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All right, thank you very much, Josh. It's an honor to be up here today and to speak with and share the stage with such wonderful speakers. I'm going to share with you some of our experience at MD Anderson, with a focus on patterns of failure following SRS, and how some of the data that we've collected has shaped and modified our treatment planning. These are my disclosures, we have some research support from foundation and industry. So as Josh and Arjun have already mentioned, with the development of IMRT, and advanced image guidance tools, as well as non-invasive immobilization, spine motive surgery is developed into a valuable tool to treat patients with spinal metastases.
At my institution, we have three primary indications to treat patients with spinal SBRT. One is, if they have radio resistant disease, two, if they have algal metastatic or algal progressive disease, and/or three in the salvage setting after they failed a prior course of radiation. In the United States, these indications have made their way into the most recent NCCN guidelines. So if you get pushback from insurance companies in the United States, please be aware that in version 1.2018, you can quote that to support your case. Clearly, prospective multidisciplinary assessment and a robust QA program are essential for ensuring safe and efficacious treatment.
So we've run prospective clinical trials at MD Anderson. Eric Chang, led this effort beginning in 2002. And similar to how things started at Memorial Sloan Kettering, we started doing multi-fraction radiosurgery, first five fractions and then three fractions all on a phase one, phase two clinical trial before moving on to single fraction radiosurgery designed for patients with radiation naive disease. And clearly, the trials demonstrated excellent local control rates range from 75% to 90%, excellent neurologic preservation rates and a very low risk of myelopathy. But the focus of my talk today is on the treatment failures and how we might be able to optimize our treatment planning to minimize the risk of treatment failure.
So Dr. Chang did publish our early experience, based on the phase one, two trials. This is a cohort of patients treated with multi fraction radiosurgery, 74 spinal sites were analyzed for these patterns of failure analysis, and there were 17 failures out of the 74 spinal metastases. Two thirds of the failures were due to under dosing secondary to the core constraint. So as the program started, we had a very conservative core constraint Dmax of 9 or 10 gy, even with multifractal treatment. And most of the failures occurred in the epidural space for the posterior vertebral body. Second most common cause of failure was inadequate coverage of the posterior elements. And subsequent to this work as well as other works, a consensus CTP guideline was published, which I'll show in the next couple of slides.
And then with fractionated treatment, we noted that there were a few infield failures of radio resistant disease. So I'll talk a little bit more about that as well. So, first, I'm going to talk about the adjacent at-risk bone marrow within the vertebrae. So we learned pretty quickly and early on in the experience, it's not only at MD Anderson, but multiple groups published on this, that if we didn't contour our CTD adequately and include at-risk bone marrow that patients were certainly at risk of developing a marginal failure within the bone. And so the international spine radiosurgery consortium provided this study in which they described a consensus guideline on defining a CTV. So as we can see, each vertebrae is divided into six anatomic segments, the vertebral body, the pedicles, the lateral elements, and the spinus process.
And experts from multiple institutions were given 10 cases and count word of how they feel a CTV should be developed based on where the gross disease was located. And so this is here for reference. Please use this paper. As you're defining your CTV in a nutshell, if gross diseases involving an anatomic segment, the rest of that anatomic segment has to be included in your CTV, and then we go one anatomic echelon beyond what's grossly involved and include that in our CTV definition. At MD Anderson, we then perform planning using a simultaneous integrated boost technique.
And so we identify the GTV based on CT and MRI imaging, and then we develop a CTV based on those consensus guidelines. If there's any paraspinal or soft tissue extensive disease, we have a five millimeter CTV margin on that. And then we do not use a PTV for either structure. Again, this is an institution specific approach, other institutions may use a PTV, a PRV, and certainly single target prescription. So the second pattern of failure, which indeed is the most common pattern of failure in spinal radiosurgery is under dosing due to critical neural tissue constraints. So I'm going to touch upon that.
Here's a patient of mine that I treated several years ago, who had algal metastatic melanoma and spinal disease centered on T 11 with a significant epidural component. And we'll discuss how we approach this case from a planning perspective. Before we do that, I want to reiterate the so called Bilski scale, the MESCC scale that Arjun had mentioned, in which we can describe in more detail to degree of epidural disease and the degree of core compression. When we discuss cases in our multidisciplinary spine tumor board, we always discuss epidural cases in terms of this scale, and it really does impact our management and conversation regarding the role of separation surgery.
