Transcript
Well, this will fit real nice with the previous talk. We sort of took the opposite approach and tried to look at those tumors at the base of the skull. Thank you for inviting me, by the way. This is a beautiful location. Kyoto was as well, too, and so was Mexico City. But, anyway. We look back at our meningioma patients and looked at a group of patients from my own series. A number of patients, of course, surgery, in our practice, is still the biggest portion of treatment for meningiomas. But I think that's changing over time. When I looked at this series, it included 87 patients that had radiation therapy as part of their treatment. There were 54 patients that were non-skull-base location, and of those patients, there were three patients that required a reoperation for symptomatic edema.
Two of those patients were cancer patients, and so it was more done just... They were both breast cancer patients. I had a very low threshold for reoperating on them. Probably could have gotten them through longer, but there was some question of the diagnosis. But this talk really focuses on those patients of the skull base, of which there were 33 patients. I broke them down into three groups: those patients who were treated with radiosurgery or fractionated radiotherapy, stereotactic radiotherapy only. And these I put in for a comparison. Patients who were treated with radiosurgery as a salvage after they had failed surgical therapy, and 13 patients who were treated with radiosurgery upfront as an immediate post-op adjuvant. And I define that as them receiving radiosurgery within two months after having a surgical resection. And as you'll see, most of those, there was a post-op residual that we treated.
This is how the patients break down. They're very similar in their demographic information. Matter of fact, the things that are interesting from this, like, the surgery group, preoperatively, the tumors were bigger, but at the time of radiosurgery, they're really comparable with those that were treated for progression or recurrence of tumor after surgical resection. The ones treated with fractionated radiotherapy are a bigger tumor volume than those treated with radiosurgery. And the breakdown was, four of the... See, that's not right. So, six patients were treated with fractionated radiotherapy, and four with stereotactic radiosurgery only as their...in this comparison group.
The other thing that's interesting to note is that, this group where we treated the patients immediately after their surgical resection or within the first two months, these are mostly cavernous sinus tumors. So, the tumor was resected up to the wall of the cavernous sinus, and then the cavernous sinus portion of the tumor was treated. And this was a planned preoperative decision that was made that... That button eludes me every time I turn it here. It was a decision made that that's how these patients would be treated.
Our hypothesis was that the lesions of the skull base may have a higher complication rate due to their proximity to neurovascular structures. We thought that there was a high rate of tumor control, but had never analyzed it directly, and thought that it could be a useful salvage technique for those patients that have failed surgical therapy.
We have an image analysis program that we use for another purpose in my laboratory, and it allows us to do volumetric measurements of serial MRIs over time. And so these patients we analyzed looking at their volume of tumor over time, as well as the T2-weighted changes, or that you might turn peritumoral edema, and follow that over time, even if it was asymptomatic. And that's one of the things that I'll show here.
So we looked at clinical factors, both preoperative and postoperative complications related to radiotherapy. There were a number of complications related to surgery, but we left those out to cranial neuropathies and postoperative problems. But those aren't included. Those were felt to be unrelated to the radiosurgical treatment. We looked at the imaging, looking at both the preoperative and postoperative serial images for treatment volumes and the peritumoral edema T2-weighted changes. And then there's a small portion where we looked at some of the molecular factors in the tumors that had been resected, that we had tissue. We looked at some molecular factors, as our first speaker alluded to.
So the first group, these are patients who were treated with surgery, then immediately treated in the postoperative period. Their pre-op volumes were about 10 centimeters, and their pre-treatment volumes decreased over time. We found that all 13 of these patients had control of their tumor. Most had decreased size, as you can see from the... Thank you. Thank you. Most had decreased size over time. And this was at an average of 33 months of follow-up.
There was one patient that had a T2-weighted change on his MRI that persisted for a couple of years, and one patient developed a delayed capsular infarct, I think unrelated. It would have been within the radiation field, but it would have been outside of the 20% isodose line. So I don't think that was related. And one patient, the same patient with the T2-weighted changes, that actually required steroids for a period of time. And I'll show that. I've got a timeline to work that out a little bit more.
The second group are those patients that had a seemingly complete surgical resection, and then at a delayed time, on average, more than six months later, developed recurrence of their tumor. As you can see, most of these patients had a complete resection. They started out with a large tumor volume, were down to what we consider either a very small residual or no residual, and then at the time of radiosurgery had recurred a sizable volume, and then, currently, most of those patients, on average, have a decreased tumor volume.
