Dr. Andrew Wilner (Host): This is Better Edge, a Northwestern Medicine podcast for physicians. I'm your host, Dr. Andrew Wilner, Associate Professor of Neurology at the University of Tennessee Health Science Center, and Division Director of Neurology at Regional One Health in Memphis, Tennessee.

Today, we are discussing the clinical management of low-grade glioma. We have three expert guests from Northwestern Medicine joining us today. Dr. Jessica Templer, an epileptologist; Dr. Karan Dixit, a neuro-oncologist; and Dr. Matthew Tate, a neurosurgeon. Welcome, Drs. Templer, Dixon and Tate.

Dr. Karan Dixit: Thank you for having us.

Dr. Andrew Wilner: Let's start with you, Dr. Tate. Please tell us a little bit about the Low-Grade Glioma Program at Northwestern Medicine. Why is it important that low-grade glioma patients receive comprehensive care?

Dr. Matthew Tate: Sure. Well, thanks again for inviting us. We're excited to talk with you about our program the patients with low-grade gliomas are kind of an interesting patient population in that it's, you know, a disease that affects relatively young people, kind of at the prime of their lives, recently having kids, getting going with work, and yet they have this disease that's going to be with them chronically and ultimately convert to a more malignant, cancerous type of tumor. And so, it's one of these diseases that we want to be quite aggressive from a medical perspective to treat the tumor, but also keep very much in mind patient's quality of life as they're going to be dealing with the consequences for often decades even.

And so, the three of us in particular have been interested in seeing these patients for quite a while and thought that it made some sense to kind of have a more focused effort at understanding the disease and how it impacts patients and their caregivers and families. And so, this culminated fairly recently in establishing the low-grade glioma program here in Northwestern.

Dr. Andrew Wilner: Thanks for that, Dr. Tate. Now, you mentioned that there might be or could be or always has been an evolution to a more malignant form. Dr. Dixit, can you tell us about that, the challenges that patients with low-grade glioma face, that it might get worse or come back?

Dr. Karan Dixit: Yeah, certainly. I mean, that's one of the challenges that we see in our every day. One of the ways we think about this disease is when you meet people for the first time, you know, we're trying to get a sense of like their understanding of the process. When we meet people for the first time with this, with the initial diagnosis, how do you communicate such a disease process to someone that, you know, right now, you just had surgery, you had a seizure which led to the diagnosis. You had some sort of operation to remove the tumor. But then, we're talking about something that has a lot of connotation, you know, people come in thinking it was brain cancer. And certainly, that's true, but you know, not all brain cancers behave the same. And the biggest challenges with people with low-grade glioma is thinking about it in such a long window, it's a long period of time.

And so, as Dr. Tate alluded to, we're thinking about the longevity for these patients. And so, the challenge is how do we follow these tumors or how do we measure response to treatment, how do we measure progression of disease. You know, the current metrics we use right now are good, but they could be better.

Our treatments currently I don't want to say are outdated, but you know, we are using treatments that have been studied, you know, over 10, 15 years ago. And as we're learning more and more about the disease biology, we're trying to bring that in into kind of a more up-to-date method of treating these patients. And so, that's also one of the challenges, you know, how do we utilize evolving knowledge on how to kind of change the behavior or change the trajectory of their disease. Again, when you think about someone who will hopefully be with us 10, 15, 20 years and hopefully even beyond, is really thinking about that from a lifespan, you know, we're thinking about from a quality of life perspective, that includes cognitive function, that includes family planning, that includes seizure control. So, so many kind of specific facets to patients with disease population that we don't see in some other brain cancers, because we're not thinking about these people in such a long period of time basically.

Dr. Andrew Wilner: Is malignant conversion inevitable?

Dr. Karan Dixit: Yes. I mean, in many cases. So when we think about low-grade gliomas, that's kind of a broad category. You know, within them as we learn more about these tumors, over the past five, six years, our understanding has evolved to the point where our classification has changed twice. In 2016, the WHO had an update to the brain cancer classification system. It was updated again in 2021. And one of the main changes is utilizing more molecular diagnosis.

As a part of that, another update was kind of changing how we classify tumors. And so, now we consider tumors based on their grade, for example, and molecular features. So an oligodendroglioma, which is a common low-grade glioma, we see their highest grade would be a grade 3. An IDH-mutant astrocytoma, that would be classified as a grade 4. Previously, those were called glioblastoma. But unfortunately, to answer your question, yes, grade 2 glioma at some point, hopefully that's really far from the time we see people and the goal of management is to delay that transformation. You know, a grade 2 astrocytoma with an IDH mutation, if we see them now, we discuss that our goal of management is to delay that malignant transformation for as long as possible. But, you know, unfortunately, we do consider it an inevitability.

