Lecture: Management of Retinoblastoma

Retinoblastoma is one of the most treatable ocular tumours but with one of the worst outcomes if care is not taken to properly manage it on time. We will be discussing with a leading expert, emphasizing timing of treatment options like chemotherapy, TTT, brachytherapy and Radiotherapy and the role they have to play to improve the outcomes in developing countries.

Lecturer: Dr. Swathi Kaliki, Head, Department of Ophthalmic Plastic & Facial Aesthetic Surgery, Orbit & Ocular Oncology
L V Prasad Eye Institute, Hyderabad, India
Panelist: Adedayo Adio FWACS, Consultant Pediatric Ophthalmologist
University of Port Harcourt teaching hospital, Nigeria.
Chairperson, Nigerian Pediatric Ophthalmology and Strabismus Society (NIPOSS)


Adedayo Adio: Hello everyone. This is Adedayo Adio. I’m speaking to you from Nigeria. And we also have a guest all the way from across the world and we’re going to be talking to you today about the Management of Retinoblastoma. It’s important for us to give you a brief background of who we are a society of pediatric ophthalmologists and I’m sharing them in Nigeria committed to ensuring the overall eye health of the Nigerian child and we are called NIPOSS. We are living in Nigeria, which is one of the 54 countries of Africa and the world’s second largest and second most-populous continent after Asia, which is about 1.3 billion people. And as we are speaking from with that brown arrow that black arrow there in Nigeria close to the west of Africa — in West Africa near the Atlantic Ocean.

In Nigeria, I’m speaking to you from Port Harcourt and there are 36 States of the country. The capital is Abuja. We are about 208 million people by yesterday’s estimates. And we have to check all these number of people just about 40 pediatric ophthalmologists, which is just about 80% of the 500 ophthalmologists in the whole country. And we’re working in about 21 centers across country. And we have very busy clinics as you can see. So we feature in this different topics for the last two years, so we’re talking about the management of this very important topic. We know it is one of the most common intraocular malignancy of childhood and Leukocoria is the most common form of presentation. It’s important for us just let you know briefly some of the challenges we have in Nigeria and all the similar low income countries. We have those associated with early presentation, delivery of care, acceptance of care, maintenance of care and follow-up.

So late presentation is generally major issue in this part of the world though is getting better in the last few years because we have better structure on ground and there’s more synergy between the pediatric ophthalmologist and oncologist. We also begin into have dedicated phone lines in some places to Whatsapp groups where we develop and discuss updates and different cases. Right now we’re developing the retinoblastoma register in the country we have a listing all the cases that we’ve had in the last few months, but in terms of delivery of care in the 21 centers where children can be treated. Precious few have the ability to offer all that is required. We have about less than four that have everything that is required to take care of these children. And that means we have we lack the basic equipment for treatment. Especially equipment for Transpupillary Thermotherapy is very difficult to find and radiotherapy also very few centers have this and therefore we have very long waiting lists.

It’s one of the cases of retinoblastoma that we have from time to time very bad cases and we have very few people to take good care of this also rather just how that should be present early. And this is one of the reasons why we have to talk about this. Now in terms of accepting and financing care, the average cost per cycle in our centers could be up to like — lift about $150 like 40 to 60,000 Naira, which is way over the minimum wage. And after one or two cycles of spending this kind of money a lot of people default. So only there — they have to have enucleation less than a quarter actually accept it. So there is a very high default rate and non-completion of treatment as one of the major challenges. And so finance is a big challenge. We would like to have retinoblastoma centers would be not getting for currently. The government is not subsidizing medication, but we managed to add the — these drugs that retinoblastoma [indiscernible] [00:04:29] National essential drug list. So the actually I really it will be a little bit costly.

So it’s really up to us to determine that we’re going to have to change and this is one of the reason why we’re having these webinar. And it’s not all grim actually those look like it’s been a great picture about this patients we know can actually live and see well. We have a few patient who have actually done very well because of early diagnosis, careful handling and in those centers they have good therapeutic equipment. And if there is availability of appropriate medications in large quantity spread all over the centers. There will be better outcome. Radiotherapy is also important to having at least every one of the six million geopolitical zones of the country. And the — with the presence of excellence counselors and social workers to follow-up properly and this we can find that this patients can actually leave and then see very well. So to help us to understand better how to where go to achieve this, we have a guest all the way from India who has goal through some of this sitting problems that we are still going through. I’m going to help us to understand have ensure that we are able to get better care for this ones.

So our guest for this fourth quarterly webinar for this year is Dr. Swati Kaliki. So in the past few years since then she has work experience have mainly LV Prasad. Just we walking they has consultant from 2013. She’s also the Head of Service of the Institute of Eye Cancer from 2016 till now. And she’s also the Head of Service currently of Oculoplasty and Oncology Service of the hospital since 2019. So healthy welcome Swathi Kaliki has our guest today speaking to about Management of Retinoblastoma. You’re welcome Swati. Thank you for joining us.

Swathi Kaliki: Thank you very much for that very kind introduction Adedayo. So I’ll be talking to you all are very like now warm welcome to everyone who have joined this webinar. So over the next 40 to 45 minutes I’ll be taking you over about retinoblastoma, talking about the basics of retinoblastoma and its management. Okay. So I hope all of you can see the slides. Just a brief historical perspective about retinoblastoma. So it has been described way back in 1597 by Peter Pawius. The clinical description of this was first in 1809 by James Wardrop. The terminology retinoblastoma was coined by Verhoeff in 1920s and finally it was adopted by the American Ophthalmological society in 1926. Since then onwards we recognized the tumor by the terminology retinoblastoma. As you all know retinoblastoma is the most common intraocular tumor in children. It’s the eighth most common pediatric cancer represents about 11% of cancers in the first year of life overall about 3% of childhood cancers and the retinoblastoma is mostly diagnosed before the ages of five years in 95% of the cases. And the incidences about 15,000 to 18,000 live births.

