Transcript
Well, I want to welcome you to the spine tumor section of Novalis Circle, and congratulate Brainlab on a really wonderful program. My name is Josh Yamada. I'm a radiation oncologist at Memorial Sloan Kettering Cancer Center. And like I said, we really have some really amazing and wonderful faculty to learn from. And I just feel an absolute honor and privilege to share the podium with them. My job is to kind of get things going and start off, and I've been asked to talk about, in essence, what's new in the field of spine radiosurgery for metastasis, which, you know, is I think, when you think about spine SBRT, at our institution, spine SBRT was really the first image-guided SBRT program in our department. And of course, if you read "The New York Times," you know how important it is for someone from Sloan Kettering to make sure that we fully disclose everything. So, you can see all my disclosures. I'm going to count to 10, so everybody knows that I gave this slide proper time. If any reporter from "The New York Times" comes and talks to you, that you can testify that I tried to do my best to disclose any interest that I might have.
All right. Well, what is new? Certainly, there's been an exponential increase in the pure literature published domain of stereotactic radiosurgery in the spine. We now have more than 23 years of published spine experience. And now we're really going into a new era. Because there are prospective and randomized trials that are now being reported. And so this is really a golden time, I think, to be involved with spine radiosurgery. There's no question that we're learning a lot, and it's resulting in better outcomes for our patients. There are a number of randomized trials, there's a Heidelberg trial that reported on their early results in terms of quality of life. We're all eagerly anticipating the results of RTOG 0631. We'll be reporting a randomized trial, multi-institutional, international collaborative effort, and our institution randomized two SBRT fractionation schedules. And then there's Origins trial, Canadian trial, which is also recruiting very well comparing conventional fractionation to 12 gray times two spine SBRT. So, you know, I think we're really coming to a real interesting and exciting era in the field.
I just did a very quick survey of clinicaltrials.gov. And without even trying very hard, came up with 21 unique prospective trials that are spine SBRT-specific. And so there are a lot of trials going on in the United States and around the world, taking a very serious look at spine radiosurgery. And of course, this is really couched in a true oncologic revolution that we're experiencing right now. And it used to be, even a decade ago, that nobody was really interested in metastatic patients. You could not make an academic career out of studying metastasis. Well, that's absolutely completely different now. And it's really in the field of metastatic disease where some of the most exciting advances in oncology are being made. There's no question that our patients are living longer, and therefore, they are demanding treatment that is durable and matches at least their expected survival, but also has minimal impact on their quality of life. And so, I believe that we're undergoing, in how we look at our patients with spine disease, we're looking at them completely different because it's no longer, you know, give them, when I was resident it was, you know, four gray times five, and then that's it. We certainly have moved much further beyond that.
And what we can do and how we should do it has become so much more sophisticated. It really requires a multidisciplinary effort to do this well, because there are so many tools that we now have available. And it's really just too much for one physician or one discipline to manage spine disease in an optimal way. So, what I've shown here is a publication from our institution looking at the outcomes for 24 gray in a single fraction. Over 800 lesions are radiated with high-dose radiosurgery, showing that at the 24-gray dose level, we're achieving a 2% local failure rate at 48 months. And so this is very different from any kind of local control curve that we might have seen in the past, suggesting that these types of fractionation schedules that we're now able to safely deliver in the spine are ablative. This is a different type of biology.
And this other paper here, it's also from our institution looking at quality of life. And there's no question that there's increasing evidence to suggest that we can deliver treatment that is much more durable and preserves patient or improves patient quality of life, and, you know, how can you do better than a therapy that is able to do that? So, again, I really think that we're in a new era in the management of spine disease.
