Transcript
I would like to welcome you to the Novalis Circle Symposium here on "Stereotactic Radiosurgery for Brain Metastases." And we will be talking about recent developments, especially also in the view of not only treating just brain metastases, but also treating multiple brain metastases.
Before I'm starting myself, personally, my name is Reinhard Wurm. I'm from Germany. So, all the other speakers, we had a slight change. So that speaker wise, it's a complete German session. We try our best to bring over the English, at least it will be not a German teaching lesson for you. And from that point of view, I also have to recognize the continued support of myself and my group for more than 20 years now by Brain Lab, research wise, and with travel grants and everything else. And also, I'm a member of the Novalis Certified Group, as such. And I'm going to start now to advance the slides here.
Okay. Just to give a little bit introduction into review, I've put up some numbers, the numbers are only there to show you how important the case when we talk about brain metastases. And there has been a lot of discussion about that, and we are facing now rising numbers of brain metastases, 40% of intracranial neoplasms. EU it's probably between 100,000 to close to 200,000. And they represent up to 45% of all cancer patients. In 9%, the CNS is the only site of metastases. Only 11% present with solitary metastases. And then, patients have about metastatic disease elsewhere. Substantial number of patients suffer from local CNS progression, and radiation is still the mainstay of treatment aiming at optimizing local control.
And so to speak, radiation for the brain for metastases was somehow introduced in 1944 by a guy called Sturzebecker [SP] in the U.S. who introduced whole-brain radiotherapy in the 1990s. We have seen the discussion done by the Patchell studies, really to put in the resection again and combinations, and then there also came stereotactic radiosurgery. First, we had a number of studies that were going on looking at combinations, stereotactic radiosurgery, plus whole-brain radiotherapy.
We have so many cases, and the question was mainly indication was solitary metastases, oligo metastases. But there was then the situation, what do you do with multiple metastases? For many, it was more or less the so-called reflex whole-brain radiotherapy or just do nothing. We personally in my group, we started almost 20 years ago, really, we only need to do a whole-brain radiotherapy only in exceptional cases. So, we started to treat more than one, two, three, even multiple metastases by stereotactic radiotherapy. When we look at the typical pictures like I brought here, this is a 48-year-old patient with a melanoma, solitary brain metastases via radiosurgery 25 gray to isocenter 80% covering this kind of situation. And it works quite well.
For one thing, the isocenter with optimized technology, it's quite easy. The treatment doesn't take that long. The treatment lasts about 15 minutes as such, and if it's done, normally nowadays, image-guided, it's also quite easy in that way, the set-up and the downstream. But if you treat several metastases, it's mainly involved that you treat several isocenters. And then, there's the question, how much time you're spending with the patient and does the patient need to spend in the treatment room? If we talk about multiple isocenter treatments in a group, and we have a heavy workload ourselves, we used to take about 9 to 12 minutes per isocenter. When we treated about five or six metastases, then it was easily an hour or more. The results for the patient was not quite comfortable. And the question was, we started then when, for instance, the high position, multileaf collimator came along with 2.5-millimeter leaf size, we started to do our treatment plans just with one single isocenter just putting the isocenter in the so-called geographical mass, within the multiple brain metastases and then do the treatment planning either with static beams or just by adding dynamic arcs.
Recently we have seen new developments, and my colleagues will talk about that later on. And that it works, it's quite clear. We see a typical situation here at treatment 3-month follow-up and 36 months' follow-up. And the studies along...and the analysis have brought more or less some prognostic factors to that Karnofsky state, age less than 65 years, controlled primary, and no extracranial metastases predicted for best prognosis in radiosurgery, and no extracranial disease is most significant for survival, maximum tumor diameter only variable associated with increased risk of unacceptable acute and/or chronic neurotoxicity.
Then by the end of the first centum of 2000. From Houston [SP], we have seen the paper in Lancet Oncology, Chang, and they looked at neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus or brain radiation, and they did randomized trials, small, randomized trial one, two three lesions, all the primaries and RPA classes I and II. And they looked also at the functional situation and normal cognition. And what I did find that the mean probability of normal cognitive decline at four months was 52% for SRS plus whole-brain radiotherapy, and 24% for SRS only, and 95% confidence interval. And from that point of view, it was really the situation, it was not only that we had acute at four months kind of situation, but we also had delayed recall, which was considerably higher in this kind of situation. When we looked in that paper, the situation of intracranial progression, there was a higher local and distant recurrence rate without whole-brain radiotherapy. And the question was really does this warrant the effort really to omit whole-brain radiotherapy?
And then there were the Japanese data around, by Yamamoto, and he looked at stereotactic radiosurgery for patients first with multiple brain metastases. And he did a Japanese multi-institutional prospective observation study, in total close to 1,200 patients. And 455 with 1 met, 531 with 2 to 4 and 208 with 5 to 10 mets. And it seemed from that that radiosurgery without whole-brain radiotherapy in patients with 5 to 10 brain mets is not inferior to that in patients with 2 to 4 brain metastases. And considering the minimal invasiveness of stereotactic radiosurgery and the fewer side effects than with whole-brain stereotactic radiosurgery, may be a suitable alternative for patients with up to 10 brain metastases.