Dr. Matthew Tate: Yeah. And if I could just add a little bit, I think it is important to clarify because we're not really talking about grade 1 gliomas, which are technically low-grade gliomas, those typically behave in a benign way, but more of grade 2 or infiltrating gliomas are really kind of what we're focusing on in our program. And classically, you know, the terminology is a little confusing. But usually when we talk about low-grade gliomas in the literature, we're referring to grade 2 or these infiltrating kind of pre-cancerous type tumors is probably the best way to think about it and they do inevitably progress if kind of classified correctly, if you will.

Dr. Andrew Wilner: Oh, that's very helpful. Now, Dr. Dixit, you mentioned seizures. And Dr. Templer, you are an epileptologist, a specialist in seizures. Can you tell us about the role of seizures in these patients? What happens and how do you treat them?

Dr. Jessica W. Templer: Yes. So unfortunately, a lot of patients with low-grade gliomas are at risk for seizures, and we've now seen that that's largely related to their IDH mutation, which is a common finding within these gliomas. And seizures, it's often the way that these patients initially present. But unfortunately, they often continue to have seizures or can continue to have seizures after resection or after their surgery.

So, one thing that we worked to do initially, myself and Dr. Tate as well as the other surgeons, is thinking what can we do as part of their initial surgery to make sure we're offering them the best possible surgery in terms of not only their oncologic treatment, but also thinking about seizures. And then, after surgery, thinking about how we can best manage their seizures. And so often, that includes their oncologic treatment if they receive radiation or any chemotherapy, but also thinking about anti-seizure medications. And that's usually where I come in, is talking about what anti-seizure medication should we be thinking about and, in collaboration with the neuro-oncologist and neurosurgeon, coming up with the treatment plan.

Dr. Andrew Wilner: Is there any role for brain mapping, you know, at the time of surgery to look for the epileptic zone? Has that been proven to be helpful?

Dr. Jessica W. Templer: So, that's something that I'm personally very interested in, as well as Dr. Tate, is really understanding. So, there's something called ECOG, which is essentially doing that electrocorticography and doing that recording at the time of the tumor resection. The challenge has been historically that the studies, a lot of them, if not all of them, have been retrospective. And what we found is that ECOG, some studies have shown that ECOG can be beneficial in terms of seizure outcome, and some studies have shown that ECOG has not been beneficial. Although that's really been a selection bias, because the patients that were often getting ECOG were the ones that were having more challenging seizures to begin with. So, we hope that at some point in the future we'll be able to do a prospective study looking at the value of ECOG and how we can hope to offer them better resection in the future. And that's something that we looked at, specifically one finding in their ECOG studies, to help us hopefully be able to offer them a better resection in terms of their epilepsy outcome as well.

Dr. Matthew Tate: Yeah. And I can comment a little further too. I think that it remains an interesting question. Classically, it's been done. And in my training, it was sort of the general paradigm was if somebody's having refractory seizures, so they're on two seizure medications and still having seizures at the time of surgery, then we kind of do a combined seizure-focused surgery as well as a tumor oncologic surgery kind of combined. I think there are probably some patients who can benefit from that, even if they have reasonable control of their seizures. And so, we have started to do that and tried to start teasing out which patients could get the most benefit from such a combined approach because we often might find something close by to that overt tumor is an area of seizure production, and we would want to include that in the resection. It makes complete sense. As seizures are really, I would say, a major factor for their, you know, long-term quality of life and things for our patients. So, I think seizures have been undervalued as part of comprehensive care for these patients is one of the reasons we, you know, want to develop such a program. And, you know, we're lucky to have an expert like Dr. Templer as part of our group.

Dr. Karan Dixit: Yeah, it's incredibly helpful for us to have someone like Dr. Templer as part of the team because, you know, I'm a neurologist, but I focus so much on the tumor aspect of their care. But when we see people who are on three, four, even five seizure meds, you know, these are things where the medication themselves have additional toxicities. And a lot of that comes down to quality of life as we're trying to balance all of these things. That's kind of one of the aspects of the longitudinal kind of care we're trying to think about these patients, is well, you know, if their seizure is very kind of short, it's very focal, do you need to be on 50 drugs just to kind of get control of a very focal seizure and then kind of collaborating and kind of really focusing on the tumor treatment aspect of it. So, there's so many kind of nuances that it's really helpful to have kind of her input. When we think about seizure semiology, what the seizure looks like, you know, when we look at our patient's scans very closely, we're trying to see is there's something that we can potentially predict? Will a tumor potentially start regrowing in an area that you may not see it on an MRI just yet? So, these are all kind of helpful things that surely adds to the dynamic in the team.

