Transcript
Good afternoon. Actually, our hospital's Spine Tumor Board just finished 2:00 Wednesday. We also have weekly tumor boards. I will elude that at our slide here. Just to show how we are surviving, I think you're surviving the same like this. This is Metro Detroit, how competitive it is. Its radius is about less than 20 miles. You have everything on the market here. When you extend it 25 to 30 miles, you have some more coming up in CyberKnife.
CyberKnife is coming off here too. And we are setting one more Novalis Tx radiosurgery center in our West Bloomfield clinic. So it is a very competitive market. And with that competitive market, we've been thriving quite well since the inception of Novalis 2001. Our brain radiosurgery volume has been increasing. Our spine radiosurgery volume also increasing in other sites. So, so far, we've approached about 2000 radiosurgery procedures and about 600 spine radiosurgeries.
And since the inception, we went ahead and planned all these studies. So we did a lot of different things, phase 1, phase 2, and our Spine Tumor Board study from 2004. We also did a lot of physics studies and also radiobiology studies, especially spinal cord tolerance and spinal cord radiobiology and mitigation of radiation effects in the spinal cord. This laboratory study is also ongoing very actively. So in this study, I'm going to concentrate more on spinal cord compressions, which will lead to RTOG and hopefully, multicenter studies.
When you look at spine metastases treatment, there is steroid, external beam radiation therapy, surgery, sometimes decompressive surgery, or sometimes so-called 360-degree surgical resection and more recently vertebroplasty has been used. I'm not going to go over all these details of pros and cons, but these are available.
Now, spine radiosurgery accuracy precision have been all well documented. This is our scheme of rationale of initial phase 2 study for solitary spine metastases or involving two contiguous segments. And we use the radiosurgery, those 12 to now 20 gray. It has been as a dose escalation paradigm. It's not a random choose of your doses and endpoints obviously pain and neurological improvement and radiographic tumor control. We documented early on with rapid pain relief after radiosurgery for solitary spine metastasis. Your pain score, 1 to 10 drops rapidly within about two-week time period. Median time to pain relief goes about 10 to 14 days.
So I now say...very confidently tell the patients that you will have pain relief within about 10 or 2 weeks time period, within that time. And pain relief has been very durable. Treating [SP] spine had more than 80% pain relief up to about a year or longer. Throughout the radiosurgery trials we've been defining the tumor volume and target volume very carefully and consistently. We made the three different scenarios, metastasis involving mostly vertebral body or sometimes a little more posteriorly pedicle or lamina or sometimes just a posterior element only.
We treated all these patients just like this, the entire vertebral body, not just tumor itself, entire vertebral body including both pedicles just like this. When there is a little more extensive involvement, sometimes you can go a little more posteriorly or entire vertical bone can be treated too. And when there is a posture element only, you can treat posterior element only. Many people ask me, "Why do you do that?" When you look at the ossification process, this compartment and this compartment ossify separately. So I believe that there is some kind of anatomical barrier in between and our clinical results shows that too.
Throughout the time we also documented spinal cord tolerance does very carefully. This is according to the dose-escalation paradigm. We use 8 gray, 10 gray, and 14, and 16, 18 gray here. This line is 14 gray or less. This pink line is 14, yellow, 16, blue, 18 gray line. So far on this dose volume histogram, cord dose, and cord volume percentage, we feel very comfortable with the so-called 10 gray, 10% cord volume provided that cord volume is defined as six millimeters above and below the target volume. Because this radiosurgery dose fall off...I didn't show the slides but radiosurgery dose fall off from 90% to 50% percent is about five millimeters. So, we felt that this is good enough.
When you actually look at Isodose curve diagram, our prescription line has been always 90% to document... That was chosen to document this spinal cord dose. Always prescription line 90% and dose fall-off occurs from this 90% to 50% line five millimeters. When you blow up this area, it goes like this. Prescription line is 90% and dose fall-off occurs about five millimeters.
