Transcript
I really appreciate the opportunity to present our work here today. And Doug had mentioned that I would be addressing some of the old rules, and that's true. I think it's important to say that, for the foreseeable future, surgery has grouped into the old roles category, I think is going to be part of our armamentarium when we're looking at taking care of these patients. And I think like any technical procedure, the degree to which any surgeon or individual center will take advantage of this set of techniques will be dependent on how effectively they can do it in hand, to what degree of morbidity with respect to the case that Doug showed here a couple of minutes ago. Assuming that the patient wanted to have surgery, we would have just taken that out. We can take out fairly large tumors with fairly small holes these days, and our patients seem to be doing quite well, particularly with new anesthetic techniques. So,
if you can't accomplish that type of result in your center, then I think that there needs to be a higher threshold for doing surgery and a lower threshold for doing other procedures. But, again, I'm going to be talking mostly on defining the role of surgical therapies in combination with other therapies for cerebral metastases. And I have really no disclosures that are relevant to this conversation.
I do want to mention that a number of our pilot studies were funded by the Brain Tumor Fund for the Carolinas. Doug had mentioned the overall issue that we face with cerebral metastases. And I think everybody is worried this is an incredibly prevalent disease and their metastases represent significant source of morbidity and mortality in society. The therapies for cerebral metastases can be largely grouped into these categories, radiation therapies, surgery and targeted therapies, and immunotherapies. As Doug had mentioned, the last category is really changing the entire playing field. I'm not going to talk about that too much other than to re-emphasize what Doug was saying in that, the way we're conceptualizing this disease, and almost monthly basis is changing because of that third category. But nonetheless, that's a very broad area. I'm going to be focusing on these areas that Doug had mentioned, or more traditional legacy therapies. And I'm going to start by saying that with respect to radiation therapies, this really has been, if you look at historically at main stain of treatment for brain metastases and isolated therapies, isolated radiation therapies have long been known to prolong survival and improve neurologic symptoms in these patients.
And really, when we look at surgery, the way we've come to define our surgical therapies really has a lot to do with the way we were originally asked questions related to what we can add, in addition to radiation therapies. And as an example, whole-brain radiation therapy used to be the standard of care for most of these patients. And so investigators, many years ago started asking this question. "Does surgical therapy produce benefit when added to radiation therapy?" Patchell was really one of the first individuals to look at this in detail in 1990. And as it turns out, yes, when you add surgery to, for example, whole-brain radiation therapy, you can increase survival of these patients, and decrease risk of local recurrence and decrease risk of neurologic death.
Various investigators were recently have looked at this, in the context of focused radiation therapy. These are two large retrospective analyses I'm throwing up here, but similar effects have been noticed. In other words, when you add surgery to focus therapies, you seem to see various improvements in patient experience. And so, therefore, surgery is thought to be a reasonable treatment option for select patients. And who are those patients? The primary indication based on the best data that we have are patients with solitary lesions, low risk of new deficit with surgery, high-performance score, likely return to a high-performance score with surgery. And an example would be a patient with a large cyst, low systemic burden, and stable disease.
And just to put things in perspective, how many patients would we potentially be looking at. Well, two-thirds of patients have oligometastatic disease as fairly described. We describe oligometastatic disease as 1 to 3 metastases. If two-thirds of patients have that, 50% of those have a solitary metastasis in the United States, you're probably looking at 100,000 patients. Even if a fraction of those patients were thought to be a candidate for surgery, you're still looking at tens of thousands of individuals who potentially benefit from that therapy. Secondary indications or a single dominant lesions, I won't get into that in too much detail. And I believe that surgery is rarely indicated for multiple metastases. If surgery does add benefit, then even if we observed a positive effect of radiation therapy in the past, it's reasonable to ask the reverse question. And that is, do adjuvant radiation process produce benefit when they are administered after resection of stream of metastases? And the answer to that is largely, yes, if you're looking at a specific outcome. That is to say, that adjuvant radiation therapy administered in conjunction with resection, decreases the risk of local recurrence. And this has been looked at prospectively in both the context of whole-brain radiation therapy, [inaudible 00:05:36] Patchell, and then also more recently, in the context of stereotactic radiosurgery.
