Chapters Transcript Retinoblastoma: Presentation and Management Daniel Willis, MD, discusses common retinoblastoma presentations. Good morning. Um And thank you for allowing me to present today. Um Let me give you an overview of retinoblastoma and hopefully how it pertains to your practice. I have no financial disclosures. And um so here are our, here's our overview for today. Retinoblastoma. Um As you'll see is a fairly common malignancy. Um And so my hope is that in this presentation, I'll be able to give you a better understanding of the way we treat these patients and the goals of treatment. Um Additionally, as you'll see, patients have a very high cure rate. And so it will be um not uncommon that you care for Retinoblastoma survivor. Um And so the second goal of this presentation is to give you context and information that will allow you to tailor your care for the patients um and understanding what their treatment look like and what impact that has on the remainder of their childhood. Um and subsequently as adults. Um And so we'll start, you know, retinoblastoma as the name suggests, is a malignant neoplasm of the retina. Um And this is a unique neoplasm that affects Children only and really only Children under the age of five, except in, in very unusual cases. Um The incidence is described to be about one in 20,000 live births, which translates to about 200 to 300 cases in the US per year here in Saint Louis. Um We see anywhere from about 4 to 10 cases at children's hospital um per year and so relatively common. Um and definitely a possibility that you will care for one of these patients. Um either while they're receiving treatment or um uh or for the survivors. Um So very briefly, a review of eye anatomy um as I am by no means, an ophthalmologist and um uh always need a refresher myself. But the cornea being the um outermost portion of the eye that overlies the iris, um which is the pigmented portion in the lens. Um behind that we have the vitreous humor. Um and the retina being this lining on the posterior surface of the globe. Um And as I'm sure you all know, the retina contains the rods and the cones which are the photoreceptor cells for vision. And this is the layer of cells um in which a retinoblastoma can develop. Um behind the retina is the choroid um depicted here in red. Um And then there's also a depiction of the optic nerve um which uh provides the, you know, the neuronal signals back to the brain for vision. Um And this is important because the retinoblastoma can invade um into the corro or the vitreous humor or the optic nerve. Um and this can place patients at higher risk. And so, um uh that may change therapy needs. And so wanted to uh start with that foundation. Um But first retinoblastoma was described as early as the 15 hundreds um in autopsy reports of pediatric patients. And it wasn't until about 1800 that we um had the first surgeons describing the um approach of a Nucleation and advocating for that approach um for treatment. And this has remained one of the hallmarks of treatment. Since that time, systemic chemotherapy really didn't start until the 19 nineties which um transformed the treatment pretty pretty significantly prior to that external beam radiation was employed. Um And you'll see in some of our retinoblastoma families um that parents received external beam radiation. Uh Nowadays, this is avoided and we'll talk a little bit more about that. Um But uh very uncommon for our patients to have received radiation therapy or external beam radiation. Um At this time, I mean, it was in 1971 that Alfred Hudson described the two hip hypothesis and um medicines to hit hypothesis has really become the uh landmark hypothesis for uh the description of heritable tumors and how they develop. Um And as you can see in this uh in this figure down here at the bottom, it posits that we have two copies of tumor suppressor genes. Um And on this top line, you see the wild type. Um where if you are born with two normal copies of um of that tumor suppression gene, it takes a mutation in one to make you a heterozygous. Um when you have loss of heterozygosity with the second is when you can have the gene totally knocked out. Um and predispose you to a malignant phenotype. Um But with the heterozygous state, you still have one normal copy of um of the gene that is preventing tumor genesis um in hereditary or heritable tumors. Um You are born in the heterozygous state and so already have one of those um hits. And so then the second hit is all that it takes to, to um to cause a malignant phenotype. Um And so this paper in 1971 was really um kind of fascinating to look at because um medicine graphed patients with retinoblastoma based on if they had unilateral or bilateral disease and their age and months of presentation. And you can see um that those with bilateral disease presented earlier um because they, they didn't require as much time to have two hits, they only needed