Transcript
Well, it's great pleasure to be here. And thank you very much for inviting me to talk to you about the clinical and technical considerations for post-operative SBRT in emerging paradigm shift. And I think Josh set the background for where I'm going to take you a little bit further in terms of where we're going. So, one indication that really wasn't explored was the issue of post-operative SBRT. And this is one that we've been very instrumental in, in terms of pushing forward as has the group at Sloan Kettering. So you see a patient like this with malignant epidural spinal cord compression, and it goes a big surgery to decompress, stabilize, and lo and behold, you've achieved your decompression, and then what happens? And the traditional norm has been to treat with conventional radiotherapy. But if you're gonna put someone through this, why would you give a palliative dose of radiation? So, we started very early on treating these patients with stereotactic radiosurgery. So, we published our first outcomes back in 2013, that was 80 patients. We've treated over 300 patients now. And when we talk about cord compression and post-op SBRT, we first have to talk about the same language of epidural disease. And one of the scales that we use is called the Bilsky scale, which is a very convenient scale. So Bilsky 3 is, no CSF, full epidural disease cord compression. Bilsky 2, still some CSF, but there is epidural disease, compressing the cord. And these have been your traditional surgical indications if they're symptomatic.
On the Bilsky 1(a), 1(b), and 1(c) have not been surgical candidates, but I'll show you how we're kind of moving that paradigm along for selected indications. So, how do we do? Well, we have like most mixed histologies, in terms of primary tumor types. And we mainly treat with 24 gray in 2 fractions or 12 gray times 2 in my institution. If you look at the pre-operative grades, 60% were high grade. And our surgeons did a good job of decompressing, but they still had about 8 patients or 10% with residual Bilsky 2 disease. Now, we had excellent local control about 80% at one year, which is very comparable to the major series. And our analysis did indicate some predictors. And this is where it was a bit exciting. First of all, the dose may matter. So, high dose one or two fraction, predominantly here with two fractions, stereotactic radiation did better than a bit more hypofractionated approach. And when you're dealing with a post-operative bed, that's hypoxic, and the environment is very hostile, maybe that high dose per fraction really does help. What we also showed was that if you downgraded patients to a zero or one versus a two, your local control was better. And this promotes us to use surgery more and more and more thoughtfully, in order to optimize the outcomes associated with stereotactic radiosurgery.
So if I have a patient like this with some low-grade Bilsky disease, like a 1(c), previous radiation then comes to you in order to treat, well, I'm gonna say, "Well, look, why don't you create some separation between the disease and the cord. And then I'll treat with stereotactic radiation because I know my outcomes are going to be better." And this is just a case of mine where she had maintained local control up to two years. And this concept of separation surgery was really coined by the Sloan Kettering group, where they talk, not only about taking out to tumor but actually going ventrally to decompress and do a full circumferential decompression. And this is something that I talk to my surgeons about. If they're gonna operate, I wanna make sure that they go interiorly, they decompress properly, and they give me a good outcome. Now, it's a challenge and it does increase the risk of complications, but there is a benefit in terms of patient local control if you are able to achieve the circumferential decompression. Now, how did the group do at Sloan Kettering? Well, they showed a reduction of pain scores and better quality of life at separation surgery, followed by radiosurgery.
Now, it's still a big operation. And in our group, we were very much more keen towards a minimally invasive approach because we don't want to put patients as I showed you who really don't have a surgical indication to undergo surgery. I mean, that is a bit of a gray zone. So, we developed a two-base technique where the surgeon goes in, this is two-base day surgery. A patient comes in at 6:00 in the morning, discharged typically at two o'clock, and he does his work through the endoscope and decompresses the spinal cord. And so this is a very elegant solution where you're not putting the patient through two to three weeks of recovery and potential complications associated with open invasive surgery. Now, what is the dosimetric impact? We've shown you some local control rates, but there is a dosimetric advantage. So, we did a planning study where we looked at the patient's pre-operative epidural disease extent, we modeled it based on the post-operative CT imaging. And we said, "Well, you know, how good were these patients do and how better off are the plans?" Well, if you look at the D min, you see a clear increase as you go from zero to 6 millimeters of separation. And that is important because the minimum dose to the tumor has been shown to be proportional to your local control rate. So, there is a gain.