And so in this particular case, we see disease entering the epidural space and displacing the cord laterally, but there's CSF still present. And so we graded this as a grade two. And grade two diseases, certainly a particular challenge for spinal radiosurgery requires a multidisciplinary evaluation and treatment plan. How can we deliver adequate dose to the radio resistant disease in the epidural space while still sparing the cord of toxicity? Do we have goals for that? Do we have specific quantitative goals for that? How much dose should we aim on delivering to the GTV here, and what data we have to support those symmetric goals for GTV in cord?
So we performed this study in 2015, looking at 332 sites treated with a variety of Fractionation schemes. And we focused on the 44 local recurrences and did an exhaustive analysis looking at various dosimetric parameters. And the single most significant dosimetric parameter which correlated with local control was GTV Dmin. And we noted that if we could achieve a GTV Dmin, BED of 33.4 gy, which means 14 gy a single fraction or 21 gy in three fractions, if we could achieve that, then we had higher one year local control rates, notably 94% at one year. And so this has now entered into our planning directive and we use this as a treatment goal.
Spinal Cord myelopathy has been a rare event of spinal radiosurgery, as you've already heard. Given limited clinical data, precise dose tolerance of the human spinal cord to SSRS has not been established. But there have been efforts to try to glean this information. This is one study published by Jim Graham and colleagues in which they looked at DVH data from Stanford's earlier experience in spinal SBRT, created a DVH risk map to give us so called low risk and high risk spinal cord dose tolerances. As you may be able to see for a Dmax, 13 gy are thought to correlate with a less than 1% risk of birth myelopathy and 14 gy with a less than 3%. Josh's group published recently their clinical data using a Dmax of 14 gy, clearly showing that the risk of myelopathy was less than 1%.
So here's the dilemma for high grade cord epidural disease. So with the Cord Dmax that we accept is generally between 10 and 14 gy. However, GTV, the minimum goal for optimal local control is 14 to 15 gy, and we assume a penumbra of roughly 2 gy or 10% per millimeter. We're clearly going to undergoes a gross disease if we're treating one C or higher with single modality. So, what are the strategies that can be done? Arjun already presented a lot of the work with separation surgery and mass surgery, and that clearly is the optimal approach, the multi modality approach to treat patients with high grade epidural disease with some form of separation, followed by stereotactic radiosurgery and those who would otherwise be candidates.
In the study out of Sloan Kettering, they reported a one year local control rate of 84%. There was a median two week hospital stay at our institution. Dr. Claudio Tatsui is pioneering and investigating a novel approach to this problem. He is looking at the role of laser interstitial thermo therapy in patients with epidural disease as a substitute for separation surgery. He's done under Mr. Thermal guidance in the operating room. We have a prospective clinical trial open right now enrolling to this treatment paradigm in which patients get thermal ablation and we follow that up with spine radiosurgery. What if patients are inoperable?
So this is a particularly high risk cohort of patients, those that have high grade epidural disease, yet they're not surgical candidates. What do we do for them? We know that they're at high risk of local failure if we go with spinal radiosurgery alone because we know we're going to under dose disease in the epidural space, perhaps they have radio resistant disease and conventional radiotherapy is not an ideal option either. So we ran this prospective clinical trial that is currently in press with the red journal, and we enrolled patients that were at high risk based on the fact that they were inoperable and had epidural disease to this cord constraint relaxation protocol.
So, phase one protocol enrolled 36 patients, of which 32 receives spinal radiosurgery. We started out at our institutional standard of a cord Dmax of 10 gy. That was the standard when this problem opened in 2010. And the trial was designed as such that if a patient suffered a local failure, then we would escalate to the next cohort. So, 4 patients received spinal radiosurgery at 10 gy, there was a tumor progression, there was no myelopathy in the cohort, so we bounced it to 12 gy, so on and so forth, up to a maximum of 16 gy. We had a median follow up for 17 months, we didn't note any myelopathies. The one year local control rate was 89%.
