Chapters Transcript Brain Tumors (for the Non-Neurosurgeon) Dr. Kumar Vasudevan, MD shares high level overview of brain tumor and some treatment options, included new non-surgical treatments. Now for our first presenter, we have Doctor Kumar Vasudevan, who earned his medical degree at Warren Alperti Medical School of Brown University in Providence, Rhode Island. He then obtained his fellowship in neurocritical care, and then his residency in neurosurgery at Emory University School of Medicine in Atlanta, Georgia. Druden also did a fellowship in skull-based neurosurgery at Brigham and Women's Hospital, Harvard Medical School in Cambridge, Massachusetts. He's currently an assistant professor of neurosurgery with the Washy physician and sees patients at Christian Hospital. Some of his research interests are survival and functional outcomes in atypical and malignant megenoma, outcomes in pituitary tumor surgery. And integration of neurocritical care, physiology and preoperative neurosurgical care. So thank you so much, Doctor Faudavan for your time today and we look forward to your presentation. Thank you so much, uh, Nicole, and I appreciate the introduction. I'm happy to be here with all of you. Um, this is, uh, a talk that, uh, I, I've given a few times and I think hopefully has been helpful for folks, um, who are, um, working on the primary care side or sort of the side of the undifferentiated patient. Uh, and, and just trying to give a bird's eye view of this, of this field and topic of brain tumors. Obviously there's a lot to cover here. My goal is to just give you a taste and a flavor of what we see on a daily basis. Um, and I may skip some slides here and there, depending on our, on our time, but, uh, but let's get started. I should mention that um there's my cell phone number and my office number. I want you all to feel free to um use that as you need to, and our website is, is there as well. See if we can get this going. So I have no disclosures to start off and just a brief overview here of what we'll discuss. So I want to talk about primary and metastatic brain tumors, just the basics, the overview of them, and then spend a good chunk of time talking about the modern approach to brain tumor care, which has really changed a lot, uh, really in the last 10 to 15 years. Um, we'll talk about some newer non-surgical treatments. are an important part of our, our manitarium. I also want to address some common questions about management, uh, about these, these tumors if you happen to discover them in your, with your patients what to do. And then, of course, to talk about any questions that, that you may have. So I would like to start out with just a few take home points. If you take away nothing else from, from this presentation, uh, I hope it's just these few things. The first is that functional preserving surgical methods are making surgery more tolerable for a wider variety of patients. Um, brain surgery still is, of course, a very big deal, um, but we've refined a lot of the things that we do to make more patients candidates for surgery. Um, and I'm going to be showing you some of those technologies as we go through. Modern brain tumor surgery is more than just a craniotomy. So, uh, we used to think of, uh, brain tumor specialists on the neurosurgical side as just opening the skull and taking things out. Um, it's become much more of a nuanced field, the types of things that we can do to treat patients, of course, are broadening, uh, by the day and, and, uh, brain tumor practitioners need to be aware of that and we want to make you aware of that as well. Brain tumor patients are doing better and living longer. Uh, this is, of course, the, this, uh, what's happening with all of our oncology patients these days, for the most part, thankfully, and, and brain tumor patients are part of that, and I will be showing you why. And last, and I think this is probably the most important thing, is that coordinated multidisciplinary care is the new paradigm of brain tumor management. Um, this really taking care of these patients takes a village, uh, and, uh, the, the talking about these patients, the interdisciplinary management could not be more important than it is right now, and I'll give you some examples of that. Um, so first of all, just to give a top-down view of intracranial tumors overall and the numbers on this vary depending on who you read, and I've sort of colored the numbers here to match up with what I see in my practice. So the far and away, the most common thing that we see is intracranial metastasis. And, um, And this makes about 50 to 60% of patients, and the number of patients that we see with this is probably going up as, as patients with, uh, with cancer surviving and doing better, we're seeing more brain metastases. About 30 to 35% are primary brain tumors. That's tumors that arise from within the brain, any of the structures within the skull really. Um, and I'll show you some examples of that. And then other less than 10% being things like pituitary tumors, um, or things from the, uh, that may creep in from outside of the skull into the brain, uh, that, uh, that present to us as looking like a brain tumor. And really what I want to talk about is when you look at the inn. metastasis and primary brain tumors, um, within the last 10 to 15 years for metastasis, there's really been a revolution in how we deal with these non-surgically. And then on the brain tumor side, we have refined the diagnosis and surgical treatment of them quite a lot. Um, and, uh, and of course, as with the rest of uh cancer care, personalized therapy and molecular diagnosis is, is, uh, is coloring everything that we do and we've had some recent advancements in, in brain tumor care that really hit upon that. So first of all, just to introduce the topic of primary brain tumors. So these are neoplasms that I classify as originating from anything within the skull. So within the brain parma, the meninges, the dura mater, specifically cranial nerves or surrounding structures, and they can cause symptoms from a number of different things. So they can compress normal structures, they can obstruct the flow of spinal fluid, they can even obstruct, uh, large vessels in rare cases. Or they can disrupt the brain activity. Most common thing that we see there is a focal neurological symptom such as numbness, weakness, uh, language difficulty, cognitive difficulty, or of course, seizures. These vary widely. Excuse me. Um, they may be slower growing and, and, uh, get quite big before they cause symptoms, or some of them, if they're more aggressive tumors can be, uh, can be highly, uh, aggressive and, and develop quite fast. Um, you've seen many of these before, I'm sure in, in, uh, in medical school. I'll revive your memory of those. Um, so a good number, about a third of the tumors that we see are meningeal tumors. So meningioma, uh, which is a tumor that grows from, uh, the meninges, the dura mater. And presses on the brain from the outside. Contrast