one hit. And um so I think that that is um really fascinating the way he described this and has become the model for how we think about cancer biology and tumor suppressor genes um for uh mini pediatric tumors. And so the simplistic thing about retinoblastoma is that it's really just one gene that causes disease. Um with um so many other tumors, there's multiple mutations and not necessarily tied to a single mutation. But um for retinoblastoma, that's not the case. And so the retinoblastoma gene is um is located on chromosome 13 and is a tumor suppressor gene. Um It has an autosomal dominant presentation with high penetrance. And so really lends itself um to pedigrees and a model of um of heritable um cancer predisposition syndromes. Uh The gene itself is a negative transcription regulator. And so it will pre prevent cell growth. Um And uh interestingly, it also has a role in differentiation and cell survival functions. Um And so this gene has been the, the subject of a lot of study. Um as you can see um in most tissues loss of RB one is insufficient for tumor genesis. But at the same time, a lot of tumors have an RB one mutation. And so if you look at um small cell lung cancer, prostate cancers, melanomas, um breast cancers, um even childhood leukemias, a lot of these will have RB one mutations. Um And so this gene is likely necessary but insufficient in those tumors um to cause tumor genesis. Similarly, patients with a germline RB mutation, um do not have an increased risk for all of these tumors. Um And so there, the um the presence of this mutation alone really only increases the risk for a handful of mutations. Um The prime one that we will be talking about is retinoblastoma really under the age of five. These patients are also at increased risk for a pine blastoma. Um And we'll talk about how um in the presence of bilateral retinoblastoma with a pine blastoma. This is referred to as um trilateral retinoblastoma. They are also at risk for sarcomas, um especially osteosarcoma or um rhabdomyosarcoma. And this would be especially after an exposure to ionizing radiation, which is um a big reason why external beam radiation is not the mainstay of treatment. Um because in those survivors, 10 to 15 years later, they can be at a higher risk of an osteosarcoma or rhabdomyosarcoma um surrounding the orbit. Um Patients are also at risk for melanoma. And by the age of 50 about a third of patients with a germline retinoblastoma mutation will have developed a um a second malignancy. And so as we transition to talk about the presentation um in the eye again, um here is the retina in kind of uh an orangish color um uh with the coro behind it in the red. Um And depending on where the tumor forms um will will change the presentation and whether or not the um the patient presents with a small tumor or a large tumor. Um As you can see here when we have tumor genesis, if it is close to the phobia or the um or the optic nerve that may impede vision um and may present earlier or may present with straus or a lazy eye, whereas a tumor that is farther away from the phobia that has less of an impact on vision until it is larger, um may not present, present as early. And these tumors can evade really um forward into the eye or back into the corro or into the um the optic nerve. Um And we'll talk about that in a little bit more detail. Um So here's what it looks like on your ophthalmologic exam. Um And so you can see this white lesion um that is here in the back, often with calcifications, often a bumpy or irregular shape. Um And on exam, this child has a leuk Coria of the left eye. And so um an absence of that red reflex in the eye appearing white with a large tumor um in the back. And so, as we talk about how these patients present, the majority of them will present with Luka Coria somewhere around 60%. Um And this is the classic presentation that's on um you know, board questions or um um exam questions where mom or grandma, um you know, it always seems to be the woman is seeing a white eye in pictures or in person or when there is a um a camera flash, they're noticing that, that um that that eye does not appear symmetric compared to the other one. Also commonly picked up by the, the primary doctors or the pediatrician, about 20% of patients will present with Arabi um or an eye that doesn't track appropriately. Um And this is often if a tumor impairs vision um in a, in a greater fashion or closer to that uh fr optic nerve um so that the vision is affected early on and that eye does not develop the tracking mechanisms normally. Um And then some patients will have a family history of retinoblastoma. And so there is a proportion of patients that are picked up in that way um already followed by a cancer predisposition clinic already having screening evaluations to um to detect tumors um and can detect them um hopefully at a very small size and um and treat them early on. And about 40% of um patients with