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The Neurotransmitters: Clinical Neurology Education
Neuro-Oncology with Dr. Ashley Aaroe
Dr. Ashley Aaroe joins us today to talk all about Neuro-oncology, from brain tumor classification, to complications of chemotherapy and immunotherapy, to the importance of patient advocacy.
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Hello and welcome back to the Neurotransmitters. I'm your host, dr Michael Kentris, and today we're going to be talking about a pretty complicated field, at least that's how I feel about it. We're going to be talking about some neuro-oncology and to help me out with that, I'm very fortunate to have Dr Ashley Aaroe, neuro-oncologist at MD God. I've already messed up at MD Anderson, where she is currently in attending also did her fellowship in neuro-oncology there after completing neurology residency at Cornell. So thank you so much for joining us.
Dr. Ashley Aaroe:Thank you so much. I'm really excited to join you today.
Dr. Michael Kentris:So first of all, tell me a little bit about for those who might be a little unfamiliar. First of all tell me a little bit about for those you know who might be a little unfamiliar. Obviously we know what oncology is, generally speaking, but what's?
Dr. Ashley Aaroe:different about neuro-oncology other than just being brains? Yeah, no, I really love to talk about it. I think even within neurology residency, you know, not all residents are exposed to neuro-oncology or have an idea of what it means, and so increasing awareness is how we get people interested in going into the field. What a neuro-oncologist does is it can be a little bit different depending on where you practice. So there are some neuro-oncologists that are really focused on prescribing chemotherapy for primary brain tumors like glioblastoma, for example, and there are other neuro-oncologists who are more focused on treating patients with neurological complications of systemic cancer and cancer therapy. What really drew me to this field is that you can do a little bit of everything, so neuro-oncology is very much at the center of all the things that I really love about neurology. So you treat cerebrovascular pathology, because patients with cancer have a higher incidence of stroke. You also see tumor-associated epilepsy. You see neuromuscular complications of checkpoint inhibitor immunotherapy. Those are just a few examples, but even you know headache and autoimmune neurology get folded into neuro-oncology.
Dr. Ashley Aaroe:I think as a neuro-oncologist too again, depending on where you practice you have the opportunity also to be in some ways like a primary care doc for your patients. For example, my glioblastoma patients aren't following with their, your PMD as frequently and I see them every one or two months for chemotherapy clearance. So you take over a little bit of family practice. You have to know a little bit of internal medicine as well, and so it's kind of you get to dabble in a lot of different things. It used to be that neuro-oncologists really came from the medical oncology training pathway, so people who go into internal medicine do a medical oncology fellowship and then are drawn into a more neuro-based practice again for brain tumor cancer treatment. But then the neurologist felt that we should be able to bridge this gap and so more and more patients are I keep saying, patients. I don't know why it's on my mind, um, but um, but more and more people are going through a neurology pathway.
Dr. Michael Kentris:Excellent. Yeah, it is something that I know. I didn't graduate residency that long ago, but it was one of those things where I didn't really consider it much unless you were going to be at one of those bigger academic institutions as necessarily being like a viable career pathway. Are we seeing more neuro-oncology, more neurology residents, I should say, entering the field of neuro-oncology in general, you think?
Dr. Ashley Aaroe:I do. I think we are doing a good job of getting neurology residents interested in and exposed to the field. I would say that you know, for me I thought I was going to be a movement disorders neurologist when I matched into neurology residency and that's when some of my background in medical school and research had been. But I just really got sucked into neuro-oncology and when I rotated at Memorial Sloan Kettering as a resident, those were the patients that I couldn't stop thinking about in the cases that I couldn't stop talking about. So really that exposure made a huge difference in my career trajectory.
Dr. Ashley Aaroe:There's very much a need for neuro-oncologists. There's a shortage of neurologists in general and neuro-oncology too. I feel like our patients often have cognitive or mobility concerns. They may not be able to make it to a large center like Sloan Kettering or MD Anderson, and so a lot of places are recruiting neuro-oncologists and you could be, you know, a neuro-oncologist in an academic medical center, but even so be only one of one or one of two, or, you know, there's also a role for neuro-oncologists in the community as well, outside academia, and so it's very much a growing field, but one that still has a shortage of practitioners compared to the patient volume and need.
Dr. Michael Kentris:No, I think that's an excellent point and definitely some good considerations for people who might be considering it as a career trajectory. So you talked a little bit about some of the common conditions that you're dealing with and how you are almost a stand-in primary care physician for a lot of these patients. I feel that is kind of an under-recognized aspect of neurology care in general. For a lot of our chronic conditions is that you sort of become the touchpoint for a lot of that person's medical care. What does a day in the life of a neuro-oncologist tend to look like?