Now, what was interesting to me when we did this analysis is over here, this is your BED D95. And what we showed was that, for some patients like here, 6 millimeters decompression continued to give you the gains. But for some people, they really didn't need it, their couple of millimeters was enough, and you got those gains in terms of your dosimetry with no further gains from more aggressive surgery. And what that tells us, as we saw before, is the need to develop some software tools so we can do interpretive mapping, and watch and see dosimetrically as we resect epidural disease, what the impact is on the stereotactic plan. And I would say that this is probably one of the most important areas for development in our field. Now, we've been doing this in a different way with ultrasound. So, this is actually a conventional ultrasound, and you can see here a micro-ultrasound. And we're seeing beautiful images with the micro-ultrasound that's used in the operating room. So we take the pre-op CT, the pre-op MR, we register with the micro-ultrasound, and then we watch the decompression so that we get the result that we want. So, this is work in development by Victor Yang's lab, but it really does show you that we're all moving to the right direction, using minimally invasive techniques, using the technology, and trying to resect or dissect as much of that epidural disease away from your structure to be spared.
Now, going back to post-op SBRT, well, one of the questions happen very early on, which is, what was the volume? So, if I have a patient, like this with circumferential epidural disease, or pardon me, sorry, lack of posterior epidural disease, what is the target volume? Do I just donor up the patient, or do I do something more tailored? And there was a big question in the field in terms of what to do. So, we looked at our patterns of failure analysis to determine what is the optimal CTV for these patients. So without going into the details of this analysis, because it was complex, one of the take-home messages is that the preoperative tumor location predicted for failure. So, you have to look at your pre-operative MR, understand what the epidural disease is, and at least cover that. Thereafter, it depends on how much margin you want to apply. What we do is if patient has pre-operative circumferential disease, we do a donor distribution. If somebody has more tailored anterior disease, then we do an anterior lateral or horseshoe approach so that we cover, not only the anterior but the lateral extent, and this has been successful in our hands. And this has also been incorporated into recent post-op SBRT guidelines in terms of contouring consensus.
So in terms of technique, I don't think there's any issues. We talked about the technique, is the same for post-op or de novo. What is important is how you contour the cord. So, there are some cases where you do need a myelogram. In our hands with proper volumetric imaging and fusion software, we don't need the myelogram. Even in the post-operative case, we can contour exactly as we see it on the myelogram. However, there are some situations where there's a lot of hardware, and if you can't see it on the MR, do a myelogram. And then there are some situations like here where there's so much hardware, you're at a cervical thoracic junction, the patient's kyphosis doesn't matter what you do, you won't see the cord. Now, the second part is to talk about instability because the first indication for these patients to surgery is malignant epidural spinal cord compression. But what about the patient who's unstable, no epidural disease or slight epidural disease, but really getting an operation for instability? Well, how do we define instability? And the SINS criteria, I think is an excellent tool that we have now that can categorize patients so that you know how to communicate with the surgeon. So it looks at location, is there mechanical pain, what type of bone lesion is, in particular, lytic tumor, what the alignment is, what the degree of collapse is pre-existing and posterior-lateral involvement. And you basically can score the patient and then talk to your surgeon and see about surgical knee.
So this is a patient of mine, where I defied every rule that I follow but it had a baseline compression fracture, epidural disease, mechanical pain, and because this melanoma had exploded, there was no time for surgery. And we talked about conventional radiation versus stereotactic radiation, his melanoma, I knew his risk was probably around 35% of further fracturing, and I treated him, and five days later lo and behold, he fractured and went and caught equine syndrome and needed surgery anyway. And this is the challenge that we have in terms of patient selection and understanding the Do No Harm principle. Maybe this patient would have been better off treated conventionally without that additional risk of stereotactic induce fracture. Now, if you look at the pathology, and this was interesting, there was lots of inflammation, but no melanoma cells. And this was biopsy positive from the same site as melanoma. So, it shows you the power of this technique in terms of inducing tumor ablation.