Now why is it important to know about retinoblastoma? Now this is a very nice article that was published in BJO, I think in the year 2019 authored by Tero Kivelä where he spoke about how the mortality rate is different in different countries. So as we can see the — it’s a huge problem. There are about 7000 to 8000 new cases which are diagnosed every year across the globe. And 50% of them they die every year due to retinoblastoma. And most of these deaths occurred in the continents of Africa and Asia. The death rate is has highest 70% in Africa and being about 42% in Asia while the mortality rates are very low in developed countries when more than 95% of the cases are life free of disease and they retain the vision as well. Now in India, specifically it’s one of the country where we have the highest number of cases and probably that has also given us more experience to deal with these cancers.

Now why does retinoblastoma occur, it occurs because of genetic mutation in the RB 1 gene, which is located on the chromosome 13 and I’m sure most of us are familiar about the Knudson’s two-hit hypothesis. Now if it is a hereditary retinoblastoma then the child is born with the mutation in every cell and one so after a second mutation occurs specifically in the retinal cell that’s when the retinoblastoma becomes a parent if it is the hereditary retinoblastoma. While if it is a non-hereditary retinoblastoma their not born with any mutation both the first and second mutations they occur after birth resulting in retinoblastoma at a little later age when compare to that hereditary retinoblastoma. So as we have spoken already, so it can be hereditary which has seen in about 40% of the cases or it can be sporadic seen in about 60% of the cases. The hereditary pattern of retinoblastoma it is associated with the germline mutation in all cells of the body, which means that they are at risk of developing second cancers elsewhere in the body. About 10% of them have a positive family history while the rest of them do not have any family history.

The tumors are bilateral in 90% of the cases, but in 10% of the cases that you must maybe unilateral. And that is where genetic testing becomes important. And all patients with bilateral retinoblastoma they have a hereditary form that means that can transmit the disease to the next generation with the risk of transformation being almost 50% to the offspring. Now the sporadic or the somatic which is a more common variety seen in what 60% of the cases where the RB 1 mutation it occurs only in the retinal cells, which is why the chances of second cancers elsewhere in the body are less. And mostly it is always a unilateral disease and it is not heritable. So it does transmit to the next generations. Now what is the clinical significance of this? That’s the hereditary retinoblastoma they occur at younger age. They are more likely to be bilateral and multifocal and they have 6 to 10% lifelong risk of second cancers while the sporadic variant here the mean age at presentation is much later and their more likely to be unilateral and unifocal.

Now what is the importance of knowing the family history? Now it is very important to ask specifically about family history because we can assess what is the risk of transmission of this disease to the next generation or even what is the chance of having this disease in the siblings. When there is a positive family history of retinoblastoma and the tumor is multifocal or unifocal or bilateral then it means that the patient is carrying a germline mutation. And the risk of transmission to the offsprings is about 50%. If the family history is negative and then the risk of transmission and the tumor is unilateral. The risk of transmission is only less than 5%. The chances of having the germline mutation, of course, is about 15%, which means that if they have a germline mutation then the risk of transmission automatically increases to 50%.

Now though as discussed most of these cases they occurred before five years of age and the mean age of presentation is about 18 months. The tumor is mostly unilateral in about 75% of the cases it can be bilateral in 25% or trilateral in 1%. That is trilateral where the tumor is present in both the eyes and they also have the [indiscernible] [00:13:23] pinealoblastoma. Now the most common way that retinoblastoma presence is white reflects in the eye or also called as Leukocoria which is seen in about 60% of the cases and Strabismus is seen in about 20%. Here are examples where the child has presented Leukocoria and these can be easily picked up on photographs as can be seen in this child where the white reflects or picked up or during the first birthday of pictures when they were taken. And then the child was brought in for an eye examination. Now though we see as Leukocoria it is not strictly a white reflect sometimes the color may vary depending upon the tumor characteristics. Like in the first one it appears some like more or less grey-ish, white in color. The second one is more yellow. So xanthocoria is not always Coats diseases sometimes when there is exhortation along with retinoblastoma they can give rise to yellow reflects or it may be more pinkish or it maybe even greenish like in the last picture when there is black staining of the cornea.

Sometimes they present strabismus where there is squinting of the eye and most of the times whenever these children present with squint they get detected with retinoblastoma much later because it is often not done that fundus examination is done in every childhood presents with squint. So it’s very important to do a fundus examination of every childhood comes to us with strabismus so as not to miss the diagnosis of retinoblastoma. They can present as of red eye in advance stages like in these cases when it is much more advanced where their most of these children may go on to develop secondary glaucoma resulting in congestion of the eye or sometimes there may be blood in the anterior chamber giving this appearance of a red eye. If these cases are gone to advanced stage they can present with orbital pseudocellulitis where there is inflammation of the — or orbital structure. That is when they present with cellulitis and they should not be mistaken as the bacterial cellulitis, but these are non-infective cellulitis. Here is an example, where the child presented with cellulitis and unless we do a fundus examination or B-scan or CT or MRI. The tumor which is present inside the eye maybe missed.

