Lecture: Modern Tools For Retinoblastoma

DR MARR: Good morning from New York City today. My name is Brian Marr. I’m the chief of the ophthalmic oncology service at Columbia University in New York City. I’ve been treating retinoblastoma for the last 20 years. The first ten years I was at Wills Eye Hospital, and after that, I was at Memorial Sloan Kettering, where we introduced modern intra-arterial chemotherapy and launched that as a new intraocular technique. Now currently chief of ophthalmic oncology at Columbia. I’m gonna talk to you today about tools to treat intraocular retinoblastoma. So really, when we treat intraocular retinoblastoma, we have a limited number of tools that we have to use. And we have to kind of know what these tools do. Know when to use them appropriately. And that way we can kind of craft our treatment to deal with the really intricate differences that you have between eyes in children. Because not every eye is the same. So we can’t just use one — excuse me — we can’t just use one tool to treat every time of retinoblastoma. It would be nice. But just like you can’t take a screwdriver and build a whole house — you kind of need a screwdriver to build a whole house, but you can’t build a whole house with it — same with the tools for retinoblastoma. So what I’m gonna do today is break down the tools we have to treat intraocular retinoblastoma. And we really have about five things that we use, and some variations. We have lasers. We have freezing treatment. We have different types of chemotherapy. We have surgery. And we have radiation. And these are kind of the five groups that we’re gonna talk about a little bit in detail. And how to use them. What they’re appropriate for. So if you look at the slides, I’m gonna have them broke down to kind of a pretty simple way of… Each tool, and then how — what we want to use it for. The benefits. What it does well. The limitations. Kind of what it doesn’t do well, or some of the side effects that are associated with it. Kind of give you these little schematic diagrams of what an eye looks like, and what type of tumors are well treated with it. And so that’s gonna be kind of the format for each tool that we’re gonna talk about today. So we’ll start with lasers. Lasers are focal treatments that we can use for small tumors. But it’s important that you have the correct laser and you use it correctly. So I like to use an 810 nanometer, which is a diode laser, infrared, that has a large spot size. And the reason for that is that when I treat the tumors, I treat the entire tumor and cover it with the largest spot. If you use a really small spot like in a green laser, it’s harder to get bigger tumors, and they’re a little bit less effective. So the way that the laser works is it basically creates a thermal effect. The energy is absorbed by the RPE, that heats up underneath the tumor. Right? Because these are retinal tumors. And really most of the energy is transferred to the RPE or the pigmented tissue. And then that thermal effect rises up, and then denatures the retina above it. And so you have to kind of remember that. So if you see a nice uptake underneath a tumor, it may not be enough to actually kill the tumor, because you’re actually just causing most of the energy change in the RPE. So you want to make sure that you kind of look three-dimensionally, and make sure that your laser spot and the thermal energy propagates to the inner retina, so you kill the whole tumor. It’s a little trick that you do. But these are important, to know these things. So what’s laser good for? Well, it’s for small posterior tumors. Right? Small subretinal seeds. It’s really good for early stage disease. So if you have a patient that has a known family history, and you screen them early, and you notice small tumors, then you can treat it with laser. And you won’t need any other treatments. The benefit is that it takes a few minutes. It’s really precise. So where you aim the beam is where you treat. There’s no systemic toxicity. Really, if you do it correctly, there’s a low rate of complications. Now, you don’t want to hit the iris with the beam. Because that can cause cataract. It can cause iris atrophy. It can cause inflammation. Pain. You have to be experienced in using it. So one of the downsides is it does take a little learning curve to get good with it. And so you have to kind of be careful. Practice. And kind of get that feel of when your uptake is correct. And it’s gonna vary on the pigmentation of your patient. So if you have a really light skinned patient with a really blond fundus, the energy that you’re gonna use is a lot more than if you have a dark skinned patient with a dark fundus. So I usually start my power at about 200 milliwatts, and then titrate, depending on the uptake. And that’s kind of a little bit of a cursory view of laser. Here’s some examples. You can see that these are tumors that were treated. There’s three tumors in the right eye of a patient. And you can see the uptake, as you look carefully at the second one off the inferior arcade. You can see that the retina