And, again, this is with SSRS alone for patients with epidural disease. We certainly noted that GTV Dmin did improve as we relaxed the cord dose as one might suspect. But I will give a note of caution. Again, this is a small study, and there were only six viable patients that received a Dmax of 16 gy on this study, so the upper 95% confidence interval is 39%. So this isn't to say that 16 gy is an appropriate dose for the general population. However, we might be able to personalize our core constraint based on how high risk the patient is, and whether there are salvage options if there's a failure. So this patient that I showed before indeed was eligible and treated on the trial.
He received 16 gy to the core 2.01 CC, we did SIV techniques with 24 gy at the GTV, 16 gy to the CTV as shown here, and he had an excellent response decompression of the canal and complete pain relief. So the third thing I wanted to touch on is our third pattern of failure that we noticed on our early experience, which was infield failure. So, thought to be inadequate prescription dosing for radio resistant disease. So, how do we prescribe dose to the target? In my institution, we look at intrinsic radio resistance, prior radiation at the site of interest and the extent of disease and location of the target. And radio resistant disease, clearly there are histologies that we all agree would be considered radio resistant such as sarcoma, renal cell carcinoma, melanoma, perhaps hepatobiliary primaries.
And then, we have some data to suggest that even non small cell lung cancer and colon cancer should be included within that group. First, I want to show you the biologic dose escalation data for radio resistant diseases. So we did a secondary analysis of a prospective clinical trials, pulling out patients that had a renal cell histology that had not seen prior radiation. This is a secondary analysis of our prospective trial. So some received three fractions, some received single correction, radiosurgery. And there were about 47 patients analyze and what we saw was that those that received 24 gy in a single fraction had significantly improved local control relative to those that received other 27 gy in three fractions were 18.1.
We did control for all those metric parameters, degree of epidural disease, etc. And the 24 gy, the single fraction appear to be...was the only factor that correlated with optimal local control. And we can see that if we look at the linear quadratic formula, understanding that there's limitations using that formula for high dose per fraction stereotactic treatments, but 24.1 is equivalent to a BED 10 of 80, whereas 27 in three or 18 in one more is more similar to a BED 10 of 50. Our institutional practice then is to treat so called radiosensitive disease to either 18 in a single fraction, or 27 in three fractions.
We grouped within so called radiosensitive disease, colon cancer, non small cell lung cancer, thyroid, breast, prostate. And we analyze that cohort and saw that not all those histologies had the same outcome. In fact, those with non small cell lung cancer and colon cancer had significantly worse local control than the other histologies. And so now our current practice is to treat those histologies to 24 in a single fraction. Lastly, I'm going to touch upon the sarcoma data. There have been multiple studies published on this. Does sarcomas behave any differently? Metastatic sarcomas to the spine? There's some concern that perhaps we're at more risk for marginal failure or adjacent failure.
So we looked at our experience, 66 patients, about 42% had leiomyosarcoma. Some had prior radiation and surgery, that median follow up of 19 months, our local control was good at 81%. Clearly, biologic dose mattered. And we did notice some paraspinal failure, so our standard practice of five millimeters in the paraspinal space for a disease extending outside of the bone, we think that may not be quite enough for sarcoma. And so we're starting to use larger margins for that histology. And then Sloan Kettering published their experience of 120 spinal mets with a median follow up of 14.4 months and a linear local control of 86%.
And one of the take home messages from their study was that most spinal failures occurred more than four or five levels away. And so there wasn't an increased risk for adjacent level of failure. So to summarize strategies for optimizing local control in spinal radiosurgery, certainly appropriate contouring the target utilizing consensus guidelines is critical. And as Arjun pointed out, there are not only consensus guidelines now for the intact case, but for the postoperative cases as well.
Epidural disease is a challenge. We may incorporate GTV Dmin as a planning objective, and certainly, multidisciplinary management for these complex cases is key. And based on our institutional data, biologic dose escalation may reduce the risk of local failure for radio resistant disease. So with that, I'll stop. I'd like to acknowledge my colleagues at MD Anderson. Thank you very much.