They can also present with pseudohypopyon that is the white or like the sediment that may be present in the anterior chamber and sometimes it may be anterior retinoblastoma where only the anterior chamber maybe involved and the immediate [indiscernible] [00:16:08] body region and retinal tumor maybe completely absent in these cases. In very, very advanced stages when the tumor outgrows the blood supply then it can cause necrosis of the tumor and the tumor and the eye can become Phthisical. So in very advanced stages the patients may come to us with phthisis bulbi. Or they can have orbital tumor extension as can be seen in these cases where the tumor has extended beyond the eye. In some cases and neglected cases they can even come with large fungating masses as can be seen in these pictures and why do they occur it’s mainly because their neglected. They are not treated on time. Like here is an example of a childhood presented with intraocular tumor in his left eye, but he did not receive — he did not get the treatment on time and he came back with extraocular extension of the tumor where the tumor was extending along the optic nerve and subsequently to the brain.

Here is an eye is another example where the first picture that you see the patient had pseudohypopyon and a very advanced tumor, but on the child was advised enucleation of the child did not undergo in enucleation and after few months the child came back with the picture that you see on the right where there is extraocular extension and also involving orbital or the bones or the forehead as well where you can see the frontal bone bossing that is noted. Here is another example where the child had undergone exenteration, but did not come for follow-up later and the tumor has extended into parotid gland and also into the long bones. Now that is about the clinical presentation then moving on to classification. So the tumors can be intraocular tumors can be grouped and that when we talk about intraocular and extraocular tumors and the general status of the patient that is when we call as staging of the disease.

Now grouping of the tumor can be there are various classification systems that have been proposed like the Reese-Ellsworth classification, Essen classification, the international classification of retinoblastoma. The one which is quite famously used is the international classification of retinoblastoma where it can be classified as Group A the tumor being less than or equal to 3 millimeters. Group B when the tumor is more than 3 millimeters or is associated with subretinal fluid or if the tumor is present in macula. Group C when it is associated with localized subretinal or vitreous seeds. Group D when it is associated with diffuse subretinal or vitreous seeds and Group E when it is very advanced tumor requiring enucleation. Now staging of the disease again there are various staging classifications that have been proposed, but the most common one that is the used is the international retinoblastoma staging system where it can be classified as stage 0 where it look salvage can be achieved. Stage 1 where the eye is enucleated, but there is no microscopic residue. Stage 2 when the eye is enucleated, but there is microscopic residue. Stage 3 being the orbital disease and Stage 4 being metastatic disease.

Now here are examples of stage 0 when the patient presents with tumor such as this within intraocular tumor that looked can be salvaged, but when the patient presents with very advanced tumor the globe may need to be enucleated but there is no microscopic residue after enucleation of the eye. Stage 2 is when the globe is enucleated but there is microscopic residue because of extraocular extension of the tumor. Stage 3A where there is overt orbital extension as can be seen in this child there is optic nerve extension of the tumor. 3B where the tumor as spread into there is extraocular extension on the tumor as spread into the regional lymph nodes here. Stage 4A where it has extended beyond the orbit, beyond it has gone the systemic metastasis has occurred like can be seen here and Stage 4B where the tumor has extended into the brain that is when there is CNS extension. The cytology picture below is the tumor cells which are present on CSF Aspirate.

Now next moving to the Retinoblastoma Management. Now whenever we talk about managing the case of retinoblastoma. There are multiple things we need to consider, the tumor laterality then the size of the tumor whether there is involvement of the macular whether it is associated with vitreous or subretinal seeding, whether after enucleation there are high-risk features, the age of patient, the general health of the patient, family history and, of course, the desires of the family. All these have to be taken into account whenever we manage a case of retinoblastoma. Now there are various treatment options that are available for retinoblastoma. Starting from focal treatment, which can be in the form of cryotherapy, transpupillary thermotherapy or laser photocoagulation. Chemotherapy which can be intravenous, intraarterial, intravitreal or subtenon’s chemotherapy. Radiotherapy where it can be external beam radiotherapy or plaque radiotherapy or sometimes enucleation.

Now we’ll talk about each of these treatment options in the next few slides. Now going back to focal treatment. Starting with cryotherapy. Now cryotherapy it was the use of cryotherapy was first reported in 1967 by Lincoff et al and it is mostly used for tumors which are small which means the thickness of the tumor is not more than 3 millimeters and their located in the equator or periphery. And whenever we treat a case of retinoblastoma we always do triple freeze-thaw cryotherapy and each session may have to be repeated every four to six weeks. The most of the tumor their respond two or three sessions and some tumors may require more than three sessions.

Now here is an example where there is a tumor that is located at the equator and if we do cryotherapy to this patient this is what the patient will look like, where it can be seen that there is a scar in the area of previous tumor. Now these are the various cryoprobes that are available generally we used a 15 degree curve rope for whenever will be treat the case of retinoblastoma. This is the cryotherapy machine that is used and the cryotherapy acts on — based on the principle of the Joule-Thompson or Joule-Kelvin effect where there is rapid freezing of the tumor tissue. The temperature reaches minus 90 degrees it results in the formation of intracellular ice crystal resulting in protein denaturation, pH changes and then the rupture the cell resulting in the secondary thrombosis and infarction of tumor tissue. So that’s the mechanism of action of cryotherapy on the tumor.

Now we also use the terminology what we call us chemocryotherapy that means here this is not the triple freeze-thaw cryotherapy that we do. We use single freeze-thaw cryotherapy and this is usually done in combination with intravenous chemotherapy usually about 24-hours before intravenous chemotherapy when we do this. This breaks the blood retinal barrier and helps in increased penetration of chemotherapeutic agents into the eye. Specifically carboplatin where it has been shown that the amount of carboplatin that enters the eye after a chemocryotherapy is 15-folds more than otherwise. Next moving to transpupillary thermotherapy. So transpupillary thermotherapy is a laser form of treatment where the laser is apply directly over the tumor. We use infrared diode laser with the wavelength of 810 nanometers and this again should be used for tumors which are small in size, which are less than or equal to 3 millimeters in thickness. The location of the tumors here it can be located in the equator or in the posterior pole and whenever we do TTT or transpupillary thermotherapy the end point is we look for if there is greying of the tumor. And this again similar to cryotherapy it needs to be repeated every four to six weeks. And TTT again usually the tumors respond in two to three sessions.