has actually changed color, uncovering the vessel that goes through it. So you know that you got your thermal energy into the inner retina. And so that’s important. You can kind of use blood vessels as a gauge. Surprisingly, if you look at the posttreatment, that didn’t occlude. And so in these young patients, you can actually give a pretty good amount of power and not cause a vein occlusion. If you look closely before and after, you see the vein was covered up with a white uptake. Actually still patent. So the important part is to treat it thoroughly, and it may take more than one treatment. So you can come back in a month, and if it looks like there’s still a little bit of residual tissue there, three-dimensionally, then I would retreat. So that’s kind of the before and afters of laser treatment for small tumors, for intraocular retinoblastoma. Laser can also be used as an adjunct for systemic chemotherapy. So if you have a large tumor, the systemic chemotherapy will shrink it down to a point, but then there’s residual fish flesh, or residual tissue that makes you uncomfortable. It may not be viable. It may be viable. You don’t know. And depending on the frequency of your follow-up, you really don’t want that tissue to propagate. And so at the time of each interval of chemotherapy, you can add adjuvant laser therapy. And you see with the combination of laser and therapy, this is a well regressed type one regression of that tumor. So it can be used in conjunction with chemotherapy, as an adjunct. It can also be used by itself, for larger tumors, after treatment with chemotherapy. That don’t respond the way you want them to. And so we’ve used ICG, where we infuse a child during the exam with ICG, which increases the uptake of the tumor, and then you treat it with laser, and you have a better uptake. So a lot of the times — in lightly colored funduses, or tumors that are on calcified scars — you’ll notice that the uptake of the laser is not as good as if it’s a small tumor on the RPE. So you’re increasing your laser power, but you’re not getting the response you want. If that’s the case, if you add ICG, then you can get a better response. So here’s a paper that we put together while I was at Sloan, showing the effects of ICG in regression of these tumors. And it actually works fairly well. And it’s a good kind of trick to know, to make your laser a little bit more effective. So let’s have the statistics on how well laser works. Well, there’s really no definitive paper on how laser works by itself. Usually it’s done in addition to other treatments, because rarely do we ever have the one focal lesion. And if we do, it’s kind of in the setting of a multifocal disease. So no one really actually publishes on it. The control rate goes anywhere from 0 to 100%. And so there’s some of these references here that you’ll have. They kind of go through that. But basically it’s really effective when it’s used in combination with chemotherapy or by itself, if you pick the correct tumors. So small tumors do very well with laser by itself. Larger tumors need the help of chemotherapy. Or even chemotherapy plus ICG, and that’s kind of a spectrum of what you can do with the laser. So it’s usually a helper, not a sole treatment modality. Except for the small tumors. So what do you do when you have a larger tumor? Well, freezing treatment or cryotherapy is a great way to take care of bigger tumors. So this is a hand held probe, initially designed for repair of retinal breaks, and you position it on the eye. Right underneath where your tumor is. And then once it’s in position, you sclerally depress the tumor, step on the pedal, it freezes the tumor, and you want to make sure the ice ball completely covers the tumor. And then you’ll thaw it out. And you usually do that once or twice, and that’s how you treat these tumors. But you are limited by a couple things. Let’s go through the indications, benefits, limitations, and complications. It’s good for small to medium sized isolated tumors, like group A or group B, if you’re using the international classification. It’s good for sterilizing injection sites. So we’ll talk a little bit later about intravitreal chemotherapy. And so we use cryotherapy to actually sterilize the needle site. And we’ll talk about that later. What are the benefits? Well, it’s a one-time use, usually. You can actually have the machine in your room, and you can use it whenever you want. It’s precise, meaning that whatever you freeze, you treat, there’s no systemic toxicity. The limitations is that it’s hard to get the probe posteriorly. And sometimes you don’t want to get the probe posteriorly, because if you have a tumor next to the optic nerve, you really don’t want to freeze the optic nerve. So it’s really better for anterior tumors that are a little bit thicker than what laser can handle. And the bad thing about it is that occasionally you can get retinal detachments. You can have hemorrhages. If you cryo the lens, you can get cataracts. It is slightly painful for the child, when they wake up. But otherwise, it’s a good remover of