In this group, we had 9 out of 10 patients with control at 33 months of average follow-up. One patient had a failure at 33 months after surgery, had recurrence of a tumor 33 months after surgery. She was treated with fractionated radiotherapy, and eight months later, had a progression. Had, essentially, meningeal mitosis, with multiple meningiomas popping up at that point. Some were treated with radiosurgery, and then she had progression. And I've put her on a clinical trial that I have, using a chemotherapeutic regimen. She's still alive and has a slowly progressive tumor at this point, almost four years after original surgery.
Five out of the 10 patients in this group developed T2-weighted changes. One of the five was symptomatic enough to require steroid therapy. One patient, as I mentioned, had persistent headaches and pressure symptoms, requiring steroid treatment. One patient had a new onset of seizure 14 months after treatment for a cavernous sinus meningioma. She had some T2-weighted changes in her temporal lobe but was controlled with antiepileptic medications, which we've kept her on for the past three years. One patient had trigeminal pain about nine months after her surgery. But that actually dissipated over time. I treated her initially with Tegretol and was able to wean her off of that, and, currently, she's without pain.
Then, finally, as a comparison, 10 patients who were treated predominantly or treated only with radiosurgery or radio fractionated stereotactic radiotherapy, all of these patients have shown a decrease in tumor volume over time. Ten out of 10 patients with tumor controlled at a median of 26 months of post-treatment. One of the 10 patients had a persistent T2-weighted change but never was symptomatic from those changes. And we had no treatment-related complications in this group.
This is a really busy slide, but it's color-coded, so don't get too nervous about it. This is over time, and this is volume of T2-weighted change seen on the magnetic resonance imaging. The color in blue is the patients that were treated in the surgery with upfront radiosurgery, and the one patient that did have persistent T2-weighted changes, which have now resolved, and required steroid therapy for quite a long time. And this was in a very low dose. Started out treating with 2 milligrams BID, but eventually was down to 0.5 milligrams BID. And a lot of it was her own...I think it was her own preference. She preferred to stay on that regimen because I think she felt good and it didn't give her a problem. And I finally was able to get her off of that around this time.
The group in green is a patient who was treated with radiosurgery only. Was not symptomatic. Started out with peritumoral edema to begin with, before the radiosurgery, had a spike, then has resolved over the space of a couple of years. And then there were patients in the radiosurgery as a salvage therapy that showed a variable pattern. One patient started out with very high peritumoral edema, and for some reason, it just dropped off after having the radiosurgery as the tumor regressed. The one patient in this group also required prolonged steroid therapy and had become symptomatic. So two patients in all the required some treatment with steroids, usually, low dose.
Then, we were lucky enough to have tissue available on 13 patients from the groups that were treated. No, I should say, 8 out of the 13 patients in the surgery with upfront radiosurgery, I had tissue available. One of those patients was one of the patients that required steroid therapy. In the group that was treated with radiosurgery as a salvage, I had tissue out of 6 out of 10 patients. Four of those were patients that had edema. And we analyzed them for vascular endothelial growth factor and hypoxia-inducible factors, the predominant regulating gene of vascular endothelial growth factor. This transcription factor is regulated tightly by hypoxia and is felt by many to be related to angiogenesis and glucose metabolism in tumors. There's also some downstream proteins, glucose transporter 1 and carbonic anhydrase 9 that are also regulated by HIF. And we looked at these as molecular markers of hypoxia and vascular angiogenesis. We also looked at proliferation rate using the Ki-67 antibody to measure MIB-1 indexes, and then microvascular density to measure the number of blood vessels within that given tumor specimen.
Now, unfortunately, these are all pre-op or pre-radiosurgery tissues. I don't have any post-op, because nobody failed and required surgery. And it's good for the patients, but not so good for, I guess, this particular study. And then tried to compare those patients that had these T2-weighted changes versus the ones that didn't, from a molecular standpoint. And it turned out, there really wasn't any difference in the mitotic or the proliferation index between the two, the edema group and the non-edema group, or the number of blood vessels. Although it appeared to have reached a significance, there was enough veritability that it did not reach a statistical difference between...
What did show a difference, of course, is vascular endothelial growth factor. And these are examples of those highly expressing VEGF versus those with very little expression of VEGF. And the same with hypoxia-inducible factor, a high expression and then low expression. And we found that these molecules, in general, were elevated in the preoperative tumor samples, suggesting that there's probably some molecular factors that we can't necessarily control for the inherent biology of the meningiomas that we may not have any control of when we perform radiosurgery on these tumors.
So, my conclusions from analyzing our data so far in this very small series is that it appears to be safe and effective for treatment of skull base lesions. There seems to be a higher complication rate, although it's not very high to begin with. In those patients that it's treated as a salvage therapy, it's probably that those patients have either worst tumors or have a worst biology because they've shown progression after a surgical resection.