retinoblastoma will have a germline mutation. Um And as some of you are paying attention and seeing that 60% plus 20% plus 40% doesn't add up to 100%. Um That's because some of these patients with unilateral disease um will have heritable disease. And so if we look back to this n patient or paper again, in 1971 you can see that 10 to 15% of the unilateral patients um will have a germline mutation. This would be oftentimes a de novo mutation without any family history. And so it is incredibly important that all patients, whether they um whether they have unilateral disease or not, um have that testing so that they can get the appropriate screening that they need to. Um The other rare presentations include loss of visual fields. Uh This is obviously challenging in a young child. You know, a, a two year old is not necessarily going to tell you that they, that they lack peripheral vision, um uh glaucoma or um an increase in pressure in the eye which can result in ocular pain, um and even a periorbital swelling and so on. In rare scenarios, you can see a patient who presents um with swelling that appears to be a precept or an orbital cellulitis. Um And it's that retinoblastoma that's causing that increased um intraocular pressure uh that is, is causing that, that swelling that looks like an infection. And so the first step in management is an exam by ophthalmology and often referred to as an exam under anesthesia or an eu a um because it really needs to be a thorough exam. Um And this is the same picture that we were showing before with this smaller retinoblastoma that you can see. Um here is a much larger tumor in the eye. Um And really, I think in incredible to see the detail um of some of these images, but this is really how the diagnosis is made. And so you need to have a skilled ophthalmologist um who can recognize this and um and ensure that this is a retinoblastoma and not a reti noma or benign tumor. Although there's not um a whole lot of um a whole lot on the differential. Um And um uh yeah. And so let me show you what it looks like then on um on MRI, which is the next step of the staging evaluation. And so here in the first image, you can see that there is a small retinoblastoma in this left eye. Um this would be a much smaller tumor. And in the second image, you can see a much larger tumor in a different patient um in the right eye. Um The purpose of the MRI uh is not really to visualize that tumor. Um Well, yes, it will. And yes, you can follow that uh to some degree. The um the more specific exam is going to be the eu a the purpose of the MRI is really to evaluate the brain. Um and to make sure that there is no evidence of uh invasion either into the optic nerve um or into the, into the CNS further. And this third image is of a patient with Pine Blastoma. And this is um this is an adult. This is not a patient with, with retinoblastoma, but um luckily pine blastoma and retinoblastoma patients is incredibly um rare. Um And so I don't have any um any images to show of a of a retinoblastoma patient. Um But this is something that you would definitely want to detect early on and then continue to, to screen as um as the patient moves forward um trilateral trilateral retinoblastoma is incredibly difficult to um to treat. Um And so, having that baseline exam and um and being able to know that we're treating a localized tumor that is confined to the um to the eye is, is extremely important. Um And so, very briefly on the classification of disease retinoblastoma are classified from A through E on um group A through group E in this international intraocular retinoblastoma classification. And so, a, a group, a tumor is a very small tumor. Um group B tumors are also localized um confined to the retina, although slightly larger um where a group C or D tumor has more spread. And so this could have localized um seeding or diffuse seeding throughout the vitreous um which is again important to have a skilled um ophthalmologist who can identify this. A group E I is a large tumor that has really destroyed the orbit. And uh these are incredibly rare to see in the United States. Um But we'll see this presentation more in underdeveloped countries and there's a high risk for metastasis in a group E tumor. Um They will say that there is some risk of metastasis in a group C or D tumor. Um by evidence, evidence of that local spread already. Um but with adequate treatment, this can um can be mitigated pretty effectively. And so next, the goals of therapy, which I think is um is, is really important to understand for deciding the treatment options for these patients. So the first goal of course, is to save the patient's life. Um And luckily, we've gotten really good at that. And so um that almost is taken for granted. And then the next question is, what are the secondary goals? Um Goal number two is really related to the first goal. And that's don't let the tumor escape the eye prevent metastasis. Um because