Most of the fibers here carry...most of them carry sensory fibers and lateral cortical spinal tract is here, anterior is here. Even though anterior cortical spinal tract is severed, you do not get motor defect. So we did not have any complications so far at all except one case that was also published in that paper. So based on this, now our RTOG is going to finalize this week about this protocol, RTOG 0631 phase 2 study of single-dose radiosurgery for solitary spine metastases. We are going to use 16 gray or higher, and follow-up information will include BPI and clinical and neuro examinations and imaging studies.
By the way, some patient of a non-primary had bone metastases like this, radiosurgery 16 gray. Somehow this patient had bone reformation with time, more osteoblastic changes. You don't see this all the time, but this is one example of it. Now, let's move to spinal cord compression. So far, what I showed you is spine metastasis, bone metastasis. Spinal cord compression is different spinal emergency, oncological emergency of the spine metastasis. So in this case, breast cancer, circumferential epidural compression, and spinal cord is being squeezed. This patient was treated at 16 gray. After about six weeks or so, you see the epidural area opening up. CSF space is well flowing. There is a little bit of residual enhancement.
This is how we do for spine radiosurgeries. For epidural compression, you will include epidural lesion, and paraspinal lesion if there is anything, and you also include entire virtual body. That's our target volume, no expansions allowed. And the spinal cord is defined as six millimeters above and below the target volume. And this analysis is in 67 patients, follow up of 6.4 months. And radiosurgery dose was 14 to 20 gray as a dose escalation paradigm. And spinal cord tolerance has been the same.
This is a tumor response radiographically based on the MRI follow-ups. Complete response occurs 27% at two months. We had MRI scans two months, four months, six...every two months. Complete response 27%. More than 80% volume reduction occurs, 14%. And meaningful volume reduction occurs in majority of the patients. And in general, 80% of the patients get some sort of epidural decompression. Remember, even one-millimeter decompression could be meaningful in this type of patients. And stable tumor, 15%. Radiographic progression also occurred in 6% of the patients. So average the volume reduction is about 65% volume reduction.
We also looked at then how much thecal sac opening occurs. This is pre-radiosurgery thecal sac compression, post radiosurgery thecal sac area. We have information of epidural tumor size at the level the most compression is occurring, and at that level, thecal sac area. And as you'll see here, epidural size decreases significantly and thecal sac area opens up significantly too. When you calculate to a percentage level which is more familiar to us, thecal sac patency improved from 56% to 77%. All these were statistically significant. These were all measured by neuroradiologist who was blinded to the clinical status.
So to summarize, this is epidural compression. The spinal cord is squished to one part. Basically, about 65% to 70% volume reduction occurs. This opens up the thecal sac. In real case, 56% thecal sac patency improves to 77%. Therefore, I think we can call this decompressive radiosurgery as opposed to decompressive surgery. Then what about neurological outcome? The one I showed you is radiographic outcome. This is a neurological outcome, which is not 100% perfect because some of these patients enrolled to hospice and refused to come to examinations. But, in patients who had a neuro exam before radiosurgery, who had no deficit, who are intact, remained intact in 86% of the patients, 14% progressed.
In patients who had a neurological deficit, 61% improved, 61% became normal, 10% improved, 10% stable, 19% progressed neurologically. So in these patients who had deficit, 80% of the patients either became normal, improved, or stable. Then many people will think, "Oh, 33% of the patients become...progressed." But when you look at all the series, it's 9 patients out of 67 patients, which is 13% of these patients. These patients might have been benefited with a front surgical resection rather than radiosurgery.
Everybody's aware of this Patchell's data. Surgery plus radiation versus radiation alone. This is external beam radiation. And they reported very good results. But these patients on this data, everybody should have surgery. But our radiosurgery experience now tells us that, no, not everybody will need surgery. Majority of the people who are ambulatory to start with, may be treated with radiosurgery, not the open spine surgeries.
So, to answer some of the questions up front, I listed the patients, the nine patients who had neurological progressions. Out of those, I would like to highlight these five cases. Five patients out of nine actually underwent surgical resection. Two of those patients showed no evidence of tumor, but there was some epidural so-called scarring effects, epidural compression on MRI scan. Three patients had a tumor present, just like Dr. Angelov's slide just right ago.
