David H. Abramson, MD: Leaps in Retinoblastoma Treatment in the Span of One Career

abramson-david

To watch a video of the lecture, search for SUNY Downstate on iTunes University.

Lecture given at the annual Alpha Omega Alpha Honor Society lecture and dinner, March 22, 2016, funded by the Downstate Alumni Association. The speaker was David H. Abramson, MD, FACS, Chief, Opthalmic Oncology Service, Sloan Kettering, Professor of Ophthalmology atWeill-Cornell Medical.

 

AOA – Alpha Omega Alpha Honor
Annual Lecture: Ocular Oncology Update, David H. Abramson, MD, FACS
Chief, Ophthalmic Oncology Service
Memorial Sloan Kettering Cancer Center
Professor of Ophthalmology, Weill Cornell Medical School
SUNY Downstate – Ophthalmology Lecture, transcript

Douglas Lazzaro, MD: What is Alpha Omega Apha? It’s a professional medical organization, actually the only one in the United States, that recognizes and advocates for excellence and scholarship and the highest ideals in the profession of medicine.

AOA was started in 1902, the first chapter in the United States, and currently 133 chapters exist for US medical schools. Downstate was Chapter 49, started in 1948. There are numerous categories one can be elected into, into AOA, as a student, as a Junior AOA, and a Senior AOA, as a house staff member, based on the size of the institution. Here at Downstate, we can have up to six house staff. Up to two alumni can be elected, up to two faculty members. There’s one honorary faculty elected every year, and then there’s a charter member of a new chapter.

What’s the mission statement of AOA? It’s dedicated that, in the profession of medicine, we will improve care by recognizing high educational achievement. You all have done that. We honor gifted teaching, by the way the faculty, in particular, the honorary faculty member is selected by the AOA students. It encouragements the development of leaders in academia and the community, supports the ideals of humanism, and promotes service to others. Even though healthcare is changing radically year by year, these are all things that you can take in your careers for the next thirty and forty years.

You can go onto the AOA website that tells you all the categories of elected positions. There are 57 Nobel laureates. Downstate had one in 1998, Dr. Robert Furchgott, for his work with nitric oxide. He was the AOA faculty member in 1967. I had the honor of having him as my pharmacology teacher. After tonight, going back to the 1940s, we will have had more than 2,200 members. By the way, you all have been nominated, but to complete the process, you will have to connect with the AOA national society, send in your dues, to be an official member of AOA.

Now, some words on our speaker today. Dr. David Abramson is a tenured professor of pediatrics and ophthalmology at the Weill Cornell Medical School, currently running the largest ocular oncology service in the United States, and the largest retinoblastoma service in the world. He actually is the founder of the ocular oncology service at Memorial Sloan Kettering after serving many years, doing similar service at Cornell. He’s a graduate of Albert Einstein Medical School, resident of ophthalmology at New York-Presbyterian. He’s published over 400 books, chapters and original articles, and over 340 peer-reviewed articles. He’s the editor of the American Academy of Ophthalmology’s instruction book on ophthalmic oncology, and he’s delivered more than 400 lectures, worldwide.

He’s received awards from all over the United States and beyond, including the Swiss Ophthalmological Society, the Association for Research in Vision, the Hellen Keller Society, a lot of teaching awards, really, really, a great teacher, and I think you’ll enjoy his lecture. He’s received the honor award, and the senior honor award, and the lifetime honor award from the American College of Ophthalmology.

He’s publishing constantly, and improving the field. When I was a resident in ophthalmology, most of the eyes that had retinoblastoma were enucleated.  Currently, under Dr. Abramson’s leadership, only 5% of these eyes currently get enucleated. These are some of the recent articles. He and his team are single-handedly changing the way this devastating disease is managed. So, without further ado, Dr. David Abramson, it’s an honor to have you give the AOA lecture.

Dr. Abramson: Thank you, my friend, Doug. Congratulations, to all of you, it truly is a huge honor, and something you will carry with you, the rest of your lives. I salute you. I’m thinking about my comments, and I think I should be giving you wisdom, since I graduated from medical school almost 50 years ago.

And then I was thinking, well, I don’t have that much wisdom, so it would be a very, very short talk. And you know, when I finished medical school, I didn’t know how much about medicine I understood. When I finished my internship, I thought I had some level of competency. When I finished my residency, I thought, I’m pretty close to the top. When I finished my fellowship, I was convinced I knew everything there was to know.

