Retinoblastoma

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 here at Cleveland Clinic overseeing our Taussig Phase I and sarcoma programs. Today, I'm happy to be joined by Dr. Arun Singh, director of the Department of Ophthalmic Oncology, and Dr. Stacey Zahler, a pediatric oncologist at Cleveland Clinic Children's. Arun was previously a guest on this podcast to discuss uveal melanoma, and Stacey was previously a guest to discuss advances in the treatment of pediatric patients with neuroblastoma. They're here today to talk to us about retinoblastoma, so welcome back guys.

Arun D. Singh, MD: Thank you. Thanks for having us.

Stacey Zahler, DO: Thank you, Dale.

Dale Shepard, MD, PhD: So just to remind us, what do you do here at the Cleveland Clinic? What are your roles? Let's start with you, Stacey.

Stacey Zahler, DO: Sure. So, I'm a pediatric hematologist-oncologist. My focus is on pediatric oncology in solid tumors and also in CNS-related tumors. I also do some other things, but that's my clinical role here.

Dale Shepard, MD, PhD: Excellent. Arun, what do you do here?

Arun D. Singh, MD: Oh, well, I'm ophthalmic oncologist for the last 20 years and my practice is limited to all eye tumors or tumor-like conditions on the surface of the eye, inside the eye orbit, and related entities.

Dale Shepard, MD, PhD: Excellent. So, Arun, let's start with you. We're talking about retinoblastoma today, so give us a background, kind of a brief description. We have a number of people who might be listening. What is retinoblastoma?

Arun D. Singh, MD: So, retinoblastoma is a primary retinal tumor. It's a malignant tumor seen exclusively in children, so it's a rare disease, and we expect maybe about 250 or so new cases per year in United States.

Dale Shepard, MD, PhD: So not very common at all. And give us a little bit of an idea. How is this diagnosed?

Arun D. Singh, MD: Well, the most common symptom is what's called white pupil. So, when people take photographs, they may randomly see a white look to the pupil. That's usually just an artifact, but rarely it can be due to a growth inside the eye, and we call it leukocoria, white pupil. That's the most common presenting symptom. And then of course, rarely in the familial situation when there's a family history of disease, these cases are detected proactively by kind of the screening programs.

Dale Shepard, MD, PhD: So, this is a pretty rare tumor. Give us an idea from a diagnosis standpoint. This isn't something that most ophthalmologists, most pediatricians would be seeing very often. Is this mostly diagnosed in the community and then sent to us, or does someone oftentimes just get sent here and say, hey, something's wrong, help me out?

Arun D. Singh, MD: So, the diagnosis is not made in the community, but they suspect the diagnosis. So, somebody, for example, even a pediatrician does like a normal well baby checkups, they have one year or two years, and they are looking at the pupillary reflex and they don't see the red glow or red reflex in the pupil. So, they'll find something is wrong or the mother or the grandparents, someone notices a little glint to the pupil and they go to the doctor and they can't figure out.

And they kind of go up the chain and they reach a pediatric ophthalmologist who tries to examine in the office and try to say, oh yeah, there is something, not sure, or doesn't look normal, but eventually, it's a clinical diagnosis and we do it after we put the baby to sleep, we examine, it's anesthesia. And that really clinches the diagnosis, is the exam and some ancillary studying, like ultrasound and some other ancillary studies will confirm the diagnosis. So, we don't really do biopsies to confirm, it's just a clinical diagnosis but requires a good exam.

Dale Shepard, MD, PhD: Gotcha. So, Stacey, give us a little bit of a background here. Arun mentioned that this is something that occurs in children. Why is this unique to children?

Stacey Zahler, DO: Retinoblastoma is, as Dr. Singh mentioned, it's because of an alteration or mutation in the RB1 gene. And Dr. Singh has actually published a lot on retinoblastoma and specifically on the genetics of retinoblastoma, majority of patients, about 60 percent, will have a sporadic mutation of the RB1 gene, which sits on chromosome 13. But in about 40 percent of cases, there is a heritable mutation we call the two-hit hypothesis. So, you'll have a germline mutation in all of the child's cells, and then the second hit would be the somatic mutation in the retinal cells, and that's what causes the tumor.