tumor for these — as shown in the picture — these medium to small-medium tumors that are anterior. So here’s a picture of me placing the cryo probe on the eye. And that’s about the size of it. And you can see here at the left hand picture there’s the picture of the ice ball. And underneath that, that kind of whitish thing is the tumor. And you see that the ice ball is actually completely engulfing the peripheral tumor. And that’s what you want to do. Sometimes you’ll see it actually turn white. But you actually want the ice to be above it. That way, you get a full solid freeze throughout the whole tumor. Otherwise, it’ll be partially treated, and tend to recur. The downside about cryotherapy is even though you have maybe a 2 millimeter, 3 millimeter tumor that you’re treating, the ice ball has to get fairly big to encompass that. And the scar that you leave is probably double the width of what you’re trying to treat. So know that. Because if you’re trying to treat something in a more visually sensitive area — that your scar is gonna be fairly big. And you can see that in the periphery, in the right side picture, you can see it’s a well treated tumor, it’s a fairly small tumor, but the scar around it is big. So how does it work? Well, it actually works really well. 79% of the time, tumors can be cured just by cryotherapy alone. And that’s pretty good numbers. Especially since we use them in conjunction with other types of chemotherapy or other treatments. And 60% of the time it only takes one cryo to do it. So it’s a good reference, and it’s a good tool to use for anterior, medium to small tumors that are… That’s what you do. So the next category that we’re gonna talk about is chemotherapy. And there’s different types of chemotherapy, and there’s different ways to administer it. So obviously chemotherapy works by chemically targeting cancer cells that are dividing. There’s different classes of agents that we use. Alkylating agents, topoisomerase inhibitors, anthracyclines, and different classes. Given those different methods of killing cells, we have different ways to give them. And the way we give them makes a difference, because the concentrations and toxicities and efficacies are all dependent on those different ways we give it. So we’ll talk about the traditional intravenous chemotherapy. And this is one of the first methods or ways that we delivered chemotherapy for retinoblastoma. It goes back to the ’90s. When we noted that people that had systemic chemotherapy — their eyes responded. And so this is good for pretty much groups — international classification groups A through D. You would also use it for extraocular disease and metastatic disease, but that’s in a different category of dosing. And so those people that are treated with extraocular disease or metastatic disease have a whole different protocol of high dose chemotherapy, which is not the same as we give for intraocular disease. Some of the benefits is… Well, we kind of know what we get when we use it. So these drugs are used for decades, and the safety profile and the side effect profile is pretty well known to most oncologists. It’s fairly standardized. So if you give intravenous chemotherapy in Africa, with the same doses and the same administration, it’s gonna be the same as if you give it in the United States. And it’s not really operator dependent, like laser and cryotherapy. You need some skills to do that. With intravenous chemotherapy, it’s pretty standardized, in that you give it through the veins, and you give the right dose, and you know what to expect. It’s widely available. And it’s good for big tumors. And the ones that aren’t amenable to focal treatment. Limitations… Well, the dose that you can get with intravenous chemotherapy is good, but sometimes it’s not enough. And really, realistically, you can’t cure retinoblastoma with just intravenous chemotherapy alone. You need something in addition. And so almost 100% of intravenous chemotherapy patients will recur if you don’t do something else. And so that something else is your cryotherapy, your laser, other types of chemotherapy to help, depending on what you’re seeing. So it’s really kind of an adjuvant method of giving chemotherapy, and not a curative method. So you always need something else with intravenous chemotherapy. It has side effects. Right? This has the typical side effects that you see with chemotherapy. Lower white blood cell counts. Risk of infections. Hair loss. And you need a good oncologist, a pediatric oncologist, to manage these complications. So you need kind of an infrastructure where somebody knows how to give chemotherapy. How to manage the side effects. And those are really important. And it also has significant complications, such as hearing loss. Second cancers. Infection. And death. So it’s not something to be taken lightly. And all the chemotherapies — because these drugs are potent. So here’s an example of intravenous chemotherapy. And you can see that a large tumor that was in the macula had shrunk down nicely. But again, there’s still some fish flesh there, and you’re