So, what I’d like to do is take you through the changes that have occurred since I finished my fellowship to now. Many of these, I’ve done, but so have many in the field. To give you a clue about how far you can go in your career, from what you think is the pinnacle of knowledge, to realize that it’s just a pimple on the surface of knowledge.

I have no financial interests at all, but I think at this point I have to declare that I do have a relationship with Downstate. It’s not that both my parents grew up in Brooklyn. It’s not that I and two brothers and father went to Brooklyn Tech, but my older brother, Allen, recently stepped down as the chair of EMT tech at Long Island North Shore-Jewish, is a graduate of the medical school here.

I am going to talk about the off-label use of drugs. You know, it’s remarkable, that we have no chemotherapy drugs that are FDA-approved for children. Everything you do is off-label.

Retinoblastoma is the most common primary cancer to affect the eyes of children worldwide. It’s a relatively rare cancer, and it’s actually not the most common cancer to affect the eyes of children. Retinoblastoma is on your left, and on your right is the most common cancer to affect the eye of children, and that is leukemia. So, depending on your institution, it is between the fourth and seventh most common pediatric cancer. There might be a slight increase in survival, but it is a cancer that affects young children. And perhaps about 10% of all children in the first year of life who develop cancer have retinoblastoma. Now, the incidence of retinoblastoma is exactly the same, worldwide, independent of who you are, where you live, what your environment is, but the incidence of melanomas of the eye, which occur in adults, is very much related to ethnicity. As a result of that, in the United States, we have about four times as many melanomas as retinoblastomas, because we have so many people of European origin.

But throughout the rest of the world, retinoblastoma is actually the most common form of cancer that occurs in the eye of children or adults. There are about 300 cases a year in the United States, making it rare. Almost all the children in the US present with the disease in the eye, which is important, which you will see in a moment. Boys and girls are the same, right and left eye are the same. In 12% of the time, there’s a family history, someone else has retinoblastoma. This is a clue that almost 100 years ago there was a gene involved. It can present unilaterally or bilaterally. When it presents, it presents like this so called leukocorially, white pupillary reflex.

It is the cancer success story of the 20th century. We have gone in 100 years, which is not when I finished medical school, to now, from 95% of children dying in the US to more than 95% of children surviving. It is, in all of pediatric oncology, the cancer with the highest cure rate. It was not that when I finished my fellowship.  Worldwide, at the present time, it’s still a devastating disease because 50% of the children who get this worldwide die. In the United States, survival in all centers is over 95%. Doug mentioned that the center I run over at Memorial is the largest by far in the world, and the oldest. And our present survival rate is actually over 99%. And, remarkably, 90% of these children have 20/20 vision in at least one eye.

In fact, the most common cause of death of children with retinoblastoma is not retinoblastoma, it is their subsequent, so called “second” malignancy related to their gene and environment. If you would ask, “Why is that 50% of the children in the world die?” Your immediate response would be, “Well, they don’t have the resources or facilities you have at Memorial Sloan Kettering.” But the reason is very simple. Children who are brought in, worldwide, are sometimes brought in like this, with very advanced disease, but are more commonly brought in and told, to cure the cancer, all you have to do is remove the eye. It’s an operation I’ve done, and Doug has done, but around the world it’s an operation that is unacceptable in most societies. So the child is seen, correctly diagnosed, goes home and is never treated. They die because they’re not treated. The treatment, which is available, and curative, they do not accept.

This is not a simple medical problem. This is a social, this is a cultural problem. In the entire continent of Africa, there is not one country with a survival rate that is even as high as 50%.

Now retinoblastoma has some very curious genetics behind it, and I suspect you’ve had this in more than one course. It is the first tumor suppressor gene that was ever cloned in 1986, and it curiously develops in two different forms: one, we’ll call it “genetic,” and the other, we’ll call it “non-genetic.” We’ll get back to that in a moment.

The retinoblastoma is a gene on chromosome 13, with 200,000 base pairs and 27 exons. It is a gene all of us have functioning, all the time. It’s a cell cycle inhibitor so it is a gene, if you will, that is built into human cells so that those cells don’t have uncontrolled division and develop cancer. It is the loss of this normal gene that gives you the cancer. So, on the simple level, it’s an autosomal dominant gene but it’s a tumor suppressor on the molecular level.