He later on extended that, like shown here in this picture. And this also extends to the topic later on the treatment with multiple brain metastases. He looked at the kind of situation where treatment results for patients with 2 to 9 versus 10 or more brain metastases. He published it again, that was in the "Journal of Neurosurgery," that was in 2014, it came from the Gamma Knife proceedings.
And he did an update then in 2017 on this study, and he looked at the kind of situation, and he did a comparison. Yeah, Irradiation-related Complications and Long-term Maintenance of Mini-Mental State Examination Scores, because that was put at question quite a lot, because obviously, when you treat more and more brain metastases, then the volume of normal brain that you're going to treat is considerably higher. And he didn't find any changes in this kind of situation or any difference between one brain metastasis, 2 to 4 and 5 to 10 even over the long run up to 60 months and also looking at radiation complications. When he looked at that, there was also no significant difference between either group 1, 2 to 4 or 5 to 10. That means, neither the mini-mental score, maintenance nor post-SRS complication incidence was different among the different groups. This longer-term follow-up study, in his own words, supported the non-inferiority hypothesis of radiosurgery alone for patients with 5 to 10 versus 2 to 4 brain metastases.
I hope, I could set the outline a little bit for that. And we now go and carry on in the meeting that we will be looking at the kind of situation, clinical utilization of elements, multiple brain metastases, mets, with stereotactic radiosurgery. This was well-done by Dr. Niyazi from Munich. And the interesting thing is, like you see down here, that multiple brain metastases most of the data you cannot only treat it with the Gamma Knife, but you can also do that with an accelerator from the same company, that is suitable for stereotactic treatments. And which is also quite interesting, it's not only down to a super classical Novalis platform, but it can be extended further wise.
And I'm quite happy we had here a little change in program that Dr. Horvath, she's also from Germany from Stuttgart. She will be talking about response patterns, earlier using elements with contrast clearance analysis. And then later on, and that will be the last presentation, I already did speak about that a little bit, that with multiple isocenters, you have an extended time, you have a long treatment time, a higher burden to the patient and to the staff. And then, with the so-called elements for multiple brain metastases, the treatment is just as quick if you're going to treat one brain metastasis.
And Manuel Todorovic, the physicist from Hamburg, he will be then showing how you can even extend it to more complex multifocal planning, and what kind of IGRS requirements, that means image-guided radio surgery requirements, you do have in this kind of situation. And we will take questions at the end. And I would like to call up the next speaker, Dr. Niyazi.
Before I'm starting myself, personally, my name is Reinhard Wurm. I'm from Germany. So, all the other speakers, we had a slight change. So that speaker wise, it's a complete German session. We try our best to bring over the English, at least it will be not a German teaching lesson for you. And from that point of view, I also have to recognize the continued support of myself and my group for more than 20 years now by Brain Lab, research wise, and with travel grants and everything else. And also, I'm a member of the Novalis Certified Group, as such. And I'm going to start now to advance the slides here.
Okay. Just to give a little bit introduction into review, I've put up some numbers, the numbers are only there to show you how important the case when we talk about brain metastases. And there has been a lot of discussion about that, and we are facing now rising numbers of brain metastases, 40% of intracranial neoplasms. EU it's probably between 100,000 to close to 200,000. And they represent up to 45% of all cancer patients. In 9%, the CNS is the only site of metastases. Only 11% present with solitary metastases. And then, patients have about metastatic disease elsewhere. Substantial number of patients suffer from local CNS progression, and radiation is still the mainstay of treatment aiming at optimizing local control.
And so to speak, radiation for the brain for metastases was somehow introduced in 1944 by a guy called Sturzebecker [SP] in the U.S. who introduced whole-brain radiotherapy in the 1990s. We have seen the discussion done by the Patchell studies, really to put in the resection again and combinations, and then there also came stereotactic radiosurgery. First, we had a number of studies that were going on looking at combinations, stereotactic radiosurgery, plus whole-brain radiotherapy.
We have so many cases, and the question was mainly indication was solitary metastases, oligo metastases. But there was then the situation, what do you do with multiple metastases? For many, it was more or less the so-called reflex whole-brain radiotherapy or just do nothing. We personally in my group, we started almost 20 years ago, really, we only need to do a whole-brain radiotherapy only in exceptional cases. So, we started to treat more than one, two, three, even multiple metastases by stereotactic radiotherapy. When we look at the typical pictures like I brought here, this is a 48-year-old patient with a melanoma, solitary brain metastases via radiosurgery 25 gray to isocenter 80% covering this kind of situation. And it works quite well.