And if we look at the second trial that was published out of MD Anderson experienced recently, in patients that were either observed after surgery or had post-operative radiosurgery, 57% of the patients had local recurrence in the observation group versus 28% in the SRS group. Patchell had seen a larger effect when he was looking at that, in the context of the whole brain.
Nonetheless, it appears to produce benefit when we're looking at local recurrence. But if we were willing to accept this, then what form of radiation therapy should be administered? Doug had mentioned these recent changes around whole-brain radiation therapy. If we just look at this very briefly, whole-brain radiation therapy improves local control. We talked about that. But it also decreases the incidence of new brain metastases, and in some centers were dramatic than the numbers that I'm putting up here. So, it improves overall brain control. But despite significant improvements in intracranial control, in general, no consistent improvement in survival has been noted with the addition of whole-brain radiation therapy to surgery or stereotactic radiosurgery, so focused therapies.
So the absence of a survival advantage, we have to ask this question. We consider this rather, that the potential risks or benefits of adjuvant cancer therapies related to the outcomes that we can influence need to be our highest consideration. And in this particular situation, the survival is off the table and that would normally relate to the quality of life and neurocognition. And I won't go into these analyses in great detail, but I will summarize a number of important studies. Doug had mentioned our paper in JAMA a few years ago, but I think there's no doubt now that most investigators believe that the addition of whole-brain radiation therapy to local therapies results in significant declines in neurocognition and quality of life, despite the fact that we are reducing the incidence of new brain metastases. And most of the studies I'm showing here, are looking at whole-brain radiation therapy, as it relates to stereotactic radiosurgery.
This last paper that Paul Brown and his colleagues published in Lancet Oncology, I think, it was particularly interesting to us because this one looked at surgical resection followed by whole-brain radiation therapy versus stereotactic radiosurgery. And they saw consistent with other information that it presented a decline in cognitive function that was more frequent when adjuvant whole-brain radiation therapy was administered versus an SRS boost, and, again, there was no difference in survival.
So their recommendation, our recommendation, and our JAMA partner was that SRS is a less toxic alternative to whole-brain radiation therapy for patients undergoing focus therapies, in this case, of after resection of brain metastases. And so, there is this growing consensus that we talked about that we need to be moving away from whole-brain radiation therapy. So, in this environment, various centers have employed novel treatment modality of providing single-session stereotactic radiosurgery boosts to the surgical resection site to achieve local control without the risk of neurocognitive effects, or at least those risk that would have been associated with whole-brain radiation therapy. This has been a particularly influential study. It was a retrospective analysis published out of Stanford, 2008. But on the basis of their experience, they recommended a non-conformal approach, which is to say to put a margin around the treatment area. And I think that this has resulted in some of the effects that we have observed over the years. Paul says this, small boxes moved over. But most of the retrospective SRS analyses, that say SRS after resection metastasis have shown fairly good local control ranging from the mid 70% to 90%. However, if you look at these various studies, as it relates to a couple important outcomes, radiation necrosis, and leptomeningeal disease that the numbers, as we saw them look a little on the high side. And at first, wasn't something that was on our radar, but it became increasingly important to us in [inaudible 00:09:55] valuations.
As Doug had mentioned, we have started doing something called neoadjuvant radiosurgery, and simply giving radiosurgery prior to resection of a tumor. We started doing this primarily because we really didn't quite know where to put the volume around some of these resection cavities were quite regular. And we decided that if we treated patients beforehand, we could achieve highly conformal plans. Regardless of the volume of brain treated, we felt that this was just an easier approach. But over time, we thought that there was a greater advantage, which is to say the pre-operative treatment could reduce the risk of intra-operative dissemination of viable tumor cells, and we'll talk about this in more detail in a second. So we adopted this approach slowly starting in around 2005 in patients with oligometastases and stable systemic disease. We adopted a 20% dose reduction from RTOG dosing standards, which I'll describe in detail during the discussion period. But we believe that this has resulted in reduced erase of radiation necrosis. And, again, these are mostly conformable dose plans.