Now this is the transpupillary thermotherapy machine that regionally use where at the spot size is about 1.2 millimeters. The power that we use as 300 to 600 milliwatts. The duration of 9000 milliseconds at the interval of 50 milliseconds and generally we limit the number of spots to less than 35, so that we are not because whenever we have to remember that when you’re doing TTT the laser is passing through the lens. So excess laser to the lens again can cause cataract. So we have to keep in mind that we have do not deliver this TTT for more than five to seven minutes. Now here is an example of transpupillary thermotherapy where there is a tumor which is present in the posterior pole and if I apply TTT or to this, this is what it will result in. So there will be a scar in the area of the tumor. Here the advantage of TTT over cryotherapy is that the scar is not large. The scar will be exactly same as the tumor size and that is why it is preferable for tumors, which are present in the posterior pole.

When transpupillary thermotherapy it results in slow and sustained temperature. The temperature increases to 40 to 60 degrees and it causes direct cytotoxic effect on the tumor cells. Similar to chemocryotherapy we also have thermochemotherapy where we do TTT has a consolidation treatment prior to chemotherapy here again the principle is the same that is to break the blood retinal barrier. So that there is increased uptake of carboplatin into the eye. The other form of focal treatment that is available is the Argon laser photocoagulation here instead of the diode laser we can use the Argon laser where the wavelength is 532 nanometers. Here generally we use about 350 to 500 milliwatts power for about 30 seconds. And this again is repeated every four to six weeks. Now the difference between TTT and Argon laser photocoagulation is that as I mentioned when we do TTT we apply this for directly on the tumor. But when we apply Argon laser photocoagulation here this spots are applied around the tumor. We apply these are two rows of laser around the tumor because the basic principle of the Argon laser photocoagulation is it causes coagulation. That is it cuts off the blood supply that is coming to the tumor and that is why we do the laser around the tumor rather than over the tumor. That was about focal treatments.

Next moving on to chemotherapy. Now first starting with intravenous chemotherapy. Now intravenous chemotherapy that drugs which have been shown effective for intravenous chemotherapy are Vincristine, Etoposide and Carboplatin. Generally these chemotherapeutic agents are given over two days we call it as day 0 and day 1. Day 0 where all three drugs are given on day 1 only at opposite is given and usually most of the cases require a total of six cycles of chemotherapy. Now we have something called as standard dose and high dose chemotherapy. I think on this is something that is important to know though standard dose chemotherapy, the dose of the drugs is slightly on the lower side when compared to that of high dose chemotherapy especially where the etoposide and carboplatin doses are higher with high dose chemotherapy. Standard dose chemotherapy is preferred for intraocular tumors while high dose chemotherapy is used when the tumor as extended beyond the eye that is whenever there is extraocular extension or sometimes even when there is advanced intraocular tumor in both the eyes then we use high dose chemotherapy.

Now here is — here on examples of intraocular tumor which have been treated with standard dose chemotherapy and as you can see the tumors have responded really well with intravenous chemotherapy. Here is on the third example where there are large tumors which are present within the eye and chemotherapy has been given to them and the tumors have completely request [00:28:52]. That is the intravenous chemotherapy. Next moving on the periocular chemotherapy. Now periocular chemotherapy generally we used to use the subtenon’s carboplatin at the dose of 20 milligram per 2cc. Now this is the very rarely moves to now because of now we use intravitreal chemotherapy. So carboplatin is subtenon’s carboplatin is redly used. But here is an example where subtenon’s carboplatin was used in this patient. So this is the patient with an endophytic tumor before chemotherapy. And after chemotherapy you can see that there are diffuse vitreous seeds and before these patient’s carboplatin was used and you can see that the tumor has nicely regress and the vitreous seeds have completely regress because of the subtenon’s carboplatin.

Now next moving to intraarterial chemotherapy. Now intraarterial chemotherapy is where the chemotherapy is deliver to the eye directly, so here we pass the catheter from the femoral artery go along the aorta along the arch of aorta then enter the common carotid artery and then the internal carotid artery. And once we enter the internal carotid artery the first branch that arises from the internal carotid artery is the ophthalmic artery. So we reach till the ophthalmic artery and then the chemotherapeutic agent is delivery. We generally use Melphalan even carboplatin and topotecan drug which are used for intraarterial chemotherapy and these drugs they directly entered into the eye. Now here is an example where we have used intraarterial chemotherapy. Now this is the patient who has failed treatment with intravenous chemotherapy where the child has receive 14 cycles of intravenous chemotherapy and then intraarterial chemotherapy was given to this patient. And you can see that the tumor has very nicely regress with intraarterial chemotherapy. Now intraarterial chemotherapy can be used either as primary treatment or as secondary treatment when other forms of treatment fail.

Now next moving to Intravitreal chemotherapy. Now this is the very important paper that was published by the Switzerland group where they showed that that intravitreal chemotherapy is effective for retinoblastoma. Now they had included all the eyes which had failed all other forms of treatment they gave melphalan of 20 to 30 microgram per 1 cc above 122 injections where given in these patients and they noted that there was no evidence of extraocular extension when we do intravitreal chemotherapy. And globe salvage was achieved in 87% of the cases over two years follow-up. The only side effect then they noted was that there is RPE mottled near injection site. So intravitreal chemotherapy is a very good form of treatment for whenever there are vitreous seeds, but we should understand that it has to be given very, very carefully because a wrong technique can result in extraocular extension of the tumor resulting in mortality of the child. So knowing the technique correctly is very, very important whenever we are doing intravitreal chemotherapy.