metastatic retinoblastoma, while rare is extremely difficult to treat, um if it uh involves the CNS, it can be a near zero likelihood of cure um distant metastasis, again, extremely rare um but would expect survival probably less than 30%. And so, um while you are treating the eye, the one of the most important things is to make sure that you have adequate control. And again, relies on that exam of the ophthalmologist. Um Again, this is another reason why that exam is important. If the ophthalmologist cannot visualize the tumor, they are unable to see if the tumor is um is having response or is being controlled. And so, if in the course of treatment, there is um development of a cataract or development of um a hemorrhage within the eye. And they are not adequately able to evaluate that tumor that really um uh puts the patient at risk because the tumor could spread um or advance without, without knowledge, goal three is to save the eye. Um And I think that this is important for a couple reasons. First of all, the eye obviously very important for vision. Um but I think the second reason is really a cosmetic um and the the eyes hold a um a special place in our mind and um and have a important role in um um in self image. Um and as well as what a a parent, you know, thinks of their child and with opportunities their child has as they're as they're growing up. Um the eye is also really important for face development and in the absence of a globe um in the orbit, um the orbit will not grow as um as it's normally supposed to. And so you will have some midface hypoplasia if you don't have um something, something there, a glob or a placeholder prosthesis. Um And then the final vision, the final goal is to preserve vision. Um And so I think that this is a important question to ask is what's the likelihood of them having good vision in that eye? Um Because if they don't have any vision, um you could treat with chemotherapy, but maybe it would be in their better interest to remove the eye, save them some of that toxicity of chemotherapy. Um because there is no vision to, to salvage. Um And then I think the other question is what is the likelihood of being able to control this tumor and to, to cure this patient um without removing the eye separate from vision. Um because if there is no chance of um getting adequate control of that tumor, then the eye should also be removed. Um And that would be the, the less morbid option. So, here's our management options. And um we're gonna go through these kind of one by one, especially in the top four A Nucleation cryotherapy or laser therapy, um systemic chemotherapy, intraarterial chemotherapy. And then very briefly, we'll talk about plaque therapy, um intravitreal chemotherapy and external beam radiation. Um And those last three are, are used pretty uncommonly. And so, um I think that there's, there's less need to spend time on them. Um And so when a Nucleation is removal of the eye, um and involves removal of everything that is seen here shaded in both the light blue and the dark blue as well. Um And the picture that I have here um um on the left is really just showing you that I, I think that a lot of people don't, don't understand how this works. I don't think that I did really before caring for these patients. And there's, there's oncologists who um who don't really understand this process. And so I think that it was important to show this process of a Nucleation here. And so you can see that they will remove the contents um um within the contents of the eye um and make an incision for an implant and then an orbital implant is inserted in the eye, um, then the sclera and conjunctiva are sutured over the implant. Um And so there's no, there's no hole here, um, after it's removed and, and insert an implant is inserted and um, sutured closed. And so that helps with that mid face development as I was, was talking about. Um, and then when the prosthesis is used, it's not removing an entire, an entire eye. And so these patients after Nucleation, when they come to, you will look um will look like this where they have a um kind of pinkish color to the sclera that you can see that was sutured over the um the ocular implant. Um and they will have a clear conformer that overlies that um while the eye is healing, while they're wearing the prosthetic eye, um it looks almost normal. And so I, I'm always just amazed by these patients and find myself just um staring at them after they've had a Nucleation. Um because of course, parents are going to be um incredibly um nervous about what this means for their child. Um And I, I think that's important to recognize um but the outcomes that I that I see and how realistic that prosthesis can look um is really pretty incredible. Um And this eye can track almost normally um as the musculature is still preserved. And so, um so really an in an incredible um advancement, I think that our um ocular prosthesis labs can, can offer