We published our original series of 47 consecutively treated patients in 2014, in the radiation oncology, Red Journal. As Doug mentioned, we're operating on mostly larger tumors and relatively smaller doses to the treatment line. And this was the bottom line of that particular paper, our local control rates were quite high when we compare the data to the post-operative radiation analysis. And we saw no evidence of radiation necrosis and original analysis, no evidence of leptomeningeal disease, but that wasn't our focus at that time.
We performed another analysis because, at this point, we were interested in starting to compare neoadjuvant versus adjuvant stereotactic radiosurgery in resected patients. This was a paper that we published a little while ago looking at our experience and Burri's experience. Burri was exclusively doing post-operative radiation therapy. The local and distant recurrence was similar, but, in this paper was the first time we really started seeing fairly significant differences in the incidence of leptomeningeal disease and radiation necrosis between these groups. And here are the numbers here are pre-operatively. The numbers were quite low single digits, whereas double-digit radiation necrosis and leptomeningeal disease in the postoperative group.
We recently... and this has actually just been accepted for publication, but sent in this new analysis looking now at 117 consecutively treated patients. We're now seeing, in a longer follow up some evidence of radionecrosis, and leptomeningeal disease in new adjuvant patients. But, again, these numbers are quite low compared to the patients treated postoperatively.
Another relevant analysis is a paper that we published last year looking at pre-op SRS versus post-op whole-brain radiation therapy because we wanted to compare our data to what was previously what we believe to be the standard of care with respect to control of leptomeningeal disease. And in this particular paper, the results of LMD pre-op SRS to patients receiving whole-brain radiotherapy were roughly similar. So we believe this approach achieves a control that says similar to what you could even for whole-brain radiation therapy. And I think there is some controversy relative to, whether or not this leptomeningeal disease and what we're observing is clinically significant. Here's an anecdote of a patient who had a gross total resection of a tumor who received postoperative radiation therapy, subsequently developed this fairly severe case of a leptomeningeal disease that was very difficult to control and quite symptomatic.
I'm going to just so we can move on just mentioned that we are going to publish this analysis. This paper has been presented at ASTRO and ASCO regarding a seven institution analysis of patients who have developed leptomeningeal disease after either pre-operative SRS, or postoperative SRS. And to me, this was a really interesting analysis for the following reasons. Eighty-eight percent of patients, again, these are patients who had resection, and then either pre-op SRS and resection or post-op, and the majority of post-op SRS. Eighty-eight percent of patients received salvage therapy for leptomeningeal disease. The majority of these patients received whole-brain radiation therapy as part of their initial salvage therapy. So they were receiving therapy that we know to be toxic from a cognitive standpoint. Sixty percent of the patients with LMD were symptomatic. And interestingly, the majority of LMD recurrences were nodular. Doug was talking about this, it may suggest that they would be treated well with focused therapies. But if we could avoid that, in the first place, it would be ideal.
So, if we look at LMD, in general, we don't think this is a radiographic phenomenon. This came up when we submitted a protocol to a CTAP recently. The patients are generally symptomatic. The patients with LMD almost always require additional treatment, in many cases, they require a toxic additional treatment.
So, I will just summarize by saying we're working with the RTOG to develop this randomized protocol, looking at post-operative versus pre-operative SRS. And we're hopeful that this will achieve approval sometime early next year. In summary, we really have achieved an end of an era in treatment of cerebral metastases, at least as we're looking at these, or traditional therapies as Doug has characterized them. We no longer routinely employ adjuvant whole-brain radiation therapy for oligometastases, we're completing a paradigm shift to routine use of focus therapies, particularly for oligometastases. And present scientific discussions are focused on the appropriate use or combination of specific target therapies and their use in combination with novel systemic therapies.
I should mention that the move away from whole-brain radiation therapy and mine has interestingly solved one problem, but has created another because we're seeing what we believe to be an unacceptable rate of leptomeningeal disease after resection then focused radiation therapy.
