Transcript
I'd like to thank the moderators, thank Dr. Selch, and the Novalis Circle for allowing us to present our information. We looked at our patients treated with shaping radiosurgery for recurrent malignant glial tumors, or at least, glial tumors that we thought are malignant at the time of recurrence due to their enhancement and growth pattern. And I worked with our colleagues in neurosurgery in medical physics and our entire radiosurgical team. The background, as Dr. Chen so nicely showed us, malignant brain tumors remain a major problem in our country, and most of them are glial tumors, and most of those are bad glial tumors. And as we all know, we don't do very well with them. Current treatment, as he has showed us, now is broken down mostly to surgery, radiation, and temozolomide. But recurrence rate over time approaches 100% for the grade 3 and 4, and even grade 1 and 2 is about two-thirds of them are gonna come back sometime during the patient's lifetime. And when they come back, they come back nastier and meaner.
Current therapy at time of recurrence is ReResection, Chemotherapy, ReIrradiation, 8 phase 2 trials for recurrent grade 3 and 4 gliomas. And one recent review showed a median survival of about 30 weeks. So, we don't do very well. Some of the data as Dr. Chen has showed us in small series using radiosurgery do a little bit better and so we continue to hope that there may be a role for stereotactic therapy. We show our most recent patients here treated since we moved to the Novalis platform. And also I want to show you at the end a possible idea for how we might be able to do better with these patients, which may tie in nicely with the previous presentation.
From May 2004 to February 2008 we treated 13 consecutive patients. Three were treated twice for progression outside the original radiosurgical area. So they had 16 treatments. A relatively young group of patients two were excluded, one because of short follow-up, although I'll show you some interesting images on this one at the end here, and one with a very extended history, having originally had an oligo-based treatment and was treated with prolonged fractionation since they had done well.
Original histologies, four were glioblastoma, two anaplastic astros, one was an anaplastic oligo, two were originally oligodendrogliomas, and two were ependymal tumors. These are a relatively good group of patients in that the median time to radiosurgery from original diagnosis is slightly greater than two years. So these are not the worst players in the world. The number of previous therapies was one to four though with a median of two. All had had previous radiation, at least 50.4 GY, and many up to 60. Twelve out of the 14 had previous chemotherapy. All of these lesions were enhancing at the time of treatment, and all had demonstrated progression prior to us treating them. The median age, again, as we said was relatively young.
Our treatment technique is not so unlike what I think many of you do, CT simulation with contrast 2-millimeter slices, MR for fusion done at 2-millimeter spacing. We take T2 , T1 axial, T1 coronal. We think that by taking a few image sets and using all of the data put together we create a composite target that may help us a bit more than just taking one image set and putting it together. Sometimes, you start to see enhancement extending out to the dura. And is it real? Is it not part of the primary lesion? And then we delineate the primary lesions. The target-enhancing tumor is generally our target. Then, we add 3 millimeters when we treat with five fractions. When we treat with a single dose, we've tried to keep consistent with what has been done in the past so we can at least compare our doses and treat without additional margin. Most of our patients were treated with fixed field, either with intensity-modulated or 3-D conformal using some manual intensity modulation using the Brainlab software. We tend to follow fairly simple dosimetric techniques for lesions over here on the left side. We bring most of our beams in from the left side. We don't come clear across the brain to get there, as we've sometimes seen in some of our outside reviews. And we try to treat along the long axis of the tumor, when possible, to help our conformality.
Doses that we gave these lesions in our hypofractionated group of 9 patients, most of them got 25GY in five fractions, usually prescribed somewhere around the 85% isodose, building the dose in the middle, building it more in the middle. If we see solid, pure enhancement in the middle, we think that area isn't functional brain. If we see this patchy enhancement, then we tend to come down to that 90% isodose and it sort of falls from Dr. Solcho's teachings. One was true at 20GY and four fractions and one with 24GY four fractions. Our single doses were 16GY to 18GY in a single fraction.
Treatment setups. Our first seven were treated with the Brainlab target positioning box, and more recently, we've moved to ExacTrac Robotic System. Post radiosurgery, all of our patients got two weeks of steroid taper, which we've done sort of empirically since we started our radiosurgeries back in 1994.