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All right, thank you very much, Josh. It's an honor to be up here today and to speak with and share the stage with such wonderful speakers. I'm going to share with you some of our experience at MD Anderson, with a focus on patterns of failure following SRS, and how some of the data that we've collected has shaped and modified our treatment planning. These are my disclosures, we have some research support from foundation and industry. So as Josh and Arjun have already mentioned, with the development of IMRT, and advanced image guidance tools, as well as non-invasive immobilization, spine motive surgery is developed into a valuable tool to treat patients with spinal metastases.
At my institution, we have three primary indications to treat patients with spinal SBRT. One is, if they have radio resistant disease, two, if they have algal metastatic or algal progressive disease, and/or three in the salvage setting after they failed a prior course of radiation. In the United States, these indications have made their way into the most recent NCCN guidelines. So if you get pushback from insurance companies in the United States, please be aware that in version 1.2018, you can quote that to support your case. Clearly, prospective multidisciplinary assessment and a robust QA program are essential for ensuring safe and efficacious treatment.
So we've run prospective clinical trials at MD Anderson. Eric Chang, led this effort beginning in 2002. And similar to how things started at Memorial Sloan Kettering, we started doing multi-fraction radiosurgery, first five fractions and then three fractions all on a phase one, phase two clinical trial before moving on to single fraction radiosurgery designed for patients with radiation naive disease. And clearly, the trials demonstrated excellent local control rates range from 75% to 90%, excellent neurologic preservation rates and a very low risk of myelopathy. But the focus of my talk today is on the treatment failures and how we might be able to optimize our treatment planning to minimize the risk of treatment failure.
So Dr. Chang did publish our early experience, based on the phase one, two trials. This is a cohort of patients treated with multi fraction radiosurgery, 74 spinal sites were analyzed for these patterns of failure analysis, and there were 17 failures out of the 74 spinal metastases. Two thirds of the failures were due to under dosing secondary to the core constraint. So as the program started, we had a very conservative core constraint Dmax of 9 or 10 gy, even with multifractal treatment. And most of the failures occurred in the epidural space for the posterior vertebral body. Second most common cause of failure was inadequate coverage of the posterior elements. And subsequent to this work as well as other works, a consensus CTP guideline was published, which I'll show in the next couple of slides.
And then with fractionated treatment, we noted that there were a few infield failures of radio resistant disease. So I'll talk a little bit more about that as well. So, first, I'm going to talk about the adjacent at-risk bone marrow within the vertebrae. So we learned pretty quickly and early on in the experience, it's not only at MD Anderson, but multiple groups published on this, that if we didn't contour our CTD adequately and include at-risk bone marrow that patients were certainly at risk of developing a marginal failure within the bone. And so the international spine radiosurgery consortium provided this study in which they described a consensus guideline on defining a CTV. So as we can see, each vertebrae is divided into six anatomic segments, the vertebral body, the pedicles, the lateral elements, and the spinus process.
And experts from multiple institutions were given 10 cases and count word of how they feel a CTV should be developed based on where the gross disease was located. And so this is here for reference. Please use this paper. As you're defining your CTV in a nutshell, if gross diseases involving an anatomic segment, the rest of that anatomic segment has to be included in your CTV, and then we go one anatomic echelon beyond what's grossly involved and include that in our CTV definition. At MD Anderson, we then perform planning using a simultaneous integrated boost technique.
And so we identify the GTV based on CT and MRI imaging, and then we develop a CTV based on those consensus guidelines. If there's any paraspinal or soft tissue extensive disease, we have a five millimeter CTV margin on that. And then we do not use a PTV for either structure. Again, this is an institution specific approach, other institutions may use a PTV, a PRV, and certainly single target prescription. So the second pattern of failure, which indeed is the most common pattern of failure in spinal radiosurgery is under dosing due to critical neural tissue constraints. So I'm going to touch upon that.
Here's a patient of mine that I treated several years ago, who had algal metastatic melanoma and spinal disease centered on T 11 with a significant epidural component. And we'll discuss how we approach this case from a planning perspective. Before we do that, I want to reiterate the so called Bilski scale, the MESCC scale that Arjun had mentioned, in which we can describe in more detail to degree of epidural disease and the degree of core compression. When we discuss cases in our multidisciplinary spine tumor board, we always discuss epidural cases in terms of this scale, and it really does impact our management and conversation regarding the role of separation surgery.