that with what we term the neuroepithelial tumors, or you may know them typically as gliomass, which are tumors that grow from within the brain. So those are far and away the most common types of primary brain tumors. that are arising from within the, the cranial vault that we see. And then you have other things like pituitary tumors, about 15%. These are probably underdiagnosed. There's probably a good number of patients walking around with pituitary tumors that we don't know about and never will know about. So these are the ones that come to our attention. And then I'll be zeroing in a little bit on, on the highlighted ones here in just a moment. Excuse me. Um, then the other sort of more rare primary brain tumors that we see are cranial nerve tumors, so things like schwannomas. In this picture, for instance, we have a large acoustic neuroma, which is growing from the, uh, from the vestibular nerve, um, and then we have things like primary CNS lymphoma and then rarer things such as hemangioblastoma that tend to be associated with familial cancer syndromes in a lot of cases. Many of these tumors are completely random. This is the most common question that I get from patients is, what did I do to cause this? Could my children get this? And, you know, most of the time, unfortunately, this is just bad luck. Uh, many of these patients, we don't really identify a reason why. If you do, however, see. Some of patients with these histories, for instance, anybody who had a radiation, maybe as a child, um, for malignancy, uh, usually leukemia or something like that. Um, we also see it in folks, uh, a long time ago who used to get radiation for things like tinnia capitus. Um, they present to us with sometimes aggressive radiation-induced tumors, meningiomas and glioblastomas. Of course, immunosuppression is a risk factor for something like primary CNS lymphoma. And then we have these familial cancer cancer syndromes that I see from time to time and we all had to memorize at one point or another, neurofibromatosis being the major one that we probably see in daily practice, that leads to a number of, uh, being higher risk for a number of these other tumors. So I want to talk about a couple of them, uh, specifically some of the more common ones that you all may see, uh, with, with your patients. So, uh, first and one of the more common, um, intrinsic brain tumors that we see is, uh, diffuse astrocytoma. This used to be called the many things diffuse glioma, um, but this is sort of the latest, latest pathological term. We call it, excuse me, diffuse astrocytoma because it has Diffuse invasion of the surrounding brain merecuma. As you can see here, this is, uh, the, the tumor that's the obviously abnormal tissue, but there's no clear boundaries with the normal brain itself. In fact, there's normal brain overlying it on all sides. Oftentimes when we go to surgically resect these, we have to go through normal brain in order to get there and, and picking the safest way to get there to cause the least amount of injury to the patient is, is an important part of the surgical treatment of these issues. On a scan, this is, this is what it looks like, and many of you may have seen pictures like this. You don't really have to be used to looking at scans to recognize that there's something wrong here. Far and away, the most common type of these sort of tumors that we're going to see is a glioblastoma, which undoubtedly many of you have seen before, which is the most aggressive subtype appears as this avidly contrast enhancing lesion here in the right frontal lobe of this patient. Another variant of this is oligodendroglioma. So where astrocytoma arises from the astrocyte glial cells, we think oligodendroglioma arises from the oligodendrocytes. The reason why I bring this up is that it illustrates a very important theme with current treatment of brain tumors, which is that oligodendroglioma was really the first tumor where we were able to identify a molecular signature, this is what we call a 1P19Q co deletion. And we know that patients who harbor that mutation are more likely to be classified under the microscope as an oligodendroglioma, and having that mutation independently predicts a better prognosis than it would with, with other histology. And this sort of set the field ablaze for, for exploring the molecular signatures of all of these different kinds of tumors. So, uh, surgery footage here, if you're sensitive to that, uh, look away for a minute, but I just want to illustrate, this is a video of taking out a glioma. What you're looking at is the normal surface of the brain, and these, these instruments are cautery instruments, and I just want to illustrate that you have to go through normal brains sometimes to get to this tumor. We have a particular light filter here that's going to make the tumor glow in the dark, and you will see that here. So there's the glowing tumor, but I just wanted to show you that these are diffusely infiltrated without that, without that light source, we couldn't necessarily make out a lot of times what is tumor and what is not, and we have to go through the normal tissue because it's diffusely invading invading the brain. This is just a basic look at the survival rates of these different kinds of tumors, and I wanted to point out to you the stark difference between them. So if you look at a lower grade diffuse astrocytoma, we see a 5 survival rate somewhere in the range of 50% to 60%, and that drastically drops when somebody unfortunately may be diagnosed with a glioblastoma, which is the most aggressive variant. And then as I told you that oligodendroglioma, which is defined by a particular molecular signature, you see that molecular signature imparts a much better 5-year survival rate of around 80 to 90%. And so, uh, the diagnosis of this is, excuse me, very important. So, how do we manage this? Well, for glioblastoma, the standard of care has been maximal safe resection with a surgery followed by radiation therapy, which is fractionated over many weeks, and a specific kind of chemotherapy called Temazolamide, which is given orally. So this is a standard care for newly diagnosed glioblastoma. And, and, you know, I say surgery is the first step in treatment, but we always have to keep in mind as surgeons, we always say location, location, location. If we see a tumor in an eloquent location where if we take it out that it's going to cause weakness, numbness, increased cognitive difficulty, um, we know that if we in surgery take away the functional capacity of a patient, they are going to do worse. No matter what the status of their tumor is, they're going to do worse. So many patients. In some cases may not be surgical candidates because of the location or the extent of involvement of their tumor. And where did this come from? Well, this was a seminal study done in 2005, what we call the Stoop protocol. Prior to this, we were treating patients with maximum resective surgery and then radiotherapy, um, but