these patients and these patients may not require any further um chemotherapy. Um as we were mentioning, if they do have an Nucleation and they see that the tumor has invaded either into the coro or into the vitreous tumor that may put them at a higher risk and may require some chemotherapy afterwards. Um but for patients with unilateral disease where that tumor is confined to the eye or is small, um it could just require a Nucleation and then no further therapy. So, moving on briefly to laser therapy and cryotherapy, um these are both procedures that can be done during the exam under anesthesia and they're effective in small tumors. Um but don't have as much of an impact on a larger tumor. Lasers are directed through the pupil and heat the tumor and directly destroy those tumor cells. Um Whereas cryotherapy uses a pin like probe on the, on the outer portions of the eye on the sclera. Um and cryo ala the tumor cells kind of through the wall of the eye. Um And you can use multiple freeze freeze thaw cycles um during a single eu a. Um And so you can see in this patient, um this is one of our ophthalmologists and she published this last year of using cryotherapy in patients. Um You can see the destruction of these tumors in this kind of before and after um image. And this can also be used in close proximity with systemic therapy because the uh destruction of that tumor increases its permeability. Um And so, systemic chemotherapy can then have a better um concentration within the tumor cells and result in um uh improved control. And so systemic the therapy, as I mentioned was um first started in the 19 nineties and Judith Kingston here, um basically uh realized that the tumor biology of a retinoblastoma was similar to a neuroblastoma and said, what agents do we have that are um effective in neuroblastoma? And can we um translate them into the treatment? And uh for retinoblastoma? Um and using vinCRIStine carboplatin and topic side has become an effective regimen for um uh for the treatment of retinoblastoma and really remains the three agents that we use for systemic chemotherapy today and just very briefly on those agents so that you can understand the side effects of in cristina of inca alkaloid. And the biggest things that we see with that is neuropathy and um and constipation. Um And in uh little babies, they may not tell us about neuropathic pain, but in that critical age development of walking, um we wanna make sure that they have that strength um continued and may need physical therapy to um to make sure that they are developing um their gait. Normally. Carboplatin is a platinum agent. And the biggest thing that we think about with carboplatinum is hearing loss and renal toxicity. Um And so these patients will get incredibly frequent hearing evaluations um because as you can imagine if we already know that vision is going to be impaired, we really, really need to protect their hearing um and make sure that they um that they don't have impairment in, in both of those. Um And so the dose could be reduced. Um We also do this in patients so that they can receive adequate hydration um and really flush that carboplatin out of their um out of their system. And then the third agent is a toy um which is a topoisomerase inhibitor, um causes a lot of the immuno suppression that we see and then also increases your risk for secondary malignancy specifically, am L. Um And so we often limit the therapy to six cycles of chemotherapy in rare circumstances. Someone may need more than that, but we also know that increasing above six cycles could really increase the risk of AM L. Um And so we need other alternatives for, for a treatment of a tumor that um that is not completely controlled after six cycles of chemotherapy. And that's really where intraarterial chemotherapy comes in. Um and intra arterial chemotherapy or I ac allows chemotherapy to, to be delivered directly to the tumor bed. Um And so the patient is sedated and a micro catheter is inserted into the femoral artery um and uh snaked past the heart and up to the carotid artery similar to a, you know, a cardiac cath, but going a little bit further and here, you can see that branch point of the ophthalmic artery coming off of the carotid um the ophthalmic artery um and its downfield branches here in retinal artery, which you can see here um going to this large tumor in the back of the eye, primarily the agent is melland that is used but can be combined with other agents to do either um dual agent or triple agent intra arterial chemotherapy. Um And it's infused into this branch point of the ophthalmic artery. Um And you can see a, a large portion of that um that therapy will give a high concentration to this tumor. Um But we'll also go into the surrounding arteries and here you can see what this looks. Um Sorry, let me make sure that advanced. There we go. Um Here's you can see what this looks like um under fluoroscopy. And so as this micro