But it appears that that group may be at some risk to develop, certainly, T2-weighted changes. And some of those are symptomatic. And then in the group that were treated with upfront radiosurgery or fractionated stereotactic radiotherapy, immediately after surgery, as an adjunct, it appears to have a very low complication rate and be a very safe way to treat patients with residual tumor after surgical resection. Thanks.
Two of those patients were cancer patients, and so it was more done just... They were both breast cancer patients. I had a very low threshold for reoperating on them. Probably could have gotten them through longer, but there was some question of the diagnosis. But this talk really focuses on those patients of the skull base, of which there were 33 patients. I broke them down into three groups: those patients who were treated with radiosurgery or fractionated radiotherapy, stereotactic radiotherapy only. And these I put in for a comparison. Patients who were treated with radiosurgery as a salvage after they had failed surgical therapy, and 13 patients who were treated with radiosurgery upfront as an immediate post-op adjuvant. And I define that as them receiving radiosurgery within two months after having a surgical resection. And as you'll see, most of those, there was a post-op residual that we treated.
This is how the patients break down. They're very similar in their demographic information. Matter of fact, the things that are interesting from this, like, the surgery group, preoperatively, the tumors were bigger, but at the time of radiosurgery, they're really comparable with those that were treated for progression or recurrence of tumor after surgical resection. The ones treated with fractionated radiotherapy are a bigger tumor volume than those treated with radiosurgery. And the breakdown was, four of the... See, that's not right. So, six patients were treated with fractionated radiotherapy, and four with stereotactic radiosurgery only as their...in this comparison group.
The other thing that's interesting to note is that, this group where we treated the patients immediately after their surgical resection or within the first two months, these are mostly cavernous sinus tumors. So, the tumor was resected up to the wall of the cavernous sinus, and then the cavernous sinus portion of the tumor was treated. And this was a planned preoperative decision that was made that... That button eludes me every time I turn it here. It was a decision made that that's how these patients would be treated.
Our hypothesis was that the lesions of the skull base may have a higher complication rate due to their proximity to neurovascular structures. We thought that there was a high rate of tumor control, but had never analyzed it directly, and thought that it could be a useful salvage technique for those patients that have failed surgical therapy.
We have an image analysis program that we use for another purpose in my laboratory, and it allows us to do volumetric measurements of serial MRIs over time. And so these patients we analyzed looking at their volume of tumor over time, as well as the T2-weighted changes, or that you might turn peritumoral edema, and follow that over time, even if it was asymptomatic. And that's one of the things that I'll show here.
So we looked at clinical factors, both preoperative and postoperative complications related to radiotherapy. There were a number of complications related to surgery, but we left those out to cranial neuropathies and postoperative problems. But those aren't included. Those were felt to be unrelated to the radiosurgical treatment. We looked at the imaging, looking at both the preoperative and postoperative serial images for treatment volumes and the peritumoral edema T2-weighted changes. And then there's a small portion where we looked at some of the molecular factors in the tumors that had been resected, that we had tissue. We looked at some molecular factors, as our first speaker alluded to.
So the first group, these are patients who were treated with surgery, then immediately treated in the postoperative period. Their pre-op volumes were about 10 centimeters, and their pre-treatment volumes decreased over time. We found that all 13 of these patients had control of their tumor. Most had decreased size, as you can see from the... Thank you. Thank you. Most had decreased size over time. And this was at an average of 33 months of follow-up.
There was one patient that had a T2-weighted change on his MRI that persisted for a couple of years, and one patient developed a delayed capsular infarct, I think unrelated. It would have been within the radiation field, but it would have been outside of the 20% isodose line. So I don't think that was related. And one patient, the same patient with the T2-weighted changes, that actually required steroids for a period of time. And I'll show that. I've got a timeline to work that out a little bit more.
The second group are those patients that had a seemingly complete surgical resection, and then at a delayed time, on average, more than six months later, developed recurrence of their tumor. As you can see, most of these patients had a complete resection. They started out with a large tumor volume, were down to what we consider either a very small residual or no residual, and then at the time of radiosurgery had recurred a sizable volume, and then, currently, most of those patients, on average, have a decreased tumor volume.
In this group, we had 9 out of 10 patients with control at 33 months of average follow-up. One patient had a failure at 33 months after surgery, had recurrence of a tumor 33 months after surgery. She was treated with fractionated radiotherapy, and eight months later, had a progression. Had, essentially, meningeal mitosis, with multiple meningiomas popping up at that point. Some were treated with radiosurgery, and then she had progression. And I've put her on a clinical trial that I have, using a chemotherapeutic regimen. She's still alive and has a slowly progressive tumor at this point, almost four years after original surgery.