We believe a new adjuvant SRS prior to surgical resection could be performed safely and effectively with low rates of radiation necrosis and LMD. Local control is excellent even in the setting of large lesions, and a strong majority of patients can avoid whole brain. And I'll leave you with this thought. We are now starting to look at even larger lesions and asking for patients that even we wouldn't treat with a single fraction radiation therapy, whether or not SRT or other fractionated approaches might be appropriate prior to resection of these patients, and we're starting to analyze that prospectively. Thank you very much.
if you can't accomplish that type of result in your center, then I think that there needs to be a higher threshold for doing surgery and a lower threshold for doing other procedures. But, again, I'm going to be talking mostly on defining the role of surgical therapies in combination with other therapies for cerebral metastases. And I have really no disclosures that are relevant to this conversation.
I do want to mention that a number of our pilot studies were funded by the Brain Tumor Fund for the Carolinas. Doug had mentioned the overall issue that we face with cerebral metastases. And I think everybody is worried this is an incredibly prevalent disease and their metastases represent significant source of morbidity and mortality in society. The therapies for cerebral metastases can be largely grouped into these categories, radiation therapies, surgery and targeted therapies, and immunotherapies. As Doug had mentioned, the last category is really changing the entire playing field. I'm not going to talk about that too much other than to re-emphasize what Doug was saying in that, the way we're conceptualizing this disease, and almost monthly basis is changing because of that third category. But nonetheless, that's a very broad area. I'm going to be focusing on these areas that Doug had mentioned, or more traditional legacy therapies. And I'm going to start by saying that with respect to radiation therapies, this really has been, if you look at historically at main stain of treatment for brain metastases and isolated therapies, isolated radiation therapies have long been known to prolong survival and improve neurologic symptoms in these patients.
And really, when we look at surgery, the way we've come to define our surgical therapies really has a lot to do with the way we were originally asked questions related to what we can add, in addition to radiation therapies. And as an example, whole-brain radiation therapy used to be the standard of care for most of these patients. And so investigators, many years ago started asking this question. "Does surgical therapy produce benefit when added to radiation therapy?" Patchell was really one of the first individuals to look at this in detail in 1990. And as it turns out, yes, when you add surgery to, for example, whole-brain radiation therapy, you can increase survival of these patients, and decrease risk of local recurrence and decrease risk of neurologic death.
Various investigators were recently have looked at this, in the context of focused radiation therapy. These are two large retrospective analyses I'm throwing up here, but similar effects have been noticed. In other words, when you add surgery to focus therapies, you seem to see various improvements in patient experience. And so, therefore, surgery is thought to be a reasonable treatment option for select patients. And who are those patients? The primary indication based on the best data that we have are patients with solitary lesions, low risk of new deficit with surgery, high-performance score, likely return to a high-performance score with surgery. And an example would be a patient with a large cyst, low systemic burden, and stable disease.
And just to put things in perspective, how many patients would we potentially be looking at. Well, two-thirds of patients have oligometastatic disease as fairly described. We describe oligometastatic disease as 1 to 3 metastases. If two-thirds of patients have that, 50% of those have a solitary metastasis in the United States, you're probably looking at 100,000 patients. Even if a fraction of those patients were thought to be a candidate for surgery, you're still looking at tens of thousands of individuals who potentially benefit from that therapy. Secondary indications or a single dominant lesions, I won't get into that in too much detail. And I believe that surgery is rarely indicated for multiple metastases. If surgery does add benefit, then even if we observed a positive effect of radiation therapy in the past, it's reasonable to ask the reverse question. And that is, do adjuvant radiation process produce benefit when they are administered after resection of stream of metastases? And the answer to that is largely, yes, if you're looking at a specific outcome. That is to say, that adjuvant radiation therapy administered in conjunction with resection, decreases the risk of local recurrence. And this has been looked at prospectively in both the context of whole-brain radiation therapy, [inaudible 00:05:36] Patchell, and then also more recently, in the context of stereotactic radiosurgery.
And if we look at the second trial that was published out of MD Anderson experienced recently, in patients that were either observed after surgery or had post-operative radiosurgery, 57% of the patients had local recurrence in the observation group versus 28% in the SRS group. Patchell had seen a larger effect when he was looking at that, in the context of the whole brain.