Dr. Ashley Aaroe:That's a great question and I think that that's extremely variable too For me. In my practice I probably, I would say I'm about 50-50 in terms of taking care of primary brain tumor patients and taking care of neurology consultations in patients with systemic cancer, and so I have, you know, two days of clinic a week and then I spend a varying amount of time on our inpatient services. So it really is, you know, kind of a week-to-week thing, but a lot of folks are strictly outpatient in terms of their practice. So I have a pretty, you know, robust mix in clinic of patients, you know, with example of glioblastoma or medulloblastoma rare tumor types I am reviewing their imaging treatment planning. I also have a very high number of patients who, for example, have peripheral neuropathy from their taxal chemotherapy, and so I'm managing that too. I happen to really like that mix and really like that variability. I find also that something that I perhaps didn't know I would be seeing as much of when I was a resident, you know, applying into neuro-oncology fellowship there's a lot of neuroimmunology, and so I don't think I appreciated how much I would be haunted by misbehaving immune cells in my practice as a neuro-oncologist, but a lot of perineoplastic disorders, complications of immunotherapy, which has very much revolutionized the care of a number of different cancers.
Dr. Ashley Aaroe:You know, I think melanoma is a really great example of that, but there are many others. And then also there are some diagnostic conundrums. So you see an undiagnosed brain mass. Is it a glioma? Is it something else? So I've stumbled across neurosarcoidosis and, you know, amyloid related angiitis and very other rare birds. That way, just by virtue of undiagnosed brain mass coming into clinic, so it's a, just by virtue of undiagnosed brain mass coming into clinic, so it's a. I think you can very much tailor your practice to what your specific area of interest is, but for me I really like the variability.
Dr. Michael Kentris:No, that's great, and I imagine neuro-oncology kind of by its nature is very much a multidisciplinary type of field where you're working very closely with both medical oncologists as well as neurosurgeons and probably general surgeons of other stripes as well.
Dr. Ashley Aaroe:Yeah, absolutely, and that's something I really love about the field. I kind of in some ways, you know, every week at least once, I see myself as a bridge between neurology and another specialty. For example, if there's a patient with lymphoma that's involving the brain, I'm going to be, you know, working with a medical oncologist who's a specialist in lymphoma neurosurgeon to figure out should be biopsy, you know, and everybody has slightly different perspectives just based on their experience of how to tackle a problem, and so I really enjoy sort of being in that liaison role. Sort of being in that liaison role. I would say, as a neuro-oncologist, I definitely work the most closely with the neurosurgeons, the radiation oncologists and the neuroradiologists and neuropathologists.
Dr. Ashley Aaroe:I would say, as a neuro-oncologist, your best friend is going to be someone in diagnostic medicine, because the classification of brain tumors in particular changed a lot in 2021 with the new WHO guidelines. There's so many intricacies about how these tumors are classified and they have significant ramifications for their treatment and prognosis, and some of these things are very much hot off the press even since the 2021 classifications came out. I would mention, too, that there are some brain tumors where they have a characteristic appearance on imaging and that is stuff that's really an active area of study, and new things are being discovered every day too. Definitely, befriending your neuroradiologist and your neuropathologist is important in my field.
Dr. Michael Kentris:No, that makes a ton of sense and I remember reading some of those guidelines just this last year, and even from the time again you know I graduated in 2017, it's been such a shift where we're kind of moving away from a lot of the kind of traditional, like microscope based diagnosis to these molecular markers and genetic markers and it is rapidly multiplying to kind of just a very labyrinthine amount of knowledge.
Dr. Ashley Aaroe:Yeah, I think the difficulty is that every time we have a new classification, our understanding of these tumors changes and then we have to look through the previous literature in a slightly different light. But I was actually listening to the continuum recently about the cephalalgias, the autonomic cephalalgias, and talking about how they have, you know, a very robust classification scheme and it makes it much easier to study these disorders and develop, you know, interventions for them and I think we're getting there with my field too, but it is very nuanced and it you know not to oversimplify too much, but it used to be. You look under a microscope, you see a glial neoplasm, microvascular proliferation. You look under a microscope, you see a glial neoplasm, microvascular proliferation, and necrosis is GBM. But now there are so many little things that have come down the pipeline that you know a patient that goes to the OR gets a resection, they may or may not have an integrated WHO 2021 classification by the time they're discharged from the hospital, because it may be that there's next generation sequencing required of the tumor tissue to know with certainty what it is, or even methylation profiling, which not all centers can do. So you might, you know your neuropathology friend may say, hey, I've sent the tissue to the NIH and once we get their result we'll know what kind of brain tumor this is. And so that can be really hard, I think, for patients, because they're waiting, you know, for an answer.
Dr. Ashley Aaroe:I've heard also of several situations where a patient is given a prelim diagnosis and then the actual diagnosis changes very radically when those specialized tests come back. So, for example, oh, it looks like a low-grade glioma under the microscope. You know it's not very proliferative, the KI-67 isn't that high, but oh, by the way, it meets these molecular features of a glioblastoma. Now we have to treat it like a glioblastoma. The prognosis is like a glioblastoma. That can be really jarring for folks. And I think the other thing too is that you know the availability of some of these specialized tests is not, it's a bit limited. And so for patients who already have, you know, barriers to accessing medical care or seeing a subspecialist, you know they may miss out on some of these things.