A lot of this has to do with the tools that are now available to us. And we have to take our hats off to our industry partners, such as Brainlab, in making these tools available and off-the-shelf. And when we first started doing spine radiosurgery at Memorial many, many years ago, over 13 years ago, we treated our first spine radiosurgery case. I remember for image guidance, we wheeled in a C-arm. And I triangulated it to the lasers inside of the treatment room. And then we had taped BBs to a piece of graph paper that was calculated for the divergence to the isocenter, and that's how we used to do image guidance. I mean, we had the wheel in a C-arm, it would take us hours to treat a patient. And now we have that capability off-the-shelf. And so the technology has made a tremendous difference.
The treatment planning tools you see in a lot of what Brainlab has to offer, the planning software, investments in imaging, and MRI imaging, particularly, I think, have been really a keynote. But also, in terms of delivery tools such as image guidance, robotic couches, and also intrafraction motion gives us the confidence to give these extremely high doses of radiation and know that we can do it safely.
Reducing the uncertainty within a millimeter. And this has really, I think, allowed anybody who's interested in doing this to be able to do this. And a common question I get is like how should I start up a radiosurgery program? I can just quickly tell you of our institutional experience, you know, we started with hypofractionation with five fractions, we went to three fractions, and to single fraction radiosurgery. What I find unfortunate is that, occasionally, there may be a program that gets very comfortable with hypofractionation, and they just can't make the jump to single fraction radiosurgery. But with this type of technology, if you're comfortable giving hypofractionated high-dose radiation and you trust your quality assurance processes, there's no reason why you shouldn't be able to safely treat patients with single-fraction radiosurgery where I think that the local control rate is going to be optimal. And this can be done in the setting of salvage radiation for patients who have had previous radiation, and challenging areas such as the cervical spine and the thoracic spine where you have esophagus and spinal cord to manage and to deal with.
One of the great benefits, of course, of technology is that, ultimately, if treatment is more effective, it's going to lower costs. And so the treatment may be more expensive up front, but more effective treatment, for example, less than 2% of local failure is going to be ultimately in the long-term for the right patient is going to be cost-effective. So, for a number of reasons, you know, we really are in an exciting era. What makes it particularly exciting is that it's not just the technology and being able to create really cool dose distributions, but it's that the biology of what we do is also unique. Classical radiobiology teaches us that increasing the shoulder of that cell survival curve results in more double-strand and more breaks and more unrepairable damage, but there's a lot more to it when you think of these very high doses of radiation. Because as I said, we believe that these doses are ablative. Hypoxia becomes less of an issue when you have an ablative therapy. When radioresistance is really a relative term and starts to lose its meaning. Because if you treat a tumor in the right way, it's not resistant.
We know that, from a mechanistic perspective, there are unique mechanisms of response. At our institution, you know, we've been drinking heavily from the Kool-Aid of endothelial apoptotic response, as an important driver of these very ablative results with radiosurgery. We know that in animal models, this happens all the time, where we get a wave of endothelial apoptosis that happens within minutes of radiosurgery. It disrupts blood flow, causes endothelial damage, which will restrict blood flow to the tumor in the long-term. But in the short-term, is an important mechanism in terms of suppressing double-strand break repair. Immunology has become a very interesting and very hot topic in oncology right now. And there's no better way to induce immune responses to rescue immune energy situations to change the microenvironment of the tumor in favor of a tumor response with immune effects, than giving high-dose radiation. So, there probably are even other mechanisms that we don't understand, but, again, I think the biology of what we're dealing with is very different from conventional fractionation.
It's necessary to have this kind of high precision and high conformality in order to make it safe. And although there are complications from radiosurgery, fortunately, severe complications are quite rare. And symptomatic vertebral body fractures, radiographic fractures, we've reported about a 39% rate of fracture. But symptomatic fractures that actually require intervention in our database is about 8% chance. Fortunately, very catastrophic complications, that's just myelopathy, are extremely rare. And in our database, out of over 800 lesions treated along the length of the spinal cord, we've had two unexplained myelopathies.