So to summarize, treatment of spine metastasis, we have these armamentariums here. Now we can add radiosurgery which has rapid pain relief, rapid neurological relief, spinal cord decompression occurs. This is non-invasive, convenience. This is just one treatment. Nothing's more convenient than this. No hospital stay necessary. And bone marrow sparing also occurs too because only the involved spine level is treated. But this radiosurgery cannot correct compression fractures or mechanical spine instabilities. These things should be corrected with surgically or maybe possibly with kyphoplasty or vertebroplasties.
Based on all this, we now have grading systems in our hospital. We have two components. One is radiographic grading system, and the other is neurological grading system. Radiographic grading system, one is only spine bone involvement. There is no canal compromise. Two is epidural tumor only, no dural compromise. Three is dura or arachnoid involvement. Four is frank spinal cord compressions. We need neurological grading system because radiographic rating system does not predict or does not reflect a patient's neurological status.
Everybody will understand that not everyone stage 4 radiographic spinal cord compression will have paralysis, right? Therefore, neurological grading system is also necessary to be used to combine. A is no abnormality, B is focal minor symptoms such as pain or radiculopathy. This is important. C is functional paralysis. Muscle strength four over five, either lower extremities or upper extremities, or root involvement. When the muscle is functional, we grade C. When muscle is non-functional, basically a three over five or less will be D. Plegic is E.
So we use both systems together. And this is very effective in treatment decisions and response evaluations too. Treatment decision for example IIa, epidural compression is present, no neurological symptoms, definitely radiosurgery in our hospital. No question about this. There is no argument anymore. But if IVd, rapid...especially with rapid neurological deterioration surgery, immediate surgery. And this is very useful for response evaluations. I think we will have to talk about more here, but given the time, I will just pass. And there is a session of spine radiosurgery tomorrow. I'll be happy to answer all these questions too.
I'd like to acknowledge our colleagues, our oncology team in our radiation oncology, medical oncology, neuro-oncology, and surgical oncology team, neurosurgery, and orthopedics. And Jack has been phenomenal on this implementation of radiosurgery here, and our physicist who does all the planning and calculation works. And our radiosurgery coordinator who's here too, and she does all the deliveries and everything. Thank you.
CyberKnife is coming off here too. And we are setting one more Novalis Tx radiosurgery center in our West Bloomfield clinic. So it is a very competitive market. And with that competitive market, we've been thriving quite well since the inception of Novalis 2001. Our brain radiosurgery volume has been increasing. Our spine radiosurgery volume also increasing in other sites. So, so far, we've approached about 2000 radiosurgery procedures and about 600 spine radiosurgeries.
And since the inception, we went ahead and planned all these studies. So we did a lot of different things, phase 1, phase 2, and our Spine Tumor Board study from 2004. We also did a lot of physics studies and also radiobiology studies, especially spinal cord tolerance and spinal cord radiobiology and mitigation of radiation effects in the spinal cord. This laboratory study is also ongoing very actively. So in this study, I'm going to concentrate more on spinal cord compressions, which will lead to RTOG and hopefully, multicenter studies.
When you look at spine metastases treatment, there is steroid, external beam radiation therapy, surgery, sometimes decompressive surgery, or sometimes so-called 360-degree surgical resection and more recently vertebroplasty has been used. I'm not going to go over all these details of pros and cons, but these are available.
Now, spine radiosurgery accuracy precision have been all well documented. This is our scheme of rationale of initial phase 2 study for solitary spine metastases or involving two contiguous segments. And we use the radiosurgery, those 12 to now 20 gray. It has been as a dose escalation paradigm. It's not a random choose of your doses and endpoints obviously pain and neurological improvement and radiographic tumor control. We documented early on with rapid pain relief after radiosurgery for solitary spine metastasis. Your pain score, 1 to 10 drops rapidly within about two-week time period. Median time to pain relief goes about 10 to 14 days.