So let’s briefly go through the two forms. In the genetic form, the first mutation happens either in the sperm or the egg, so that there is a hit, there’s a defect in chromosome 13 in every cell of the body. Now, that defect has to occur in the sperm or the egg. It would be most interesting to see the future generation tell me, how many of you think that occurs in the sperm? Okay, how many of you think it’s most commonly in the egg? (Not everyone votes.) Is there something else in Brooklyn I don’t know about?

So, it’s actually more than 95% of the time found in the sperm; which is true about many genetic diseases, so this is when I point to the men in the room and say, “Your biological clocks are ticking.” So, the first mutation occurs, and if there’s a second mutation, you lose the protein, you lose the cell-cycle control, and you develop retinoblastoma. But there are other consequences of this. Your gametes, the child, now have one haplotype that’s affected. So, you’ve got a 50% chance of passing this on to your children. It’s an autosomal dominant.

Because you have one of the most important chromosome gene defects known to give cancer, you are at risk for cancers, through life; so called “second” cancers. And, because every cell in the body is affected, it is likely you will get multiple tumors, including multiple in the eyes, and retinoblastoma is, in fact, in both eyes, 30% of the time.

The second form, nothing wrong with the sperm or the egg, you don’t pass it on, you don’t have second cancers, and just one cell in the retina of one eye, when it gets that second hit, will develop retinoblastoma and, characteristically, one tumor in one eye.

So, as I mention, I thought I would, for fun, go through ten major shifts we have undergone in the treatment of retinoblastoma management since I finished my fellowship. The first is, the introduction of PGD. How many of you even know what PGD is? Okay. I’ll tell you about PGD. We were the first to do it for retinoblastoma, but not the first to do it. PGD stands for preimplantation genetic diagnosis, so it is an assisted reproductive technique. In one sense it is very simple. It is in vitro fertilization but, if you wait three days – in three days, you’re an eight-cell embryo. We go ahead and remove one cell. Now, you’re a seven-cell embryo. Seven-cell embryos develop quite normally.

With nested PCR techniques, you can say whether this embryo has the retinoblastoma gene or not. It takes about an hour and a half in the lab. You then implant the embryo or embryos that have mom’s genes and dad’s genes, you haven’t added a gene, you haven’t taken away the gene, you’ve pre-selected the embryo that doesn’t have the gene defect.

This is what we did for the first case that was done for retinoblastoma, done by us in 2003. I decided to go through the alphabet to find at least one example for every letter of PGD that’s been done for genetic diseases. It’s now been done for large numbers of genetic diseases. The first family that was done in the world was done for my patients. This is a child that, many years ago, had bilateral retinoblastoma, grew up, had normal vision in one eye, got married years later, had a child who had bilateral retinoblastoma. There was a 50/50 chance. That child went on and developed a second cancer, a brain tumor, pineal tumor. They liked mom’s genes, they liked dad’s genes, they were not so crazy about the retinoblastoma gene. So we did PGD, and this is the child at birth, perfectly normal eyes, and actually, ultimately, in this family, three of these four children were born with PGD, all looking like each other, because they’re brothers and sisters, three of them don’t have the retinoblastoma gene, the one does. She’s gone on and gotten a third cancer.

The introduction to PGD is major. When I finished my fellowship, there was not one survival of metastatic retinoblastoma in the world. Not one. Not even a case report. One-hundred percent of those children died. We introduced some protocols that are now used worldwide, and in all centers adopting these protocols, more than 75% of these children survive. They still die, we don’t salvage all of them, but I’ve seen, from the end of my fellowship, go from zero to 75%. That’s a big step. Similarly, these children are at risk for what is called trilateral retinoblastoma, the so called “third eye,” the pineal gland. They go on to develop cancers in the pineal gland, which often kill you.

When I finished my fellowship, we just described trilateral retinoblastoma, it wasn’t even known. There were no survivors of this disease at all. Now, worldwide, with protocols we introduced, about a third of these children are surviving. Again, that may not sound good, but when you’re coming from zero percent and you’re a family, that is a step up.

Now, during my residency, when we saw a child with retinoblastoma, we did X-rays routinely to look for calcification because retinoblastoma calcifies in the eye.  When CT scans were introduced in the early 70s, we switched to CT. It was obviously more elegant. But then we’ve come to recognize that CT scans in children are something you really, really want to avoid. This is the alert sent out by the National Institute of Health in 2003 on the web, pointing out that CT scans, especially in children, contribute to the development of subsequent cancers. Figures published by the NIH, those that are interested in this, we can talk and argue, point out that 2.2% of all deaths in the United States are from diagnostic radiation. This year in the United States, there will be more X-ray procedures on humans, than there are humans in the United States.