the Stoop protocol showed us the effectiveness of adding this temazolamide chemotherapy, which, um, uh, improved the overall survival of these patients, as you can see on this chart. So we add temazolamide chemotherapy, um, for everyone. Excuse me, this is the, um, uh, the basically the standard of care now for treating these patients, and I'll just highlight for you the, the adjuvant treatment, um, these patients. Uh, so in, in, uh, otherwise healthy patients with good performance status. Uh, we typically are going to be treating after surgery with standard brain radiotherapy, uh, concurrent temozolamide or, uh, chemotherapy. And then there's a line here about alternating electric fields. That's a, that's a newer therapy. Um, I don't really have the time to cover it, but it is something that, uh, a neuro oncologist may choose to, um, to add on to the care here. Um, it's, it's an option for these patients. So I wanted to use this to highlight the newer directions that we're moving in in taking care of patients with, with gliomas and astrocytomas more specifically. So this was a seminal article that was published in 2009, the New England Journal that basically looked at isocitrate dehydrogenase mutations in in gliomass and identified that. Excuse me, no matter what these tumors look like under the microscope. So you can see here, um, a histopathological diagnosis of either a glioblastoma or a slightly lower grade tumor called an anaplastic astrocytoma. If those tumors had a mutation in IDH1 or IDH2, that mutation was independently associated with a better prognosis, a greater probability of survival, more so than tumors that had a wild type IDH. And so, This led to sort of lots of theories of why this may happen. We theorize that there is something different in the tumor agenesis of these two kinds of tumors that IDH mutates in a selection of normal glial cells, and that's an important early event in the genesis of gliomass, but there's a subset of tumors that are gliomass, but the IDH does not mutate and somehow in a way that's probably too much to go into right now. They develop into a completely different kind of much more aggressive tumor and so Basically, this is a very busy slide, but I want to point out that where we, until recently, the first step was to look under the microscope at these tumors as in terms of diagnosing what they are. Our first step now is to check for an IDH mutation. So that the Genetic mutation is really driving how we classify these tumors. For instance, in order now to be called a glioblastoma, you have to have no IDH mutation. You have to have a wild type IDH, um, and of course along with that. You know, we look for histological clues that pathology colleagues do of things like necrosis and microvascular proliferation that suggests a more aggressive tumor, but that IDH lack of an IDH mutation is necessary to be called a glioblastoma now as opposed to If somebody does have an IDH mutation, then it goes down a different select pathway to look for other clues as to the aggressiveness of the tumor. But we, at least at this institution would not call a tumor, no matter how aggressive it looks under the microscope, would not call a tumor a glioblastoma if unless it had a wild type IDH. So it's important because our classification is completely changing. For this. And so we've gone from the phenotype driving the treatment and the prognosis of these patients to the genotype driving the treatment of prognosis. So for instance, as I illustrated before, if you have a wild type IDH, you can be classified as a glioblastoma. If you have a 1P19Q co deletion, you are more likely to be classified as an oligodendroglioma. And again, these things independently predict the prognosis for these patients. And then I've also included this other mutation called the H3K27M. which is present in another subset of patients with diffuse midline glioma. So why does this matter? Well, we're getting into the latest and greatest studies here. So this was published this year, sort of a hot topic amongst your oncology providers. Boroitinib is a, is an inhibitor of IDH, and for the longest time, we did not have a medical, medical treatment option for patients with a lower grade glioma who have this IDH mutation. They would get surgery, they would get radiation. There were some chemotherapy regimens we could try for progressive tumors, but this study showed that this inhibitor of IDH independently extended the progression-free survival of these patients. Now, this is still undergoing and awaiting FDA approval, but just to illustrate the power of checking for these IDH mutations and, and the power of that approach, um, it's evolved already into a new treatment paradigm for those. Um, this was a study that was published in Nature Medicine, and again, this other Genetic variation of H3K27M. Um, they trialed a vaccine targeted mutation in patients and were able to show regression in a good number of patients. So, so this classification really matters and it's going to change fundamentally the management of these patients, uh, going forward. So that's enough about that. Completely shifting gears now to meningioma. Meningioma, as you recall, is another type of primary brain tumor that now this time originates from outside the brain, not from within the brain, from outside the brain. We think arising from the arachnoid cap cells, uh, in the dura modern. Most of these, you may have seen many patients who have these, most of these are Benign and slow growing and low grade tumors. A lot of them, I just observe. I watch patients with focal, uh, with serial exams and serial MRIs, and these don't change and they never need anything for them. But of course, as with any intracranial tumor, they can start to cause focal neurological symptoms. They can grow, they can get aggressive. This right here, what you see here, this large sort of enhancing lesion that should not be there on this picture. This is a quote unquote benign tumor. If you look at it on the microscope, it might be classified as a benign tumor. Obviously this is not benign for this patient. What you're looking at here on the left side, this glowing structure is the internal carotid artery. This tumor has grown surround it, maybe compressing it in some ways. You can see it's invading a little bit into the nasal cavity. This tumor, this supposedly benign tumor is causing a lot of problems for this patient. There are higher grade meningiomas as well, grade 2 and grade 3, for, as I mentioned, folks who have a history of something like neurofibromatosis type 2, or have a history of radiation, they can get very aggressive tumors that for all the world may look like a malignancy, you know, they can recur like a malignancy, they can spread these those aggressive tumors unfortunately, will, will kill these patients and have to be monitored, uh, very, very carefully. Um, for these sorts of tumors, we don't have, uh, really great medical options yet. Surgery is really the