gonna need focal treatments to make that durable response. So timing with intravenous chemotherapy is really important. You can’t just be willy nilly and say… All right. I’m just gonna send them to the ocular oncologist or the pediatric oncologist, and they’ll come back, they’ll be all fine, and I’ll see what I can do. You have to do serial exams, where you get intravenous chemotherapy, you do your focal treatments, and you work as a team, on a monthly kind of repetitive, consistent basis, and you’ll get good results. So if you look at some of these different papers, of how intravenous chemotherapy works, well, it works really pretty good for groups A through C. Up to 100%. And groups D and E, not so much. About 50% of the time, you can save eyes with those. And these are specific eyes that you can save. A lot of these studies are biased in the fact that eyes we couldn’t save we enucleated and only published those that we thought we could save, and of those, we only saved 50%. So keep that in mind when you’re thinking of intravenous chemotherapy. There are some limitations to it. So that gave us a reason to look for something better. Right? A lot of times you give intravenous chemotherapy, and you would have recurrent subretinal seeds. Once the retina is detached from these tumors, the subretinal fluid in that space is filled with microscopic and macroscopic seeds. As the chemotherapy reduces the size of the big tumors, some of these subretinal seeds don’t get a toxic enough dose of chemotherapy. And then some time later, they recur. So because of that, we started to say… Hey, we need more drug into the eye. So let’s try to give periocular chemotherapy, and that way, we can increase the levels to get some of these recurrent seeds. And so what’s the advantage of this? Let’s go through our chart. Well, it’s good for advanced intraocular retinoblastoma with seeding. Subretinal versus vitreous. It’s not used very much anymore. Because really, it doesn’t have the punch that we need. But it’s still kind of an adjuvant, and occasionally — I’ll give you some stats on how it does work — it just wasn’t as good as we thought it would be. So it does increase the interocular levels of chemotherapy. It’s fairly safe, because you don’t give it in the eye. So there’s no risk of spreading outside the eye. But the problem is that it’s just not quite enough absorption to get the complete kill that you’d need to sterilize the eye from tumors. Although it will help, and perhaps it will help enough that you can salvage the eye with other means, such as focal treatments. Some of the complications that are associated with it is: It is fairly toxic to the extraocular tissues. And you’ll get scarring, eye muscle dysfunction, a lot of inflammation. Which, when you’re trying to save an eye, that’s kind of an acceptable side effect if it worked. But again, it is something in your tool box that you should know about. Use it when you can. So here’s the stats on it. So in about 12% to 39% of the eyes, we found that it actually made the difference, and we could save the eye. We noticed that at least — almost half of them had these periocular side effects. And this was a large 12-year study that I did on all the periocular carboplatinums that we did. So it’s kind of a good resource. It’s a helpful tool, but not kind of a game changer. So the next way to get chemotherapy to the eye was intra-arterial. So the Japanese started to do this probably… Maybe 10 to 15… Actually, probably more like 20 to 25 years ago. And we in New York basically kind of use some of the modern day catheters to say… Hey, well, why don’t we just give really small amount of chemotherapy to the eye, and get a high dose? And so we can do that, as shown in the video. Here’s a catheter that’s going into the ophthalmic artery. And you can see the perfusion of the dye into the eye. And this is a way to get kind of a short lived high dose, significantly higher dose, of chemotherapy into the eye. And so when we first started this, we were actually fairly amazed at how well it worked. The nice thing is it’s good for similar classes of retinoblastoma. So basically groups A through E. It has better control of subretinal seeds. And even vitreous seeds. And it has a lower systemic level of chemotherapy, compared to intravenous chemotherapy. So it was kind of like… Yeah. This seems like it’s gonna work really well. The problem is that you really need a big setup of people that are skilled in interventional neuroradiology. So you need a good interventionalist that can find the artery, number one, use limited radiation when doing so, and kind of learns how to use chemotherapies. Because most of these specialists that have really great skill in catheterizing aneurysms, and different brain lesions, they’re using different chemicals than chemotherapy. And so when they’re given the chemotherapy, they kind of treat it like a dye, or they’re not familiar with how it affects the blood vessels, and they can get a lot of early complications, until they figure out that this stuff is really kind of vascular toxic. And if