Dr. Ashley Aaroe:And you know, to give an example, when I first started working as an attending, I had a patient with a glioma that had an Ntrek fusion, and Ntrek fusions are only in 1% or 2% of primary brain tumors. It's quite rare. But we identified it when he came to us and you know we started an N-TREK inhibitor and that can actually shrink these kinds of tumors and in neuro-oncology we have better treatments than we used to but we still don't have a whole lot that will shrink or make a tumor go away. And unfortunately we started this, you know, too late for this patient and he ultimately succumbed to his disease relatively quickly, especially because there was a period of time where we were fighting with insurance with a prior authorization, but when I saw him it was about eight months after his initial diagnosis.
Dr. Ashley Aaroe:It's just that he was at a place that was not able to identify, not able to perform the fusion testing to identify that NTRK fusion, and so I do very frequently wonder, you know, he would have had a very different outlook and in clinical course had he been at a place that could order and perform that testing expediently right from the get go, and that kind of inequity bothers me and so you know I think the field is is racing forward, but we got to make sure everybody you know is able to benefit from that, and I kind of went in a weird little tangent on that. But I think those are a couple of elements about my field that I think are really interesting problems.
Dr. Michael Kentris:No, I really appreciate the perspective. That kind of dovetails well into my next question was and you hinted at this a bit some of the challenges that are more unique to a neuro-oncology practice.
Dr. Ashley Aaroe:Yeah, I would say definitely. Access to things like clinical trials and to advanced tumor testing is something that is very much. They're buzzworthy topics in my field as we try to tackle these issues for our patients. I think that disparities in neuro-oncology are, you know, it's an emerging field but not fully studied yet. I think it's thought of, you know by a lot of folks that, for example, glioblastoma is a disease of elderly white males, and you know definitely that is the demographic that we see most commonly. But it's still important to address, you know, populations of patients that are not, you know, that demographic and try to some things where there's no 100%. This is the answer to how we do things and, to give an example, there's a type of low-grade glioma called an oligodendroglioma, or an oligo for short, and these are tumors that are relatively slow-growing, indolent. Patients tend to live with them for a long time before they progress or ultimately limit their life expectancy. And so, because of how rare they are compared to things like lung cancer, because they're relatively indolent to begin with, you know, recruiting patients into a clinical trial, then waiting for that data to mature takes a lot of time, and so there's still some equipoise about you know, two different chemotherapy regimens. There's camp temozolomide and there's camp PCV, which is a three drug regimen. We should have answers to that, you know, pretty soon. But even now, when you go to one center for another, it's very practice dependent because we still don't have that final answer. And so there's a lot of gray. There's a lot of you know I do this because I was trained this way, but I think there's a lot left to be explored.
Dr. Ashley Aaroe:I guess my other thought about a unique thing in neuro-oncology and it's certainly something that's not surprising or strange to neurologists who treat a number of rare and serious conditions is just the access to new drugs and to clinical trials and then also compassionate use.
Dr. Ashley Aaroe:It's something that patients are very interested in and it's sometimes really hard to get them these therapies, and if you can't get someone, you know the new drug that's on the market.
Dr. Ashley Aaroe:I think there are also a lot of people who you know are filling in the gaps with other things and so, for example, trying to, there's a lot in the neuro-oncology community about things like CBD or ivermectin and the, you know, fibendazole, and those are things that I don't prescribe in my practice, but I think, because you know, we don't have the cure for glioblastoma. You know there's such a serious and horrifying condition to be diagnosed with, you know, for a patient. But I think people are just looking for every possible thing that they can do to fight these tumors. And so I think it's tough because as a neuro-oncologist I feel like my job is to have, you know, conversations where I can really help people vet what's out there. But the truth is people are looking to complementary and alternative approaches just because, you know, we don't have very good chemos yet, we don't have the cure for GBM quite yet. So I think handling misinformation and we all know that that's proliferating in the social media age is another element to what makes practice neuro-oncology a little bit challenging sometimes.
Dr. Michael Kentris:No, that's great, and I mean not great, but it's great thoughts on it. One of the things you mentioned earlier you had this patient who you were trying to get a drug approved and the prior authorization process held things up and, as you said, with many rare conditions, not necessarily unique to neuro-oncology or even neurology at large, is that we have these pathophysiologic theories of how things may work and a medication that theoretically should have an effect on a pathway which we know it doesn't always work that way. But when we don't have necessarily an quote-unquote FDA-approved option, I find that we often are reaching for some of these options. How often do you find that the insurance issue is a blockage for trying treatments in hospitals what may otherwise be appropriately selected patients?
Dr. Ashley Aaroe:So I would say I'm pretty privileged, practicing where I do, that I feel like there are several small armies that will help me navigate insurance issues, and a lot of oncologists don't have access to that kind of support.
Dr. Ashley Aaroe:I would say that there are emerging sort of tumor agnostic indications.
Dr. Ashley Aaroe:So, for example, if my patient with a glioma that glioma has the BRAF V600E alteration, which is more classically known to be associated with melanoma, it is increasingly easier for me to borrow a melanoma drug or a targeted therapy and use it to treat my patient with glioma, especially because some of the basket trials that have been done, which are it's, you know all comers, solid tumor types with this alteration, I think so it's getting easier.
