Transcript
Thank you for the introduction. And okay, I will talk about the clinical outcomes for single isocenter radiosurgery in patients with up to 10 brain mets. So this is the outline. I will touch mainly two questions, why we should use radiosurgery for patients with up to 10 mets and how effective and safe is new techniques, single-isocenter techniques compared with single-target radiosurgery. So we know that radiosurgery is the recommended treatment for a limited number of mets, usually four or five. This is basically based on the fact that whole-brain radiation therapy doesn't give an additional survival to patients treated with radiosurgery alone and more important, that whole-brain radiation therapy is associated with detrimental effect on quality of life and neurocognitive decline.
So this is an interesting study because the main question is, how many mets should be treated with radiosurgery alone? This is an interesting Japanese study showing that for more than 1,000 patients with up to 10 brain mets, the survival was similar for people having between 2 and 5 mets or more than 5 mets. And similar experiences have been published by several institutional papers.
For example, this is a typical...this is a young patient with breast cancer. She was treated for six mets, and we had excellent results. But this is really time consuming because we spend a lot of hours for both treatment planning and dose delivery. It requires for six single-target radiosurgery, at least a couple of hours, three hours. So it's really time-consuming. So with the aim of reducing the time of treatment, some single isocenter techniques have been developed in the last years, which means that we can deliver the dose in one session to all lesions.
And I'm gonna show our preliminary experience with patients using this Brainlab Elements software, which usually is dynamic conformal arcs, radiosurgery, single-isocenter radiosurgery for multiple brain mets. I don't wanna go through the technical details. But basically, they are then usually pre-selected, so automated, then dynamic arc in five-gauge position is an automatic planning requiring just few minutes, and then the physical because you can optimize, if it's necessary, the planning.
So this is our preliminary experience. Actually, we have treated more than 50 patients. This is limited to our 26 patients with a median number of lesions of seven lesions. You can see some treatment characteristics. So the median GTV was 0.3cc and the median PTV adding 1 millimeter margin from GTV to PTV was 0.54cc, although it's quite interesting. And again, let me skew in all these details. I wanna just show that these are the individual characteristic of treated patients. Because it's quite interesting that the target coverage was quite good, usually can deliver 100% of the dose to 90% of the PTV. So, we treat all these patients, as you see, with five arcs, these milli units. And also, when you look at the conformity index, gradient index, they are in the range of the best parameters when we treat all these mets with single-target radiosurgery.
Okay. So what we have evaluated in our experience, simply efficacy in terms of local control and toxicity, and the accuracy. Also Emmanuel has already spoken a lot about the accuracy. I will touch just a couple of points from a clinical point of view. Okay, this is the results because I believe that any techniques should be validated by the results, by clinical results. So at median time, for up of 15 months, our control was...so local control for 26 patients with 182 lesions was 87% at 12 months. Which means that we have nine recurrent tumors in four patients. Well, this is consistent with our results in all the last years with single-target radiosurgery.
And this is just a couple example. So we can choose the dose, different doses for the different targets according to the volume of target. And also, in this treatment, in this automatic planning, this is in respect of constraints. In this case, we have one lesion, which is this one, which was very closely up the pathway. And we wanted the dose less than 80 gray to the pathway. But in this case, where this lesion was very close to the brainstem, we wanted also less than 12 gray. But if you look, the dosimetry was quite good. Just but this is a visual approach to large lesions, this was a lesion more than 3 centimeters in the motor area. So I prefer to treat with fractionated radiosurgery, but this is another story. So it's very important that we had very good dosimetry and we can treat all these lesions in a successful way, as you see here. In one single session, it lasts more or less 20 minutes. And this is another case. Let's just show this case because in these two lesions, one is quite good, quite large, was 3cc, where in the motor cortex area, we have good symmetry with very small overlapping region of high doses. So I think from a clinical perspective, really I'm happy with the symmetry of these plans.