Our treatment results. Here we can see the enhancing recurrent tumor. This was at six weeks. This is at six months, and we get the idea that we pull the enhancement out of back here and perhaps have a necrotic area there. And again, the trouble is that as we've necrosed this area out, we see progression at the margin, as we well know. And this is now at 10 months out. So, at least some short-term control of this lesion. Our median survival from the date of radiosurgery was slightly over a year with a range of 15 to 82 weeks. And it really didn't seem to matter, at least in our hands, whether you had a grade four originally, or an oligo originally. They all come in here at slightly over a year. Perhaps, if we had greater numbers they'd select out differently. But we think most of these tumors by this point have dedifferentiated back into the nastier-acting group.
Symptom relief. Nine of 14 patients had symptoms at the time of treatment, and eight of the nine improved at least for a short term, five were asymptomatic, and one of the five worsened acutely and went the wrong way.
Steroid use. Two increased acutely after two weeks post-radiosurgery taper and at least three others increased at a later time, most likely due to radiation effects. And as we know, it's very difficult at times to try to tell if this is due to recurrent tumor, due to necrosis from the high-dose area. We do a lot of bringing our follow-up exams back into the treatment planning exam, fusing them, and trying to sort out where and what might be going on.
In these highly selective patients, stereotactic radiosurgery and the hypofractionated form also offered symptom relief with reasonable toxicity. MR improvement was often seen, but the significance of this is how it relates to ultimate survival, I don't think it's really truly known. Are we merely yes, treating the part that doesn't count anymore? I don't think so. I think it can help. And in the few minutes, I think hopefully I've left myself, I'd like to show you not only some caveats but also where we might be taking this in the future. Our patient population was relatively young. It was a relatively long time to progression pre-radiosurgery. We had a number of oligo histologies, which we think tend to do a bit better, although we didn't really show it in these limited numbers. And other agents were given to these patients post radiosurgery. We'd like to use the time to progression.
But when we try to determine when is the exact time to progression, sorting out the scans, what's necrosis? What's not? I don't know that I am good enough to tell time to progression. One of the interesting things we're starting to see though, and I think many of you may be seeing this as well, is now that a vast Bevacuzimab, the antibody against VEGF, is being used more and more is there a potential role for combining those together? This is a patient in 2005 that had a grade two non-enhancing astrocytoma treated with subtotal excision 50.4GY. Two years later, it recurred here, This was resected. Now, grade three on pathology, at least, and what had a gross total excision was placed on Temodar. By January he is starting to progress here, with enhancement and sort of patchy enhancement, and much more substantial T2 changes. This was up where they had operated on earlier. And so, we went after this and treated five fractions at 85%. We put in the pseudo structures here when we don't like how the computer is helping us shape the dose, and we push the dose back to where we want it to be.
This is the CT. You can see it's picking up a little bit of contrast. Even on our planning CT, we always give it just to be sure that we really are matched well. But here, we targeted the whole area. And we prescribed this at about 85%. And really our most of our [inaudible 00:12:07] was only about 5.5GY, We were a little worried about that. Nevertheless, we made the thing madder than the dickens. And though it kicked up a ton of edemas, it's like Dr. Chen has shown here, we've got all this enhancement in here. We think this is a big necrotic area. And when we look inferiorly, to make matters worse, we now see some enhancement outside the area. The patient's having hemiplegia. We're discussing possible hospice. But since he's relatively young, we put him on steroids and the Bevacuzimab. In the area of enhancement, the new enhancement, I should say or question of progression, we saw some improvement here, at least modest improvement. The patient's symptoms got better. But I think even more interesting in the area that we thought might be necrosis versus that, and this is a relatively short period of time between the scans, we haven't done surgery. Is this improvement here all steroids? Is this the steroids and the VEGF antibody not only cutting our enhancement but maybe taking out some of the vascular supply leaky vessels and helping this status?