Dr. Andrew Wilner: So, your comprehensive approach really allows you to individualize therapy for each patient.

Dr. Matthew Tate: Yeah, absolutely. That's the idea. Yeah.

Dr. Jessica W. Templer: I think our patients really appreciate that too. Our patients see us walk in the room together and have that conversation together, or maybe one or two of us talk about a plan together or as Dr. Dixit is discussing next steps in terms of chemotherapy or Dr. Tate, we're all in the room when we're talking about an upcoming surgery. I think the patients see that comprehensive element too, and really appreciate us talking to them about what are their goals and what is most important to them in these upcoming months, in these upcoming years. And that's something that's always been a key part of our discussion and the plan and the treatment plan.

Dr. Andrew Wilner: Thanks for that, Dr. Templer. Well, let's talk about a particular case. Dr. Dixit, do you have an example?

Dr. Karan Dixit: Yeah. There's a very nice young lady we saw. She established care with us, I think about two years ago. She lives in, I think, middle of Illinois, diagnosed with oligodendroglioma, so lower grade glioma with an IDH mutation and a 1p19q codeletion. So for the board exams, that's an oligodendroglioma. And so, she was diagnosed over a decade ago, had a resection, and then was kind of followed for years. And these tumors can grow so slowly, you know, millimeters per year. And that's one of the things that we're following, we're trying to track, is how do these tumors grow volumetrically. Meaning that these tumors are not just a two-dimensional slice on an MRI, they're three-dimensional structures that invade the surrounding brain.

And when something grows very, very slowly, you know, it's hard to actually see if it's growing. I use the analogy with patients, if a ship is going off course, if you only look back to the last point, you won't know until you look back to where you started. And, you know, she was doing really, really well. Then over the course of the past few months, she started having increasing seizures to the point where she had a major seizure while she was driving. And then, she had a motor vehicle accident and then, this led to further imaging. And then, you know, looking back at it all, it's like, "Oh, this tumor's grown actually quite a bit over the course of a decade." And then, she saw us. And then, we had a group discussion. You know, we discussed from Dr. Tate's perspective that, "You need surgery." But each time we think about the role for surgery is there shouldn't ever be just a discussion for surgery in and of itself. It should be, "Well, we do one thing, what comes afterwards?"

The winter was coming. This patient has young children, and one of the things that we discussed is this patient never received chemotherapy or radiation, which is kind of standard of care for these tumor types. The traditional sequence would be surgery followed by radiation, either with chemotherapy or followed by more chemotherapy. But there's some data to support that, does the sequence really matter so much? So because she lived far away and we wanted to utilize a specific kind of radiation, which is proton radiation, there's not many places around the country that offer this. You know, Northwestern has a proton center out in the west suburbs. Part of the discussion was she lives far away, you know, winter's coming, she's got young kids. You know, after surgery, do we start with chemotherapy first, kind of get control of the tumor? We saw shrinkage on imaging. And then, after she finished several cycles of chemotherapy, we call it neoadjuvant chemotherapy, if you will, she received proton radiation kind of in the summer, and she's doing really well now. Now, we're just kind of observing.

So when I look back at it, I was kind of just reminded that we have all these tools that we use to kind of help patients with this, but the sequence is important. You know, when we think about kind of when to do things, how to do things, and then we just kind of took things out a little outside the box, if you will. And then, you know, in her specific situation, we decided to be a little bit different with the sequence and it worked. And this is something that we, you know, try to think about with every patient, is for the specific patient, the specific family dynamic, the specific, you know, where you live, do you have kids. You know, these are all things that are important to, making a decision on the right next step. And from a seizure standpoint, she's doing great now. I'll let Dr. Templer comment on her seizure frequency, but this was a major aspect. You know, she couldn't drive for a period of time because she had a major seizure, her kids were in the car with her. These are really important things that we have to think about when we see these people.

Dr. Andrew Wilner: You mentioned the surgery. Dr. Tate, where does surgery usually fit in with these patients?

Dr. Matthew Tate: Yeah. Well, that's a great question. So, there's kind of two different times points, and the kind of considerations are different at these different time points. So, first of all is when we first find out about the tumor. So relative to what we've been discussing prior, probably 80% or so of these patients actually present with a seizure. So, they're a normal 30, 40-year-old patient, fine, no problems whatsoever, just have out of the blue have a generalized seizure or a major seizure. They come into the ER, get an MRI and a CT scan and shows this lesion. And then, you know, that's kind of the first time I generally meet folks.