But of course, we have also to look at the safety of our treatment because we know that the main toxicity of radiosurgery is the risk of brain radiation use brain necrosis. So in our planning experience, we had this 12 months radionecrosis, estimated the risk of radionecrosis of 9% and slightly increased at two years over 14%. This is just radiological evidence for radionecrosis. So we had the less than 5% symptomatic radionecrosis, which is, again, in the range of single-target radiosurgery according also to our previous experience. So we can say that with the use of 1-millimeter margin, as we did in these 26 patients, the risk of radionecrosis was exactly the same as expected for frameless radiosurgery. But I think this is the most important issue when we do frameless radiosurgery, which margins should we use?
This is very important because margins add a significant amount of normal tissue, of normal brain tissue to the treatment volume. For example, if you put 1-millimeter margin to a lesion of 8 millimeter, you double your normal brain irradiated to high doses. And the same when you put a 1.5-millimeter margin to a lesion of 12 millimeter you double your normal irradiated tissue. And again, 2-millimeter margin to a 50-millimeter lesion. This is important because we know there is a strong correlation between the normal brain irradiated to high doses, specifically the V12, which means the normal brain which is irradiated with 12 gray, and the risk of radiation necrosis.
For example, this is a normal target, a little bit like less than 15 millimeters. If you put 1 millimeter GTV to PTV margin, you have a final volume of 1.9cc and with very good conformity index. We have a V12 of 4.6, 4.7cc. But if you put 2-millimeter margin, you have just a small increase on your final volume is 2.8, so you have almost double V12. This is very important because even if we have a small increase on the final volume, at least in our experience, we have shared this experience with a lot of centers. So this means four times risk of increase the rate of necrosis. So just the difference between 1 millimeter and 2 millimeters for this small lesion. So, this is very important because this means that we have to try to reduce margins when we do radiosurgery. This is the most important point when we do radiosurgery.
But on the other hand, with the new techniques, we have to consider also there is a possible risk of a compromised coverage. So we know, as also Emmanuel said, even if you have a small rotation or translational shift of a single isocenter, this can result in a very big shift of small lesions away from the isocenter. So for this reason, together with the clinical results, we looked also at the accuracy of our system. I don't wanna go to the details, as Emmanuel say, as we work. So we have this setup with ExacTrac, then we have a repeat ExacTrac. In our institution, we do also cone-beam just to look at the agreement of cone-beam CT and ExacTrac. We then apply shift according to the cone-beam CT and then we follow the radiosurgery with ExacTrac.
So what we have seen that in all almost 200 lesions we had, there is non-overlapping GTV of about 10%, which means 6% non-overlapping PTV volume of 6%. And the impact on V95 variation, which means the volume irradiated by 95% of the prescribed doses was less than 2% BET. This means that in 20% of our targets, we had this variation of V95, significant variation of V95 in 25 targets. Which means a missing target coverage BET. Because we used 1-millimeter margins, we had no deviation, we had no missing target coverage. So this demonstrates, at least in our preliminary experience, when we add 1-millimeter margin, we can cover perfectly all our targets even if there are these residual error over this shift of the isocenters.
This is a typical case in which we have this geometric variation of GTV because of these residual errors even if it's in the tolerance of the system, but as you see is still covered by the PTV because we use this 1-millimeter margin. So this is very important. So we can use, even if we treated 10 mets, maybe more than 10 mets, we actually use this same margin that people use with single-target radiosurgery. So using this system, we don't have seen a worsening of geometry and dosimetry.
And also, it's important we found clear correlation between the target coverage expressed as V95, and the distance from the isocenter, and the size of the lesion. Which means that small lesions away from the isocenter, more than 4 centimeters are at high risk of target coverage missing.
So, this is our agreement between the two systems. We use ExacTrac, maybe use also cone-beam CT at least the beginning, before starting the treatment, we need this agreement which means less than 0.5 millimeter shift, translational shift, and less than 0.5 degree rotational shift. So you see there was a good agreement between the two systems. There are still some differences, which means depending on the different isocenter systems, which we do as part of our quality assurance every morning, usually we have this shift from isocenter but 0.3, 0.4. So this is the reason because we still see some deviation between the two techniques.