And so in this particular case, we see disease entering the epidural space and displacing the cord laterally, but there's CSF still present. And so we graded this as a grade two. And grade two diseases, certainly a particular challenge for spinal radiosurgery requires a multidisciplinary evaluation and treatment plan. How can we deliver adequate dose to the radio resistant disease in the epidural space while still sparing the cord of toxicity? Do we have goals for that? Do we have specific quantitative goals for that? How much dose should we aim on delivering to the GTV here, and what data we have to support those symmetric goals for GTV in cord?
So we performed this study in 2015, looking at 332 sites treated with a variety of Fractionation schemes. And we focused on the 44 local recurrences and did an exhaustive analysis looking at various dosimetric parameters. And the single most significant dosimetric parameter which correlated with local control was GTV Dmin. And we noted that if we could achieve a GTV Dmin, BED of 33.4 gy, which means 14 gy a single fraction or 21 gy in three fractions, if we could achieve that, then we had higher one year local control rates, notably 94% at one year. And so this has now entered into our planning directive and we use this as a treatment goal.
Spinal Cord myelopathy has been a rare event of spinal radiosurgery, as you've already heard. Given limited clinical data, precise dose tolerance of the human spinal cord to SSRS has not been established. But there have been efforts to try to glean this information. This is one study published by Jim Graham and colleagues in which they looked at DVH data from Stanford's earlier experience in spinal SBRT, created a DVH risk map to give us so called low risk and high risk spinal cord dose tolerances. As you may be able to see for a Dmax, 13 gy are thought to correlate with a less than 1% risk of birth myelopathy and 14 gy with a less than 3%. Josh's group published recently their clinical data using a Dmax of 14 gy, clearly showing that the risk of myelopathy was less than 1%.
So here's the dilemma for high grade cord epidural disease. So with the Cord Dmax that we accept is generally between 10 and 14 gy. However, GTV, the minimum goal for optimal local control is 14 to 15 gy, and we assume a penumbra of roughly 2 gy or 10% per millimeter. We're clearly going to undergoes a gross disease if we're treating one C or higher with single modality. So, what are the strategies that can be done? Arjun already presented a lot of the work with separation surgery and mass surgery, and that clearly is the optimal approach, the multi modality approach to treat patients with high grade epidural disease with some form of separation, followed by stereotactic radiosurgery and those who would otherwise be candidates.
In the study out of Sloan Kettering, they reported a one year local control rate of 84%. There was a median two week hospital stay at our institution. Dr. Claudio Tatsui is pioneering and investigating a novel approach to this problem. He is looking at the role of laser interstitial thermo therapy in patients with epidural disease as a substitute for separation surgery. He's done under Mr. Thermal guidance in the operating room. We have a prospective clinical trial open right now enrolling to this treatment paradigm in which patients get thermal ablation and we follow that up with spine radiosurgery. What if patients are inoperable?
So this is a particularly high risk cohort of patients, those that have high grade epidural disease, yet they're not surgical candidates. What do we do for them? We know that they're at high risk of local failure if we go with spinal radiosurgery alone because we know we're going to under dose disease in the epidural space, perhaps they have radio resistant disease and conventional radiotherapy is not an ideal option either. So we ran this prospective clinical trial that is currently in press with the red journal, and we enrolled patients that were at high risk based on the fact that they were inoperable and had epidural disease to this cord constraint relaxation protocol.
So, phase one protocol enrolled 36 patients, of which 32 receives spinal radiosurgery. We started out at our institutional standard of a cord Dmax of 10 gy. That was the standard when this problem opened in 2010. And the trial was designed as such that if a patient suffered a local failure, then we would escalate to the next cohort. So, 4 patients received spinal radiosurgery at 10 gy, there was a tumor progression, there was no myelopathy in the cohort, so we bounced it to 12 gy, so on and so forth, up to a maximum of 16 gy. We had a median follow up for 17 months, we didn't note any myelopathies. The one year local control rate was 89%.