There is some data from our colleagues in the Netherlands where they actually took a biopsy right before vertebroplasty, or surgery, or the second day after radiosurgery. So they did radiosurgery and then they did vertebroplasty or surgery, and they took biopsies pre and post. And what they found was that there was a significant increase in apoptosis, vascular damage, and visualization of necrosis. And this is just one or two days after 18 gray in a single fraction. So, again, potential for ablation, but we have to respect the issue of complication, because, unlike the brain, the tumor and the normal tissue are intertwined, and we're treating it all to a therapeutic dose. And this is why early on, we were seeing increasing rates of fracture, and we pooled our data with the MD Anderson and Cleveland Clinic. And we looked at our fracture rates. So, we said 14%, great, we're all doing good, excellent. But what we understood was really upon analysis of the predictors, so who are your high-risk patients? Well, those with the vertebral body collapse, and that has shown to be consistent in the literature as high risk if you have spinal malalignment, if you have lytic tumor, and the dose per fraction. As Josh pointed out, 24 and 1 may have very high efficacy, and you may have a 2% versus 7% risk of failure, but you have a 40% risk of fracture. What I do 12 gray times 2, 10% risk of fracture, and we've shown it over and over again.
Now, the good news, as Josh mentioned, is that the minority of them, and typically, if you look at the literature, it's about a third of all VCF induced by SBRT need a procedure. And typically it's a cement augmentation. You may say, "Well, that's not so bad." But your patient is going through that procedure unnecessarily, or maybe they were to develop anyway, but you did add to that patient's risk by treating them with stereotactic radiation. And these procedures may seem excellent, and they do dull pain but it's not necessarily alleviated. So, we're going near the end is the rationale to prophylactically stabilize because this is where we are at in the field in terms of determining, who should we actually try and mitigate that risk of fracture by stabilizing them first? So, this is a patient with a sclerotic, solitary metastasis from breast cancer, great candidate for stereotactic radiation but has a baseline fracture. I put a risk at about 35% of further fracture. So, should I stabilize this patient first? And if so, which procedure should I use? Should I use kyphoplasty? Well, it's sclerotic and not lytic. So, probably would not be a good candidate for kyphoplasty, percutaneous stabilization, or open invasive surgery.
And this is something where we talked to the surgeons, I said, "Well, look, I don't want you to touch the tumor, I want long-term stability. Let's do a percutaneous stabilization." And it's an elegant solution where the instrument above and below it's usually one or two days in the hospital. We get them on the table, simulate them and treat her. And this is just our treatment plan, where you can see her about nine months later, it's about a year and a half now, totally under control and mechanically stable. But it is a leap if somebody does not have mechanical pain to still put them through this procedure for a complication that's secondary to your treatment. Now, I wanted to just kind of briefly touch on some of the inadequacies of SINS because this is certainly something that we've been talking with Brainlab about, but there are issues in terms of defining what type of bone lesion because, again, lytic tumor is one of the most significant factors of fracture development and the degree of vertebral body collapse. And you can see that they're quite subjective.
So, we've been trying with auto segmentation to segment vertebra and then quantify, say, for example, the amount of lytic disease in this situation, or quantify the amount of baseline fracture using segmentation. And the dream of it all would be to have a patient in your software, put it in there, add in some of the qualitative issues like if they have mechanical pain or not, and get a readout in terms of what the fracture risk is. That's ultimately where we need the software to go. But what's interesting when we did our segmentation analysis for lytic tumor, we did find a threshold. If you have a volumetric threshold of 12%, your fracture risk increases significantly, odds ratio was 51. Now, we also found that there really is no such thing as a purely lytic tumor. There's always some component of blastic tumor or mixed tumor. And it was very interesting to do it, but it is an area of further research and one that we have to understand further as we use this modality more and more.
So in terms of as a summary, in particular for prophylactic intervention, because I think this is becoming more and more apparent in our practice and discussions. We did summarize this in a recent review. What I do is this, if someone has a mechanical pain and the SINS is greater than six or potentially unstable, and lytic disease baseline fracture or I'm gonna treat with very high doses, then I would prophylactically stabilize, hopefully, or typically with a cement augmentation procedure. If it's post but pre, I don't like to tumor to be damaged, and we do percutaneous instrumentation. So, overall, given cord compression and fracture, this is our schema. Symptomatic epidural disease Bilsky 2/3 or asymptomatic Bilsky 3, so high-grade epidural disease goes for surgery, then do post-op SBRT. Now, if you have asymptomatic Bilsky 2 and are SBRT eligible, you can consider a minimally invasive surgery followed by SBRT, or still SBRT alone, because it's still not there yet, and clear that a Bilsky 2 needs surgery. If you have asymptomatic low-grade epidural disease SBRT. And if you have a fracture more than 50% and mechanical pain, then we want to do cement augmentation or percutaneous followed by SBRT.