Arun D. Singh, MD: Let me add a little bit here. So, retinoblastoma arises from a precursor cell, and this precursor cell is an undifferentiated cell, a cell that has not fully matured yet. So therefore, it can only happen in immature retina. And the retina is not mature, just like brain at birth. And it takes some years for the retina to mature. And we say by age four and a half or five, the retina fully matures. And as these cells mature, they lose their capacity to become cancerous. So therefore, this is confined almost always to children less than four or five years of age.

Dale Shepard, MD, PhD: Makes sense. Stacey, give us a little bit of an idea, what kind of treatment options are available? So, there's certainly, for most cancers, a wide range of things, and I'm guessing retinoblastoma is no different?

Stacey Zahler, DO: It is no different, but it is a little different because the way that we give treatment for retinoblastoma is focal treatments that Dr. Singh does in the operating room, which he can talk a lot about. And then my role is helping with the chemotherapy options that we have. And so, there's the obvious systemic chemotherapy, and actually, in retinoblastoma, the majority of the time we're able to avoid systemic chemotherapy. This is typically a localized solid tumor type of pediatric cancer, and so focal therapies often are successful in curing 95 percent of patients that are cured in the United States.

This is a very curable disease, and so we can give chemotherapy systemically, through a central venous catheter. We can give it in the back of the eye or via a very specialized procedure that we do here call intra-arterial chemotherapy. And that is basically where the child has what starts as a, similar to a cardiac catheterization, where the femoral artery is accessed by a neuro-interventional surgeon and a catheter is snaked all the way up to the ophthalmic artery into the internal carotid artery and into the junction of the ophthalmic artery and chemotherapy, very small doses of chemotherapy, are injected into the back of the eye. And that has been very successful and we can talk more about that.

Arun D. Singh, MD: So just another viewpoint, in a very broad perspective, we say, well, surgery, so enucleation still is the most common treatment for retinoblastoma across the world and even in the United States. Enucleation is the removal of the eye, and that's for usually advanced disease where there's no vision in the eye or there's no vision potential. So, this is an important aspect. And the second alternative really is chemotherapy, and that can be delivered different ways. But the last thing, which is the radiation is pretty much not used in retinoblastoma.

So, unlike other tumors where you have external radiation, et cetera, very commonly used, on retinoblastoma it's a big no-no, and that's because the children when they have the germline mutation will get second tumors from radiation itself, which are lethal. So, the shift has been away from radiation, more towards chemotherapy, but still in many, many cases where there is no vision potential in the eye, then you just remove the eye, enucleate the eye. And of course, we have focal therapies, laser, freezing, and intraocular, intraorbital chemotherapies. So, there are many options, depends upon the tumor size, really, and what's happening to the eye overall.

Stacey Zahler, DO: That's right. So, the classification system that we use now, nowadays, probably over the last couple of decades, is an international classification where we group, it's groups A through E. And so, Group A is the smallest tumor, less than three millimeters, Group B just very basically is a little bit bigger. Group C, you start to have seeding of the tumor, some of that seeding can be more diffused in Group D, and then Group E is the largest, usually over 50 percent of the globe is involved. That's certainly a case where Dr. Singh will consider enucleation.

Dale Shepard, MD, PhD: So, Arun, I guess just walk us through, you said something about how vision and ability to restore vision might be one of the factors that plays into whether you do an enucleation versus another focal therapy or chemo. How do these compare in terms of local control rates and really restoration of vision, survival, things like that?

Arun D. Singh, MD: So overall, you say retinoblastoma has one of the highest cure rates, we say in United States overall, almost from 96 to 97 percent cure rate. And the risk of death from metastasis is very, very low, so maybe five to 10 cases in the US per year. So at least in the US, we say we have excellent outcomes, so that's number one, the survival outcomes. Then because they can be genetic or germline mutations, they also are at a risk for second malignant neoplasms later on in life, osteosarcomas and other tumors as they get older, and so that can be lethal also.

But one other aspect in childhood is the pineal tumor, pineoblastoma, which is related to retinoblastoma from the pathogenesis point of view, and that can also be lethal. So, they can die three different ways, but from retinoblastoma, primarily, it's very uncommon to see that happen in the US because we are still catching it relatively early, so that's the survival outcomes.