Esophageal fistula, these are all severe complications, but fortunately not very common. As our patients are living longer, they're outliving conventional palliative radiation to the spine. And probably one of the most common indications United States for spine SBRT is salvage radiation. And that's the one indication, by the way, that it's easiest to get insurance approval for, but it's extremely effective as a salvage strategy, and showing that we can repeat or even give a more aggressive course of radiation the second time around without hurting the patient. So, again, all these kinds of things are possible because of the marriage of image-guided technology, highly conformal treatment, and resulting unique biology.
So, what are some things that I see for the future? If we have time, later on, I'd love to hear what our other panelists would add to this list, but here's some things that I thought of. I think that we could see a change towards treating multiple levels of the spine with radiosurgery in the same way we've moved away from treating just one, or two, or three, or four brain metastases. Certainly, if the treatment is safe for one or two levels of the spine, shouldn't it be safe for multiple levels of the spine? So I think we may be seeing more of that in the future. We're very interested in moving away from spine metastasis as our sole targets of treatment. And because our local control rates are so good for radioresistant tumors that we're now applying stereotactic radiosurgery paradigms for the upfront primary treatment of primary tumors of the spine such as sarcomas, chordomas, and these types of tumors that are perhaps in the past not traditionally considered a radiation oncology disease. But with stereotactic radiosurgery and its ablative treatment might be a very good approach to treat spinal primary tumors.
Of course, there's increasing interest and an increasing body of literature in using spine radiosurgery to manage benign tumors in the spine such as schwannomas, and meningiomas. In our institution, we've actually just started a schwannoma clinic with the neurosurgeons, and we see patients jointly for patients who have benign schwannomas in the spine. And so I think that we're going to be able to branch out and move beyond even malignancies. And then why not just, as I said, move out of, not just metastases, not just primary tumors, but move out of malignancies altogether. And we're developing an IRB to treat chronic back pain using the same type of approach that you would for trigeminal neuralgia to try to alleviate failed back syndrome, which in the U.S. is the largest consumer of Medicare dollars in the entire healthcare system is back pain. And so, I think that, as we look forward into the future, the indications and the ways that radiosurgery in the spine can be used to help patients is just going to get bigger and bigger. So, there's a really bright future ahead, I think, in this field.
One thing that I think we could immediately do, and many people have talked about this concept in other sessions, is to move away from randomized controlled trials, and look towards prospective registry trials. This is a really interesting schematic I got from "Forbes Magazine." And this is really talking about, really make the point of how expensive randomized controlled trials are. And so, for example, AstraZeneca, this is, I think, from 2016, spent over $11.5 billion developing five drugs. I could send all my children to private school in New York City for $11 billion. That's just one drug company. It is very expensive to bring new drugs to the market. A tremendous amount of money and resources are spent on this. Not all the costs, of course, are validating in a randomized trial, but it's a big part of the cost. And registry trials are not expensive. Randomized controlled trials are very expensive. Randomized trials are still the gold standard, don't get me wrong, but because of the cost and the complexity, they're often only done by those who have a commercial interest in doing it. It takes a long time to complete and get the results. And we have to remember that randomized trials give outcomes in highly select populations.
An evidence-based approached away from randomized trials as a prospective registry trial. It's more observational and more about effectiveness than it is about efficacy. They're relatively cheap, whereas randomized trials are very expensive. Randomized trials often answer one question, registry trials can answer multiple questions. It's an unselected population as opposed to a randomized controlled trial. There are some downsides. Data quality, of course, can vary, you have to make sure you have good data to get anything meaningful out of it. It's difficult to adjust for confounders, and it's very difficult to get...it's like herding chickens, getting all the chickens together to cooperate and to do this. But I think we all agree, this is an idea whose time has come.