mainstay of treatment, so trying to get as much of the tumor out as we safely can with an initial operation. This is just showing a grading scale that's debated amongst neurosurgeons, but we think that the more of this tumor you're able to take out, the more of the dura from which the tumor is originating, you're able to take out the lower the chance of, of recurrence. I want to show you now, this is, this is one of my cases, um, and this is looking at, uh, taking out a meningioma here. And what you're looking in, in my right hand here is a cautery device and uh this is the meningioma that is growing from the base of the skull. I'm disconnecting it here from the base of the skull and you can see it's growing from The skull and pushing on the brain tissue, which is where, what I'm pulling it away from now, and there I am pulling the tumor out completely. So there's some bleeding there that we're going to stop and you can see I've stopped the bleeding and this is what it leaves kind of a hole there where that tumor was and was pressing on the brain tissue and this is just me getting some, some hemostasis and coagulating the dura from which that tumor originated to try to reduce the chance of it recurring and coming back. So I hope you're able to see the difference between the, the two different kinds of tumors. So we'll leave that behind, excuse me for a moment. I want to talk to you a little bit about the, the, the methods that we're using to, to take these out. So functional preserving surgical methods for a wide variety of patients. So the reason I say that is because What we classify as resectable is rapidly changing. We're able to do a lot of things in the operating room and before the operating room to try to figure this out. So for instance, on the left here we have some advanced tumor imaging. This very colorful picture that you see is we're able to using preoperative MRI imaging, map out the white matter pathways, including pathways for language, for cognition. Um, and see to what extent the tumor deforms those, moves those, and to see if we can safely resect tumor or if there are things that we need to, to leave behind, because again, what we do in terms of leaving function behind for these patients is so important for their ultimate prognosis from these tumors. We want to make sure we're trying to preserve that as much as possible. This is, um, something we call an awake craniotomy. This is quite dramatic if you've had a chance to see it, but here we have a tumor that's located close to the, uh, the motor strip and close to the parietal regions. And so, here we have a patient who is awake. Uh, we've exposed the brain surface. This is not one of my cases, but we do it similarly, um, where the patient is being asked to do tasks while we're stimulating on the surface of the brain. And so if, while we're stimulating and disrupting activity in that part of the brain, we see that function is affected, we can mark that area and say, stay away from this area in our resection. So it's increased, uh, the safety, particularly of, of, um, those cases where tumors are diffusely infiltrated of the brain. We're also changing how we can access these tumors in order to make it safe. So this is one of my early cases here on the left. You can see on the left-hand side scan a very kind of deep-seated tumor. This happened to be a glioblastoma. And to take this out, we basically had to traverse a fair amount of normal brain and you can see the path that I had to take to, to take this tumor out, and we had to do a big opening in the skull and go through the normal brain in order to get there. Well, this is, you know, one of the later cases that you might see here on the right. Which is a tumor marked by this arrow and you know, able to take out the tumor but not really leave much of a path there and through a much smaller craniotomy. And the way we're able to do this is with a newer technology called the tubular retractor, which you see here. We're able to insert a tubular device to the surface of the tumor and we do this with sort of a GPS navigation system and basically instead of destroying the brain tissue, spreads it apart, so we're able to get a pathway, access to that tissue and as you take out that, that tubular retractor, The brain tissue just collapses in on itself and much less damage is done. So that's a much safer way of doing it. We're also able to use more minimal incisions such as this incision that I was able to hide in this patient's eyebrow. And then we have things like glioan, which is a dye that can help us to mark where, where glioblastoma tissue is and, and maximize our extensive resection and, and be as safe as possible as well. So we have all, all these intraoperative technologies that, that make more patients a candidate for surgery than previously. Yeah Excuse me. Um, so I want to get into a little more of a different topic now and, and talk about how, uh, modern brain tumor surgery is more than just a craniotomy, and there's a lot of other things that we need to think about. And nowhere is this more, more relevant than in the discussion of brain metastasis. Now, like I told you, this is one of the most common things that I see, and, uh, for many of you who have patients with cancer diagnosis, I'm sure you've seen this many times as well. Um, you know, we probably are undercounting the number of new brain metastases that are out there. It's estimated greater than 100,000 new cases annually and, uh, anywhere from 10 to 30% of adults with cancer, you see the most common sources there. Um, interestingly enough, you know, many kinds of cancer like to go to the brain. There's a few, for instance, prostate cancer, uh, does not really like to go to the brain, likes to go to the to the spine, uh, you know, bones and soft tissues of the spine, of course, but, but not really the brain. Um, but you know that we see these very, very commonly. And it's a very heterogeneous disease. So all of these pictures that you see here are pictures of brain metastases. You see, uh, a very large one here on the left-hand side, which is causing some brain compression. You can see in the second picture from the left, uh, uh, a cerebellar brain metastasis, which is causing compression of the fourth ventricle and severe hydrocephalus. And so this disease can look like a lot of different things, and, um, this is another entity, something we call leomgeal carcinomatosis, which is almost meningitis that has to, uh, that, that is from tumor cells. And so, um, this independently imparts a very, a very poor prognosis. Um, many folks, uh, if you're working on the inpatient side, you may have seen that we try to do lumbar puncture to see if we can diagnose these, look for tumor cells in the CSF, uh, but a single lumbar puncture has a, High false negative rate. And so oftentimes this diagnosis has to be made clinically. If you have somebody with known metastatic cancer and they come to us with a new cranial neuropathy that we can't