As far as the local control rates, we say with enucleation, well, 100 percent. You remove the eye, there's very little chance that there'll be local orbital recurrence. But following these chemotherapies, and if you took kind of a very broad view of it, say, approximately 75 percent local control rates. So, if you start the journey of chemotherapy overall at two years or even four years, we say approximately 75 percent of the time you'll be able to save the eye. And still 35 percent, after all these complex treatments, the eye may have to be enucleated, because for whatever reason, somehow the chemotherapy didn't work or the tumor continued to come back.

And talking about the vision, we don't have good data about the visual outcomes. And that's again, because the children are small, it's hard to measure vision objectively. And they're also busy doing the treatments, being put to sleep every month or so, and in the OR we can't objectively check vision. But I have to say that in cases you can have excellent vision, you can have 20/20 vision, it just depends upon the location of the tumor itself and the size of the tumor.

Dale Shepard, MD, PhD: And I guess just another really quick question from a standpoint of the disease itself, you talked about how this is from sort of the development of the retina. There's a gene abnormality, but this usually occurs in one eye, not both. Is that true?

Arun D. Singh, MD: Well, 60 percent of the time it's unilateral, but 40 percent it can be bilateral. So, if they have a germline mutation, then they will affect more than one cell, and they tend to be bilateral. So, in general, if they're a germline or bilateral disease, they're talking of about five tumors between two eyes, so they can have multiple tumors, it's not just one eye or the other eye. Last case we have, we were treating, has 10 tumors between two eyes.

Dale Shepard, MD, PhD: Wow. Tell us a little bit about specifically here at Cleveland Clinic, we have a retinoblastoma center, we have the ability to do a wide range of treatments. So, tell me a little bit about what we have set up here.

Arun D. Singh, MD: So, it's not a one-man show, not at all. Of course. We are a big hospital; we have advantage of multidisciplinary teams who offer all kinds of services. So here, Dr. Zahler is a pediatric oncologist, so she'll drive the chemotherapy, the dosing, how it's delivered, et cetera, and make sure she's on board to take care of all the issues related to chemotherapy. And we talked about intervention neurosurgery, we have Dr. Hussain, Shazam Hussain nowadays, who's doing all the catheterizations.

And then we have people in genetic counseling and medical genetics who will help handle the samples for testing for gene mutations, et cetera. And then we have nursing coordinators who will counsel the families and the mothers and the parents who need so much support. So, it's such a complex web of things that are needed, but we are able to all work together. So, I think I would say I'm very proud to have this kind of team together, and they can, it's like one-stop shop. They come here, usually start with our nurse coordinator, Jackie, and then after that, everything kind of falls into place. So, we're trying to do it all in one place without making them come many times over and reducing the burden of the treatment.

Dale Shepard, MD, PhD: That's fantastic, we have that in place for such a rare tumor. Stacey, we've talked about the genetic component and we've talked about the risk for other tumors, but tell me a little bit about what we have in place in terms of the genetic counseling survivorship. I mean, these are very young children that are coming into this, so what do we do in those situations?

Stacey Zahler, DO: As Dr. Singh mentioned, genetic counseling is a standard and mandatory part of each child's retinoblastoma care here at the clinic. We have wonderful genetic counselors that will automatically see the babies and send off genetic testing, really write a diagnosis. And so by about a month or two after diagnosis, we know whether or not they have the heritable RB1 alteration or somatic. And so then, the genetic counseling team will do their counseling and inform the families if it is a germline mutation, what is the risk? This is an autosomal dominant mutation, so what is the risk of the child's eventual siblings having retinoblastoma? It's 50 percent, and et cetera.

And then Dr. Singh will also, in patients with germline disease, will also examine any siblings of this child. The parents will be tested as well. And so, we have that whole process in place. And then as patients who have germline mutation of RB1 get past the retinoblastoma diagnosis and are treated and do well and they're in survivorship, we do send them off to our survivorship program here in pediatric oncology, which is led by Dr. Seth Rotz.

But we also make sure that someone in our group will see them annually, especially as they get older into their teenage years. Because as we mentioned, the risk of other cancers that are related to the heritable RB1 mutation such as osteosarcoma or other sarcomas, melanoma, breast cancer later on in life, these need to be monitored. And so, we will see these patients annually throughout their lives.