Five out of the 10 patients in this group developed T2-weighted changes. One of the five was symptomatic enough to require steroid therapy. One patient, as I mentioned, had persistent headaches and pressure symptoms, requiring steroid treatment. One patient had a new onset of seizure 14 months after treatment for a cavernous sinus meningioma. She had some T2-weighted changes in her temporal lobe but was controlled with antiepileptic medications, which we've kept her on for the past three years. One patient had trigeminal pain about nine months after her surgery. But that actually dissipated over time. I treated her initially with Tegretol and was able to wean her off of that, and, currently, she's without pain.
Then, finally, as a comparison, 10 patients who were treated predominantly or treated only with radiosurgery or radio fractionated stereotactic radiotherapy, all of these patients have shown a decrease in tumor volume over time. Ten out of 10 patients with tumor controlled at a median of 26 months of post-treatment. One of the 10 patients had a persistent T2-weighted change but never was symptomatic from those changes. And we had no treatment-related complications in this group.
This is a really busy slide, but it's color-coded, so don't get too nervous about it. This is over time, and this is volume of T2-weighted change seen on the magnetic resonance imaging. The color in blue is the patients that were treated in the surgery with upfront radiosurgery, and the one patient that did have persistent T2-weighted changes, which have now resolved, and required steroid therapy for quite a long time. And this was in a very low dose. Started out treating with 2 milligrams BID, but eventually was down to 0.5 milligrams BID. And a lot of it was her own...I think it was her own preference. She preferred to stay on that regimen because I think she felt good and it didn't give her a problem. And I finally was able to get her off of that around this time.
The group in green is a patient who was treated with radiosurgery only. Was not symptomatic. Started out with peritumoral edema to begin with, before the radiosurgery, had a spike, then has resolved over the space of a couple of years. And then there were patients in the radiosurgery as a salvage therapy that showed a variable pattern. One patient started out with very high peritumoral edema, and for some reason, it just dropped off after having the radiosurgery as the tumor regressed. The one patient in this group also required prolonged steroid therapy and had become symptomatic. So two patients in all the required some treatment with steroids, usually, low dose.
Then, we were lucky enough to have tissue available on 13 patients from the groups that were treated. No, I should say, 8 out of the 13 patients in the surgery with upfront radiosurgery, I had tissue available. One of those patients was one of the patients that required steroid therapy. In the group that was treated with radiosurgery as a salvage, I had tissue out of 6 out of 10 patients. Four of those were patients that had edema. And we analyzed them for vascular endothelial growth factor and hypoxia-inducible factors, the predominant regulating gene of vascular endothelial growth factor. This transcription factor is regulated tightly by hypoxia and is felt by many to be related to angiogenesis and glucose metabolism in tumors. There's also some downstream proteins, glucose transporter 1 and carbonic anhydrase 9 that are also regulated by HIF. And we looked at these as molecular markers of hypoxia and vascular angiogenesis. We also looked at proliferation rate using the Ki-67 antibody to measure MIB-1 indexes, and then microvascular density to measure the number of blood vessels within that given tumor specimen.
Now, unfortunately, these are all pre-op or pre-radiosurgery tissues. I don't have any post-op, because nobody failed and required surgery. And it's good for the patients, but not so good for, I guess, this particular study. And then tried to compare those patients that had these T2-weighted changes versus the ones that didn't, from a molecular standpoint. And it turned out, there really wasn't any difference in the mitotic or the proliferation index between the two, the edema group and the non-edema group, or the number of blood vessels. Although it appeared to have reached a significance, there was enough veritability that it did not reach a statistical difference between...
What did show a difference, of course, is vascular endothelial growth factor. And these are examples of those highly expressing VEGF versus those with very little expression of VEGF. And the same with hypoxia-inducible factor, a high expression and then low expression. And we found that these molecules, in general, were elevated in the preoperative tumor samples, suggesting that there's probably some molecular factors that we can't necessarily control for the inherent biology of the meningiomas that we may not have any control of when we perform radiosurgery on these tumors.
So, my conclusions from analyzing our data so far in this very small series is that it appears to be safe and effective for treatment of skull base lesions. There seems to be a higher complication rate, although it's not very high to begin with. In those patients that it's treated as a salvage therapy, it's probably that those patients have either worst tumors or have a worst biology because they've shown progression after a surgical resection.
But it appears that that group may be at some risk to develop, certainly, T2-weighted changes. And some of those are symptomatic. And then in the group that were treated with upfront radiosurgery or fractionated stereotactic radiotherapy, immediately after surgery, as an adjunct, it appears to have a very low complication rate and be a very safe way to treat patients with residual tumor after surgical resection. Thanks.