Welcome back, everybody. So now we're going to dive into malignant tumor management. And again, there's my cell phone, my email. Please use it if you need it. And I am going to hit the highlights. So I'm going to leave a little bit of the data in my slides for you to come back and look at at your leisure. And feel free to contact me after you do that. And I can help you with any questions that you have. OK, here we go. So again, if you look at the pie chart for primary brain tumors, the malignant tumors make up a small part of that chart. In the spinal cord, we really don't see many malignant tumors there. There are all these benign tumors that we already mentioned earlier. If you create a pie chart of only primary malignant brain tumors, you quickly see why the focus is on glioblastoma. This is half of all malignant primary brain tumors. And it is a very bad actor. So that is why all of our research focuses on that. And that's what my talk is going to focus on. So again, the malignant glioblastomas are a bit more common in SFLAs, unfortunately. Most important thing to think about is the World Health Organization classification. That gets updated every few years. And the last one, in 2021, for the very first time, incorporated genomic information that is required to make the diagnosis. So for these patients, you have to get a sample of tumor for this analysis to make the diagnosis. It's very important. So if you have patients who, for some reason, will not do surgery, explain to them about the benefits of at least doing a biopsy. OK, so if you look at that classification scheme, you could go to this paper in 2021 and see the full report. And you'll see hundreds of tumor types. So there are hundreds of tumor types. But again, the vast majority of the malignant gliomas are glioblastoma. And these are the genomic changes that are required to make that diagnosis. There are two grade four tumors that we want to think about. So the IDH wild type, grade four tumors, we still call glioblastoma often. And the IDH mutant grade four, we call astrocytoma. But those definitions require this genomic information. We're going to focus on the grade four, the malignant ones. They can look like anything. So they can be little tiny tumors, or they can be great big tumors that are massive with midline shift. And they grow across the corpus callosum to the other side of the brain. So lots of variability in imaging. The key things that we do look for. So on MRI, these tumors are classically some ring-enhancing sort of pattern, kind of like this. They tend to be much more irregular. But ring enhancement is a common feature. Lots of edema. This is a fast-growing, malignant, irritating process. Lots of edema, lots of midline shift. These tumors, they grow very different from all the other tumors I've mentioned. These are infiltrating tumors. They grow away from the central focus where they start. And those tumor cells just slowly migrate through the brain parenchyma. They do not grow as a nice little discrete ball like a meningioma or like a metastatic tumor. They infiltrate. So they often follow white matter pathways, for example, across the corpus callosum. There's not a great single diagnostic feature to tell you you're dealing with a GBM. This picture looks exactly like an abscess. It can look exactly like a metastatic tumor. It can look like lymphoma. This is an example of where AI could be very helpful for us down the road to figure out these very different pathologies. The standard of care for GBM was established in 2005. And unfortunately, it has not changed. It is the maximally safe resection followed by concurrent radiotherapy plus temozolomide, which is a very nonspecific chemotherapy for at least six months. And if you have patients who can successfully navigate that very complex treatment, then their survival is, at best, about a year and a half. Unfortunately, that's the best that it gets. I pointed out in this landmark study, the average age of these study patients is about 56. That's about 10 years younger than the average patient with GBM. So there's a lot of interest in trying to understand how to treat patients who are older, because our standard of care is really not based on the more common age group for this tumor. Because it's such a bad actor, there are still lots of skeptics out there about treating this malignant tumor. But there are plenty of studies out there, such as this meta-analysis, that show if we can do a gross total resection, that clearly favors long-term survival over subtotal resections or biopsies. Even in the older population, there is plenty of data that says if we can get them through surgery, gross total resection favors a longer survival. What does gross total resection mean is an important question. I just told you that these are infiltrated tumors. You cannot resect out every tumor cell. You can't see it. When you take out these tumors, there's a good chance there are tumor cells that have already migrated to the other side of the head. So the way we define gross total resection today is resecting everything that enhances on the MRI. And that's our marker for gross total resection. Survival in