And rarely do the people who have X-ray procedures, CT scans or whatever, have it only once. So, abandoning CT is something we’ve done. We no longer do CTs. During my fellowship, and residency, I learned about radiation for retinoblastoma. Retinoblastoma is one of the very few solid cancers that can be cured with radiation alone. That’s a powerful statement. An entire generation of children worldwide were treated with external beam radiation, they were cured, their eyes were saved, their vision was saved and they lived.

I wrote an entire book on radiation and retinoblastoma and, as you mentioned, I’m tenured in radiation oncology, and we haven’t used it in ten years. And the reason why we haven’t used it in ten years is we realized that, long term, the children with this RB1 defect are exquisitely sensitive to the damaging effects of radiation. And so the exact treatment that allowed them to live, to save their eyes and vision, shortened their lives because of the cancers we induced.

So, when I finished my fellowship, I was an expert on radiation, but knew that, over the years, we’d develop better and better radiation techniques. I had no idea that I’d be the one responsible for it being abandoned in the world, but I am.

When radiation was abandoned, everyone decided, well, if radiation is bad, then chemotherapy must be good, right? It certainly had shorter follow-up, and everything with shorter follow-up looks better. So, systemic chemotherapy for retinoblastoma was introduced. You know, unfortunately, systemic chemotherapy rarely causes a cure for a solid cancer. And, in fact, it doesn’t cure retinoblastoma, but it does cause it to shrink, and if it gets small enough, you can laser it and cure it. But there are significant problems with the systemic chemotherapy in children. There are deaths reported from the chemotherapy in China. Ten percent of children given systemic chemotherapy die from the chemotherapy alone. Obviously, they have transfusions, fever and nutropenia, permanent hearing loss from Carboplatin, and they too develop second cancers, so-called “secondary AML,” mostly induced by the topoisomerase inhibitors.

As Doug mentioned, when he was a resident, retinoblastoma was treated by the removal by one or both eyes. It’s a very good treatment for the cancer, it’s not such a great treatment for the eye, and certainly isn’t a good treatment for vision. And so you’ll hear, very shortly, about the technique I introduced so that we don’t have to do as many enucleations. And, in fact, we are now treating eyes with very advanced disease that, years ago, I and everyone else would have removed. Not only that, but using the same treatments, we have enabled us from removing, just ten years ago, 95 % of the eyes in unilateral blastoma, to only about five percent.

Now, if you want to go into something where you can make a difference, please figure out how to screen for cancer, because the previous generation has done a lousy job.  The most common cause of death in the United States is rapidly becoming cancer, as you know, as our disease management as gotten better and better, or its outcomes have gotten better and better. And we have increasing numbers of people living, and increasing numbers with cancer. You know it’s coming, but the screening has been very disappointing. In pediatrics, the only cancer pediatricians are required to screen for is retinoblastoma, even though it’s not the most common cancer. So, we don’t pick up cancer any earlier today than we did when I was a medical student. We’re better at treating it, but we’re not picking it up any earlier.

We’ve been interested in this for the second cancers because the children from conception have a gene that is ticking, waiting to give them multiple cancers. And we’ve instituted a screening program, and published on this, and our data would suggest that the screening program that we have not only picks up on it earlier, which is simple, but actually prolongs life and doesn’t just have, so called, lead time bias. I think that’s an important development.

Now, when we give systemic chemotherapy, it always causes a response, as it does in most cancers, and almost never cures the cancer. And why is that? That bothered me for years. Think about phase 1 trials. What you do in phase 1 trials is determine, basically, what kills 50% of animals, humans, whatever you’re studying. Then you take that dose and decrease it, because you really can’t have a treatment that kills 50% of your patients can you? Or can you? And you go down in the dose. So you use a dose that is toxic, but a toxic that we can handle, that doesn’t kill your patient, or doesn’t often kill your patient. That makes no sense. That guarantees that you’ll fail. Why would you ever think that a cancer cell is more susceptible to chemotherapy? The way they got to be a cancer cell is that they’re devious in a variety of mechanisms and can survive, not dying. So you’re doomed by that.