But what is more important, even if cone-beam CT, ExacTrac are most effective systems, image system for repositioning, I think it's most important what Emmanuel said that we need really to follow this patient during radiosurgery, otherwise we have later to large margins to cover the target. Also because I have a similar experience like Emmanuel. So we know that at least 30% of our repositioning are out of tolerance. So we have correct this position. So we really need every [inaudible 00:14:17] like Emmanuel say, we need to correct at least in one-third of our patients. So if we want to use strict margin, we really need to monitoring continuously our radiosurgery.
So the last one minute, just to say that also what we did show...I demonstrated that with 1-millimeter margin, we didn't have any loss target coverage. But what we did is simulated the effects of a 0.5-millimeter margin and no margin at all. And as you see, when we use 0.5-millimeter margin, so reducing the margin, we had very good results. So 90%, more than 90% of treated lesions had no variation in the dosimetry. And more important, when we stratified for sides and for distance to isocenter, so you see that usually we have variation just in a small lesion, less than 0.3cc, sorry this is cc, it's not millimeter, 0.3cc and away from...more than 4 centimeter from isocenter.
So, this means, I'm gonna be complicated. This means, for example, in these patients, we can treat with different margin, we can reduce margin. So, we still use 1 millimeter for small lesions away from isocenter. But we use 0.5 millimeters for large lesions more than 4 centimeters from isocenters, and we don't use margin for large lesions within 4 centimeters from isocenter. So, with these techniques, we can even reduce margin and use more than 1-millimeter margin in a safe way. But there are other techniques just for try to reducing the risk of toxicity.
My favorite is just to use a fractionated. And now we started to use also three fractions, which means 9 gray times 3 also using the single isocenter when we have patients with four or five mets more than 1 centimeter, used three fraction we can use with the systems. And also, what we can do just for reducing margin is clusterize just subgrouping the mets with aim to reduce the distance from isocenter.
So, in summary, I think that our preliminary experience with single isocenter multi-targets dynamic conformer arc radiosurgery was quite effective approach for patients up to 10 brain mets that use the ExacTrac X-Ray, we knew that, was important just because the impact, just to see the impact of residual translational and rotational errors on target coverage are really modest. So usually, we advise for 1-millimeter margin, but we can reduce this margin, especially for lesion more than 1 centimeters that are close to the isocenter without decreasing the accuracy and the precision of the treatment. And also, we have started to look at not just radionecrosis, but to look at the neurocognitive outcome of these patients because we believe that other parameters then the V12 need to be used for looking at this aspect. Thank you.
So this is an interesting study because the main question is, how many mets should be treated with radiosurgery alone? This is an interesting Japanese study showing that for more than 1,000 patients with up to 10 brain mets, the survival was similar for people having between 2 and 5 mets or more than 5 mets. And similar experiences have been published by several institutional papers.
For example, this is a typical...this is a young patient with breast cancer. She was treated for six mets, and we had excellent results. But this is really time consuming because we spend a lot of hours for both treatment planning and dose delivery. It requires for six single-target radiosurgery, at least a couple of hours, three hours. So it's really time-consuming. So with the aim of reducing the time of treatment, some single isocenter techniques have been developed in the last years, which means that we can deliver the dose in one session to all lesions.
And I'm gonna show our preliminary experience with patients using this Brainlab Elements software, which usually is dynamic conformal arcs, radiosurgery, single-isocenter radiosurgery for multiple brain mets. I don't wanna go through the technical details. But basically, they are then usually pre-selected, so automated, then dynamic arc in five-gauge position is an automatic planning requiring just few minutes, and then the physical because you can optimize, if it's necessary, the planning.
So this is our preliminary experience. Actually, we have treated more than 50 patients. This is limited to our 26 patients with a median number of lesions of seven lesions. You can see some treatment characteristics. So the median GTV was 0.3cc and the median PTV adding 1 millimeter margin from GTV to PTV was 0.54cc, although it's quite interesting. And again, let me skew in all these details. I wanna just show that these are the individual characteristic of treated patients. Because it's quite interesting that the target coverage was quite good, usually can deliver 100% of the dose to 90% of the PTV. So, we treat all these patients, as you see, with five arcs, these milli units. And also, when you look at the conformity index, gradient index, they are in the range of the best parameters when we treat all these mets with single-target radiosurgery.