Now here is an example when we have done intravitreal chemotherapy. So this is a patient who had an endophytic tumor with vitreous seeds and this tumor really did not respond very well after six cycles of chemotherapy. So we gave the patient another six cycles of chemotherapy, but the vitreous seeds were not just going away. And so in this patient we again restarted systemic chemotherapy and we also gave adjuvant periocular carboplatin, but it really didn’t it. So that is — so this is the like know after the first cycle of chemo along with periocular carboplatin and this again second cycle of carboplatin was given and it still didn’t help then we gave external beam radiotherapy to this patient, it still didn’t tell. And this is when — this is the patient where we have tried all forms of treatment and patient still had these vitreous seeds. That’s when we gave intravitreal chemotherapy to this patient and this patient responded really well after intravitreal chemotherapy.

Now intravitreal chemotherapy, here is another example where you can — so the vitreous seeds they can be there are basically three types of vitreous seeds. That is it can be dust where there are fine particles of vitreous seeds, there can be spherules like here where there are well-defined large vitreous seeds or they can be cloud. That is a previous case where you have seen where there is cloud of vitreous seeds. Now in these cases when we can give intravitreal chemotherapy it really helps the vitreous seeds. Now this is another case where we gave systemic chemotherapy for this patient, but the patient had these vitreous seeds which were just not going away with systemic chemotherapy. And that’s when we gave intravitreal chemotherapy for this patient and you can see that with each intravitreal injunction. The tumors come — the seeds completely went away, but you can also note that it has caused some toxic effects on the retina.

So intravitreal chemotherapy is not free of complications it can have side effects as well and these side effects are mostly seen when you give Melphalan. So now we have slowly shifted to giving intravitreal topotecan and we have seen that the side effects with topotecan is much less when compared to that of intravitreal Melphalan. And these are given usually every three to four weeks and most of these cases require treatment for almost about six to eight months. Now the technique of intravitreal chemotherapy is that you give it through the pars plana route. So you identify the pars plana so we have to understand that in children the pars plana will not be presented 4 millimeters. It depends on the age of the child if the child is only 2 years of age the pars plana will be 2 millimeters away from the limbus of the child is 3 years it will be 3 millimeters away of the child is 4 years or more then it will be 4 millimeters away from the limbus.

So we give the injection in the pars plana and once it is given the most important step. So and also the correct sight should be or chosen. So it should not be an area where there are active vitreous seed. So generally we chose a [indiscernible] [00:35:08] where there are no vitreous seeds such that we are not causing the vitreous seeds to come out of the eye when we are taking of the needle. Now the important step when we do intravitreal chemotherapy is that we have to do cryotherapy at the sight of injection even before the needle is withdrawn from the eye. So that is what is being done in this case and then we complete the triple freeze-thaw cryo at the sight of injection and after that we just shake the eye a little bit. So that the drug disperses within the eye and then we give thorough wash with saline, so that even if there is any extraocular extension that is washed away and that’s how the intravitreal chemotherapy is done.

Now next moving to Radiotherapy. Now radiotherapy can be external beam radiotherapy or plaque radiotherapy. Now external beam radiotherapy is very rarely used nowadays because we have other forms of treatment especially the intravitreal chemotherapy, but here is an example where this patient was not responding to systemic chemotherapy and then radiotherapy was done and then the child showed very good response. The other form of radiotherapy that can be done is the plaque radiotherapy these are the ruthenium plaques that we generally use. The above one is notch plaque and the below one is round plaque. So it can be done as primary treatment or secondary treatment when other treatments fail and usually the amount of radiation that we give us 40 Gy to tumor Apex. Now here is an example of where the patient as received multiple forms of treatment, but still there are areas of tumor which are active. So we do plaque radiotherapy for these patients and you can see that the tumors nicely regress after plaque radiotherapy. Here is another example, where the tumor is active after multiple forms of treatment we again did radiotherapy for this patient and the tumor nicely regressed with radiotherapy.

Now it can also we use for subretinal seeds such as this where the subretinal seeds are present in the periphery not responding to cryotherapy in such cases we can took lock and you can see that the tumor nicely regresses after radiation treatment in such cases. Now last coming to enucleation. Now enucleation is performed when the tumor is very advanced and there is no extraocular extension of the tumor. So that is one thing to remember that whenever there is extraocular extension of the tumor please do not do primary enucleation. It has to be done only when the tumor is limited to the eye. Now the technique of enucleation is the shown in this video. So first and eyelids specular miss applied and if needed a small canthotomy and cantholyssis can be done if you feel that there is not enough space to do enucleation then set 360 degrees peritomy is done save as much as conjunctiva as possible. And then tenotomy is done you open up the tenon’s on all four quadrants and once that is done then the extraocular muscles of who this is media. So we always start with the muscle which is closest to the limbus that’s the medial rectus. So first attraction suture is placed with the any suture it can be absorbable or non-absorbable and then about 4 to 5 millimeters away from this suture we put that track that suture. This we use absorbable suture and then the muscle is cut in between. So this is done for in the order of first the medial rectus then the inferior rectus, then the later rectus and the superior rectus based on the distance of these muscles from the limbus.