catheter is up there and infusing um the chemotherapy, you can really visualize and make sure that it's going um uh exactly where you want it to. And this is a uh very useful modality, especially if you have either bilateral disease that needs more therapy after systemic treatment or if we have a large unilateral tumor um where there is still vision left to preserve. Um This may be a good option for those patients as well. And here was our first patient that we treated. We, we developed our I AC program about two years ago. Um So just wanted to show you the effect that this can have because I think that it's pretty incredible to see um this, these are images from this patient's eu a same patient with the tumor before and after um I believe, two I ac treatments. Um And so really had a very, very good result, um was able to save this patient um in a Nucleation, um was also able to save them from um uh from requiring systemic therapy. Um And the, the um treatment can be combined with EU A s. And so as the ophthalmologist looks, they can provide that sclerotherapy or laser therapy um and can also affect or can also um measure the effect that I ac is having. And if a tumor is not responding well after one or two initial treatments, then the therapy could be intensified. And so, rather than just Methylin adding in to pecan or carboplatin for um for double or triple therapy. And so, as you can imagine, this takes quite the team. Um and I'm actually not performing the eu A or the I AC. And so I'm a relatively minor part of this team. Um But uh as you can imagine, these patients are young, um they are being sedated and having a neuro interventional radiology procedure performed at the um adult hospital because that's where the neuro ir um um lab and spaces are um they are passing a micro catheter in someone who's maybe 6 kg. Um They're passing the barrow receptors in the um in the carotid artery. And one of the rare possibilities with this therapy is that a patient can, can have an arrhythmia or code code. Um And so this obviously takes a, a huge team, a huge partnership with anesthesia um with neuro interventional radiology and with ophthalmology um to accomplish this, the um chemotherapy is also primarily Methylin, as I mentioned, which um has to be infused within about an hour of making. Um and it may take a half hour or so for the for the patient to be uh sedated and to get the micro catheter in the right spot. And so you really have to have a pharmacy team that is um is willing to make it at the exact moment that you're ready for it. Um So we're one of about 20 patients or 20 centers that can offer this therapy. And I think that it's a really, really great uh therapy that we can offer for, for the region. Um The other thing that I'll mention is that it does of course, have some risks associated with that sedation. Um As well as we're, we're infusing a fairly high volume of um chemotherapy about 20 mL into a tiny artery. And so those patients can have significant swelling around that eye. Um It can sometimes um affect the musculature or the tracking of that eye and cause a palsy. Um oftentimes, which is um temporary. Uh and then finally, patients who have germ germline mutations, as I mentioned with the absence of that tumor suppressor gene are at higher risk of ionizing radiation. And this is done under fluoroscopy. And so you have to be mindful of that um and minimize the time under fluoroscopy as much as possible. Um So that these patients don't have an increased risk of um of a second malignancy Um because of that fluoroscopy and ionizing radiation. The last three that we'll talk about just briefly um is plaque therapy um where a where radioactive seeds are placed in a plaque that is affixed to the outside of the eye next to the tumor and this allows for a targeted radiation um right next to the tumor. Um and really to, to treat the tumor there. Um This is often used in um patients who have already gone through a lot of other treatments and don't have a lot of other options. Um And I would say that this is, is pretty rarely used. Um I would maybe consider this if there was um vision in this eye, perhaps they had already had a Nucleation of the other eye. And we're really talking about what can we do to save this eye because otherwise they're gonna have a bilateral ale. Um But, but pretty rare. Um overall intravitreal chemotherapy is one that um that I think will be used a little bit more than than plaque therapy. Um And this is especially used when we have vitriol seeding. And so in those group c and group dis um where there are tiny tumor implants in the vitri. Um this puts them at a higher risk of having treatment failure. And so often that systemic therapy can control the um primary tumor. But one of these vitriol seeds can then um grow or re implant and um and cause um recurrence of disease. These can also be hard to target, right with laser or cryotherapy. Um And so intravitreal