the older population is good compared to the others if you can get them through all those therapies. So if we can, we want to try that. An important marker for ability of successfully getting through surgery and the other therapies is their KPS, their performance status. And as a rough general rule of thumb, if they have a KPS of at least 70, then that's probably a good time to get them through surgery. A good surgical candidate. I recommend you come back and just study this description of the KPS system. So a KPS of 70 is a patient who can pretty much care for themselves, but they may be unable to carry out normal activities or do active work. So that's kind of our goal for selecting good surgical candidates. As I pointed out, if we can get gross total resections of the enhancing part of these malignant tumors, they have better survival. If they get post-op radiotherapy, they have better survival. Nowadays, we're doing more stereotactic radiosurgery as that radiotherapy. If you have older patients who might be more frail and you're worried about their ability to tolerate all those therapies, if you can get them through surgery and get them started on temozolomide in a short course of radiotherapy, they will have better survival. So the blue curve here are patients showing a better survival who at least got temozolomide with a short course of radiotherapy. And this is in an older population. If you feel like you can't do it all, there is a way to figure out if temozolomide by itself would be better than radiotherapy. And the way to do that is to test their MGMT status. That is not part of the definition for diagnosing these tumors, but it is so well-established in the literature. And it is strongly supported by lots of studies as a good marker to figure out this question. So there is superiority of using temozolomide over radiotherapy in older patients if their MGMT, which is a DNA repair enzyme, if the promoter is methylated, which turns off that gene expression. So the green line are older patients who have MGMT promoter methylation, and they got temozolomide. They have a better survival over radiotherapy. So there's a lot of interest in looking at the molecular profiling of malignant gliomas and trying to figure out if we can target them. There's a lot of existing drugs out there that target a lot of genetic mutations. Malignant gliomas, unlike the other tumors I talked about earlier, are genetically very heterogeneous. They have a lot of mutations. They have a lot of differences between individual patients. Those genetic mutations change over time for that specific patient. So it's a very genetically unstable tumor. And the hope is that we can fine tune this sort of strategy and come up with some good, actionable mutations that we can target down the road. All right, I'm going to leave that up to you. There are some other FDA-approved treatments that could be considered. So the most recent is tumor treating fields. It's a cap that looks like this. It delivers low-intensity frequency electrical fields to the skin. There are clinical trials that have demonstrated that it helps. It adds about two months to survival. That is similar to the other thing. So surgery has the greatest impact on long-term survival. If you only do a biopsy in a GPM patient, their survival is probably on the order of a couple months. If you are able to do surgery, you extend that out to six to 10 months. If you add radiotherapy, that's a couple of months. If you add temozolomide, that's a couple more months. And these tumor treating fields can add a couple of months. The problem, though, is that patients don't like wearing this 24-7 for the rest of their life. So unfortunately, it's not widely accepted and used. Tumor treating fields can help out in the elderly. So here's a good example of a survival curve showing elderly patients who got that therapy, and they had a little bit better survival. So this is an option that could be considered in older, more frail patients if they're willing to wear that cap. And oddly, it actually favors patients who have MGMT promoter methylation as well. You probably have heard about some other therapies. So there are carmustine wafers that can be implanted in the resection cavity. This is the Gliadel that you've heard about. It's FDA approved. There are good clinical studies from really decades ago that show that this can add a couple of months to survival. It's a very risky therapy to use. So it has not gained wide acceptance. More recently, you're probably seeing a lot about gametile. So this is another little wafer that you can put in the resection cavity at the time of surgery, and it delivers some radiotherapy. We've been testing very similar strategies for decades, so we'll see if this makes a big difference Of course there are lots of other things being studied out in the world for this tumor take home points GBM most common malignant primary tumor average age is about 64 imaging is not diagnostic. It's a there's a broad differential you need to Rapidly consider things like a metastatic workup infectious workup At the least you need to do a needle biopsy to figure out the diagnosis And if it's GBM to