So I now say...very confidently tell the patients that you will have pain relief within about 10 or 2 weeks time period, within that time. And pain relief has been very durable. Treating [SP] spine had more than 80% pain relief up to about a year or longer. Throughout the radiosurgery trials we've been defining the tumor volume and target volume very carefully and consistently. We made the three different scenarios, metastasis involving mostly vertebral body or sometimes a little more posteriorly pedicle or lamina or sometimes just a posterior element only.
We treated all these patients just like this, the entire vertebral body, not just tumor itself, entire vertebral body including both pedicles just like this. When there is a little more extensive involvement, sometimes you can go a little more posteriorly or entire vertical bone can be treated too. And when there is a posture element only, you can treat posterior element only. Many people ask me, "Why do you do that?" When you look at the ossification process, this compartment and this compartment ossify separately. So I believe that there is some kind of anatomical barrier in between and our clinical results shows that too.
Throughout the time we also documented spinal cord tolerance does very carefully. This is according to the dose-escalation paradigm. We use 8 gray, 10 gray, and 14, and 16, 18 gray here. This line is 14 gray or less. This pink line is 14, yellow, 16, blue, 18 gray line. So far on this dose volume histogram, cord dose, and cord volume percentage, we feel very comfortable with the so-called 10 gray, 10% cord volume provided that cord volume is defined as six millimeters above and below the target volume. Because this radiosurgery dose fall off...I didn't show the slides but radiosurgery dose fall off from 90% to 50% percent is about five millimeters. So, we felt that this is good enough.
When you actually look at Isodose curve diagram, our prescription line has been always 90% to document... That was chosen to document this spinal cord dose. Always prescription line 90% and dose fall-off occurs from this 90% to 50% line five millimeters. When you blow up this area, it goes like this. Prescription line is 90% and dose fall-off occurs about five millimeters.
Most of the fibers here carry...most of them carry sensory fibers and lateral cortical spinal tract is here, anterior is here. Even though anterior cortical spinal tract is severed, you do not get motor defect. So we did not have any complications so far at all except one case that was also published in that paper. So based on this, now our RTOG is going to finalize this week about this protocol, RTOG 0631 phase 2 study of single-dose radiosurgery for solitary spine metastases. We are going to use 16 gray or higher, and follow-up information will include BPI and clinical and neuro examinations and imaging studies.
By the way, some patient of a non-primary had bone metastases like this, radiosurgery 16 gray. Somehow this patient had bone reformation with time, more osteoblastic changes. You don't see this all the time, but this is one example of it. Now, let's move to spinal cord compression. So far, what I showed you is spine metastasis, bone metastasis. Spinal cord compression is different spinal emergency, oncological emergency of the spine metastasis. So in this case, breast cancer, circumferential epidural compression, and spinal cord is being squeezed. This patient was treated at 16 gray. After about six weeks or so, you see the epidural area opening up. CSF space is well flowing. There is a little bit of residual enhancement.
This is how we do for spine radiosurgeries. For epidural compression, you will include epidural lesion, and paraspinal lesion if there is anything, and you also include entire virtual body. That's our target volume, no expansions allowed. And the spinal cord is defined as six millimeters above and below the target volume. And this analysis is in 67 patients, follow up of 6.4 months. And radiosurgery dose was 14 to 20 gray as a dose escalation paradigm. And spinal cord tolerance has been the same.
This is a tumor response radiographically based on the MRI follow-ups. Complete response occurs 27% at two months. We had MRI scans two months, four months, six...every two months. Complete response 27%. More than 80% volume reduction occurs, 14%. And meaningful volume reduction occurs in majority of the patients. And in general, 80% of the patients get some sort of epidural decompression. Remember, even one-millimeter decompression could be meaningful in this type of patients. And stable tumor, 15%. Radiographic progression also occurred in 6% of the patients. So average the volume reduction is about 65% volume reduction.
We also looked at then how much thecal sac opening occurs. This is pre-radiosurgery thecal sac compression, post radiosurgery thecal sac area. We have information of epidural tumor size at the level the most compression is occurring, and at that level, thecal sac area. And as you'll see here, epidural size decreases significantly and thecal sac area opens up significantly too. When you calculate to a percentage level which is more familiar to us, thecal sac patency improved from 56% to 77%. All these were statistically significant. These were all measured by neuroradiologist who was blinded to the clinical status.