So, I guess our hypothesis here is, you know, by closing down the leaky vessels in necrotic regions, breaking inflammatory cascade, allowing healing, can Bevacuzimab allows us to use the radiosurgery more safely? You know, can you bang the dickens out of the area, and then cut off some of the blood vessel's supply to it, and then potentially improve your therapeutic ratio somewhat by this combination? We continue to try to use stereotactic radiosurgery, both single-dose for the smaller areas and five fractions for recurrent tumors. And we're putting many of them now on to Bevacuzimab and potentially using it as a prospective future course.
Thank you for your time. I'd also like to thank all of our colleagues back at Loyola who've helped make these treatments possible.
Current therapy at time of recurrence is ReResection, Chemotherapy, ReIrradiation, 8 phase 2 trials for recurrent grade 3 and 4 gliomas. And one recent review showed a median survival of about 30 weeks. So, we don't do very well. Some of the data as Dr. Chen has showed us in small series using radiosurgery do a little bit better and so we continue to hope that there may be a role for stereotactic therapy. We show our most recent patients here treated since we moved to the Novalis platform. And also I want to show you at the end a possible idea for how we might be able to do better with these patients, which may tie in nicely with the previous presentation.
From May 2004 to February 2008 we treated 13 consecutive patients. Three were treated twice for progression outside the original radiosurgical area. So they had 16 treatments. A relatively young group of patients two were excluded, one because of short follow-up, although I'll show you some interesting images on this one at the end here, and one with a very extended history, having originally had an oligo-based treatment and was treated with prolonged fractionation since they had done well.
Original histologies, four were glioblastoma, two anaplastic astros, one was an anaplastic oligo, two were originally oligodendrogliomas, and two were ependymal tumors. These are a relatively good group of patients in that the median time to radiosurgery from original diagnosis is slightly greater than two years. So these are not the worst players in the world. The number of previous therapies was one to four though with a median of two. All had had previous radiation, at least 50.4 GY, and many up to 60. Twelve out of the 14 had previous chemotherapy. All of these lesions were enhancing at the time of treatment, and all had demonstrated progression prior to us treating them. The median age, again, as we said was relatively young.
Our treatment technique is not so unlike what I think many of you do, CT simulation with contrast 2-millimeter slices, MR for fusion done at 2-millimeter spacing. We take T2 , T1 axial, T1 coronal. We think that by taking a few image sets and using all of the data put together we create a composite target that may help us a bit more than just taking one image set and putting it together. Sometimes, you start to see enhancement extending out to the dura. And is it real? Is it not part of the primary lesion? And then we delineate the primary lesions. The target-enhancing tumor is generally our target. Then, we add 3 millimeters when we treat with five fractions. When we treat with a single dose, we've tried to keep consistent with what has been done in the past so we can at least compare our doses and treat without additional margin. Most of our patients were treated with fixed field, either with intensity-modulated or 3-D conformal using some manual intensity modulation using the Brainlab software. We tend to follow fairly simple dosimetric techniques for lesions over here on the left side. We bring most of our beams in from the left side. We don't come clear across the brain to get there, as we've sometimes seen in some of our outside reviews. And we try to treat along the long axis of the tumor, when possible, to help our conformality.
Doses that we gave these lesions in our hypofractionated group of 9 patients, most of them got 25GY in five fractions, usually prescribed somewhere around the 85% isodose, building the dose in the middle, building it more in the middle. If we see solid, pure enhancement in the middle, we think that area isn't functional brain. If we see this patchy enhancement, then we tend to come down to that 90% isodose and it sort of falls from Dr. Solcho's teachings. One was true at 20GY and four fractions and one with 24GY four fractions. Our single doses were 16GY to 18GY in a single fraction.
Treatment setups. Our first seven were treated with the Brainlab target positioning box, and more recently, we've moved to ExacTrac Robotic System. Post radiosurgery, all of our patients got two weeks of steroid taper, which we've done sort of empirically since we started our radiosurgeries back in 1994.
Our treatment results. Here we can see the enhancing recurrent tumor. This was at six weeks. This is at six months, and we get the idea that we pull the enhancement out of back here and perhaps have a necrotic area there. And again, the trouble is that as we've necrosed this area out, we see progression at the margin, as we well know. And this is now at 10 months out. So, at least some short-term control of this lesion. Our median survival from the date of radiosurgery was slightly over a year with a range of 15 to 82 weeks. And it really didn't seem to matter, at least in our hands, whether you had a grade four originally, or an oligo originally. They all come in here at slightly over a year. Perhaps, if we had greater numbers they'd select out differently. But we think most of these tumors by this point have dedifferentiated back into the nastier-acting group.