Dr. Ashley Aaroe:I would say that it's still a process and it's not infrequent that in my mind, as I decide you know what therapy should a patient be receiving next, and as I decide you know what therapy should a patient be receiving next, that one factor in my mind is well, how quickly can I get something that's off label or, you know, compassionate use? You end up working pretty closely with some of these pharmaceutical companies and really in some ways relying on their medical liaisons to say you know, hey, can you help me get this paperwork processed as soon as possible, or is there any way that you can help us out? It's definitely getting easier, but still tough.
Dr. Michael Kentris:No, that makes sense. In neuro-oncology, obviously we're dealing with people who have usually very serious, often disabling types of diseases. There's the medical piece of it. But in terms of working with therapists, whether speech therapists, physical therapists, other types of assistive device type programs, is that a common part of your practice and, if so, what are the unique hurdles that you might have to jump through there?
Dr. Ashley Aaroe:Absolutely, I would say. The majority of my patients with brain tumors are actively participating in physical, occupational, speech or cognitive therapy. It's also part of our institutional guidelines that folks with brain tumors that you consider getting a baseline neurocognitive assessment and also repeating that assessment at certain intervals following treatments like radiation, most classically, that you're monitoring for cognitive disability. So it really does become multidisciplinary, and we are lucky to have a great neuropsychology team and I think their input is really valuable as well. I would say that there's an emerging understanding of the importance of neuropalliative care in brain tumors and so often involving a supportive care team or a multidisciplinary palliative care team early on, you know, not only improves quality of life but can actually help folks with brain tumors live longer too, and so I think very much continuing to destigmatize palliative care and really emphasizing, you know, we need to take care of you as a person and not just try to, you know, kill as many tumor cells as possible that too, but you know it should be a kind of integrated thing.
Dr. Ashley Aaroe:I think all of those elements are really important. Sometimes patients, you know, will have issues related to chronic pain as well, and so, you know, will have issues related to chronic pain as well, and so you know, for example, I've had patients who had, you know, an extensive spinal surgery for their spinal cord ependymoma and they have no evidence of disease, but they do still follow frequently with me with supportive care, you know, with pain management, as they're on surveillance, and for physical therapy, rehab, getting Botox, you know, for spasticity. All of those are really crucial pieces of the care.
Dr. Michael Kentris:Gotcha and that's a great point that you bring up is that even if we have, let's say, surgical, or someone goes into remission, that doesn't necessarily mean that they're going to be symptom-free.
Dr. Ashley Aaroe:Yeah, I think that's very true, and I think we also have to be very cognizant of what we can do iatrogenically with the treatments that we have.
Dr. Ashley Aaroe:You know, for example, a lot of folks with low-grade glioma are diagnosed when they're in their young adulthood, and you know, if you treat them with radiation and granted, there are new radiation techniques, like protons specifically, that may have a lower risk of delayed memory or neurocognitive sequelae but that's still something that you have to think about, where you know, if you jump to radiation for a patient with a low-grade glioma, you know chances are that they are going to have some memory trouble after that, and so you know that plays into selecting patients for different treatment options and also knowing when is the right time to initiate treatment, and so for some patients with a low-grade glioma, you might reasonably observe them after resection before going to radiation, just due to that concern.
Dr. Ashley Aaroe:A lot of patients also are, you know, glioblastoma patients. Again, classically are older males, but we do see glioblastoma and other high-grade gliomas affect younger folks too, and so you have to think about will you be impairing someone's fertility by giving them alkylating chemotherapy? So you know, fertility preservation is something that we have to talk about and there are even more. You know specific preservation is something that we have to talk about, and and there are even more, you know specific considerations for adolescent and young adult patients too. So those are all things that that are also in the back of my mind, you know, when I see a patient with a new diagnosis of a brain or spine tumor.
Dr. Michael Kentris:No, that's her. Yeah, I, I always forget about the fertility aspect, you know, even for you know, young men as well as women. So do you work pretty closely with like a certain are there. I guess this is a bit of a strange word. Are there specialists within reproductive medicine who specifically work with like kind of those pre-treatment oncology patients?
Dr. Ashley Aaroe:Yeah, oncofertility is also a very growing field For us at my center. Growing field For us at my center it's housed within the adolescent and young adult medicine practice. So those patients for example, if I refer a brain tumor patient to their practice, they're assessing them for physical occupational therapy needs. How are they doing with if they're still in school or if they're working? How are they navigating that with their brain tumor? There's emotional support support groups and then also there will be someone from gynecologic oncology or urologic oncology that's helping with fertility preservation. Those folks also get genetic testing.
Dr. Ashley Aaroe:I really love the practice of that group because I do think that it sort of it highlights how many resources are needed to take the best care of patients with cancer. And I think also they remind me of survivorship considerations, like we were just talking about. Because I think you know, of course, when you're dealing with a brain tumor, especially an incurable brain tumor, you want to be aggressive, you want to keep that from recurring for as long as possible, but I think that you can't forget about the survivorship piece too.