Now the nuance here is if somebody can tolerate the SBRT, what I'll do is I'll deliver first and then immediately cement them. And that's this approach in the Netherlands that I like very much because you don't disturb the tumor. When you put cement in there, it does cause tumor extravasation, so I'd rather treat it first. Baseline fracture and no mechanical pain, SBRT followed by some interpretation, post-SBRT fractures. Now here, if somebody fractures down and you're following them and they don't have any pain, you can observe them. But if they do have some sort of...they have mechanical pain, then I would treat them. But if they have minor pain or no pain, observe them and only treat them if it worsens, because it may settle down, but we don't have very good metrics to know who those patients are. And with that, I thank you very much.
On the Bilsky 1(a), 1(b), and 1(c) have not been surgical candidates, but I'll show you how we're kind of moving that paradigm along for selected indications. So, how do we do? Well, we have like most mixed histologies, in terms of primary tumor types. And we mainly treat with 24 gray in 2 fractions or 12 gray times 2 in my institution. If you look at the pre-operative grades, 60% were high grade. And our surgeons did a good job of decompressing, but they still had about 8 patients or 10% with residual Bilsky 2 disease. Now, we had excellent local control about 80% at one year, which is very comparable to the major series. And our analysis did indicate some predictors. And this is where it was a bit exciting. First of all, the dose may matter. So, high dose one or two fraction, predominantly here with two fractions, stereotactic radiation did better than a bit more hypofractionated approach. And when you're dealing with a post-operative bed, that's hypoxic, and the environment is very hostile, maybe that high dose per fraction really does help. What we also showed was that if you downgraded patients to a zero or one versus a two, your local control was better. And this promotes us to use surgery more and more and more thoughtfully, in order to optimize the outcomes associated with stereotactic radiosurgery.
So if I have a patient like this with some low-grade Bilsky disease, like a 1(c), previous radiation then comes to you in order to treat, well, I'm gonna say, "Well, look, why don't you create some separation between the disease and the cord. And then I'll treat with stereotactic radiation because I know my outcomes are going to be better." And this is just a case of mine where she had maintained local control up to two years. And this concept of separation surgery was really coined by the Sloan Kettering group, where they talk, not only about taking out to tumor but actually going ventrally to decompress and do a full circumferential decompression. And this is something that I talk to my surgeons about. If they're gonna operate, I wanna make sure that they go interiorly, they decompress properly, and they give me a good outcome. Now, it's a challenge and it does increase the risk of complications, but there is a benefit in terms of patient local control if you are able to achieve the circumferential decompression. Now, how did the group do at Sloan Kettering? Well, they showed a reduction of pain scores and better quality of life at separation surgery, followed by radiosurgery.
Now, it's still a big operation. And in our group, we were very much more keen towards a minimally invasive approach because we don't want to put patients as I showed you who really don't have a surgical indication to undergo surgery. I mean, that is a bit of a gray zone. So, we developed a two-base technique where the surgeon goes in, this is two-base day surgery. A patient comes in at 6:00 in the morning, discharged typically at two o'clock, and he does his work through the endoscope and decompresses the spinal cord. And so this is a very elegant solution where you're not putting the patient through two to three weeks of recovery and potential complications associated with open invasive surgery. Now, what is the dosimetric impact? We've shown you some local control rates, but there is a dosimetric advantage. So, we did a planning study where we looked at the patient's pre-operative epidural disease extent, we modeled it based on the post-operative CT imaging. And we said, "Well, you know, how good were these patients do and how better off are the plans?" Well, if you look at the D min, you see a clear increase as you go from zero to 6 millimeters of separation. And that is important because the minimum dose to the tumor has been shown to be proportional to your local control rate. So, there is a gain.
Now, what was interesting to me when we did this analysis is over here, this is your BED D95. And what we showed was that, for some patients like here, 6 millimeters decompression continued to give you the gains. But for some people, they really didn't need it, their couple of millimeters was enough, and you got those gains in terms of your dosimetry with no further gains from more aggressive surgery. And what that tells us, as we saw before, is the need to develop some software tools so we can do interpretive mapping, and watch and see dosimetrically as we resect epidural disease, what the impact is on the stereotactic plan. And I would say that this is probably one of the most important areas for development in our field. Now, we've been doing this in a different way with ultrasound. So, this is actually a conventional ultrasound, and you can see here a micro-ultrasound. And we're seeing beautiful images with the micro-ultrasound that's used in the operating room. So we take the pre-op CT, the pre-op MR, we register with the micro-ultrasound, and then we watch the decompression so that we get the result that we want. So, this is work in development by Victor Yang's lab, but it really does show you that we're all moving to the right direction, using minimally invasive techniques, using the technology, and trying to resect or dissect as much of that epidural disease away from your structure to be spared.