Okay. So what we have evaluated in our experience, simply efficacy in terms of local control and toxicity, and the accuracy. Also Emmanuel has already spoken a lot about the accuracy. I will touch just a couple of points from a clinical point of view. Okay, this is the results because I believe that any techniques should be validated by the results, by clinical results. So at median time, for up of 15 months, our control was...so local control for 26 patients with 182 lesions was 87% at 12 months. Which means that we have nine recurrent tumors in four patients. Well, this is consistent with our results in all the last years with single-target radiosurgery.
And this is just a couple example. So we can choose the dose, different doses for the different targets according to the volume of target. And also, in this treatment, in this automatic planning, this is in respect of constraints. In this case, we have one lesion, which is this one, which was very closely up the pathway. And we wanted the dose less than 80 gray to the pathway. But in this case, where this lesion was very close to the brainstem, we wanted also less than 12 gray. But if you look, the dosimetry was quite good. Just but this is a visual approach to large lesions, this was a lesion more than 3 centimeters in the motor area. So I prefer to treat with fractionated radiosurgery, but this is another story. So it's very important that we had very good dosimetry and we can treat all these lesions in a successful way, as you see here. In one single session, it lasts more or less 20 minutes. And this is another case. Let's just show this case because in these two lesions, one is quite good, quite large, was 3cc, where in the motor cortex area, we have good symmetry with very small overlapping region of high doses. So I think from a clinical perspective, really I'm happy with the symmetry of these plans.
But of course, we have also to look at the safety of our treatment because we know that the main toxicity of radiosurgery is the risk of brain radiation use brain necrosis. So in our planning experience, we had this 12 months radionecrosis, estimated the risk of radionecrosis of 9% and slightly increased at two years over 14%. This is just radiological evidence for radionecrosis. So we had the less than 5% symptomatic radionecrosis, which is, again, in the range of single-target radiosurgery according also to our previous experience. So we can say that with the use of 1-millimeter margin, as we did in these 26 patients, the risk of radionecrosis was exactly the same as expected for frameless radiosurgery. But I think this is the most important issue when we do frameless radiosurgery, which margins should we use?
This is very important because margins add a significant amount of normal tissue, of normal brain tissue to the treatment volume. For example, if you put 1-millimeter margin to a lesion of 8 millimeter, you double your normal brain irradiated to high doses. And the same when you put a 1.5-millimeter margin to a lesion of 12 millimeter you double your normal irradiated tissue. And again, 2-millimeter margin to a 50-millimeter lesion. This is important because we know there is a strong correlation between the normal brain irradiated to high doses, specifically the V12, which means the normal brain which is irradiated with 12 gray, and the risk of radiation necrosis.
For example, this is a normal target, a little bit like less than 15 millimeters. If you put 1 millimeter GTV to PTV margin, you have a final volume of 1.9cc and with very good conformity index. We have a V12 of 4.6, 4.7cc. But if you put 2-millimeter margin, you have just a small increase on your final volume is 2.8, so you have almost double V12. This is very important because even if we have a small increase on the final volume, at least in our experience, we have shared this experience with a lot of centers. So this means four times risk of increase the rate of necrosis. So just the difference between 1 millimeter and 2 millimeters for this small lesion. So, this is very important because this means that we have to try to reduce margins when we do radiosurgery. This is the most important point when we do radiosurgery.
But on the other hand, with the new techniques, we have to consider also there is a possible risk of a compromised coverage. So we know, as also Emmanuel said, even if you have a small rotation or translational shift of a single isocenter, this can result in a very big shift of small lesions away from the isocenter. So for this reason, together with the clinical results, we looked also at the accuracy of our system. I don't wanna go to the details, as Emmanuel say, as we work. So we have this setup with ExacTrac, then we have a repeat ExacTrac. In our institution, we do also cone-beam just to look at the agreement of cone-beam CT and ExacTrac. We then apply shift according to the cone-beam CT and then we follow the radiosurgery with ExacTrac.