Dr. Michael Kentris:No, that's a great point To switch gears. Just a little bit about the systemic toxicities of cancer treatment. So you mentioned obviously a lot of times we have patients with chemotherapy-induced neuropathy and does your practice you know obviously a lot of us in medicine we know about gabapentin, pregabalin, kind of the usual neuropathy meds. Does your practice differ in any particular way or do you have any special tricks for these types of patients?
Dr. Ashley Aaroe:Yeah, so that's a great question. There are many, many different ways to delve into that. I would say there's for chemotherapy-induced peripheral neuropathy specifically, there's a lot of benefit at least in the literature and in my practice to things like Cymbalta or the TCAs. I think the other thing that's important to know is that in order to get a benefit from things like gabapentin or Lyrica, you may actually have to up titrate to a pretty hefty dose. Too often I've seen folks that get started on like 300 of gabapentin at night and then it doesn't do anything and then we just stop it saying it didn't work, so really giving it a little bit of time. This is purely anecdotal, but I do like some compounding creams with like amitriptyline and ketamine that can be applied topically. I think in general we have better interventions for paresthesia and pain than we do to restore a lack of sensation from chemotherapy related neuropathy, and you see patients that are really debilitated due to gait instability because they can't feel the ground. I've seen, actually, a couple of patients get into motor vehicle accidents because they have issues with gauging the pressure on the gas or the brake pedals, and so it's, I think, something that is important to hone in on One area specifically with neuropathy that I'm interested in is how do you identify patients that are at particular risk?
Dr. Ashley Aaroe:So we know certain drugs are associated more highly with neuropathy, like taxols, platinum-based chemotherapies notorious culprits but how do we identify patients who are at particularly high risk? So I would say, maybe once or twice I've seen a patient that had really high arches and had specific sort of leg and foot anatomy. That made me think, oh, maybe they have charcomeree tooth, which is an underlying heritable neuropathy, and we did actually diagnose it. And then we are neuropathy and we did actually diagnose it, and then we are out. We should probably try to think, you know, of other non platinum based chemotherapies, and so that was like a really nice you know being able to talk to the oncologist about hey, I'm really worried that this is a high risk patient, even though he doesn't subjectively have a lot of symptoms from it. He probably will if we give him something very neurotoxic. So I think you know, aside from that very specific kind of situation, we need to do a better job of realizing who's at risk.
Dr. Ashley Aaroe:I think my major takeaways would be that there are certain chemotherapy-associated neurotoxicities that are really well described in the literature. For example, cytarabine causes cerebellar dysfunction, Methotrexate causes leukoencephalopathy, among other things, and so for a neuro-oncologist, those associations get kind of baked into us and so we can help folks, you know, understand, you know, is the patient developing this neurological symptom due to their therapy or due to something else? And I think that that's a way in which we can advise our medical oncology colleagues. I would say.
Dr. Ashley Aaroe:Also, with regards to immunotherapy, I would say that immunotherapy associated toxicities that mimic idiopathic neurological conditions are different animals. So, for example, you can have a Guillain-Barre-like syndrome from checkpoint inhibitors. In many ways that's similar to an idiopathic Guillain-Barre. That happens after somebody has a diarrheal illness, but it can behave differently too. So, for example, I have seen some cases, certainly less common, where they can have multiple sort of relapses instead of being a monophysic illness like it would be obviously for regular Guillain-Barre, if you will. I think it's also really important to know oh gosh, I'm going off on another tangent here, so feel free to stop me.
Dr. Michael Kentris:No, no, I'm loving it.
Dr. Ashley Aaroe:For my field it's really important to know the history of treatment somebody has received and the sequence, and also to know the mechanisms of action. So my first question for anybody who is on a clinical trial is that a bispecific T-cell engager that I might expect to have a risk of developing encephalopathy? Or, you know, is it something conjugated to a taxol that might also produce neuropathy, even though that hasn't been described in the literature? Because this is the first, you know, phase one study that this is being used for. So stuff like that, I think, is kind of unique to my field too.
Dr. Michael Kentris:No, that's super important to know. I know. I've know at least even where I am at a non-academic community hospital, probably at least two or three times a year I'll see someone who has some complication of immunotherapy, like all the CAR T-cell type stuff, and I've seen a myositis, a myasthenia type and, as you said, a GBS type presentation all within just the last year. And, as we know, sometimes we have our traditional treatments for these disorders and sometimes we don't see the same kind of responses to treatment that we would normally expect. So I guess what I would say is so, let's say I have a lot of times where I would be doing steroids or IVIG or plasma exchange. Is there any evidence for going kind of beyond that to like we would in some of those refractory cases where we're using, like rituximab or even cyclophosphamide or you know, ironically treating chemotherapy induced problems with more chemotherapy?
Dr. Ashley Aaroe:Yeah. So I would say we see that pretty frequently here. So for here you know and I think a lot of institutions are similar you know that they use a grading system for neurotoxicity and if it's a high enough grade or severity you will treat it very aggressively. So I've seen patients with Rituxan and Fliximab like pretty early on, just jump straight to Plex, you know, hit it with everything, just because these toxicities can be so severe.