really explain or new hydrocephalus that we can't really explain, we have to think about this as well. But I want to talk to you a little bit about the treatment of these and how they have, they have really changed over the last few years. So up until, you know, 1520 years ago, the standard of care was to try to surgically resect these tumors if we can, at least ones that were larger or were causing symptoms, and of course ones that we safely could get to and Those that we couldn't resect or after the resection was done, we, they were subject to whole brain radiotherapy. The theory being that once you've got one brain metastasis, you've probably got smaller brain metastasis within the brain that we can't really see, so we should radiate the entire brain in order to, to kill those. But what we were seeing is that a large number of these patients that were living longer, were developing severe cognitive side effects. And I'm going to talk about, you know, that in just a moment. Where, where does that treatment paradigm come from? Well, these are a couple of studies that were published. This is probably one of the most famous studies in neurosurgery. It's one of the only randomized controlled trials that we, uh, that we really have in neurosurgery and, um, was published in 1990, looked at 48 patients, which were randomized to either, um, uh, receive only whole brain radiotherapy or surgery followed by whole brain radiotherapy. And the vast majority were non-small cell lung cancer patients. And what you see here was that both the overall Survival and the time to recurrence for the metastases were longer in patients who had surgery followed by radiation as opposed to just whole grain radiation alone. And the important thing is that all of these patients only had a single metastasis, so patients who had widespread metastatic disease were not randomized in the study. So this gave us the ability to say, OK, surgery is doing something. Surgery is, is greater than whole brain radiotherapy alone. And so this, uh, you know, for larger, safer metastases, we wanted to move to resect those. Similarly, we looked at another study looking at postoperative radiotherapy, so saying, OK, surgery works. Now, what if we just did surgery alone without radiation? What is the difference, uh, look like? And for this, it also showed that for patients that had, uh, surgery followed by whole brain radiotherapy. They had a longer time to recurrence. And so whole brain radiotherapy was helping reduce, uh, the recurrence in those, uh, brain metastases that had been, that had been operated on. Importantly, it didn't really, uh, whole brain radiotherapy did not improve the overall survival of these patients. More the functional status. And the theory is on that is that something else and probably systemic disease is driving the survival of these patients, and we'll, we'll come back to that in just a moment. And so again, because now we've gotten so many good newer systemic therapies, uh, brain tumor patients are doing better. They're living longer and so we're seeing more of these brain metastases. We're seeing multiple brain metastases pop up and perhaps some that are not really, uh, safely amenable to resection. We are also seeing The cognitive effects from folks who have had whole brain radiotherapy in the past. And so these folks come in with difficulties with their, in particularly their short term memory or their executive function, their ability to make decisions. And of course, as you all know, that can have profound impact on the functional status, the lifestyle of the patient and so. We were on the search for better ways of handling that. And so now we have these new modalities that have popped up. Of course you all know about just the explosion and targeted therapies, immunotherapies, disease specific personalized therapies for cancer patients that are revolutionizing how we treat these patients. Many of those, not a lot of them. But many of them, we are starting to understand how we may use those for folks with smaller brain metastases such that they may not even require surgical therapy, but we may be able to treat those with just medical therapy. Um, the other very powerful thing is something called stereotactic radiotherapy. And so stereotactic radiotherapy. It is very different from whole brain radiotherapy, which is what we had previously discussed. So where before the whole brain was getting irradiated because trying to kill those micrometastases that we may not even see on an MRI scan. Stereotactic radiotherapy takes the opposite, uh, tack, which is to focus radiation on a lesion, be it, um, usually a brain metastasis, but we also treat meningiomas, we treat acoustic neuromas with this. Focus radiation such that we minimize the spillover of radiation to the surrounding areas and focus it on the disease. And we have seen that in doing this, we can actually control local disease very, very well. And in many cases, such as the ones we've highlighted here, you can see some of this disease get smaller or even regress. And so we, we never promised that to patients. We say, look, we do this because we're trying to control your disease and it's very good at doing that. But we have seen that by not irradiating the entire brain, we can hopefully reduce the amount of those neurocognitive side effects that, that we're seeing. And so, The goals of therapy for folks with brain metastasis because of these newer technologies have basically completely shifted. Where we used to be focused on eradicating all the CNS disease, getting rid of even disease that we can't even see on a scan, we have shifted our goals to say, look, if somebody has a large metastasis that is causing neurological symptoms or could cause them to deteriorate neurologically. We will treat those. If we safely can do it with surgery, we will treat those, but we would rather treat with surgery where possible, supplement with a focal radiation and control the CNS disease while their systemic disease is being treated by our oncology colleagues or, or anyone else. And so we have patients with Small metastases that show up on scans. We treat them with surgery and or radiation, and we, we monitor those. We watch those for years and years and they may be stable, and they also may be stabilized by the systemic therapy that patients are on, and we're OK with that. And so the treatment paradigm has, has really completely changed. And, and where do we sort of get this from? Well, there, there are a lot of larger scale randomized trials that are still going under, but I thought I'd show you some of these phase 3 trials, which basically showed that in this particular set of patients, if they had a complete resection of a brain metastasis and we treated them in that brain metastasis to the cavity with postoperative stereotactic focused radiosurgery versus just leave them alone and watch them. The group that had radiosurgery after a complete resection had superior local control. They had greater