But wait. If you give a dose that kills the patient, you’ll kill the cancer. All right. There’s a little problem with that. I understand that. But the point is, that’s how high you have to go in the dose to kill a cancer. Maybe even higher. You say, “Thank you very much, you taught me how to cure cancer – kill my patients.” Very good. So, I wondered one day if we could deliver a dose so high that that concentration would kill the cancer, but the exposure to the patient would be so low, it wouldn’t make the patient sick. Could we put a catheter in the groin of babies, pass it up through the abdomen, bypassing the heart, go through the abdominal aorta, thoracic aorta, into the internal carotid artery, on that side … And then, could I go – and now I’m injecting to see exactly where we’re going, and could I pass a catheter into the ophthalmic artery? The ophthalmic artery is 900 microns. It’s pretty thin. It’s like Doug’s cornea that he operates on. It’s actually the size of angel hair pasta when it’s dry. I have no financial relationship with angel hair pasta.

If I put that catheter directly into that blood vessel remotely, I could deliver an extremely high concentration in an extremely small volume. So here we are going up in the internal carotid artery I’m going to go up to the first major branch of the internal carotid artery, which is the ophthalmic artery. It’s not the first branch of the internal carotid artery. No one had been able to do this, ever. Obviously, I wasn’t the first person to think of this. They couldn’t do this because the ophthalmic artery does kind of an abrupt, right-hand turn. Kind of like some of the streets here in Brooklyn. You’re driving and the next thing, you want to go that way (he gestures sharply to the right).

So, what we did was develop a technique where you go above, and it’s a flow-directed catheter so when I get to the ophthalmic artery, it’s going to pop in. Pop. And now I inject dye, and I’m in the ophthalmic artery. Yea, you can do that. When you do that, you can show the ophthalmic artery. And here, you’re actually seeing the eye and the branches. And as we do that, this is the kind of angiogram you see of the eye with all of the blood vessels that you memorized for exams.

Now, I have what I call a “parentheses,” here. I’ve had the opportunity to write a chapter for the newest Gray’s Anatomy. When you do that, you don’t have a lot of original work, but you do add some things. And this is the drawing from Gray’s Anatomy. This anatomy, we’ve now done 1,600 angiograms we have never seen in a human. Nonetheless, it’s the way you’ll pass the exams and get to the boards, but we’ve yet to see a human that has this. But it’s not that simple, because, the ophthalmic artery, though it is very small, has laminar flow, and the ophthalmic artery itself has branches that go to the muscle, the lid and the eye. So, if you inject directly into the ophthalmic artery, it will go down the center of the ophthalmic artery, and not get into the eyeball.

So what we realized we had to do is create eddy currents, so we actually physically push once a minute for 30 minutes with a push that creates these currents and now they’ll get to the sidewall and into the eye. The largest branch of the ophthalmic artery is not to the eye. You’d think it is, wouldn’t you? The largest branch of the ophthalmic artery is actually – doesn’t anyone know this? Now, it’s been awhile since you had anatomy, right? The largest branch of the ophthalmic artery actually goes to the supratrochlear artery, which supplies the upper inner part of the orbit onto the lid. Here it is. And that’s why, in these children, sometimes they’ll have this hyperemic area because we injected it in the eye. Can you see some of the lashes are lost? Because the supratrochlear artery is supplying that, and it’s all transient. At least it’s telling you you’re in the right place.

So in May 2006, after my IRB was approved, we did our first patient, and this was our first patient. Scheduled for an enucleation, I think you can appreciate that this eye is largely filled with cancer, total retinal detachment, the vessels that you see are on the surface of the retina, which is detached behind the lens. There’s a little bit where there’s no cancer. This is an eye that is appropriate to take out.

We did it. We had no animal experiments before to tell us what dose, we chose the drugs and waited three weeks. And three weeks later, the cancer was almost completely gone. We realized, boy, we are on to something. Since then, there are more than 200 publications on this technique, most of them ours.  More than 45 countries in the world have come to us, and we’ve trained them on how to do it. Interestingly, more than half of them are in developing nations. Remember I said the main cause of death is children not being treated. But even in countries where you’d be shocked to think that medical care couldn’t do this, they can do this, and there, the children can come once or twice for this treatment, and don’t have to have blood transfusions, they don’t have complications, so it’s actually being adopted in developing nations.