And certainly, in radiosurgery, I would like to suggest that that would be like job number one for us right now is to think about getting together and creating good registry database for us to answer our questions. It's an idea whose time has come. Longer and improved outcomes demand more effective palliation. And our job is to make Stage 4 cancer, if not curable, then at least a chronic illness. Technological and biologic breakthroughs favor radiosurgical approaches in the spine because of its durability and our ability to preserve quality of life. And long-term and mature prospective data is now becoming available, specifically in the realm of spine radiosurgery. And we're looking to the future, we're looking at new indications for the tools that we have to help patients in new and different ways. So, I really think that we're really in a wonderful time, and that there's plenty to be optimistic and happy about. So, thank you very much for your attention.
All right. Well, what is new? Certainly, there's been an exponential increase in the pure literature published domain of stereotactic radiosurgery in the spine. We now have more than 23 years of published spine experience. And now we're really going into a new era. Because there are prospective and randomized trials that are now being reported. And so this is really a golden time, I think, to be involved with spine radiosurgery. There's no question that we're learning a lot, and it's resulting in better outcomes for our patients. There are a number of randomized trials, there's a Heidelberg trial that reported on their early results in terms of quality of life. We're all eagerly anticipating the results of RTOG 0631. We'll be reporting a randomized trial, multi-institutional, international collaborative effort, and our institution randomized two SBRT fractionation schedules. And then there's Origins trial, Canadian trial, which is also recruiting very well comparing conventional fractionation to 12 gray times two spine SBRT. So, you know, I think we're really coming to a real interesting and exciting era in the field.
I just did a very quick survey of clinicaltrials.gov. And without even trying very hard, came up with 21 unique prospective trials that are spine SBRT-specific. And so there are a lot of trials going on in the United States and around the world, taking a very serious look at spine radiosurgery. And of course, this is really couched in a true oncologic revolution that we're experiencing right now. And it used to be, even a decade ago, that nobody was really interested in metastatic patients. You could not make an academic career out of studying metastasis. Well, that's absolutely completely different now. And it's really in the field of metastatic disease where some of the most exciting advances in oncology are being made. There's no question that our patients are living longer, and therefore, they are demanding treatment that is durable and matches at least their expected survival, but also has minimal impact on their quality of life. And so, I believe that we're undergoing, in how we look at our patients with spine disease, we're looking at them completely different because it's no longer, you know, give them, when I was resident it was, you know, four gray times five, and then that's it. We certainly have moved much further beyond that.
And what we can do and how we should do it has become so much more sophisticated. It really requires a multidisciplinary effort to do this well, because there are so many tools that we now have available. And it's really just too much for one physician or one discipline to manage spine disease in an optimal way. So, what I've shown here is a publication from our institution looking at the outcomes for 24 gray in a single fraction. Over 800 lesions are radiated with high-dose radiosurgery, showing that at the 24-gray dose level, we're achieving a 2% local failure rate at 48 months. And so this is very different from any kind of local control curve that we might have seen in the past, suggesting that these types of fractionation schedules that we're now able to safely deliver in the spine are ablative. This is a different type of biology.
And this other paper here, it's also from our institution looking at quality of life. And there's no question that there's increasing evidence to suggest that we can deliver treatment that is much more durable and preserves patient or improves patient quality of life, and, you know, how can you do better than a therapy that is able to do that? So, again, I really think that we're in a new era in the management of spine disease.
A lot of this has to do with the tools that are now available to us. And we have to take our hats off to our industry partners, such as Brainlab, in making these tools available and off-the-shelf. And when we first started doing spine radiosurgery at Memorial many, many years ago, over 13 years ago, we treated our first spine radiosurgery case. I remember for image guidance, we wheeled in a C-arm. And I triangulated it to the lasers inside of the treatment room. And then we had taped BBs to a piece of graph paper that was calculated for the divergence to the isocenter, and that's how we used to do image guidance. I mean, we had the wheel in a C-arm, it would take us hours to treat a patient. And now we have that capability off-the-shelf. And so the technology has made a tremendous difference.