local control than the folks who were just observed without radiotherapy, OK? And again, this did not have an impact on the overall survival, suggesting that there's something else that is driving the overall survival of these patients. And again, this is another trial comparing head to head. OK, if somebody had a resected brain metastasis, if we do focused radiotherapy versus whole brain radiotherapy, does that make a difference? And this basically validated that if you do whole brain radiotherapy, those patients have a cognitive decline much sooner than the, the folks that had the focused radiotherapy again, probably because of, you know, you're not radiating normal tissue, um, such as the hippocampus that may, um, That may cause a deterioration in in cognition. So, again, putting all that aside, just to wrap it up, what we know about these folks. So we have good evidence now that surgery with radiation is better than surgery alone, that surgery with radiation is better than radiation alone. We have evidence that post-op stereotactic or focused radiosurgery is better than observation alone, and we have evidence that post-op stereotactic focused radiosurgery is better than whole brain radiotherapy. So putting all that together, we've settled on this kind of surgery plus postoperative stereotactic radiotherapy as a new paradigm for how to treat these patients. And then, of course, watching them very carefully with serial imaging to make sure nothing changes. I wanted to highlight this. This is a technology that, um, we have at Watch you and a couple of my partners, Doctor Kim and, uh, Doctor Luhart are very skilled at and, and really great with this. Uh, this is a newer technology called laser interstitial thermal therapy. So for, um, if, if somebody's metastasis is very deep or grows despite radiotherapy, This is a minimally invasive method to insert a small focused laser into the tumor and essentially ablate it with with the laser, and this is done under active MRI guidance with the patient in the MRI scanner. And there's lots of other indications this is expanding greatly in terms of how we can use this and it's really kind of the frontier of how to treat these, how to treat these problems. And so I'll apologize for the busy slide here, but I just kind of wanted to show you again how we, how we think about these folks, because I know inevitably many of you will see them. If somebody has a diagnosis of a brain metastasis, we first evaluate, is it surgically resectable or not, and then they'll go to surgery. If they have a number of different metastases, uh, any of which are unresectable, then we'll treat those first with radiation therapy and of course with systemic therapy alongside it. And then if they were to, despite those, have progression of their CNS disease, we might have the option of going back and doing more radiotherapy or at that point might proceed to whole brain radiotherapy, um, at the advice of our radiation oncology colleagues. And again, newer things that may be on the forefront here. We talked about laser interstitial thermal therapy as an, uh, as an option if the CNS disease were to progress in spite of those other things that we did. And then I'll point out in the bottom left here, we have newer agents which may penetrate the blood-brain barrier and obviate all of this to where you don't need surgery, you don't need radiation. You can just stay on your, uh, on your targeted therapy or, or immunotherapy and, and have regression of brain metastasis. We are starting to see that. And so the last thing I want to touch on here is really to build on all of that, which is, uh, coordinary, coordinated multidisciplinary care and how important that is for, uh, for these patients. And I, I think that's where all of you, um, will, will come into play as well. So I want to spend a little time here sort of talking about all of this. So this is what I kind of view as the, the care of the brain tumor patient. You know, I think the obvious ones are, yes, a neurosurgeon should be involved, I think, in the care of all of these patients to first of all, figure out if surgical management is necessary for these folks. Um, oncology, of course, uh, oncology colleagues are driving the systemic disease management of these patients, um, and helping us to understand that and what, what their specific tumor might be a candidate for in terms of treatment. And of course, our radiation oncology colleagues are, um, helping us with the management of radiotherapy, but we see how, um, folks from various different, uh, disciplines might contribute to the management of these patients. So as I said, the, the primary determinant of the prognosis of these patients is their functional status, their overall disease status, how they're otherwise doing with their medical comorbidities. And we rely on the help of, uh, primary care physicians, of medicine physicians, of, uh, family care docs, of, uh, emergency medicine physicians to help us to understand. And triage those, uh, those, those, uh, issues for these patients because, um, we need to address them as we are learning more about what we can do for these patients. Of course, we're always learning about the systemic side effects of what we are doing as well. And, um, those need to be studied, those need to be evaluated, those need to be adjudged and, um, and weighed against the benefits potentially of, of these treatments too. Um, I really wanted to highlight this, this slide and, um, you know, again, if this is one of those slides that I hope you all could, could take away from this talk if you don't take away anything else, which is that If you happen to come across somebody with an initial diagnosis of a brain tumor, what, what should you do? And so this may be, say, you know, somebody who's complaining of headache, you ordered an MRI scan, something like this pops up, um, you have a known cancer patient who has a new focal neurological symptom, you get a scan, something like this pops up, and a similar thing, you know, could be said for, for spine tumors as well. What I tell folks is, in most cases, a new brain tumor or a new brain metastasis is typically an urgent but not emergent issue. By which I mean that you have the time and I will encourage you to reach out to the appropriate provider to collaborate with and help us figure out what to do, what to do for these folks, um, and you know, oftentimes we can review scans and those sorts of things to help get them triaged. So, so the way to think about it in my, in my mind is to say, OK, first of all, does this patient need to go to an ER? Do they need emergency care? In most cases, no. The exception would be if a radiologist calls you or you see in the report that the patient is developing hydrocephalus, that is, that is an indication for a neurosurgeon to emergently evaluate that patient, um, to see if there's anything that needs to be, if the patient needs to be admitted and handled on the inpatient side, um, or watched