Dale Shepard, MD, PhD: Tell me a little bit about what we're doing in terms of research and any studies we might be doing.

Stacey Zahler, DO: Sure. So, the Children's Oncology Group is one of the main central centralized and collaborative groups that study pediatric cancer. And so actually, just several months ago, a new retinoblastoma study opened up through the COG, and this is studying systemic chemotherapy in patients who have Group D tumors, but that also need intravitreal chemotherapy. And so intravitreal chemotherapy, remember, is chemotherapy that's injected directly into the eye by Dr. Singh.

And we have studied, there have been lots of data out their sort of retrospectively to give us the safety, the feasibility, but it's never been studied prospectively. And so, the COG is wanting to study the combination of intravitreal melphalan given concurrently with systemic chemotherapy. And the chemotherapy that we typically give is carboplatin, etoposide and vincristine. So, they get a total of six cycles of the systemic chemotherapy and also can get a total of six cycles of intravitreal melphalan.

Dale Shepard, MD, PhD: Excellent. What are the biggest gaps? Great survival numbers, the local recurrence is low, in many cases we're studying chemotherapy options. Arun, we'll start with you. What are the gaps? What do we still need to resolve?

Arun D. Singh, MD: Well, the treatment delivery is very complex. So, this intra-arterial chemotherapy, it's a huge process, very expensive. You need very specialized, trained people. And if you think about retinoblastoma globally, we say 90 percent of it is in Asia and Africa. So, in those countries, this is not available, or can hardly be done. So, if you look retinoblastoma globally, we only represent maybe 5 percent of all cases. So, the rest of it is outside the US, and these kinds of treatments are not accessible at all. Even in the US, it's a challenge.

So, this isn't the final treatment. I think there are going to be new ways to deliver chemotherapy, and there's some research going on in that, so that's one area of what's new on the horizon. And second is moving away from chemotherapy. So, we know the mutations, we know the genetic profile of retinoblastoma, so there are targeted therapies that will be tested for intravitreal injections, for example, instead of chemotherapy, because chemotherapy has toxicity to retina. So, the aim is to save the vision and save the globe, survival being so good, there is an attempt to move away from this toxic drug. So, there are certain agents that will be tested and are being tested.

And the last I would say is the aspect of these liquid biopsies and circulating tumor cells. Like in other cancers, we have biomarkers to tell you, oh, there's a residual disease, minimal residual disease, or, you're fully cured, et cetera. And there are cells that liberate DNA from the tumor that circulate, and that can be detected in blood that can be sampled from the eye itself and can be a marker of prediction, for example, to say whether the eye is going to survive this treatment or the tumor is coming back if you're not sure, et cetera. So, there are exciting features that will come along that will help improve the prediction, I guess, or the outcome of patients in all different facets. So, I don't think we are there yet in terms of treatment of retinoblastoma, I think there's still more steps to be taken.

Dale Shepard, MD, PhD: What a great multidisciplinary team. So as a surgeon, Arun talks about chemotherapy as one of the things to, instead of surgery, so that's awesome. So, Stacey, what do you think? What's your view of the biggest gaps that remain?

Stacey Zahler, DO: Yes, I would agree with Arun that there are these new sorts of treatments on the horizon. We are really good at carrying these kids with this disease. So, reducing toxicity, I would agree, is the primary goal. We have plenty of patients who are alive and well, but maybe they have their globe, they have their eye, but maybe their vision is not great. So how do we reduce that?

Dale Shepard, MD, PhD: Excellent. Well, you guys have given us some great insights today, and thanks for being with us.

Arun D. Singh, MD: Thanks for having us.

Stacey Zahler, DO: Thank you very much, Dale.

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'll receive confirmation once the appointment is scheduled.

This concludes this episode of Cancer Advances. You'll find additional podcast episodes on our website, clevelandclinic.org/canceradvancespodcast. Subscribe to the podcast on iTunes, Google Play, Spotify, SoundCloud, or wherever you listen to podcasts. And don't forget, you can access real time updates from Cleveland Clinic's Cancer Center experts on our Consult QD website, at consultqd.clevelandclinic.org/cancer.

Thank you for listening. Please join us again soon.