The treatment planning tools you see in a lot of what Brainlab has to offer, the planning software, investments in imaging, and MRI imaging, particularly, I think, have been really a keynote. But also, in terms of delivery tools such as image guidance, robotic couches, and also intrafraction motion gives us the confidence to give these extremely high doses of radiation and know that we can do it safely.
Reducing the uncertainty within a millimeter. And this has really, I think, allowed anybody who's interested in doing this to be able to do this. And a common question I get is like how should I start up a radiosurgery program? I can just quickly tell you of our institutional experience, you know, we started with hypofractionation with five fractions, we went to three fractions, and to single fraction radiosurgery. What I find unfortunate is that, occasionally, there may be a program that gets very comfortable with hypofractionation, and they just can't make the jump to single fraction radiosurgery. But with this type of technology, if you're comfortable giving hypofractionated high-dose radiation and you trust your quality assurance processes, there's no reason why you shouldn't be able to safely treat patients with single-fraction radiosurgery where I think that the local control rate is going to be optimal. And this can be done in the setting of salvage radiation for patients who have had previous radiation, and challenging areas such as the cervical spine and the thoracic spine where you have esophagus and spinal cord to manage and to deal with.
One of the great benefits, of course, of technology is that, ultimately, if treatment is more effective, it's going to lower costs. And so the treatment may be more expensive up front, but more effective treatment, for example, less than 2% of local failure is going to be ultimately in the long-term for the right patient is going to be cost-effective. So, for a number of reasons, you know, we really are in an exciting era. What makes it particularly exciting is that it's not just the technology and being able to create really cool dose distributions, but it's that the biology of what we do is also unique. Classical radiobiology teaches us that increasing the shoulder of that cell survival curve results in more double-strand and more breaks and more unrepairable damage, but there's a lot more to it when you think of these very high doses of radiation. Because as I said, we believe that these doses are ablative. Hypoxia becomes less of an issue when you have an ablative therapy. When radioresistance is really a relative term and starts to lose its meaning. Because if you treat a tumor in the right way, it's not resistant.
We know that, from a mechanistic perspective, there are unique mechanisms of response. At our institution, you know, we've been drinking heavily from the Kool-Aid of endothelial apoptotic response, as an important driver of these very ablative results with radiosurgery. We know that in animal models, this happens all the time, where we get a wave of endothelial apoptosis that happens within minutes of radiosurgery. It disrupts blood flow, causes endothelial damage, which will restrict blood flow to the tumor in the long-term. But in the short-term, is an important mechanism in terms of suppressing double-strand break repair. Immunology has become a very interesting and very hot topic in oncology right now. And there's no better way to induce immune responses to rescue immune energy situations to change the microenvironment of the tumor in favor of a tumor response with immune effects, than giving high-dose radiation. So, there probably are even other mechanisms that we don't understand, but, again, I think the biology of what we're dealing with is very different from conventional fractionation.
It's necessary to have this kind of high precision and high conformality in order to make it safe. And although there are complications from radiosurgery, fortunately, severe complications are quite rare. And symptomatic vertebral body fractures, radiographic fractures, we've reported about a 39% rate of fracture. But symptomatic fractures that actually require intervention in our database is about 8% chance. Fortunately, very catastrophic complications, that's just myelopathy, are extremely rare. And in our database, out of over 800 lesions treated along the length of the spinal cord, we've had two unexplained myelopathies.
Esophageal fistula, these are all severe complications, but fortunately not very common. As our patients are living longer, they're outliving conventional palliative radiation to the spine. And probably one of the most common indications United States for spine SBRT is salvage radiation. And that's the one indication, by the way, that it's easiest to get insurance approval for, but it's extremely effective as a salvage strategy, and showing that we can repeat or even give a more aggressive course of radiation the second time around without hurting the patient. So, again, all these kinds of things are possible because of the marriage of image-guided technology, highly conformal treatment, and resulting unique biology.