By 2014, which is eight years after I did the first, the survey, in the world, showed that this treatment that I introduced is the main treatment for children with unilateral retinoblastoma. We’ve learned it can be done worldwide, we learned that it can save eyes that were previously enucleated. We’ve learned that for very advanced eyes, we can save most of the eyes. This is what you asked me earlier, Doug. This is our experience, published lately, showing our experience between 2006 and 2009, then, 2010 and 2014 for very advanced eyes. And doing the same technique, but simply getting smarter.

We’ve moved the curve up so that 95% of these eyes are saved. Some of these results are so good, they’re hard to believe. So here’s an eye largely filled with tumor, an ultrasound showing the vitreous completely filled with tumor. One treatment, three weeks later, the tumor is completely calcified, flattened down, calcific here, just about gone. One treatment, one drug.

So, these very advanced eyes, before and after, are nothing less than dramatic. With total retinal detachment, the retina settles down. Now, I mentioned earlier that the systemic chemotherapy causes tumors to shrink, but doesn’t cure them. What do you do in cancer when you do a treatment and you have regrowth?

Unfortunately, that’s common in cancer, and rarely do you have a patient survive that. The reason is, you’ve done the most potent, appropriate treatment in the first-line treatment. Second-line treatment is second line because it doesn’t work very well. But actually, we’ve been able to salvage about three quarters of the eyes that have failed conventional treatment, offering them a treatment that never existed.

Same for subretinal seeds. Vitreous seed populates the vitreous and grows like crazy, but it has no blood supply, and has been very difficult to defeat because they don’t respond to anything.  Here’s an eye before and after treatment with intra-arterial chemotherapy, it’s extremely effective for this. Now, I was taught, in my residency, so were you Doug, that if you have a retinal detachment that’s there for more than – some people say hours, some people say a day or two – that even if you get it back, surgically, you never regain vision. And that’s definitely true, unfortunately, in adults. And that’s why retinal detachment is a semi-emergent procedure for ophthalmic surgeons. So, when we had children like this, with total retinal detachment, we said to the families, we’ll save the eye, but this retina has been detached for weeks, maybe months, we really have no hope for vision. The family said, “Well, at least, if you can save the eye,” but 30% of these eyes, this is the ERG tracing, have regained vision. Eyes with total detached retinas, with total blindness, the exact indication for removing a human eye. Hopeless eye. But that was hopeless when I was in your seat. Not hopeless. Now I’m here (indicating podium).

Money. Deans care about money, don’t they? Well, one way or another. It’s nice to have new treatments but, you know, some of our new treatments for cancer are thousands of times more expensive than the old treatments, and people question whether that increased money is truly worth it. So I decided to look into this. Two-thirds of the money you spend in treating childhood cancer is not treating the childhood cancer, it’s treating the complications caused by treating the cancer. It’s a huge amount of money. These children don’t have ports. These children don’t develop fever/neutropenia, or need transfusions. We compared the costs at Memorial Sloan Kettering of the two treatments we’ve had, and then the same study was repeated in Argentina, and in Chile, and this treatment, which is more expensive, per day, is half the price of the standard treatment.

Well, are we compromising lives by trying to save these eyes? That’s a very good question. So, just about three months ago, we got together with the three largest centers in the world, Argentina, Philadelphia and Switzerland, to look at our collective results, and out of 634 cases that had been treated up to that point, there was one death. So, clearly, we’re not increasing the chance of patients dying.

Well, it obviously avoids the side effects of chemotherapy and radiation, but it does something very interesting. Years ago, I was intrigued and published extensively on the observation that, with time, in children with retinoblastoma, new tumors develop – remember they’re genetically primed, every cell in the body is affected – and, with time, even if you cure tumors in the back of the eye, within a few months, they’ll develop tumors in the mid-part of the eye and, a few months later, in the periphery of the eye. And that’s something we’ve all dealt with, and published extensively.

And it’s common, if at birth, or in the first months of life, you have retinoblastoma in an eye, 96% of the time you’ll develop a new tumor. It varies with age. By six months it’s 50%, and overall, in the world it’s 25-50%, and at Memorial, previously published, it’s about 53%. So commonly, these children develop new tumors, and when people ask me, since I’m the one who wrote about this, I always said, well, the retina develops from the optic nerve out, cell division, Thymidine, however you want to do it, ends more at the posterior pole than it does in the periphery, so it’s those dividing cells at the end which ultimately get the second hit and develop cancer. I said that. I wrote it many times. I got some awards for it. Nobody ever questioned it. Of course, I was wrong.