Symptom relief. Nine of 14 patients had symptoms at the time of treatment, and eight of the nine improved at least for a short term, five were asymptomatic, and one of the five worsened acutely and went the wrong way.
Steroid use. Two increased acutely after two weeks post-radiosurgery taper and at least three others increased at a later time, most likely due to radiation effects. And as we know, it's very difficult at times to try to tell if this is due to recurrent tumor, due to necrosis from the high-dose area. We do a lot of bringing our follow-up exams back into the treatment planning exam, fusing them, and trying to sort out where and what might be going on.
In these highly selective patients, stereotactic radiosurgery and the hypofractionated form also offered symptom relief with reasonable toxicity. MR improvement was often seen, but the significance of this is how it relates to ultimate survival, I don't think it's really truly known. Are we merely yes, treating the part that doesn't count anymore? I don't think so. I think it can help. And in the few minutes, I think hopefully I've left myself, I'd like to show you not only some caveats but also where we might be taking this in the future. Our patient population was relatively young. It was a relatively long time to progression pre-radiosurgery. We had a number of oligo histologies, which we think tend to do a bit better, although we didn't really show it in these limited numbers. And other agents were given to these patients post radiosurgery. We'd like to use the time to progression.
But when we try to determine when is the exact time to progression, sorting out the scans, what's necrosis? What's not? I don't know that I am good enough to tell time to progression. One of the interesting things we're starting to see though, and I think many of you may be seeing this as well, is now that a vast Bevacuzimab, the antibody against VEGF, is being used more and more is there a potential role for combining those together? This is a patient in 2005 that had a grade two non-enhancing astrocytoma treated with subtotal excision 50.4GY. Two years later, it recurred here, This was resected. Now, grade three on pathology, at least, and what had a gross total excision was placed on Temodar. By January he is starting to progress here, with enhancement and sort of patchy enhancement, and much more substantial T2 changes. This was up where they had operated on earlier. And so, we went after this and treated five fractions at 85%. We put in the pseudo structures here when we don't like how the computer is helping us shape the dose, and we push the dose back to where we want it to be.
This is the CT. You can see it's picking up a little bit of contrast. Even on our planning CT, we always give it just to be sure that we really are matched well. But here, we targeted the whole area. And we prescribed this at about 85%. And really our most of our [inaudible 00:12:07] was only about 5.5GY, We were a little worried about that. Nevertheless, we made the thing madder than the dickens. And though it kicked up a ton of edemas, it's like Dr. Chen has shown here, we've got all this enhancement in here. We think this is a big necrotic area. And when we look inferiorly, to make matters worse, we now see some enhancement outside the area. The patient's having hemiplegia. We're discussing possible hospice. But since he's relatively young, we put him on steroids and the Bevacuzimab. In the area of enhancement, the new enhancement, I should say or question of progression, we saw some improvement here, at least modest improvement. The patient's symptoms got better. But I think even more interesting in the area that we thought might be necrosis versus that, and this is a relatively short period of time between the scans, we haven't done surgery. Is this improvement here all steroids? Is this the steroids and the VEGF antibody not only cutting our enhancement but maybe taking out some of the vascular supply leaky vessels and helping this status?
So, I guess our hypothesis here is, you know, by closing down the leaky vessels in necrotic regions, breaking inflammatory cascade, allowing healing, can Bevacuzimab allows us to use the radiosurgery more safely? You know, can you bang the dickens out of the area, and then cut off some of the blood vessel's supply to it, and then potentially improve your therapeutic ratio somewhat by this combination? We continue to try to use stereotactic radiosurgery, both single-dose for the smaller areas and five fractions for recurrent tumors. And we're putting many of them now on to Bevacuzimab and potentially using it as a prospective future course.
Thank you for your time. I'd also like to thank all of our colleagues back at Loyola who've helped make these treatments possible.