And so at that time, if it looks like we're quite certain of the diagnosis, then we would proceed with surgery essentially at that time. Sometimes if it's more subtle, because it can be confused with the ARC, could be confused with other things on imaging, then we might follow it very carefully every two or three months for a bit to show that it grows. And if so, then we kind of proceed with surgery. So, that's kind of an upfront surgery. It's been pretty clearly shown now that for these tumors, the more you can remove even actually past what's obvious on the MRI, the better patients do.

On the other hand, if we cause any difficulty in the patient, if there's any complication with surgery, any neurologic deficit from surgery, they might have that for 30 years in the prime of their life. So, we have to be very, very careful thinking about that. And what I try to do before, during, and after surgery, at least at this phase, is trying to better understand what is the patient's functional anatomy, which you can't find any textbook or not really relative to the tumor location. It's a dynamic process, much, much more dynamic than we thought. Usually in a good way, patients can have these actually quite impressive, very large lesions and be, for all intents and purposes, just fine. So, we do very comprehensive testing, neuropsychological testing, imaging studies, sometimes EEG if seizures are in the fold. Get all of this information at our fingertips to design the best surgery for them, with the goal of removing as much tumor as we can safely while not harming the patient. And it's kind of a tailored approach. It might make a difference, how old the patient is, what are their goals, what are their jobs, what are their hobbies. You know, if they're a dancer, then we have to be very concerned with visuospatial function, whereas that might not be as prominent for another patient. And so, for example, we might map that out during surgery with stimulation-based mapping. That's something, you know, I work a lot on and is kind of my expertise, is trying to remove tumors inside the brain while not harming critical structures. And so, that's really the focus.

And then inevitably, these tumors recur or, more precisely, they grow. They grow and they were stable for years, and then now they're growing again. And that's another time we come into play from a surgical standpoint. Or if they're having refractory seizures, that's another time we might think about surgery for them, if it makes sense. And you know, it's actually not well known or well understood what is the right time to come back to operate again. If you think about this tumor, it's slowly, slowly growing, well, when is the right time to intervene? We don't actually know the answer to that. We have some general guidances, but those are, you know, not actually that well worked out. And so, that's one of the other things we're trying to study, is what's the best time to do surgery upfront? It's an initial diagnosis, it's fairly straightforward, but it's not nearly as straightforward when you're 10 years out. Should we do it now? Should we wait six months from now? What is our trigger going to be to operate? That's, I think, a much more open question.

Dr. Andrew Wilner: Understood. Now, Dr. Templer, in terms of seizure control, Dr. Dixit was telling me that this oligodendroglioma patient presented with a seizure and then seizures really affected her quality of life. How did you manage those seizures?

Dr. Jessica W. Templer: So upfront, her local neurologist had started levetiracetam, which is the most common medication that we see used. And it's commonly used because people generally tolerate it well. It doesn't interact with other medications. We can quickly get it to a therapeutic dose. The challenge, I would say, is that more commonly if you ask the right questions, you'll find that patients have mood side effects, irritability, some depression. Especially if you ask their partner, we see it more commonly acknowledged if you ask the right questions. But that being said, in general, it's tolerated. But despite the increasing levetiracetam, she was on a relatively high dose when she had that car accident. And so, we talked about other agents. And for her, I use lacosamide because she's a young otherwise healthy person and no cardiac comorbidities.

Another piece to her care though, which I think is important to acknowledge is what Dr. Dixit mentioned about the sort of traumatic component of the fact that her seizures began in her left foot and she was driving and was unable to stop the car fast enough. And she knew she was having a seizure and her kids were in the backseat. And so to comment on, I think, just how traumatic that could be, that she knew it was happening and she couldn't do anything to stop it and knew that she was putting her children at risk and she had been stable otherwise, and then this kind of happened and quickly progressed to a bigger seizure, was pretty traumatic for her. So, we also try to acknowledge that and work with our patients in getting them to see a therapist or working on connecting them with the right people. But for her seizure component, we started lacosamide and the most important thing for her was getting the repeat imaging, seeing that we did see progression and having surgery. And then after surgery since then, it's always important too to reassess at every visit that I meet with patients do they need these medications and do they need this dose of the medications. And for her, we've been able to lower her meds. She's on Vimpat or lacosamide monotherapy now and is doing very well.

Dr. Andrew Wilner: Oh, that's great.