So now are the three muscle — two muscles have been cut the third all the four recti muscles have been cut. And then the oblique muscle, this is the superior oblique. Now this muscle we simply cut it we do not reattached and this is the inferior oblique muscle and same thing even for the inferior oblique muscle we do not reattach the muscle, so we simply cut the muscle. Once this is done the globus relaxed out of the globe the optic nervous drummed till the apex and then the optic nerve should be cut in one single cut. No hesitance cut should be given and then the globus removed. Once this is done we always examine the globe to see there is any extraocular extension, the length of the optic nerve. And then this is the posterior tenon’s would be whole posterior tenon’s and put an adequate sized implant in the intraconal space. Then the posterior tenon’s is suture within absorbable suture where here we are losing a 6-0 Vicryl suture. The posterior tenon’s is sutured well and once the posterior tenon’s is sutured here comes the important step where we will do the myoconjunctival technique.

For this the extraocular muscles that the tack sutures that are there for the extraocular muscles. These are exteriorized. So these are extraocular muscle sutures where we have putting free needle and then bringing them out via the conjunctiva at the fornices where we will be attaching the muscles there. And then the anterior tenon’s is then closed after the anterior tenon’s is closed and then we close the conjunctiva. So basically three it is — three layer closures. First is the posterior tenon’s, second is the anterior tenon’s and then third is the conjunctiva. So that’s the conjunctiva be closed. And once the conjunctiva is closed then it is important to place a conformer. So that’s the conformer which is been placed in the eye because if we do not place a conformer correctly then putting prosthesis for the patient is going to be difficult. And then we close the eyelid by doing a suture tarsorrhaphy which is removed after one week. This is the suture tarsorrhaphy that is being done. So that’s what we do for very advanced tumors.

Now what we do for such tumors where there is a extraocular extension. As I mentioned whenever the tumor is extending outside the eye please do not do enucleation or exenteration as a primary procedure. You have to first chemo reduced and then do the procedure. So the protocol that is used for tumors which have extended beyond the orbit is this. What is shown here? That is first give six cycles of high-dose chemotherapy and then you’ll see that the globe will become Phthisical and then you go ahead and do enucleation of that eye followed by external beam radiotherapy where you deliver about 35 to 40 grey of radiation to the socket. And then complete six more cycles of high-dose chemotherapy. So in total, we are going to give 12 cycles of high-dose chemotherapy and sandwich treatment of enucleation and external beam radiotherapy is done in between. This is how we treat whenever there is extraocular extension of the tumor. Now here is an example, where you can see that the tumor is extending into the optic nerve and after chemotherapy this is what happens when the globe has become Phthisical and even the optic nerve looks much tenon when compared to what it was before. And at this stage you go ahead and do enucleation and radiation and then complete another six cycles of chemotherapy.

Here is the next case where there is obvious extraocular extension that is present look at what happens after six cycles of chemotherapy. You can see that the globe has become nicely Phthisical which where you can go ahead and remove the eye and then follow it up with radiation and for this six cycles of chemotherapy. And it has dramatic effect even such cases where there is extensive extraocular extension you can see that the — here again the larger the tumor better is the effect where it just shrinks even after the first cycle itself you can see the changes. And one if after chemotherapy there is still extraocular extension only then you do orbital exenteration. So 99% of the cases even if the eye needs to be removed enucleation is sufficient you do not need orbital exenteration. Orbital exenteration is only done if there is residual tumor is the extraocular space in spite of chemotherapy. And as I mentioned please do not do primary enucleation or exenteration in such cases.

And after like enucleation and then you go ahead and do a customized ocular prosthesis like in this case where the customized ocular prosthesis. This is can be placed after six weeks of enucleation in such cases. So that is how we manage the cases of retinoblastoma. So with this I end my talk. I think we have sufficient time for questions. I’ll be happy to take any questions.

Adedayo Adio: And thank consanguinity and retinoblastoma. What do you think about consanguinity and retinoblastoma?

Swathi Kaliki: Yes. So the consang – whenever it is consanguineous marriages it results in autosomal recessive diseases, but retinoblastoma is an autosomal dominant transmission. So consanguinity really shouldn’t influence the transmission for retinoblastoma it’s just that if there is a family history of retinoblastoma then, of course, because it is autosomal dominant transmission then the risk of transmission is has higher 50%. So the first question for second time intravenous chemo for recurrent or resistant tumor, do you same VC regime or change regiment?

Swathi Kaliki: Yes. So unfortunately for retinoblastoma we do not have an ineffective second line chemotherapy drugs. We see that’s Vincristine and [indiscernible] [00:44:24] carboplatin are the drugs which have been shown to be effective RB cases. So in these cases if there is tumor recurrence after completion of chemotherapy you can give second round of the same VC drugs. The other drugs really they do — cyclophosphamide, of course, can be used, but these three drugs are more effective. So if VC drugs do not help then we have to think of intraarterial chemotherapy I understand that intraarterial chemotherapy maybe a challenge in many countries. In such cases then changing to high dose chemotherapy is another option.

Now the next question –

Adedayo Adio: What about intrathecal chemo?

Swathi Kaliki: Yes. Intrathecal chemotherapy we used to do whenever there is intracranial extension that is when the CSF metastasis has already occurred. We used to do intrathecal chemotherapy in these cases, but the mortality rate is extremely high once it has gone into the CNS. Whatever treatment we do it’s the mortality is like no happens. But of course, we can for long life in these cases by giving intrathecal chemotherapy. So intrathecal chemotherapy is reserved for cases where there is intracranial extension. Okay. So the next question is, can you tell differential diagnosis of Leukocoria? So there is a whole list of differential for Leukocoria the most common being Coats disease. So you have to rule out Coats disease. There will be lots of exudation that will be present and there will be retina – peripheral retinal telangiectasia. So that helps us in the diagnosis of Coats disease. The ROP obviously will not have an intraocular mass calcification whereas in retinoblastoma there will be an intraocular mass.