very carefully for the development. Of serious symptoms. Um, and then the rest of it is sort of what you all have in terms of your, your gestalt and your instinct about these patients. If they're lethargic, if they've had a rapid functional decline over the course of the last few weeks, or if there's just a very large tumor of greater than 3 centimeters, those folks should probably go to the ER and you can alert one of us to see if they need to be evaluated. Um, consider steroids or anti-epileptics. I'm gonna touch on this in a minute, but Most patients who have a brain tumor, um, and they have a headache or they have some sort of focal neurological symptom could benefit from the addition of, of steroids, namely dexamethasone. I'll cover that in a minute. And then anti-epileptics, um, as well, typically Keppra is what we would use. And then where we could use your help as somebody who knows these patients the best usually is to try to help us understand what is their overall functional status, what are their goals of care been, what is their social situation. And, um, to help us understand, you know, this, this patient, they're sicker than they let on. They have some comorbidities, which makes them really a surgical concern, because oftentimes we're trying to make decision making for these patients on the fly and trying to act for these patients as quickly as we can and, and we rely on you all to really help us understand them better than anyone else might. Um, and so if you feel somebody would just not be a, a, a great candidate, we, we want to hear from you. And then last, of course, to, to contact the appropriate neuro oncology provider. I've, I've given you my information, of course, but, um, if you have a radiation oncologist or oncologist you trust for a suspected malignant disease, they would be good contacts as well. And then for a suspected 9 tumor, uh, a neurosurgeon is usually the person to contact. Again, why does this matter? It's because most brain tumors are not found by us. They're found by folks who are getting scans for other reasons. And so I want you all to, um, to understand, you know, how you can help us to treat those patients and, and how best to act for those patients. Um, and then, as I have said multiple times now, the prognosis of these patients is frequently not driven by their intracranial disease. And so we could use your help to understand those other determinants of their health, which are going to be so important in their care going forward. Why does this matter? Why does the multidisciplinary care of this, these patients matter? Because as I've said again and again, the field is changing. And I want to highlight for you here one particular change. So this scan is from a melanoma patient. Who was not treated with surgery, was not treated with radiation, was only treated with systemic therapy, um, with targeted therapy in this case. And you can see that the two brain metastases, uh, that are lighting up on the scan have progressed with, with, uh, without any sort of other treatment other than systemic treatment. So this is going to become a thing. We're going to see this more and more often. And right now, this is just a flavor. I want to give you of the, of some clinical trials that are underway looking at systemic treatment alone for brain metastases that may not be needed to, uh, be treated surgically initially. So, um, we have, uh, these two trials that have been completed already on the top. For instance, uh, looking at CTLA 4 and PD1 inhibitors, monoclonal antibodies, uh, for these patients, 60% of these patients so regression by radiologic criteria without any surgery or radiation. And then we have, uh, two phase 2 trials here that, that you see as we evolve our understanding of these patients. So the, the first two patients on the top, these were symptomatic metastases. Now we've started to branch out and say, OK, if somebody has no prior systemic therapy and they have asymptomatic disease, Can we just treat them without surgery with targeted therapy and or er radio surgery and reduce their, uh, neurological cause of death, um, or improve their overall survival. And so these are going to become very, um, Important questions that as oncology providers we have to be aware of, but to let you all know that this is going to be on the forefront where you have patients with brain metastasis where a melanoma brain metastasis, when I started training, uh, you know, a little while ago, but not that long ago, that, that was a very poor prognostic sign and it doesn't have to be anymore. I'll skip a couple of these things here. So many of you know that, um, dexamethasone is sort of a go to when somebody's diagnosed with a brain tumor, and, and we do that because oftentimes these tumors are associated with cerebral edema. So if you get a report back that shows that these patients have a lot of cerebral edema, um, dexamethasone is a good place to start. Many of these patients will also have symptoms go along with that. The most common thing, of course, being severe, uh, headache or worsening headache, um, You may also see folks with focal neurological symptoms such as subtle weakness on one side, stroke-like symptoms like a, uh, a facial droop or a hemiparesis. You may see folks with a, a new cranial neuropathy, um, like some double vision or some difficulty with swallowing. For those people, um, there, there is no level one evidence to suggest that if we keep them long term on dexamethasone, that they will improve. So ultimately, of course, they need treatment of that tumor with the surgery, radiation, or what have you. But for folks with mild symptoms or moderate symptoms, dexamethasone is a good place to start. So I typically, um, for folks with mild symptoms, I'll start with about 2 to 4 mg of dexamethasone a couple 2 to 3 times a day. I'm very, very aware of the effect that, uh, dexamethasone has on these patients' lifestyle, and I'm sure you all have seen that as well, where their appetite, uh, really increases and then many of them. Their sleep is severely disrupted. And so if you are starting somebody on this, I would, I would encourage you to try to, um, uh, dose their last dose of dexamethasone 3 to 4 hours before they go to bed, uh, because, uh, and don't have them take it right before because many of those folks will not be able to sleep. As you all know, dexamethasone is a very potent, glucocorticoid, and so, um, it can cause these sorts of effects. For somebody with moderate symptoms. I we'll up that to about 4 mg Q 6 hours. I typically will reserve this for folks who are hospitalized who I meet in the hospital. I'll start them on, on that dose of medicine. Anybody who has severe symptoms, so if somebody comes to see you for those things that I said were emergent, like they're getting lethargic or they've had a rapid functional decline because of the size of a tumor, steroids probably are not going to do very much. You could, you could start them, but those patients really