And, again, this is with SSRS alone for patients with epidural disease. We certainly noted that GTV Dmin did improve as we relaxed the cord dose as one might suspect. But I will give a note of caution. Again, this is a small study, and there were only six viable patients that received a Dmax of 16 gy on this study, so the upper 95% confidence interval is 39%. So this isn't to say that 16 gy is an appropriate dose for the general population. However, we might be able to personalize our core constraint based on how high risk the patient is, and whether there are salvage options if there's a failure. So this patient that I showed before indeed was eligible and treated on the trial.
He received 16 gy to the core 2.01 CC, we did SIV techniques with 24 gy at the GTV, 16 gy to the CTV as shown here, and he had an excellent response decompression of the canal and complete pain relief. So the third thing I wanted to touch on is our third pattern of failure that we noticed on our early experience, which was infield failure. So, thought to be inadequate prescription dosing for radio resistant disease. So, how do we prescribe dose to the target? In my institution, we look at intrinsic radio resistance, prior radiation at the site of interest and the extent of disease and location of the target. And radio resistant disease, clearly there are histologies that we all agree would be considered radio resistant such as sarcoma, renal cell carcinoma, melanoma, perhaps hepatobiliary primaries.
And then, we have some data to suggest that even non small cell lung cancer and colon cancer should be included within that group. First, I want to show you the biologic dose escalation data for radio resistant diseases. So we did a secondary analysis of a prospective clinical trials, pulling out patients that had a renal cell histology that had not seen prior radiation. This is a secondary analysis of our prospective trial. So some received three fractions, some received single correction, radiosurgery. And there were about 47 patients analyze and what we saw was that those that received 24 gy in a single fraction had significantly improved local control relative to those that received other 27 gy in three fractions were 18.1.
We did control for all those metric parameters, degree of epidural disease, etc. And the 24 gy, the single fraction appear to be...was the only factor that correlated with optimal local control. And we can see that if we look at the linear quadratic formula, understanding that there's limitations using that formula for high dose per fraction stereotactic treatments, but 24.1 is equivalent to a BED 10 of 80, whereas 27 in three or 18 in one more is more similar to a BED 10 of 50. Our institutional practice then is to treat so called radiosensitive disease to either 18 in a single fraction, or 27 in three fractions.
We grouped within so called radiosensitive disease, colon cancer, non small cell lung cancer, thyroid, breast, prostate. And we analyze that cohort and saw that not all those histologies had the same outcome. In fact, those with non small cell lung cancer and colon cancer had significantly worse local control than the other histologies. And so now our current practice is to treat those histologies to 24 in a single fraction. Lastly, I'm going to touch upon the sarcoma data. There have been multiple studies published on this. Does sarcomas behave any differently? Metastatic sarcomas to the spine? There's some concern that perhaps we're at more risk for marginal failure or adjacent failure.
So we looked at our experience, 66 patients, about 42% had leiomyosarcoma. Some had prior radiation and surgery, that median follow up of 19 months, our local control was good at 81%. Clearly, biologic dose mattered. And we did notice some paraspinal failure, so our standard practice of five millimeters in the paraspinal space for a disease extending outside of the bone, we think that may not be quite enough for sarcoma. And so we're starting to use larger margins for that histology. And then Sloan Kettering published their experience of 120 spinal mets with a median follow up of 14.4 months and a linear local control of 86%.
And one of the take home messages from their study was that most spinal failures occurred more than four or five levels away. And so there wasn't an increased risk for adjacent level of failure. So to summarize strategies for optimizing local control in spinal radiosurgery, certainly appropriate contouring the target utilizing consensus guidelines is critical. And as Arjun pointed out, there are not only consensus guidelines now for the intact case, but for the postoperative cases as well.
Epidural disease is a challenge. We may incorporate GTV Dmin as a planning objective, and certainly, multidisciplinary management for these complex cases is key. And based on our institutional data, biologic dose escalation may reduce the risk of local failure for radio resistant disease. So with that, I'll stop. I'd like to acknowledge my colleagues at MD Anderson. Thank you very much.