So, what are some things that I see for the future? If we have time, later on, I'd love to hear what our other panelists would add to this list, but here's some things that I thought of. I think that we could see a change towards treating multiple levels of the spine with radiosurgery in the same way we've moved away from treating just one, or two, or three, or four brain metastases. Certainly, if the treatment is safe for one or two levels of the spine, shouldn't it be safe for multiple levels of the spine? So I think we may be seeing more of that in the future. We're very interested in moving away from spine metastasis as our sole targets of treatment. And because our local control rates are so good for radioresistant tumors that we're now applying stereotactic radiosurgery paradigms for the upfront primary treatment of primary tumors of the spine such as sarcomas, chordomas, and these types of tumors that are perhaps in the past not traditionally considered a radiation oncology disease. But with stereotactic radiosurgery and its ablative treatment might be a very good approach to treat spinal primary tumors.
Of course, there's increasing interest and an increasing body of literature in using spine radiosurgery to manage benign tumors in the spine such as schwannomas, and meningiomas. In our institution, we've actually just started a schwannoma clinic with the neurosurgeons, and we see patients jointly for patients who have benign schwannomas in the spine. And so I think that we're going to be able to branch out and move beyond even malignancies. And then why not just, as I said, move out of, not just metastases, not just primary tumors, but move out of malignancies altogether. And we're developing an IRB to treat chronic back pain using the same type of approach that you would for trigeminal neuralgia to try to alleviate failed back syndrome, which in the U.S. is the largest consumer of Medicare dollars in the entire healthcare system is back pain. And so, I think that, as we look forward into the future, the indications and the ways that radiosurgery in the spine can be used to help patients is just going to get bigger and bigger. So, there's a really bright future ahead, I think, in this field.
One thing that I think we could immediately do, and many people have talked about this concept in other sessions, is to move away from randomized controlled trials, and look towards prospective registry trials. This is a really interesting schematic I got from "Forbes Magazine." And this is really talking about, really make the point of how expensive randomized controlled trials are. And so, for example, AstraZeneca, this is, I think, from 2016, spent over $11.5 billion developing five drugs. I could send all my children to private school in New York City for $11 billion. That's just one drug company. It is very expensive to bring new drugs to the market. A tremendous amount of money and resources are spent on this. Not all the costs, of course, are validating in a randomized trial, but it's a big part of the cost. And registry trials are not expensive. Randomized controlled trials are very expensive. Randomized trials are still the gold standard, don't get me wrong, but because of the cost and the complexity, they're often only done by those who have a commercial interest in doing it. It takes a long time to complete and get the results. And we have to remember that randomized trials give outcomes in highly select populations.
An evidence-based approached away from randomized trials as a prospective registry trial. It's more observational and more about effectiveness than it is about efficacy. They're relatively cheap, whereas randomized trials are very expensive. Randomized trials often answer one question, registry trials can answer multiple questions. It's an unselected population as opposed to a randomized controlled trial. There are some downsides. Data quality, of course, can vary, you have to make sure you have good data to get anything meaningful out of it. It's difficult to adjust for confounders, and it's very difficult to get...it's like herding chickens, getting all the chickens together to cooperate and to do this. But I think we all agree, this is an idea whose time has come.
And certainly, in radiosurgery, I would like to suggest that that would be like job number one for us right now is to think about getting together and creating good registry database for us to answer our questions. It's an idea whose time has come. Longer and improved outcomes demand more effective palliation. And our job is to make Stage 4 cancer, if not curable, then at least a chronic illness. Technological and biologic breakthroughs favor radiosurgical approaches in the spine because of its durability and our ability to preserve quality of life. And long-term and mature prospective data is now becoming available, specifically in the realm of spine radiosurgery. And we're looking to the future, we're looking at new indications for the tools that we have to help patients in new and different ways. So, I really think that we're really in a wonderful time, and that there's plenty to be optimistic and happy about. So, thank you very much for your attention.