chemotherapy with Methylin allows you to inject chemotherapy directly into the Vitria. Um again performed by the ophthalmologist. Um and this provides a really high concentration of chemotherapy to these areas um and may improve the ability to, to salvage the eye. Uh There is a current cog study, children's oncology group study that's looking to evaluate the feasibility and the toxicity of um of this treatment with um systemic chemotherapy in patients who have vitriol seeding. And so, um as that study progresses and the the results of it, we may see that this um ends up becoming um part of the standard of care for patients who have uh vitriol seeding if they have better outcomes with this external beam radiation, as I mentioned, far less common. And part of the reason is that it can affect the growth and development of the midface. Um And here is what you will see and you almost have that frontal bossing appearance um uh with the midface um hyperplasia around the around the or orbits. Um You can also have dental issues and tooth decay from that um uh from that treatment. And so we often don't use this uh the the final reason being that it increases the risk of a um osteosarcoma 10 to 15 years later, um around that that orbit or a soft tissue sarcoma with a rhabdomyosarcoma um or even a Ewing sarcoma. The reason I include these pictures um is really that you could see it in family members. And so, in a patient with a um a germline retinoblastoma and known family history, um it's not uncommon to see that the um parent had um external beam radiation as this was much more common 30 or 40 years ago. And so you may see this phenotype um uh when looking at, when looking at a parent. And so I'd like to switch gears a little bit and talk about disease monitoring. Um And um there's really two things that you're monitoring for in this case, one is to make sure that there's no recurrence within the eye. And two is to evaluate the CNS disease um especially in germline patients, as we were mentioning um for the monitoring of trilateral retinoblastoma. Um unlike other solid tumors um in which we rely heavily on cross sectional imaging for surveillance, we really rely on the eu A. Um And so as I mentioned uh multiple times, you know, this, this really can't be done without a skilled ophthalmologist because the the ophthalmology exam is really um all that matters. Um The MRI as I mentioned is surveillance for pineal blastoma and this is indicated for any patient who has germline mutations um or in a patient who has high risk factors for metastasis with that invasion into the corro for instance, or into the optic nerve. Um And these are done until the patient reaches age five. primarily every uh six months. And we have a uh cancer predisposition clinic that follows these patients and will help perform those screenings. Um Luckily, trilateral retinoblastoma is um in incredibly rare, especially because it is um near impossible or impossible to cure. Um And the rates have really dropped um since the advent of systemic chemotherapy. And the thought behind that is that the systemic chemotherapy, while they have a baseline exam, that doesn't have a pineal blastoma um treats the pineal gland and prophylaxis against the development of a um of a pineal blastoma. And so the incidence of trilateral retinoblastoma has really declined uh quite rapidly. Um which is um an incredibly good thing for our patients uh because of that advent of systemic chemotherapy. And so as I've alluded to the survival of retinoblastoma is phenomenal and this um consortium, the research into visual endpoints and retinoblastoma health outcomes after treatment or the Riverboat consortium is a network of survivorship programs up and down the Mississippi River. Um And it has analyzed a group of um of retinoblastoma survivors um of about 4 to 500 patients. Um And the survival with unilateral retinoblastoma is, is over 99% approaching 100%. Um And what I think is equally or perhaps even more impressive is in patients with bilateral retinoblastoma. The survival is also phenomenal and approaching 100%. Um And so that's why I mentioned that cure really is almost taken for granted. Um And that the secondary goals of what else do we need to do for this patient really become the the focus um where we can see that work is still needs to be done. Here is that 58% of these patients will have an enucleation. Um And in patients with bilateral disease, the vast majority, 80 to 90% will receive chemotherapy and in unilateral disease, half of those patients will receive chemotherapy. And so it's important to know how this will affect our patients. Um because we'll, we'll really be seeing a lot of the late effects as almost all of these patients um survive. And so a large reason, um and so part of what we need to watch for is these late effects, as I mentioned. Um And a large reason that they have a lot of these late effects is that retinoblastoma