Now, going back to post-op SBRT, well, one of the questions happen very early on, which is, what was the volume? So, if I have a patient, like this with circumferential epidural disease, or pardon me, sorry, lack of posterior epidural disease, what is the target volume? Do I just donor up the patient, or do I do something more tailored? And there was a big question in the field in terms of what to do. So, we looked at our patterns of failure analysis to determine what is the optimal CTV for these patients. So without going into the details of this analysis, because it was complex, one of the take-home messages is that the preoperative tumor location predicted for failure. So, you have to look at your pre-operative MR, understand what the epidural disease is, and at least cover that. Thereafter, it depends on how much margin you want to apply. What we do is if patient has pre-operative circumferential disease, we do a donor distribution. If somebody has more tailored anterior disease, then we do an anterior lateral or horseshoe approach so that we cover, not only the anterior but the lateral extent, and this has been successful in our hands. And this has also been incorporated into recent post-op SBRT guidelines in terms of contouring consensus.
So in terms of technique, I don't think there's any issues. We talked about the technique, is the same for post-op or de novo. What is important is how you contour the cord. So, there are some cases where you do need a myelogram. In our hands with proper volumetric imaging and fusion software, we don't need the myelogram. Even in the post-operative case, we can contour exactly as we see it on the myelogram. However, there are some situations where there's a lot of hardware, and if you can't see it on the MR, do a myelogram. And then there are some situations like here where there's so much hardware, you're at a cervical thoracic junction, the patient's kyphosis doesn't matter what you do, you won't see the cord. Now, the second part is to talk about instability because the first indication for these patients to surgery is malignant epidural spinal cord compression. But what about the patient who's unstable, no epidural disease or slight epidural disease, but really getting an operation for instability? Well, how do we define instability? And the SINS criteria, I think is an excellent tool that we have now that can categorize patients so that you know how to communicate with the surgeon. So it looks at location, is there mechanical pain, what type of bone lesion is, in particular, lytic tumor, what the alignment is, what the degree of collapse is pre-existing and posterior-lateral involvement. And you basically can score the patient and then talk to your surgeon and see about surgical knee.
So this is a patient of mine, where I defied every rule that I follow but it had a baseline compression fracture, epidural disease, mechanical pain, and because this melanoma had exploded, there was no time for surgery. And we talked about conventional radiation versus stereotactic radiation, his melanoma, I knew his risk was probably around 35% of further fracturing, and I treated him, and five days later lo and behold, he fractured and went and caught equine syndrome and needed surgery anyway. And this is the challenge that we have in terms of patient selection and understanding the Do No Harm principle. Maybe this patient would have been better off treated conventionally without that additional risk of stereotactic induce fracture. Now, if you look at the pathology, and this was interesting, there was lots of inflammation, but no melanoma cells. And this was biopsy positive from the same site as melanoma. So, it shows you the power of this technique in terms of inducing tumor ablation.
There is some data from our colleagues in the Netherlands where they actually took a biopsy right before vertebroplasty, or surgery, or the second day after radiosurgery. So they did radiosurgery and then they did vertebroplasty or surgery, and they took biopsies pre and post. And what they found was that there was a significant increase in apoptosis, vascular damage, and visualization of necrosis. And this is just one or two days after 18 gray in a single fraction. So, again, potential for ablation, but we have to respect the issue of complication, because, unlike the brain, the tumor and the normal tissue are intertwined, and we're treating it all to a therapeutic dose. And this is why early on, we were seeing increasing rates of fracture, and we pooled our data with the MD Anderson and Cleveland Clinic. And we looked at our fracture rates. So, we said 14%, great, we're all doing good, excellent. But what we understood was really upon analysis of the predictors, so who are your high-risk patients? Well, those with the vertebral body collapse, and that has shown to be consistent in the literature as high risk if you have spinal malalignment, if you have lytic tumor, and the dose per fraction. As Josh pointed out, 24 and 1 may have very high efficacy, and you may have a 2% versus 7% risk of failure, but you have a 40% risk of fracture. What I do 12 gray times 2, 10% risk of fracture, and we've shown it over and over again.