you give it in a high concentration — i.e., don’t let it kind of ooze in with blood — you’re gonna get some serious occlusion of arteries, and really a high profile of toxicity. So it takes a big learning curve to get those people on board with how to use it safely. But once that’s done, it’s a really great tool. You get higher rates of chemotherapy into the eye. There are some variations, where people don’t have an ophthalmic artery. About 15% of patients will have their ophthalmic artery fed from the external carotid. So you have to kind of know the vascular anatomy. Know shortcuts to get in through the middle meningeal artery, to backflow it into the eye. So there’s different ways to give it, and it does require a skilled person. The complications, as we spoke about, can be fairly significant. Vascular occlusion of the ophthalmic artery, and that can lead to blindness, inflammation, you can get rashes. There’s a possibility of CNS complications, if things aren’t taken care of properly. If you don’t use the adequate anticoagulation. There’s also reactions that you can get, where patients go hypotensive, as kind of a carotid spasm. And so there’s these subset of new complications that your interventionalist has to be aware of. Most of all of these are all handled by experienced people, and aren’t a major issue. Except in the beginning, when you’re trying to get somebody to do it correctly. But the results are actually amazing. And so eyes that we would consider hopeless before we’re saving. And even saving with functional vision. And here’s an eye where basically the tumor is up to the back of the lens, filling the eye. And then after intra-arterial chemotherapy, everything has regressed and it’s still a functional eye. So if we look at the stats on this, it works well for groups A through C. Almost 100%. And for group D, much better than intravenous chemotherapy, which was around 50%. You can get up you… I think modern day it’s probably about 85%. And maybe group Es, which were almost always enucleated, we could save maybe a third or almost half of those now. It decreases the length of chemotherapy. And you have a higher rate of salvage, and there are some papers that we published that can give you a lot of details about that. But the problem is, with intra-arterial chemotherapy, we still have a challenge with vitreous seeding. Even though the dose that gets into the eye is about 100 times higher than that of intravenous chemotherapy, occasionally — and in all the cases that we can’t salvage — it’s usually because vitreous seeds don’t get enough concentration of drug, and recur, and have multiple recurrence after seeding. So Francis Munier kind of revitalized — and everybody was really scared to stick a needle into an eye that had retinoblastoma, because it has such a high rate of extraocular extension, and if that happens, you kind of lose the game. And move your patient from a contained intraocular disease to a systemic disease. So no one really actually wanted to biopsy retinoblastoma or stick a needle in the eye, because of that high rate. But with modern techniques, using a very fine needle, and cryoing the needle site, we’ve had really limited complications of giving intravenous chemotherapy for vitreous seeding. So that’s what this is. We use melphalan or topotecan, and inject directly into the vitreous to get rid of vitreous seeds. The drug lasts a short time in the vitreous, but it has a very high level, and that can actually cause great success in getting rid of those seeds. So here’s a picture of kind of the technique we use. We use a small syringe. And go about 3 millimeters from the limbus, or 3.2 millimeters from the limbus. And inject, and then as we’re pulling out, we freeze the needle and the needle track. With a cryotherapy. Remove the needle. Seal and sterilize the site. And then that’s there. So topotecan has this unique characteristic of fluorescing. And so we used blue light in this picture to show you the topotecan that we’re injecting. And then you can see it within the vitreous, kind of swirling around. And also you can see that there’s none leaking out. Because you don’t want to have anything leaking out, including retinoblastoma. So it’s a neat way to kind of demonstrate that. And you can see some of the results. So this is a patient that had intra-arterial chemotherapy, and you can see in the bottom left picture that there’s multiple recurrent vitreous seeds. These are clumping and they’re actually falling down onto the retina and even starting to embed. After injections of intravitreal chemotherapy, all those seeds had dissolved. And we can see in this patient where there’s this giant cloud of really diffuse microscopic viable vitreous seeds, after a couple treatments of intravitreal chemotherapy, you can see that cloud slowly dissipates. Now, in the beginning, when we were first giving these injections, we would see a dramatic effect of the injection. But then there would still be this kind of debris and calcified stuff, and we couldn’t tell… Is this viable? Is this not viable? And we would keep on