get tissue to do the genomic analyses you need to urgently treat these patients I've had patients walk in with no symptoms with a bad-looking GBM tumor, and they do great I've had other patients with a very similar looking picture walk in and they they start to Almost herniate right before your eyes. It's it's a very hard to predict Impact on the patient so You want to treat them quickly? Consider pre-op steroids even hypertonic saline to help decrease mass effect If you see a lot of edema midline ship, and then you want to quickly get them to surgery radiotherapy temozolomide Genomic data is required meaning survival is about a year and a half if they get through all that complex therapy Surgery has the greatest impact if you can get them through surgery all the tumors progress Research repeat surgery will have the biggest impact if your patient is still a good surgical candidate Consider biopsy at time of progression because there's lots of genetic heterogeneity that I talked about They almost always have some degree of radiation necrosis after the radiotherapy and that looks just like tumor progression sometimes There are medicines that can help reduce symptoms from radiation necrosis for example steroids bevacizumab You might get your radiation Oncologist to help you think about this and treating that Occasionally you have to go back to surgery and resect out radiation necrosis because it's so Symptomatic from the edema that it can cause I mentioned there are other some other FDA approved options to that could be think about if it's possible for you I would consider getting your patients to a dedicated neuro oncologist Because that's really all they treat are malignant gliomas They help with other tumors too, but this is really their focus And so they're going to be familiar with things like clinical trials and other things that might be helpful At our facility we recently started testing all of our samples Against various chemotherapies so that when that tumor progresses there might be a backup option for these patients In the elderly who are frail There are ways to modify the treatment that we talked about And it's important to check that MGMT status and that's common most People who do the genomic testing on these tumors People who do the genomic testing on these tumors include that And I would get palliative care Teams involved early in these patients. They can be very helpful to help keep these patients as healthy as possible for as long as possible Okay I know that was a quick introduction to GBM But hopefully I hit the highlights. I want to just take a couple minutes and talk about other malignant tumors largely metastases so These actually are going to be more common for us to see and we're probably going to see these more in the future metastases Grow very different in the brain than the malignant gliomas. So metastases Are not infiltrating tumors. So what happens is that one little tumor cell wherever it gets lodged in the brain Typically near the surface near the gray white junction It's going to then proliferate and clonally expand into a little ball and then just push tumor Oh, I'm, sorry push brain away from it so metastases When it's indicated You can take those out On block and and not take out any brain They often will have a capsule that kind of helps that process So they're much easier surgeries in the right situation Okay, so these are the primary tumors that still metastasize to the brain the most common are lung cancer For those that spread to the brain, you'll see that lung cancer still has the highest chance of spreading to the brain These on imaging can look a lot like GBM. They can look like lymphoma. They can look like infection So this is another area where AI might be helpful at predicting Predicting what we're looking at on various imaging some interesting things about this topic, so There are actionable genetic mutations in these cancers that Can differ from the tumor that shows up in the brain compared to the primary tumor so In the near future, I suspect we're going to have more oncologists coming to us asking us for biopsies of the brain metastases To help identify these new different actionable mutations Radiotherapy for metastases has greatly evolved And improved over the years. So for example Traditionally we did whole brain radiotherapy And sometimes we still need to do that but there are ways to do things like hippocampal sparing in order to Save these patients from the neurocognitive changes from whole brain radiotherapy More recently, we're doing more stereotactic radiosurgery Instead of whole brain radiotherapy and that's showing great control of these tumors I've seen examples from radiation oncologists where they'll do SRS On 10, 15, 20 individual metastatic tumors in the brain sounds like a lot, but it's still probably better than whole brain radiotherapy A couple quick examples. This picture looks similar to that GBM picture I showed you so you can see how it's hard to know What you're dealing with If they're large tumors in surgically accessible areas, for example, the frontal lobe. This is something that can be easily successfully resected Sometimes they do present