Now, the good news, as Josh mentioned, is that the minority of them, and typically, if you look at the literature, it's about a third of all VCF induced by SBRT need a procedure. And typically it's a cement augmentation. You may say, "Well, that's not so bad." But your patient is going through that procedure unnecessarily, or maybe they were to develop anyway, but you did add to that patient's risk by treating them with stereotactic radiation. And these procedures may seem excellent, and they do dull pain but it's not necessarily alleviated. So, we're going near the end is the rationale to prophylactically stabilize because this is where we are at in the field in terms of determining, who should we actually try and mitigate that risk of fracture by stabilizing them first? So, this is a patient with a sclerotic, solitary metastasis from breast cancer, great candidate for stereotactic radiation but has a baseline fracture. I put a risk at about 35% of further fracture. So, should I stabilize this patient first? And if so, which procedure should I use? Should I use kyphoplasty? Well, it's sclerotic and not lytic. So, probably would not be a good candidate for kyphoplasty, percutaneous stabilization, or open invasive surgery.
And this is something where we talked to the surgeons, I said, "Well, look, I don't want you to touch the tumor, I want long-term stability. Let's do a percutaneous stabilization." And it's an elegant solution where the instrument above and below it's usually one or two days in the hospital. We get them on the table, simulate them and treat her. And this is just our treatment plan, where you can see her about nine months later, it's about a year and a half now, totally under control and mechanically stable. But it is a leap if somebody does not have mechanical pain to still put them through this procedure for a complication that's secondary to your treatment. Now, I wanted to just kind of briefly touch on some of the inadequacies of SINS because this is certainly something that we've been talking with Brainlab about, but there are issues in terms of defining what type of bone lesion because, again, lytic tumor is one of the most significant factors of fracture development and the degree of vertebral body collapse. And you can see that they're quite subjective.
So, we've been trying with auto segmentation to segment vertebra and then quantify, say, for example, the amount of lytic disease in this situation, or quantify the amount of baseline fracture using segmentation. And the dream of it all would be to have a patient in your software, put it in there, add in some of the qualitative issues like if they have mechanical pain or not, and get a readout in terms of what the fracture risk is. That's ultimately where we need the software to go. But what's interesting when we did our segmentation analysis for lytic tumor, we did find a threshold. If you have a volumetric threshold of 12%, your fracture risk increases significantly, odds ratio was 51. Now, we also found that there really is no such thing as a purely lytic tumor. There's always some component of blastic tumor or mixed tumor. And it was very interesting to do it, but it is an area of further research and one that we have to understand further as we use this modality more and more.
So in terms of as a summary, in particular for prophylactic intervention, because I think this is becoming more and more apparent in our practice and discussions. We did summarize this in a recent review. What I do is this, if someone has a mechanical pain and the SINS is greater than six or potentially unstable, and lytic disease baseline fracture or I'm gonna treat with very high doses, then I would prophylactically stabilize, hopefully, or typically with a cement augmentation procedure. If it's post but pre, I don't like to tumor to be damaged, and we do percutaneous instrumentation. So, overall, given cord compression and fracture, this is our schema. Symptomatic epidural disease Bilsky 2/3 or asymptomatic Bilsky 3, so high-grade epidural disease goes for surgery, then do post-op SBRT. Now, if you have asymptomatic Bilsky 2 and are SBRT eligible, you can consider a minimally invasive surgery followed by SBRT, or still SBRT alone, because it's still not there yet, and clear that a Bilsky 2 needs surgery. If you have asymptomatic low-grade epidural disease SBRT. And if you have a fracture more than 50% and mechanical pain, then we want to do cement augmentation or percutaneous followed by SBRT.
Now the nuance here is if somebody can tolerate the SBRT, what I'll do is I'll deliver first and then immediately cement them. And that's this approach in the Netherlands that I like very much because you don't disturb the tumor. When you put cement in there, it does cause tumor extravasation, so I'd rather treat it first. Baseline fracture and no mechanical pain, SBRT followed by some interpretation, post-SBRT fractures. Now here, if somebody fractures down and you're following them and they don't have any pain, you can observe them. But if they do have some sort of...they have mechanical pain, then I would treat them. But if they have minor pain or no pain, observe them and only treat them if it worsens, because it may settle down, but we don't have very good metrics to know who those patients are. And with that, I thank you very much.