comes in and says, "There's something that's just not right about this eye here. To me, it seems like it's wandering or I see something's just not right there." More times than not, they're onto something. Now, again, it's not always retinoblastoma. It may not be present all the time. It may be that the eye's not drifting all the time. But, you know, it's really important to listen to the parents, when they are describing some concern with the eyes.

Host: I agree. So in your opinion, I mean, obviously, as you said, these programs aren't common because they require so many highly trained doctors, when should you refer to a center that offers intra-arterial chemotherapy and when shouldn't you?

Dr. Bill Harbour: I would always recommend sending a child with retinoblastoma or likely retinoblastoma to a center that can do intra-arterial chemotherapy, because I use it as my primary treatment in most patients at this point. Even if the tumor is in both eyes, I can usually treat both eyes at the same time. And there are only occasional circumstances where I have to use traditional systemic chemotherapy.

Now, sometimes, let's say the process starts in the pediatrician's office. They send the child to a pediatric ophthalmologist who takes a look and says, "Gee, there's something in the eye, but I'm not sure what it is. It could be retinoblastoma, I'm not sure." If there is not a center with intra-arterial chemotherapy nearby, then that patient perhaps could be sent to a local specialist, an ocular oncologist, or a retina specialist to become more clear what the diagnosis is. But if there's a pretty good likelihood that it's retinoblastoma, then I would recommend referring that patient to a center that can do intra-arterial chemotherapy.

Host: Yeah, it definitely sounds like intra-arterial chemotherapy is the gold standard. And what you would want a patient to be able to have the option to do. So, it would seem like that referral would make sense. From what I understand, you are the only program in North Texas. Tell us a little bit about how that affects your patient rate and, you know, your reach. And then, do you have any take-home messages for our listeners today?

Dr. Bill Harbour: Well, you're correct. We're the only program in North Texas. I came here to be the chair of the department a little over four years ago. And I practiced ocular oncology full time and was doing intra-arterial chemotherapy for a decade before coming here at my previous institution.

So, I brought that technology here and assembled the team that we now have. And what we're seeing is that many patients that previously had to be referred to New York or Philadelphia or far away can much more easily come to see us and get the same high quality care as they can anywhere in the United States. And so, that's been a tremendous help for families. Many of these, most of these are actually young families, working parents without a lot of disposable income to be flying long distances every three or four weeks. So, having this expertise right here in North Texas where people can drive from around Texas and neighboring states has been a huge help for our region.

And it is worth emphasizing that this does require very close care not only for the intra-arterial chemotherapy, but for the follow-up examinations under anesthesia. Sometimes we're doing additional treatment under anesthesia where I'm doing laser treatment or injecting other medications in the eye, and so forth.

So, it's an ongoing process that can last several years, even though the intra-arterial chemotherapy may only be three or four sessions. So, it's really been a benefit for patients to have a center in our region where they can have easier access.

Host: Well, thank you, Dr. Harbour, for taking the time to speak with us today, and thank you for the work you're doing. It's truly amazing, and I am sure your patients and their families are just eternally grateful to have a center that they can come to with such ease. If you'd like more information about retinoblastoma at Children's Health, please visit childrens.com/retinoblastoma.

Thank you so much for your time and joining us today and to our audience for listening to Pediatric Insights, advances in Innovations with Children's Health, where we explore the latest in pediatric care and research. You can find more information at childrens.com. And if you found this podcast helpful, please rate, review and share this episode, and please follow Children's Health on your social channels.