Nonetheless, it appears to produce benefit when we're looking at local recurrence. But if we were willing to accept this, then what form of radiation therapy should be administered? Doug had mentioned these recent changes around whole-brain radiation therapy. If we just look at this very briefly, whole-brain radiation therapy improves local control. We talked about that. But it also decreases the incidence of new brain metastases, and in some centers were dramatic than the numbers that I'm putting up here. So, it improves overall brain control. But despite significant improvements in intracranial control, in general, no consistent improvement in survival has been noted with the addition of whole-brain radiation therapy to surgery or stereotactic radiosurgery, so focused therapies.
So the absence of a survival advantage, we have to ask this question. We consider this rather, that the potential risks or benefits of adjuvant cancer therapies related to the outcomes that we can influence need to be our highest consideration. And in this particular situation, the survival is off the table and that would normally relate to the quality of life and neurocognition. And I won't go into these analyses in great detail, but I will summarize a number of important studies. Doug had mentioned our paper in JAMA a few years ago, but I think there's no doubt now that most investigators believe that the addition of whole-brain radiation therapy to local therapies results in significant declines in neurocognition and quality of life, despite the fact that we are reducing the incidence of new brain metastases. And most of the studies I'm showing here, are looking at whole-brain radiation therapy, as it relates to stereotactic radiosurgery.
This last paper that Paul Brown and his colleagues published in Lancet Oncology, I think, it was particularly interesting to us because this one looked at surgical resection followed by whole-brain radiation therapy versus stereotactic radiosurgery. And they saw consistent with other information that it presented a decline in cognitive function that was more frequent when adjuvant whole-brain radiation therapy was administered versus an SRS boost, and, again, there was no difference in survival.
So their recommendation, our recommendation, and our JAMA partner was that SRS is a less toxic alternative to whole-brain radiation therapy for patients undergoing focus therapies, in this case, of after resection of brain metastases. And so, there is this growing consensus that we talked about that we need to be moving away from whole-brain radiation therapy. So, in this environment, various centers have employed novel treatment modality of providing single-session stereotactic radiosurgery boosts to the surgical resection site to achieve local control without the risk of neurocognitive effects, or at least those risk that would have been associated with whole-brain radiation therapy. This has been a particularly influential study. It was a retrospective analysis published out of Stanford, 2008. But on the basis of their experience, they recommended a non-conformal approach, which is to say to put a margin around the treatment area. And I think that this has resulted in some of the effects that we have observed over the years. Paul says this, small boxes moved over. But most of the retrospective SRS analyses, that say SRS after resection metastasis have shown fairly good local control ranging from the mid 70% to 90%. However, if you look at these various studies, as it relates to a couple important outcomes, radiation necrosis, and leptomeningeal disease that the numbers, as we saw them look a little on the high side. And at first, wasn't something that was on our radar, but it became increasingly important to us in [inaudible 00:09:55] valuations.
As Doug had mentioned, we have started doing something called neoadjuvant radiosurgery, and simply giving radiosurgery prior to resection of a tumor. We started doing this primarily because we really didn't quite know where to put the volume around some of these resection cavities were quite regular. And we decided that if we treated patients beforehand, we could achieve highly conformal plans. Regardless of the volume of brain treated, we felt that this was just an easier approach. But over time, we thought that there was a greater advantage, which is to say the pre-operative treatment could reduce the risk of intra-operative dissemination of viable tumor cells, and we'll talk about this in more detail in a second. So we adopted this approach slowly starting in around 2005 in patients with oligometastases and stable systemic disease. We adopted a 20% dose reduction from RTOG dosing standards, which I'll describe in detail during the discussion period. But we believe that this has resulted in reduced erase of radiation necrosis. And, again, these are mostly conformable dose plans.
We published our original series of 47 consecutively treated patients in 2014, in the radiation oncology, Red Journal. As Doug mentioned, we're operating on mostly larger tumors and relatively smaller doses to the treatment line. And this was the bottom line of that particular paper, our local control rates were quite high when we compare the data to the post-operative radiation analysis. And we saw no evidence of radiation necrosis and original analysis, no evidence of leptomeningeal disease, but that wasn't our focus at that time.