Dr. Ashley Aaroe:I would say that in terms of immunotherapy related toxicities, you also have to balance your interventions with the risk of interfering with the treatment efficacy.
Dr. Ashley Aaroe:So I would say, as a general phenomenon, a lot of the patients who develop neurotoxicities will also be the ones that develop a response, a positive therapeutic response from a cancer perspective.
Dr. Ashley Aaroe:So, for example, there are some CAR T therapies that have an off switch, if you will like. If you develop a severe enough toxicity from it, you can give something that will effectively shut the CAR T cells down. And the decision about when to do that is, I think, obviously a very high stakes one, not just from the neurological perspective but from the oncologic one too, and that's something that I've observed also. I've been fortunate to be, you know, asked by some of my medical oncology colleagues who are working to develop new therapies. You know we see X symptom, that you know neurological symptom develop, but we also notice that that's happening more in the patients who are also having their tumor shrink. So how do we layer out, you know, what doses or what interventions are appropriate so that someone can get the maximal benefit but also not, you know, accrue more neurological injury at the same time? And that's a very fine balancing act too.
Dr. Michael Kentris:Those are great considerations. I know it's easy for us as specialists to sometimes get our blinders on and just like we have to stop the neurologic process. And then what about the cancer? It does definitely become very tricky in those situations, and this was something I just became familiar with. I think you had mentioned it just briefly. Was some of these like infliximab, which, if I remember correctly, is IL-6. Correct me if I'm wrong there.
Dr. Ashley Aaroe:For infliximab TNF-alpha.
Dr. Michael Kentris:Oh, okay, Now is this one of those new protocols that is sort of like for these CAR-T immunotherapy type adverse reactions.
Dr. Ashley Aaroe:So it is something that's in the therapeutic armamentarium. But what I would say is so if we're talking about CAR-T neurotoxicity, there's a couple of. I think you may have been thinking of tocilizumab, which is anti-IL-6. Yes, yes, so with regards to how CAR-T cell neurotoxicity is usually managed, so I can go on a whole separate thing about that. So we know that these patients are at risk for developing encephalopathy and also seizures and also cerebral edema, which can cause attendant ICP issues if it's severe enough. But typically what we'll see is that patient receives CAR T cells. Then they might develop what's called cytokine release syndrome. A few days later, with fever, hypoxia, some systemic manifestations, you'll see their cytokine levels in the serum and then, a few days after that, you may start to see them develop encephalopathy, and so typically these patients become inattentive and have difficulty with language first, and so there's actually a grading system, now called the ICE score, where it's a score out of 10 and you take away a point for everything that the patient is not able to do For example, listing days of the week backwards, naming things, writing a sentence, because these are all thought to be sort of sensitive indicators of neurotoxicity, and those patients will receive steroids.
Dr. Ashley Aaroe:Now the cytokine release syndrome that often is associated with and precedes the development of neurotoxicity can be managed with an anti-IL-6 agent like tocilizumab. But tocilizumab does not treat neurotoxicity, and so the mainstay of intervention is dexamethasone. For the neurotoxicity piece I have read, and every single time, I have to be honest, I forget the mechanism. I learn it because I think it's fascinating, and then I immediately forget it. But there is a mechanism by which tocilizumab may paradoxically increase the amount of circulating IL-6 within the CNS because it doesn't cross the blood-brain barrier, and so just the takeaway would be that tocilizumab does not fix CAR-T neurotoxicity it's really steroids and if severe enough then you may consider other agents like infliximab or rituxan or you know if the CAR T product has sort of one of these off switches, if you will.
Dr. Ashley Aaroe:But I think it's, the story of CAR T neurotoxicity is a really fascinating one because you know, obviously this drug, this treatment, comes down the pipeline. That is, you know we're seeing amazing therapeutic responses. But when we first started to see neurotoxicity we didn't know how to identify it quickly, grade it, and so if you look at the literature, the incidence of neurotoxicity in the early studies for CAR T is all over the place. It's a very wide range and the morbidity and mortality from neurotoxicity was also quite high. So I think it's kind of for neurologists in general, you are sort of at the forefront of, you know, as these drugs come down the pipeline, trying to figure out what is the neurological piece of things and how can we manage toxicity.
Dr. Michael Kentris:No, yeah, that's very challenging. I would be remiss if I didn't ask a subject that's very much on the mind of many neurologists when we encounter patients with weird symptoms who have a history of cancer, whether systemic or neurology, is perineoplastic syndrome, which I know is. You know, there's been a proliferation of antibody markers over the last decade and there seems to be no end in sight. One of the things I always read about in the guidelines is that we need to be looking for clinical signs and symptoms that map onto a perineoplastic syndrome and not just sending antibodies willy-nilly. But I would be curious to get your perspective as someone who's more in the weeds of it.
Dr. Ashley Aaroe:Yeah, I think it's definitely hard to know when to order the panel. Do we do serum, Do we do CSF, Do we do both? It's always a difficult decision. Classically, perineoplastic syndromes are those that the neurological symptoms are before the diagnosis of cancer and so leading up to a diagnosis-known, well-documented, longstanding history of cancer after they receive immunotherapy, if they develop neurotoxicity. It's very situation dependent.