So what we have seen that in all almost 200 lesions we had, there is non-overlapping GTV of about 10%, which means 6% non-overlapping PTV volume of 6%. And the impact on V95 variation, which means the volume irradiated by 95% of the prescribed doses was less than 2% BET. This means that in 20% of our targets, we had this variation of V95, significant variation of V95 in 25 targets. Which means a missing target coverage BET. Because we used 1-millimeter margins, we had no deviation, we had no missing target coverage. So this demonstrates, at least in our preliminary experience, when we add 1-millimeter margin, we can cover perfectly all our targets even if there are these residual error over this shift of the isocenters.
This is a typical case in which we have this geometric variation of GTV because of these residual errors even if it's in the tolerance of the system, but as you see is still covered by the PTV because we use this 1-millimeter margin. So this is very important. So we can use, even if we treated 10 mets, maybe more than 10 mets, we actually use this same margin that people use with single-target radiosurgery. So using this system, we don't have seen a worsening of geometry and dosimetry.
And also, it's important we found clear correlation between the target coverage expressed as V95, and the distance from the isocenter, and the size of the lesion. Which means that small lesions away from the isocenter, more than 4 centimeters are at high risk of target coverage missing.
So, this is our agreement between the two systems. We use ExacTrac, maybe use also cone-beam CT at least the beginning, before starting the treatment, we need this agreement which means less than 0.5 millimeter shift, translational shift, and less than 0.5 degree rotational shift. So you see there was a good agreement between the two systems. There are still some differences, which means depending on the different isocenter systems, which we do as part of our quality assurance every morning, usually we have this shift from isocenter but 0.3, 0.4. So this is the reason because we still see some deviation between the two techniques.
But what is more important, even if cone-beam CT, ExacTrac are most effective systems, image system for repositioning, I think it's most important what Emmanuel said that we need really to follow this patient during radiosurgery, otherwise we have later to large margins to cover the target. Also because I have a similar experience like Emmanuel. So we know that at least 30% of our repositioning are out of tolerance. So we have correct this position. So we really need every [inaudible 00:14:17] like Emmanuel say, we need to correct at least in one-third of our patients. So if we want to use strict margin, we really need to monitoring continuously our radiosurgery.
So the last one minute, just to say that also what we did show...I demonstrated that with 1-millimeter margin, we didn't have any loss target coverage. But what we did is simulated the effects of a 0.5-millimeter margin and no margin at all. And as you see, when we use 0.5-millimeter margin, so reducing the margin, we had very good results. So 90%, more than 90% of treated lesions had no variation in the dosimetry. And more important, when we stratified for sides and for distance to isocenter, so you see that usually we have variation just in a small lesion, less than 0.3cc, sorry this is cc, it's not millimeter, 0.3cc and away from...more than 4 centimeter from isocenter.
So, this means, I'm gonna be complicated. This means, for example, in these patients, we can treat with different margin, we can reduce margin. So, we still use 1 millimeter for small lesions away from isocenter. But we use 0.5 millimeters for large lesions more than 4 centimeters from isocenters, and we don't use margin for large lesions within 4 centimeters from isocenter. So, with these techniques, we can even reduce margin and use more than 1-millimeter margin in a safe way. But there are other techniques just for try to reducing the risk of toxicity.
My favorite is just to use a fractionated. And now we started to use also three fractions, which means 9 gray times 3 also using the single isocenter when we have patients with four or five mets more than 1 centimeter, used three fraction we can use with the systems. And also, what we can do just for reducing margin is clusterize just subgrouping the mets with aim to reduce the distance from isocenter.
So, in summary, I think that our preliminary experience with single isocenter multi-targets dynamic conformer arc radiosurgery was quite effective approach for patients up to 10 brain mets that use the ExacTrac X-Ray, we knew that, was important just because the impact, just to see the impact of residual translational and rotational errors on target coverage are really modest. So usually, we advise for 1-millimeter margin, but we can reduce this margin, especially for lesion more than 1 centimeters that are close to the isocenter without decreasing the accuracy and the precision of the treatment. And also, we have started to look at not just radionecrosis, but to look at the neurocognitive outcome of these patients because we believe that other parameters then the V12 need to be used for looking at this aspect. Thank you.