So to summarize, this is epidural compression. The spinal cord is squished to one part. Basically, about 65% to 70% volume reduction occurs. This opens up the thecal sac. In real case, 56% thecal sac patency improves to 77%. Therefore, I think we can call this decompressive radiosurgery as opposed to decompressive surgery. Then what about neurological outcome? The one I showed you is radiographic outcome. This is a neurological outcome, which is not 100% perfect because some of these patients enrolled to hospice and refused to come to examinations. But, in patients who had a neuro exam before radiosurgery, who had no deficit, who are intact, remained intact in 86% of the patients, 14% progressed.
In patients who had a neurological deficit, 61% improved, 61% became normal, 10% improved, 10% stable, 19% progressed neurologically. So in these patients who had deficit, 80% of the patients either became normal, improved, or stable. Then many people will think, "Oh, 33% of the patients become...progressed." But when you look at all the series, it's 9 patients out of 67 patients, which is 13% of these patients. These patients might have been benefited with a front surgical resection rather than radiosurgery.
Everybody's aware of this Patchell's data. Surgery plus radiation versus radiation alone. This is external beam radiation. And they reported very good results. But these patients on this data, everybody should have surgery. But our radiosurgery experience now tells us that, no, not everybody will need surgery. Majority of the people who are ambulatory to start with, may be treated with radiosurgery, not the open spine surgeries.
So, to answer some of the questions up front, I listed the patients, the nine patients who had neurological progressions. Out of those, I would like to highlight these five cases. Five patients out of nine actually underwent surgical resection. Two of those patients showed no evidence of tumor, but there was some epidural so-called scarring effects, epidural compression on MRI scan. Three patients had a tumor present, just like Dr. Angelov's slide just right ago.
So to summarize, treatment of spine metastasis, we have these armamentariums here. Now we can add radiosurgery which has rapid pain relief, rapid neurological relief, spinal cord decompression occurs. This is non-invasive, convenience. This is just one treatment. Nothing's more convenient than this. No hospital stay necessary. And bone marrow sparing also occurs too because only the involved spine level is treated. But this radiosurgery cannot correct compression fractures or mechanical spine instabilities. These things should be corrected with surgically or maybe possibly with kyphoplasty or vertebroplasties.
Based on all this, we now have grading systems in our hospital. We have two components. One is radiographic grading system, and the other is neurological grading system. Radiographic grading system, one is only spine bone involvement. There is no canal compromise. Two is epidural tumor only, no dural compromise. Three is dura or arachnoid involvement. Four is frank spinal cord compressions. We need neurological grading system because radiographic rating system does not predict or does not reflect a patient's neurological status.
Everybody will understand that not everyone stage 4 radiographic spinal cord compression will have paralysis, right? Therefore, neurological grading system is also necessary to be used to combine. A is no abnormality, B is focal minor symptoms such as pain or radiculopathy. This is important. C is functional paralysis. Muscle strength four over five, either lower extremities or upper extremities, or root involvement. When the muscle is functional, we grade C. When muscle is non-functional, basically a three over five or less will be D. Plegic is E.
So we use both systems together. And this is very effective in treatment decisions and response evaluations too. Treatment decision for example IIa, epidural compression is present, no neurological symptoms, definitely radiosurgery in our hospital. No question about this. There is no argument anymore. But if IVd, rapid...especially with rapid neurological deterioration surgery, immediate surgery. And this is very useful for response evaluations. I think we will have to talk about more here, but given the time, I will just pass. And there is a session of spine radiosurgery tomorrow. I'll be happy to answer all these questions too.
I'd like to acknowledge our colleagues, our oncology team in our radiation oncology, medical oncology, neuro-oncology, and surgical oncology team, neurosurgery, and orthopedics. And Jack has been phenomenal on this implementation of radiosurgery here, and our physicist who does all the planning and calculation works. And our radiosurgery coordinator who's here too, and she does all the deliveries and everything. Thank you.