with emergent situations. So here's a tumor in the cerebellum Pushing on the fourth ventricle causing obstructive hydrocephalus So metastases in the posterior fossa You have to look very carefully and think about obstructive hydrocephalus that might require an emergent ventricular drain And of course we see cases like this where surgery, you know cannot have any impact I described how these things grow and that makes them a little bit Easier to take them away from eloquent areas in the brain Compared to malignant glioma. So here's an example of a tumor that was a renal cell carcinoma close to some critical structures, so we did a mapping of these pathways And the blue represents the descending motor pathways coming from the primary motor cortex and the green represents the arcuate fasciculus connecting some of those speech pathways and you can see that the The tumor is is separate from those pathways. So that makes this a very amenable to surgical resection Okay, quick take-home points for metastases These patients can be very sick and frail so Remember first do no harm. You cannot always take these patients to surgery You need to understand the extent of the cancer before thinking about surgery So you need to get CTs of their chest, abdomen and pelvis to look for the extent of their tumor You need your oncologist to help you understand what their prognosis is If it's less than six months Some people would lower that to three months Then they're really not a good surgical candidate Again, get your palliative care teams involved quickly Again, MRI is not always diagnostic The imaging can look very much like a GBM with ring-enhancing cystic mass Think about urgent concerns like obstructive hydrocephalus for tumors in the in the posterior fossa Surgery helps the neurologic functions. It does not always impact long-term survival That tends to depend on how well their primary tumor is treated So for surgery, we tend to focus more on helping their neurologic symptoms Fortunately, there's a rapidly growing interest in identifying actionable mutations and those can differ between the brain tumor and the primary tumor And I mentioned the growing use of SRS over whole brain radiotherapy Okay, that's it. So, please when you have some time go back and spend a few extra minutes on those slides Especially now while it's fresh on your mind And then reach out to me and let me help you with questions I'm going to see if our moderator has some questions for us now Thank you so much, Dr. Adamson. Yet another great presentation on malignant tumors Some interesting things in the chat talking about, you know, who's experienced with the Gamma Tile You know, you mentioned the gliodel wafers. I worked with Dr. Tony Asher here in Charlottesville And you know, we tried the gliodel wafers and to your point, we did have some issues post-operatively Can you comment more about the Gamma Tile? And do you think this is going to be Something that we try to continue to use or how is this evolving? Yeah, so I'll comment about the gliodel That's the little wafer that has the BCNU chemotherapy on it I have a lot of experience using that and the challenge there is it causes it does kill Nearby tumor cells, but it causes an extreme robust Irritation to the brain with edema I've had occasional patient where I had to rush them back to surgery and take it out because I Occasional patient where I had to rush them back to surgery and take it out because there was so much edema causing midline shift and herniation So for that therapy your surgeon has to be extremely comfortable using it and you usually have to Be very aggressive with post-op steroids and maybe things like hypertonic saline and you just have to watch those patients very closely The Gamma Tile I have not used that yet. I've had lots of colleagues In my recent past have used it And I don't know yet If that's going to you know be a breakthrough My guess is you probably need to be very cautious with it. It probably can cause some edema And shift and so you you need to watch those patients carefully Like I mentioned we have tried Radiotherapy in the resection cavity for decades. In fact when I was a resident training In the late Or I'm sorry early 2000s We were helping with a trial where we put a balloon in that resection cavity and we filled it with a fluid containing radioactive material And you know it helps some in a few select patients, but it didn't It wasn't good enough. So I don't know about Gamma Tiles I think it's worth the try if you have a surgical team that's comfortable using it. You also need to Make sure your radiation oncologist Agree with it, you know it interferes with their planning for The standard of care radiotherapy, so you just want to make sure that they're on board as well Great. Thank you so much I understand you're going to be around for us after the next lecture for our Q&A session. Is that true? Dr. Adamson? That's right. I'll be here. Wonderful. We'll ask our Colleagues to continue to put questions in and we'll keep moving. Thank you so much again. Dr. Adamson

glioblastoma

genomic analysis

tumor treating fields

Gamma Tile

neuro-oncologists

personalized treatments