And then the other differentials can be familial exudative vitreoretinopathy that can occur this again you have thoroughly examine the eye whereby FEVR obviously is bilateral and though families may also have it. So all these kind of help you to differentiate retinoblastoma from other conditions causing Leukocoria. Okay, the third question is, in case of routine fundus examination of child with squint any specific things to look out or rule out RB. So whenever we are seeing the child with squint. Fundus examination when you do you have to look for if there is any tumor intraocular tumor that is present. Most of the cases it should not be difficult because — whenever there is a squint because of the retinoblastoma because a tumor is present in the posterior pole. So it is really easy to diagnose the case of retinoblastoma whenever it is presenting with squinted just needs fund examination. If necessary I think we should not hesitate to take the child under anesthesia and examine the child.

Adedayo Adio: Yes.

Swathi Kaliki: The next question is, are there any contraindications for intravitreal chemotheraphy? Yes, intravitreal chemotherapy it helps mainly for the vitreous seeds. It is not a replacement for intravenous chemotherapy because it is not much helpful for a solid tumor. Though it may have some effect on the solid tumor and subretinal seeds, but intravitreal chemotherapy is mainly for vitreous seeds. Now the other contraindication is that if it is diffusive, if the eyes completely filled with vitreous seeds where there is no area aware. There are no vitreous seeds it is not safe to going with the needle. So you need to have at least clock hour where there are no vitreous seeds for going and inject the chemotherapy into the eye. So that was about the contraindications for intravitreal chemo.

The next question is, histopathology reported tumor extension 218 millimeters of 21 millimeters of optic nerve. Would you advise high-dose or standard chemotherapy as a child was classified as intraocular disease. Yes. So if the optic nerve transaction is free, which is what I understand it is because you have put us that the optic nerve was stamp was 21 millimeter which is very good. And the optic nerve extension was 18 millimeters which means that the optic nerve cut end it’s free of tumor. In such cases, you can give standard dose chemotherapy six cycles is sufficient. If there was other optic nerve cut end is involved or of if there is extraocular extrascleral extension that is if the outer layers of the sclera are involved. Then you have to treated as which 12 cycles of high-dose chemo and also radiation. But otherwise, you do not need the radiation and 12 cycles of chemo.

The next question is, any experience with prophylactic external beam radiotherapy to regressed D or E residual eye to prevent recurrence? Yes. We do not give prophylactic external beam radiotherapy but yes, there has been at least one publication where they have given chemotherapy and prophylactic EBRD and they have shown that the chances of tumor recurrence is low. But in this day and age, it is always better to avoid external beam radiotherapy whenever possible. So we do not give external beam radiotherapy unless like it is really required as in — if there is extraocular extension of the tumor or if it is the only eye and — all other forms of treatment have failed only then we give external beam radiotherapy otherwise we do not.

The next question is, what do we do for unilateral retinoblastoma group D with vitreous seeding? We do not have mortality such as Melphalan or topotecan intravitreal. Okay. So when the intravitreal option is not available then I think, of course, we have then the limited choices of only intravenous chemotherapy. But having said that I think I don’t know how difficult it has to get Melphalan is maybe a little difficult to get but topotecan should be easy to procure. So if you can get hold of topotecan then I think you can start giving intravitreal, but as I said you have to be well worse with the technique and do it the correct way. So as not cause any hydrogenic complications in these patients. But intravitreal is just not possible then I think the only modality of the treatment that can be tried as intravenous chemotherapy.

Okay, the next question is how do we determine whether would be start intraarterial or systemic chemotherapy? Yes. If it is bilateral tumor then it is better to give intravenous chemotherapy, if it is unilateral tumor then you can always give an option of intravenous or intraarterial chemotherapy. Intraarterial chemotherapy is a very good option as a primary treatment if it is a unilateral disease. The next question is if a patient has RB in one eye how should we screen the other eye, how often and for how many years? Okay. So the standard protocol that we follow is. The first year, like, whenever we see the patient first, if we are giving chemotherapy we see the patient every three weeks. After completion of chemotherapy and tumor has completely regressed then we see the patient once in three months in the first year, once in four months the second year, once in six months a third year and thereafter, we see the patient once a year for life. So we always explain to the patient that the follow for RB is very important. We have to even if the other eye is normal. We still have to examine the eye, but if you have the facility to do genetic testing, and if you know that it is germline mutation then probably you do not need lifelong follow-up.

If it is germline mutation you need lifelong follow-up because you have to also monitor them for second cancers. But if it is somatic mutation it is not a germline mutation in such cases you can examine the child till 5 years of age and thereafter you really don’t have to examine if it is a somatic mutation. What are the investigations to be done before and in the course of the chemotherapy and your experience with side effects of this chemotherapy? Okay the investigations that we do offered every patient of retinoblastoma is orbital imaging preferably MRI should be done because CT again causes radiation exposure. So MRI is preferable, if you do not have access to MRI then CT should be done. The reason that why do we do CT is especially if it is germline mutation we have to rule out pinealoblastoma [00:53:11]. So that is where — that is why CT is important.

Now during chemotherapy it is just the blood investigations that are require we do not need any imaging. Just the blood investigations, just to see if they have pancytopenia investigations would be needed. The side effects for with chemotherapy, yes, they do for side effects, but these are — it is important to counsel the parents that these are temporarily, these are present only when the child is getting chemotherapy and after completion of chemotherapy. The child — the children will do okay. So the side effects, of course, these are the common side effects like hair loss, vomiting, weight loss and the child not able to eat properly metallic taste. All these are the common side effects that we see and they — we have to just monitor the patients. And of course, the pancytopenia may occur and they may require repeated blood transfusions, but they generally do after — well after chemotherapy. It is extremely rare though there have been side effect of like no leukemia that that has been reported, but these are very, very rare side effects.