diagnoses occurs during, during a um critical age for vision development. Um And we know that vision is important for a lot of different reasons. But I think that it's also important for co ordination and things that we um that we don't and social interactions, things that we don't necessarily think of. Half of patients will report vision impairment. And a quarter of survivors will have um difficulty in school um with one in eight patients having an IEP and then the parents will also report concerns um with their child's learning um and express that they either have an objective or just a subjective concern that um that their child is having impaired learning. Um Doctor Reynolds, one of our ophthalmologists has evaluated the SADs or rapid eye movements of survivors. Um and found that universally, these patients will have decreased parameters in um in accuracy as well as latency of um both lateral and vertical psychos. Um And so I think this is uh important and a and a movement that a lot of us take for granted with this act, with this um rapid eye movement, the obvious implication is on reading. Um But it also leads to a whole host of other vision problems. Um And doctor Reynolds observed that these changes occurred universally in these patients, as I mentioned. Um And that uh simple visual acuity tests may be an oversimplification of the visual capabilities um or the deficits that these patients have. Um And it may have implications on coordinations on learning um as well as uh motor development. So I also want to highlight this recent publication which demonstrated that patients um are also reporting decreased quality of life um and activities of daily living. Um And as I mentioned, parents will report on surveys that they worry about their child's quality of life and report difficulty. Um We're now coming to this realization that um it's important to screen these patients early um because these deficits will be seen um really universally within this population. And so, back to the Riverboat Consortium, this data set collected information on financial toxicity quality of life and a whole host of data on the treatment and demographics for these patients. Um and impaired mental and physical quality of life metrics were seen in retinoblastoma survivors and this was tied to um financial toxicity or metrics of stress and difficulty that was related to finances. Um And so you can see this um this progression where you can have a developmental delay which can lead to impaired social interactions um and an intellectual delay. Um And then consequently, as adults, this can lead to decreased financial stability um and poorer quality of life. And so as I as I wrap up, the the late effects of retinoblastoma are becoming truly the next frontier. And um those late effects come in um from therapy um with a Nucleation leading to depth perception issues with the chemotherapy carboplatin and topside, increasing the risk for hearing deficits or secondary malignancies. Um but then also separate from the treatment and just the development of the tumor during this critical time period, um likely leads to impaired learning even if they don't receive any therapy. Um or say a patient just needed cryotherapy or laser therapy and didn't need a Nucleation or systemic chemotherapy. We still see some of these deficits that can affect um their life dramatically. I mean, we often think about ringing the bell as the um as the end of therapy and as the finish line. Um and using the, the metaphorical ice iceberg, this is really the the tip of the iceberg and cure um is is often easier to accomplish and we still have these school difficulties, these social interactions, um employment challenges and decreased um average income that are important for us to um identify early in our patients so that we can ident so that we can intervene earlier for these patients. Um And so on that note, I will conclude um and uh not to end on too much of a of a sour note. I think that it's important to recognize that we have an incredible array of options for treatment of retinoblastoma and the crates um approach 100%. And so the advancements now look to minimize toxicity. Um and survivors can have significant late effects of chemotherapy as well as effects of the diagnosis themselves. And this can affect quality of life. Um And the primary doctors and the pediatricians I think are really poised to um to monitor for this and to partner with the survivorship programs. Um because they know these patients so well and having an understanding of the, the treatment that the the patients receive, I hope will um will help you to be um uh in tune with those um those possibilities and complications. So with that, I will conclude, um and I can't see the chat from here, but I'm happy to take any questions. Created by Presenters Daniel Willis, MD, MPHS Assistant Professor, Division of Pediatric Hematology/OncologyWashington University School of Medicine