injecting. Some people would inject maybe 20 times. Because they didn’t see it go away completely. The trick is that we wrote a couple papers on the regression patterns of seeds, but sometimes you’ll have a little dusting that’s left over, and you have to kind of watch that closely. But you don’t need to continually inject those patients. And that’s one of the kind of downfalls, that people weren’t sure of in the beginning. But we’ve kind of parsed that out. And it works really well. So if you look at some of the early papers, there’s people like… Oh yeah, it works 100% of the time. Never say anything works 100% of the time. But it does work well. The problem is, though, it’s toxic. And so for every injection, we actually did a study where we inject, we took an ERG before and after, and with every injection, the ERG falls about 4 or 5 points per injection. So it is toxic. And it can cause some significant toxicity, locally, to where the high concentration of the drug gets to the retina. So you have to use it sparingly, because you can get rid of all your vitreous seeds, but then you can also chemo-enucleate the eye, because you just burn out the retina from the toxicity of all the injections. So it’s a balancing act of control versus salvage of visual function. And you have to be mindful of that. Surgery. Well, we’ve talked about all these high-tech things. But enucleation still is a wonderful treatment, and a great tool to take care of advanced group D and group E eyes. In an hour, you can cure a patient with unilateral retinoblastoma for life. And so you have to kind of weigh the risks and benefits of all these fancy treatments, to one hour of surgery to save the life. And depending on what kind of infrastructure you have, if you have a big intra-arterial suite, that’s no problem, then yeah, perhaps you can go down that road. But you can also save the patient’s life in an hour, by doing a good enucleation. What I will stress is that you have to look at the pathology afterwards. And you have to assess whether this enucleated eye is a high risk for metastatic disease. And then treat that appropriately. And that’s a whole different talk. About the pathology of enucleated eyes. But something that’s important if you use that technique. But it’s quick. It’s easy. If it’s done well, you really make a difference in the patient’s life. So don’t forget about enucleation. And here’s an enucleated eye. One trick is you do want to get a long section of optic nerve. Because you don’t want to have a positive margin. Because if you do have a positive margin, then it changes your classification from intraocular disease to extraocular disease, if there’s a tumor within the nerve. And so that’s your safety margin. You want to practice on getting a long section for that. Brachytherapy. So plaque brachytherapy is where we use these small discs that have radiation on them. Typically we use radioactive iodine, I-125, but there are other isotopes like ruthenium, that are good for this. And it’s the secret weapon of retinoblastoma treatment. It’s good for large recurrences that are localized. Or localized vitreous seeding. Sometimes it’s the salvage, where you have this last eye of this patient, and unfortunately there’s this big recurrence that snuck up on you. And you can’t give them intravenous or intra-arterial chemotherapy anymore, because it’s just resistant to that. And if you use a plaque, you can get rid of that, because these tumors are very radiosensitive. And it’s kind of a way that in a lot of the papers that you see — the stats in the intravenous days — it’s the way that we got those high stats. We were using these plaques to try to salvage these eyes. So let’s go through the chart. It’s good for solitary tumors. Recurrent tumors that are larger than those that can be handled with cryo or laser. Or can be used for localized seeding. Either subretinal, mostly, but sometimes even localized vitreous seeds. It has a high local tumor control rate, because of the sensitivity of retinoblastoma to radiation. It’s a short surgical procedure. And it can avoid chemotherapy, or it can work when chemotherapy doesn’t. It does require a hospital stay or monitoring. You do need a radiation oncologist, and somebody that can custom make these plaques. There’s a risk of cataract, because of the radiation. And there’s all the complications that are associated with surgery. But like I said, it’s a really good tool to use for those situations. And it doesn’t have the same effect on second cancers, like external beam radiotherapy, and it doesn’t increase the risk of second cancers. And that’s important to know. Because it’s such a localized, high dose to the eye, low dose to the surrounding tissues, we haven’t seen the increased rate of second cancers like we have with external beam therapy. So here’s a picture of a plaque under a muscle. This is a dummy plaque. And you can see we marked on the sclera where the tumor is. We position the dummy plaque there. Mark the suture islets, and put anchoring sutures there, and then replace it with the live plaque. Let it sit