Dr. Ashley Aaroe:But I think one thing about neurology in general that I find myself constantly sort of trying to explain to folks in medicine or neurosurgery is that it really isn't just the lab test, and I think that's particularly true of perineoplastic disorders.
Dr. Ashley Aaroe:So you might get something that has a low or moderate positive titer, but it may not fit the clinical syndrome and it may not fit the underlying cancer too, and so then you really have to question does that result mean something or not? And I think that's the beauty and pain of neurology is that it really is everything together the history, the exam and also the data points. So using those panels in a circumspect way is challenging, I have to admit. There are cases where I look back and I think to myself why did I order the panels? It was just we did not have a satisfactory other explanation, but it was my suspicion for a paraneoplastic disorder really high enough to justify doing it. I've had situations where I thought the exact opposite. So it's all that to say that it's tough, but I think that you touched upon or alluded to that it really has to be in the appropriate clinical setting.
Dr. Michael Kentris:Yeah, I've definitely been in that same boat where I've had this like yeah, this is a strange constellation of symptoms and I order a perineoplastic panel and I get a weak positive back on. Something like this doesn't fit at all. But now I have to spend all this time explaining to the patient. You know all the things that you just said and you know sometimes it goes over well, sometimes I'm referring for a second opinion. But yeah, it can be a challenging situation when you open that Pandora's box.
Dr. Ashley Aaroe:For sure.
Dr. Michael Kentris:One other thing I was curious to ask you when I was reading through your profile is that you've done a lot of work with advocacy, with public policy, with the American Academy of Neurology as well as the National Brain Tumor Society, and for those of our listeners who work in healthcare, whether they're nursing physicians et cetera what does that look like? How does one become involved, and what kind of career personal satisfaction have you gotten from your work there?
Dr. Ashley Aaroe:Yeah. So I first got into advocacy through the American Academy of Neurology with their event Neurology on the Hill, and that was really eyeopening. So at the time that I participated I was in residency and I think a lot of folks will have the residency clinic experience in which there are limited resources to help your patients. You're kind of like a safety net sort of, and there are so many things about the practice of medicine that you wish you could change but you feel helpless to, especially when you're still a trainee. And so I felt like by getting to go to one of these events where they have folks that will train you in how to be an effective advocate, how to convey something about your very, very specialized field and the thing that you really care about, how do you explain that to somebody that has no background in what it is that you're talking about and how do you get them as passionate about it as you? I think that was a really exciting experience, and so I continued some of the work through Head to the Hill with the National Brain Tumor Society as well. So there are a variety of events through medical societies and patient advocacy groups that you will be able to either go to Capitol Hill to meet with lawmakers and their staff, or even locally, you know having meetings with your local legislators, or even locally, you know, having meetings with your local legislators.
Dr. Ashley Aaroe:Something that stays with me about these experiences is that I think when I was at a neurology on the Hill you know these little cafes underground as you go from one building to another in DC and there was a representative from a group for rare genetic disorders, mitochondrial disorders, and they had been doing their advocacy work for a really long time and they said you know, the thing about it is that everybody can generally agree that we should help people who are sick and that we should try to advance science and medicine, but nobody's really against that. But where that falls in terms of somebody's priority list, as they're also juggling considerations about education and infrastructure and other things, it's easy for for things to get lost in the wayside, um, especially if, if they're more rare conditions, um, and so really, I think being an effective advocate is being a good teacher and a good storyteller of hey. This is why you should spare a moment to think about this specific issue and how do we make this better? Advocacy for me really mitigated a lot of symptoms of burnout that I was experiencing as a resident, because I felt empowered to have a voice and address some of the systemic things that I didn't think I could do anything about otherwise, and I really enjoyed meeting with other like-minded.
Dr. Ashley Aaroe:You know neurologists and other healthcare providers, but also you know patients and family members, who are the most important. You know pieces of of advocacy work. It just it's very modifying, motivating and satisfying. That was modifying, that's a new word for today, so I'm really passionate about it and, again, I think it's something that we're starting to talk about in neuro-oncology as a field and a lot of folks are doing great work, like Joshua Boudou up at Memorial Sloan Ketter.
Dr. Michael Kentris:Awesome, that's great, and I'd just like to get your final thoughts. This is a very fast-moving field, lots of developments in the pipeline. What do you hope to see in the next five years or so?