Can intravitreal chemotherapy itself cause vitreous seeding during injection? That’s a next question. So if the intravitreal chemotherapy is done in the right technique it will not cause seeding, so that is why knowing the technique are please important before the technique has is started. Okay, the next question is where do you attach extraocular muscles after enucleation? So the extraocular muscles if you’re doing the myoconjunctival technique. The extraocular muscles are attached to the conjunctiva. So you saw that there will be tack sutures, the tack sutures are taken out through the conjunctiva and you tied them. So you tied to the conjunctival fornices. The next question is, I have a patient with bilateral RB right eye is advance stage and I planned to do enucleation after two cycles of chemo. Left eye has stage B tumor, but measures more than 3 millimeters. It’s about 10 millimeters situated in inferiorly which focal treatment should be attempted cryo or TTT.

Okay. So that if you’re doing enucleation for one eye after two cycles of chemo. Yes, the one important point here is that if chemotherapy is started before enucleation, please make sure to complete six cycles of chemotherapy. That means if say you’re doing two cycles of chemotherapy before enucleation please complete the remaining four cycles even after enucleation. Even if you’re, like, the histopathology does not show high-risk features because the histopathology that you get after chemotherapy will not give the true picture and that is why it is important to complete the six cycles of chemotherapy. Then about the second part of the question whether to use TTT or cryo it depends on the exact location of the tumor. If it is present in the anterior portion then you use cryotherapy if it is present in the equator or the posterior pole you use TTT. Okay, the next question is, can retinoblastoma occurring another child from parents who are not relevant? Father has EBV and same when wife was pregnant. If it is a germline mutation then the sibling does have a chance, but otherwise no, it doesn’t.

Now in case — the next question is, in case of orbital inflammation is it necessary to give systemic particles steroid to relieve inflammation? Yes, so if the patient has orbital pseudocellulitis then we give 48 hours of intravenous steroids to these patients, we do not have to give antibiotics just give steroids. The inflammation reduces and then you go ahead with the routine treatment of retinoblastoma. So the next question is, is chemotherapy management in conjunction with oncologists? Yes, so always the medical oncology should be part of your team. So I think RB management it requires a team of ophthalmologist, a medical oncologist and the radiation oncologist whenever it possible. So they should be part of your team as well. The next question is, what is the survival rate of a child with intracranial extension? Yes, in our, like, practice it’s the mortality rate is almost certain in all cases who had intracranial extension. The only with treatment we may possibly delay the death, but we may not be able to prevent death. So that is why it is important to diagnose the cases early so that we do not get the cases when there is already extraocular, when there is intracranial extension.

A child with intraocular disease, the survival rate is almost 95%. Our child with extraocular disease, the survival rate is about 70%. A child with the intracranial disease, the survival rate is less than 5%. That’s the reality. So one some the intracranial extension is there high chance of death. Okay, the next question is, can you tell us more about anterior chamber RB without the posterior segment mass? Yes, so there is a variant called as anterior retinoblastoma where there is the patient presence with pseudohypopyon and there would be tumor that would be present in the scenery, in the iris area. This could be because of the — like, the development of the eye there could be the abnormal cells with the mutation that maybe present in this area while the retinal cells are normal. So there will not be retinal tumor, but there would be pseudohypopyon. So that is why whenever you see is pseudohypopyon in a white eye that means if the patient has pseudohypopyon without any conjunctival congestion always keep in — and if it is a child always keep in mind that it could be retinoblastoma.

If there is pseudohypopyon and there is conjunctival congestion had other science of endophthalmitis then, of course, it could be endophthalmitis. But if it is white eye and pseudohypopyon please rule out retinoblastoma and how do you rule out. This can be done by you can just do a FNAC from the pseudohypopyon. You do anterior chamber tap. Do it in a clear corner — through the clear cornea and once you do the tap, you do cryotherapy at the sight of where — at the sight of needle entry. Just so that if there are tumor cells it is taken care of cryotherapy. And these cells that you have taken from the anterior chamber, please send it for cytology and if it confirms the diagnosis of retinoblastoma then you have to treat it as retinoblastoma where you may have to give systemic chemotherapy or sometimes enucleate the eye or sometimes do plaque radiotherapy. If not if it is just infective cause then of course, you treated us endophthalmitis.

The next question is, how many cases of retinoblastoma in your country and what do you do for early diagnosis? Yes, so the estimate has shown that there are about 1000 to 1500 the new cases of retinoblastoma every year in India. At LVPEI we see about 250 to 300 cases a year. A lot of work has gone into increasing awareness about retinoblastoma, increasing awareness among general public by using the mass communication methods like newspapers and TV, radio and we also do activities to involve the public. We also do retinoblastoma awareness run, which kind of, like, gets people involved in such activities and we educate the school teachers, the pediatrician. So I think it’s a lot of effort that needs to be putting to increase awareness about retinoblastoma, like, I may talk to you about very good globe salvage rates and very good survival rates. But unless, there is good awareness about retinoblastoma the cases they do not come in to us in early stages then it becomes very difficult to treat such cases. So I think the first step always has to be about increasing awareness of retinoblastoma.

Adedayo Adio: And thank you so much Swathi. Sure we can call you next time?

Swathi Kaliki: Sure.

Adedayo Adio: If you want to talk about it. Never stop talking about retinoblastoma because it’s always there with us.

Swathi Kaliki: Yes.

Adedayo Adio: And we have many pictures from all over the world. And I’m so happy that Swathi was able to join us. Thank you much, Swathi.

December 6, 2020

Last Updated: October 31, 2022

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