We performed another analysis because, at this point, we were interested in starting to compare neoadjuvant versus adjuvant stereotactic radiosurgery in resected patients. This was a paper that we published a little while ago looking at our experience and Burri's experience. Burri was exclusively doing post-operative radiation therapy. The local and distant recurrence was similar, but, in this paper was the first time we really started seeing fairly significant differences in the incidence of leptomeningeal disease and radiation necrosis between these groups. And here are the numbers here are pre-operatively. The numbers were quite low single digits, whereas double-digit radiation necrosis and leptomeningeal disease in the postoperative group.
We recently... and this has actually just been accepted for publication, but sent in this new analysis looking now at 117 consecutively treated patients. We're now seeing, in a longer follow up some evidence of radionecrosis, and leptomeningeal disease in new adjuvant patients. But, again, these numbers are quite low compared to the patients treated postoperatively.
Another relevant analysis is a paper that we published last year looking at pre-op SRS versus post-op whole-brain radiation therapy because we wanted to compare our data to what was previously what we believe to be the standard of care with respect to control of leptomeningeal disease. And in this particular paper, the results of LMD pre-op SRS to patients receiving whole-brain radiotherapy were roughly similar. So we believe this approach achieves a control that says similar to what you could even for whole-brain radiation therapy. And I think there is some controversy relative to, whether or not this leptomeningeal disease and what we're observing is clinically significant. Here's an anecdote of a patient who had a gross total resection of a tumor who received postoperative radiation therapy, subsequently developed this fairly severe case of a leptomeningeal disease that was very difficult to control and quite symptomatic.
I'm going to just so we can move on just mentioned that we are going to publish this analysis. This paper has been presented at ASTRO and ASCO regarding a seven institution analysis of patients who have developed leptomeningeal disease after either pre-operative SRS, or postoperative SRS. And to me, this was a really interesting analysis for the following reasons. Eighty-eight percent of patients, again, these are patients who had resection, and then either pre-op SRS and resection or post-op, and the majority of post-op SRS. Eighty-eight percent of patients received salvage therapy for leptomeningeal disease. The majority of these patients received whole-brain radiation therapy as part of their initial salvage therapy. So they were receiving therapy that we know to be toxic from a cognitive standpoint. Sixty percent of the patients with LMD were symptomatic. And interestingly, the majority of LMD recurrences were nodular. Doug was talking about this, it may suggest that they would be treated well with focused therapies. But if we could avoid that, in the first place, it would be ideal.
So, if we look at LMD, in general, we don't think this is a radiographic phenomenon. This came up when we submitted a protocol to a CTAP recently. The patients are generally symptomatic. The patients with LMD almost always require additional treatment, in many cases, they require a toxic additional treatment.
So, I will just summarize by saying we're working with the RTOG to develop this randomized protocol, looking at post-operative versus pre-operative SRS. And we're hopeful that this will achieve approval sometime early next year. In summary, we really have achieved an end of an era in treatment of cerebral metastases, at least as we're looking at these, or traditional therapies as Doug has characterized them. We no longer routinely employ adjuvant whole-brain radiation therapy for oligometastases, we're completing a paradigm shift to routine use of focus therapies, particularly for oligometastases. And present scientific discussions are focused on the appropriate use or combination of specific target therapies and their use in combination with novel systemic therapies.
I should mention that the move away from whole-brain radiation therapy and mine has interestingly solved one problem, but has created another because we're seeing what we believe to be an unacceptable rate of leptomeningeal disease after resection then focused radiation therapy.
We believe a new adjuvant SRS prior to surgical resection could be performed safely and effectively with low rates of radiation necrosis and LMD. Local control is excellent even in the setting of large lesions, and a strong majority of patients can avoid whole brain. And I'll leave you with this thought. We are now starting to look at even larger lesions and asking for patients that even we wouldn't treat with a single fraction radiation therapy, whether or not SRT or other fractionated approaches might be appropriate prior to resection of these patients, and we're starting to analyze that prospectively. Thank you very much.