When we began to do the intra-arterial one day, I realized, we’re not seeing any of the new tumors. This is something I treated every week of my life for thirty years. I took me about a year to realize, I wasn’t seeing them. Why wasn’t I seeing them? What was wrong with my explanation?

So, in 2015 we published a very nice paper in Nature on the cell of origin for retinoblastoma to be a cone precursor. Then we realized that there is no cell division in the human retina after birth. In fact, cell division during the third trimester. And we realized that the molecular events that occur are such that all these retinoblastomas form between 26 and 28 weeks intrauterine. On a molecular level, they form. Now, the children at birth may not have any visible tumors in the eye, but they’re there. And what the intra-arterial is doing is treating these tiny tumors that are not visible ophthalmoscopically, but are visible, if you will, on a molecular level. So, it’s not preventing cancer, it’s treating tumors that were there all along. It’s an interesting observation.

Now, we’ve broken two golden rules of cancer. When you go to break the golden rules of cancer, I strongly suggest you get tenured before you do it. The first is, don’t use a single agent, drug, for chemotherapy. Why? Because you develop resistance. No doubt about that. In the conventional doses that you give intravenously, you cause tumors to shrink. But if you only use one drug, it will come back with a vengeance. You will regret it. So, when I started treating these children with single agent … a drug first used in the 1950s, so it’s not a new drug, people said, Dummy, don’t you know that single agent leads to resistance? Yea, but intravenous chemotherapy is like a gentle rainstorm. You get wet, it’s a little messy, some side effects. But the intra-arterial chemotherapy is like a tsunami. If you give a does that is 100 to 1,000 times what kills humans, you kill all the cells. You don’t have to worry about resistance. There are no cells to give resistance. So, this is the first major time that single agent chemotherapy for solid cancers has worked. It has worked before, and, historically, the first person to ever do this at the NIH, for choriocarcenoma, when she first did it, and had survival, was fired from the NIH.

The second, I don’t understand, but we’ve broken the rule. If you treat a patient with cancer, with some modality, and the cancer then regrows, you say, “It didn’t work well enough,” right? Therefore, the next time you treat shouldn’t be that same treatment. It makes no sense. When we talk about resistance, we talk about all kinds of molecular mechanisms. And so we have a golden rule, if it didn’t work the first time, don’t do it. But of course, we’re not going to do it a second time, because that treatment’s not that good.

So, we have children, we have a reoccurrence rate that’s about 10%, and with those children, we went back and treated them the same way, with the exact same drug, same dose, and 90% of those eyes have been saved. We published on that. It’s now been done in Philadelphia, done and published from Switzerland, the other large centers. I don’t really understand why this works, but we now have years of experience with this. It’s quite dramatic. There’s something wrong with our understanding. Fortunately, we didn’t pay attention to what we thought we knew. Overall, we’ve done it more than 1,600 times.

And finally, the other advance that was inconceivable to me, at the end of my fellowship, was the idea of injecting chemotherapy directly into the eye. This is something people have tried over the years. The concern is we know that if you do operations on children with retinoblastoma and enter the eye, a cataract operation, glaucoma operation, a retinal detachment operation, in all of these, it’s been reported, that through that tiny opening, the cancer cells come out, the cancer grows and the children dies.

So, it is a large no-no, to do this. But we’re doing it. Frances Munier from Switzerland introduced modifications of the technique, and we then modified his technique. We do an electro-retinogram, there’s a softening of the eye, so when the needle goes in, the likelihood of fluid coming out is less. Under sterile conditions, it’s a very small needle, a 33-gauge needle, right into the eye, and before removing it, that is, the needle, we freeze where the needle is, so there is no hole in the eye because it’s just ice. And this is the kind of result you can get from vitreous seeds, this cloud. Vitreous seed, gone. These balls of vitreous seed, going away and, ultimately, gone. These recurrent seas of vitreous seeds, disappearing.

Originally Frances thought you needed weekly injections, between eight and 17. We now do them monthly, and the average child is only getting two or three. They get .072 CCs. We’re getting down to minimalism.

It has some toxicity. We have published on the safety of this. We have washed all of our needles and looked at them to see if there were cells, and published a series of 200 consecutive needle samples and there were none. We washed the surface of the eye, collected the effluvient, there were no cells in 200 consecutive series also. So these are ten shifts, some of them absolutely something I was told I should never do, when I was in your position. All of which have helped humans. I look at you and I think, my goodness, what you’re going to do in the future. I hope to be there for part of it. Thank you, very much.

 


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