Dr. Ashley Aaroe:And again, I think we're doing better at exposing residents to it, getting residents excited about it. I think also, you know, from a therapeutic perspective for the primary brain tumors, I'm really hopeful about unlocking things like targeted therapy. For example, the IDH inhibitor voracidinib is getting a lot of buzz based on a trial called Indigo out of Sloan-Kettering last year. I think we'll start to see more targeted therapies. I think we'll start to be able to integrate them into how we treat patients. So it's not just having the drug available but knowing when and how to use it. I think that we need to learn more about, but I'm hopeful about that. I'm also hopeful about unlocking the potential of immunotherapy for brain tumors. So, historically, you know things like CAR-T for gliomas, you know vaccines, you know have been less promising but less effective, you know in old studies. But there's more and more strategies that are coming down the pipeline that I do think we're on the brink of incorporating immunotherapies and targeted therapies into our day-to-day practice. So I'm hopeful about that. I'm hopeful for helping patients with brain tumors live longer and live better and ultimately, you know, the thing we're all shooting for is a cure for brain tumors and gliomas, and you know so I have hope for that too. With regards to cancer neurology, I think that again, we need to do a better job of identifying the populations of patients most at risk for developing things like chemotherapy, associated cognitive impairment and neuropathy. I think we'll do a better job of identifying biomarkers of patients who are developing those issues, hopefully while they're still mild or even potentially preclinical. It could be someday that we see a lab value that tells us ah, this is increasing. I don't know if that's going to be something like a change in BDNF or a neurofilament line chain, but maybe, oh, we should watch this patient a little bit more closely for the emergence of some neurological process related therapy. I think those are the things that I look forward to Ultimately.
Dr. Ashley Aaroe:I mean, I'm super biased, but I think my field is an extremely exciting one. I feel like you know the feeling I get when I come to work is is what it must have. I imagine okay, I'm being a little melodramatic here, but I can't stop myself I imagine it's similar to what it would have been like working at NASA in the in the sixties, because there's just stuff happening. There's a lot of passionate, interested, motivated you know people from different backgrounds across medicine and science that are doing amazing work, and the field is changing every day. So that's that's what I what I think is is exciting about my field and I am quite certain that five years from now, sure there'll be things that are advanced in immunotherapy, targeted therapy, stratifying patients. I'm sure something's going to happen that I have no faint idea what that is and it's just going to come out of nowhere and it's going to revolutionize how we approach patients with cancer and brain tumors. That I think is awesome. So, anyway, I'll stop myself reigning in a little bit there.
Dr. Michael Kentris:But yeah, no, the enthusiasm is infectious. This is making me excited, you know, if someone who's normally I'm not going to say super enthused about neuro-oncology, this is very exciting to me as well, and you know, obviously practicing in a more general neurology setting it's. I think it behooves us to be aware of these advancements and how we can further treat our patients who may, as you said, not have ready access to these more tertiary or even quaternary academic centers where there are these other things available. What can we still do in these other settings to improve quality of life and outcomes.
Dr. Ashley Aaroe:If I can say, one final soapbox that I have is keep an open mind, because care of patients with cancer is changing so quickly.
Dr. Ashley Aaroe:For example, it used to be thought of that, you know, a patient with cancer that has a large vessel occlusion for stroke is not going to benefit from a thrombectomy because they have cancer right. So challenging those kinds of stigmas I think is important. There were some studies that came out that showed, even though there is a higher risk of symptomatic ICH in patients with large vessel occlusion stroke that undergo thrombectomy, who have cancer, that they can have comparable functional outcomes and benefits and that there are patients with cancer that you know, even stage four cancer that can live for a long time. You know, even stage four cancer that can live for a long time, you know. So I think it's just about keeping an open mind. You know, for the general neurologists that are out there, that you know having cancer and what that means really looks very different than it did a couple decades ago, and so I think, again, keeping an open mind is super important.
Dr. Michael Kentris:That's very well said and, to borrow a phrase or a concept from our neuro ICU colleagues, we have to make sure that we avoid medical nihilism, right? This belief that everything's going to be bad and then we do nothing and it is bad and we were right the whole time. It's very much a self-fulfilling prophecy if we just let it be that way.
Dr. Ashley Aaroe:I think that's a great point and it's funny that you mentioned that. I feel like there's a very odd thread that links neuro-oncology and neuro-critical care and it's something that I would have never appreciated as a resident, because neuro-ICU was not my thing and any of my faculty who trained me could probably tell you that. But my husband's a neuro intensivist and he says neuro oncology is neuro critical care in slow motion and I think there's something to that. But I think that it's kind of a nice little phrase that he came up with. I think it rings true and I think that you're exactly right about one of those kind of connections being that how you approach a patient and how you approach a situation can have significant bearing on the outcome, and avoiding therapeutic nihilism is really important much for coming on and talking with us today.
Dr. Michael Kentris:I certainly feel uplifted by your enthusiastic outlook on the future and I appreciate you sharing all of your insights. If people want to find some of the work you've done or find you online, where should they look? How should they reach out?
Dr. Ashley Aaroe:I do. I'm not great at X, but I am on X, if you find me, which I still want to call it Twitter anyway, but I am always happy to connect about neuro-oncology, and thanks for letting me ramble at you. It was just about the thing that I love talking about.
Dr. Michael Kentris:No, I appreciate it. That's why I love being able to have folks like yourself on here is to hear about their passions and hear like the good things that are coming in the future. So thank you very much again. If people want to find me, I'm also on x slash Twitter at Dr Kentris D-R-K-E-N-T-R-I-S, and you can also find our past work on the website at theneurotransmitterscom. Thank you so much again for coming on and I really appreciate it. Thank you.