need to be urgently evaluated. The one caveat to all of this is that if you have a suspicion of lymphoma, please either call one of us or do not start steroids until one of us gets to evaluate the patient, a neur oncology provider, because, um, starting these folks on dexamethasone, um, even, One dose, uh, potentially these folks may need to be biopsied to confirm that diagnosis, and that biopsy can come back negative. It could just be non-specific even with one dose of, of dexamethasone. So if you have, for instance, a immunocompromised patient, um, who, uh, there's a suspicion for, um, a new enhancing lesion on the scan and the radiologist brings up the possibility of lymphoma, please do not start steroids. Talk to one of us to see what's most appropriate to, to manage that patient. The other question is anti-epileptics, so Uh, Keppra gets started on a lot of folks these days, uh, to try to ward off, uh, seizures. So this is for anybody with a new brain tumor. I just want to show up a, uh, show you a Cochrane review here that basically shows there's not great evidence to, for this. Of course, addressing this problem, uh, in. In space fashion is very difficult because the practice patterns are very heterogeneous. They're, of course, trying to use meta-analysis to try to understand this problem, very difficult to randomize these patients. And so the quality of evidence, as you can see across the board here for early seizures, late seizures, or death, the quality of evidence is, is very low. Um, there were a couple, uh, trials that showed, they were pretty small that showed if you start somebody on phenytoin, you may have a lower number of seizures overall in these patients. Uh, phenytonin, of course, is a drug that we have moved away from because of the, uh, the side effect profile of that. It may not be well tolerated. And of course, the systemic effects sometimes of phenytoin. I want to share with you my, my practice for anti-epileptics and these folks. So the Congress of Neurological Surgeons guidelines for metastases only, but this can really be broadened to most brain tumors, which is that Um, you know, prophylactic ADs and somebody who has not had a seizure, if you just discovered somebody that has a brain tumor, there's level 3 evidence that you do not start these patients on, on prophylactic AEDs, um, but there's a lot of caveats that go along, go along with that. In my personal experience, I have seen a person who undergoes a, uh, brain tumor operation and has a single seizure. That is such a setback in terms of their overall recovery, uh, that I have erred on the side of really starting, um, starting anti-epileptics prophylactic. in many of these patients. And so anybody who has an intra-axial tumor, by that I mean a tumor that is inside, uh, the brain, so a glioma or metastasis, um, or anybody that I have a suspicion has had a seizure before and in getting my history from that patient. I will start them before I do any sort of surgery or treatment on, on an anti-epileptic, typically Keppra, and typically about Keppra 500 mg twice a day, um, for, for those folks. Um, and then I will personally continue that postoperatively as well. I will usually manage that and, um, if they did not have any seizures preoperatively, I will wean them off of the medicine. If they have had seizures in any of the course of their treatment, I will hand that off to our neurology colleagues to help us manage their Anti-epileptics. And again, this, this is my practice and it's based on just how the, the outstanding safety profile of most modern antiepileptics and, and what I have seen a single seizure, uh, do, do for these patients. So in conclusion, I know that that's a lot. I know it was a, it was a whirlwind. I just want to say that, um, going back to our, our, uh, basics that we talked about, that we have many surgical methods now that we didn't have before that can preserve function for these patients, um, that modern brain tumor surgery is not just a craniotomy, it involves us knowing a lot about the medical and radiation-based therapies for these patients and inserting our surgical therapy into all of that. Um, that as you all know, brain tumor patients are now living longer. We have better ways of classifying them, diagnosing them, treating them. You all are going to see more and more brain tumor survivors, um, and more and more brain tumor diagnoses, and I think it's important that we talk about them. And lastly, I want to emphasize that I personally believe that coordinated multidisciplinary care for these patients is not really a luxury, it's a requirement. Uh, we've seen evidence to that effect multiple times. And I'll just put in a plug here, um, uh, as, as Nicole mentioned, I, uh, just started my practice here in July. I'm predominantly based at, at Christian Hospital up in the, in the North, uh, County. We have the ability now to see all these patients, to handle them. We have the full breath of, um, neurosurgical care for both brain and spine patients. And so I'm happy to help with these patients and many times, uh, this may be a more convenient option for patients that need to be seen sooner or may geographically be up here. And of course, Um, we have a way into, uh, to the Sitement Cancer Center and, uh, the WaHU subspecialized care if that is needed. But, um, I want to emphasize that we are here. We've steeped ourselves in the community. Uh, we want to be here where the patients are and, and try to focus all of their care here, um, with your collaboration and, and with your support. And, uh, thank you very much. I've included my, uh, my information there. I want you all to feel free to call or text me anytime. And, um, if you do need to consult us, uh, there's the CH neurosurgery, Christian Hospital neurosurgery, and EPIC will come, will come right to us and, and we're happy to help at any time. And of course, I'm happy to take any questions that we may have. Doctor Holsher, excellent talk. Welcome to our community. Doctor Holsher is up in Alton. He's one of the internal medicine specialists up there. So, Thanks very much. Yeah, thank you. And you know, if anyone has any questions, please, you're always welcome to um email me or I'm also going to go ahead and usually after this program, I will send out an email with a summary of, you know, all the speakers information. I you can contact them if you need to contact them, so I'll I'll get all that out for you. And if you have any questions for Doctor Faudavan, um, later on, you're welcome to send them to me or I'll send, I'll be sending you his email address so you can send them to him as well. Does that sound good, Doctor Faudjavan? I'm happy to do that, no problem. Perfect. All right, thanks so much. Um, another one that just said Kimberly Box, she said great info. OK, thanks very much, everyone. I really appreciate the chance. Thanks. Have a great day. You too. Created by Presenters Kumar Vasudevan, MD Assistant Professor of Neurosurgery View full profile