in there for usually 3 to 7 days, depending on which isotope you use. And like I said, it works very well. So here’s a patient that failed intra-arterial chemotherapy with a large recurrent peripheral tumor. And we plaqued that, and you can see afterwards there was a nice regression. And no recurrence. And we were able to salvage the eye. So if you look at the papers, and the stats on how this works, it works about 73% to 95% of the time, and you get anywhere from 2 to 40% side effect profile. And the biggest side effect is vitreous hemorrhage. And that can happen later down the road, where some of these already compromised vessels treated with radiation will bleed a little bit. And that can complicate things as well. And one of the reasons why we lose the eyes — and it’s not 100% control. Then external beam radiation. And prior to the chemotherapy age, external beam was one of the mainstays of treatment. Until we found out, down the road, that this increased the rate of second cancers. And so in the field of radiation — risk of osteosarcomas could seem to be significantly elevated by using external beam. And there’s been a wide movement to minimize radiation to these children that have bilateral disease or germline mutations, because of that. So currently, I haven’t used external beam radiotherapy for over a decade. Maybe even almost 15 years now. For that reason. But as a last resort, it still has some merit. And its efficacy — we can use specialized IMRT or different ways to minimize the dose into surrounding tissues, but you still carry the risk of second cancers. And it works around… 50%. And the side effect profile is around 100%. So it is a last resort, if you’re trying to save and salvage one eye, in a monocular patient. But the risks, the secondary cancer risks, are real. So that kind of summarizes all the tools for intraocular retinoblastoma. And I’m just gonna run through a few questions, to see if you guys are interested in kind of showing me what you learned. And what do you think. So the first question: So what is the question? Can we move this? Vitreous seeds are best handled with intravenous chemotherapy, three drugs, for six months. So the majority — two thirds of us thought that was false. I think that’s a good answer. Remember when we were talking about the different problems of different tumors, vitreous seeds are the ones that are floating, and the chemotherapy has the hardest time to get to it. So currently intravenous chemotherapy has the worst control rate of vitreous seeds. And that’s when we would say: All right. We’re giving intravenous chemotherapy, but because we have vitreous seeds, we’re gonna add intravitreal injections to boost that effect. And so that’s why we would do that. So that’s a good answer from everybody. Let’s do the next one. Another true or false. Brachytherapy, radiation, has been associated with increased risk for second cancers in patients with germline mutations and bilateral retinoblastoma. It’s not fair, because we just talked about that. But let’s see how you guys do. Excellent. So just like we said before, plaque is kind of a precise way to give a low dose radiation — or a high dose radiation to the tumor, low dose radiation to the surrounding tissue. And has not been associated with the increased risks that we see with external beam. Let’s go to the next one. Cryotherapy can… Sorry about the typo. Is best used for the anterior tumors greater than 4 millimeters thick. True or false? It’s a little bit of a trick question. But see how you do. Excellent. So it’s tricky, because cryotherapy can — and is used for anterior tumors. And it’s the better treatment for that. But usually if they’re greater than 4 millimeters thick, they kind of get outside the range of what the cryo can handle. So that’s kind of the upper limit of what I use it for. You can kind of push the limit for bigger tumors, but again, the efficacy falls dramatically. So I like to keep it under 4 millimeters of thickness for that. If it is greater than 4 millimeters, then that would be a good tumor, if you don’t have chemotherapy, or if you already use chemotherapy, for a plaque. So if you want to treat it without using chemotherapy, plaque brachytherapy would be great for an anterior tumor that’s greater than 4 millimeters. Let’s see what we have next. One common side effect of… Another typo. Intravitreal melphalan chemotherapy is decreased ERG function. Correct. Good. I think everybody jumped on that one pretty well. So yeah, intravitreous melphalan can cause significant toxicity and decrease the function of the ERG. All right. Last one. For extrafoveal, international classification retinoblastoma group A, tumors are best treated with which? That’s excellent. I think everybody got that. So for that, group A is small tumors. Extrafoveal. I put that in, because you don’t want to laser or cryo the fovea. So if you have an extrafoveal small tumor, local treatment is best with laser or cryo. So I think everybody got that. Well, I really appreciate you attending this webinar, and if you have any questions, let me know.