For one thing, the isocenter with optimized technology, it's quite easy. The treatment doesn't take that long. The treatment lasts about 15 minutes as such, and if it's done, normally nowadays, image-guided, it's also quite easy in that way, the set-up and the downstream. But if you treat several metastases, it's mainly involved that you treat several isocenters. And then, there's the question, how much time you're spending with the patient and does the patient need to spend in the treatment room? If we talk about multiple isocenter treatments in a group, and we have a heavy workload ourselves, we used to take about 9 to 12 minutes per isocenter. When we treated about five or six metastases, then it was easily an hour or more. The results for the patient was not quite comfortable. And the question was, we started then when, for instance, the high position, multileaf collimator came along with 2.5-millimeter leaf size, we started to do our treatment plans just with one single isocenter just putting the isocenter in the so-called geographical mass, within the multiple brain metastases and then do the treatment planning either with static beams or just by adding dynamic arcs.
Recently we have seen new developments, and my colleagues will talk about that later on. And that it works, it's quite clear. We see a typical situation here at treatment 3-month follow-up and 36 months' follow-up. And the studies along...and the analysis have brought more or less some prognostic factors to that Karnofsky state, age less than 65 years, controlled primary, and no extracranial metastases predicted for best prognosis in radiosurgery, and no extracranial disease is most significant for survival, maximum tumor diameter only variable associated with increased risk of unacceptable acute and/or chronic neurotoxicity.
Then by the end of the first centum of 2000. From Houston [SP], we have seen the paper in Lancet Oncology, Chang, and they looked at neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus or brain radiation, and they did randomized trials, small, randomized trial one, two three lesions, all the primaries and RPA classes I and II. And they looked also at the functional situation and normal cognition. And what I did find that the mean probability of normal cognitive decline at four months was 52% for SRS plus whole-brain radiotherapy, and 24% for SRS only, and 95% confidence interval. And from that point of view, it was really the situation, it was not only that we had acute at four months kind of situation, but we also had delayed recall, which was considerably higher in this kind of situation. When we looked in that paper, the situation of intracranial progression, there was a higher local and distant recurrence rate without whole-brain radiotherapy. And the question was really does this warrant the effort really to omit whole-brain radiotherapy?
And then there were the Japanese data around, by Yamamoto, and he looked at stereotactic radiosurgery for patients first with multiple brain metastases. And he did a Japanese multi-institutional prospective observation study, in total close to 1,200 patients. And 455 with 1 met, 531 with 2 to 4 and 208 with 5 to 10 mets. And it seemed from that that radiosurgery without whole-brain radiotherapy in patients with 5 to 10 brain mets is not inferior to that in patients with 2 to 4 brain metastases. And considering the minimal invasiveness of stereotactic radiosurgery and the fewer side effects than with whole-brain stereotactic radiosurgery, may be a suitable alternative for patients with up to 10 brain metastases.
He later on extended that, like shown here in this picture. And this also extends to the topic later on the treatment with multiple brain metastases. He looked at the kind of situation where treatment results for patients with 2 to 9 versus 10 or more brain metastases. He published it again, that was in the "Journal of Neurosurgery," that was in 2014, it came from the Gamma Knife proceedings.
And he did an update then in 2017 on this study, and he looked at the kind of situation, and he did a comparison. Yeah, Irradiation-related Complications and Long-term Maintenance of Mini-Mental State Examination Scores, because that was put at question quite a lot, because obviously, when you treat more and more brain metastases, then the volume of normal brain that you're going to treat is considerably higher. And he didn't find any changes in this kind of situation or any difference between one brain metastasis, 2 to 4 and 5 to 10 even over the long run up to 60 months and also looking at radiation complications. When he looked at that, there was also no significant difference between either group 1, 2 to 4 or 5 to 10. That means, neither the mini-mental score, maintenance nor post-SRS complication incidence was different among the different groups. This longer-term follow-up study, in his own words, supported the non-inferiority hypothesis of radiosurgery alone for patients with 5 to 10 versus 2 to 4 brain metastases.
I hope, I could set the outline a little bit for that. And we now go and carry on in the meeting that we will be looking at the kind of situation, clinical utilization of elements, multiple brain metastases, mets, with stereotactic radiosurgery. This was well-done by Dr. Niyazi from Munich. And the interesting thing is, like you see down here, that multiple brain metastases most of the data you cannot only treat it with the Gamma Knife, but you can also do that with an accelerator from the same company, that is suitable for stereotactic treatments. And which is also quite interesting, it's not only down to a super classical Novalis platform, but it can be extended further wise.
And I'm quite happy we had here a little change in program that Dr. Horvath, she's also from Germany from Stuttgart. She will be talking about response patterns, earlier using elements with contrast clearance analysis. And then later on, and that will be the last presentation, I already did speak about that a little bit, that with multiple isocenters, you have an extended time, you have a long treatment time, a higher burden to the patient and to the staff. And then, with the so-called elements for multiple brain metastases, the treatment is just as quick if you're going to treat one brain metastasis.
And Manuel Todorovic, the physicist from Hamburg, he will be then showing how you can even extend it to more complex multifocal planning, and what kind of IGRS requirements, that means image-guided radio surgery requirements, you do have in this kind of situation. And we will take questions at the end. And I would like to call up the next speaker, Dr. Niyazi.