Dr. Matthew Tate: And I would just say that, you know, relative to what we're discussing in terms of surgery for this individual patient, you know, as Dr. Templer mentioned, she had a seizure involving her leg. And so, this was very close to the primary motor area and that was the key function really at risk that was near nearby. And so, we did the case with motor mapping during surgery to kind of, again, maximize how much you can remove while minimizing any permanent neurologic risk. And she's done well from a strength perspective as a result of that.

Dr. Andrew Wilner: Oh, that's great. Well, Dr. Tate, before we wrap up, is there anything else your team is working on to improve survival and quality of life for patients with low-grade glioma?

Dr. Matthew Tate: Well, yeah, you know, there are a number of projects, some of which we've alluded to earlier. One of the things we're trying to assess, and we have some funding through Northwestern to look at this, is better assessing quality of life in our patients. I think we use kind of some old school cancer metrics that maybe aren't as relevant for this patient population. This is a very different patient than say a 72-year-old gentleman with a glioblastoma and expected survival of 18 months with maximal therapy. So, you know, that's very different. And so, we want to make sure that we're kind of assessing how we're doing frankly. We're decent at understanding progression from a tumor standpoint with imaging primarily, although that could be improved as well. But what we're not as good at determining, I think, is how the patient's doing functionally. And what Dr. Templer mentioned earlier has been pretty eye-opening for me, just for a good example from a seizure perspective, if you ask patients the right questions, often they're having seizures and don't know it, or they're not telling us about it, not volitionally, they just don't know what to look for. Even us, as neurosurgeons or as physicians, don't know what to look for or side effects from medication.

So, those are things that we're wrapping into these. We're developing a new quality of life skill here at Northwestern to kind of assess that and tell us how we're doing in terms of really instead of patting ourself on the back all the time, trying to figure out how can we really improve how each patient is doing in a real way. And then, you know, obviously, the other thing is developing this cohort of patients, you know, it makes all the sense in the world to include those folks for like IDH inhibitors trials such as that where we're trying to study things that have an impact on the tumor biology itself. We're also doing things like longitudinal assessment of the patient's functional anatomy. So, that's important for us from a surgical standpoint or even from radiation oncology standpoint to understand because we know now that function actually moves in these patients or is redistributed, I should say. And so, maybe we want to take advantage of that, wait a little bit longer to do surgery, for example, to give the patient time for their anatomy to not rewire, but redistribute, take a parallel pathway. And so, understanding that ahead of surgery might be useful as well and just different ways to map out function in the brain. You know, we use the typical technique of stimulating in the operating room with a small electrical current. The honest truth is that's what Dr. Penfield did in the 1930s. And we're doing the same thing, which is impressive and sad at the same time, right? So, there probably are better ways to assess function than that. It works, at least to some degree. But, you know, it's incumbent upon us to improve it for our patients and so we can make surgery safer and make more intelligent decisions about when to intervene in this very longitudinal kind of disease process.

Dr. Andrew Wilner: Oh, thanks for that. Well, to conclude, and I'll open this up to all of you, are there any final recommendations for providers who are managing patients with low-grade glioma?

Dr. Karan Dixit: Yeah. You know, these are complex patients with many needs that are seen. You know, some are kind of obvious, right? You know, tumor. As an oncologist, we always think about survival. We also think about, you know, what does the MRI look like, are things progressing or not. But, you know, what I encourage all providers, who see patients like this is to really kind of delve down into kind of the nitty gritty of their life, right? You know, these are people who are young. They are people who have-- I mean every patient has this, but these are patients who often have no other medical issues. These are people who are often kind of trying to advance their careers in some sort of professional realm. And these are all aspects of their care that really should be taken to account when we think about the appropriate treatment plan.

And from a practical perspective, I mean, this is kind of where it comes down to expertise. I mean, having an impressive first surgery, the more you remove up front, there's a lot of data to support, you know, what we call maximal safe resection with the least amount of tumor that is left behind volumetrically. There's a lot of retrospective data that shows that really kind of helps. That helps everything we do afterwards. You know, a good surgery up front really helps the next phase, which is chemoradiation. And so, you know, for anyone who sees patients with low-grade glioma, I would advocate for ensuring that these patients are able to kind of get the most, I don't want to say the most aggressive surgery, but I should say the most advanced surgery if possible.

Dr. Matthew Tate: Yeah. I think one of the things I would say is that the philosophy has really changed that these used to be patients 20 years ago where you would get a biopsy and just watch them because they did so well, and that's true. If you do nothing, they'll do well for a little while and then the next thing you know, they'll be progressing. And so, I think as physicians we need to be more aggressive for these tumors and less aggressive maybe for the higher grade tumors, which is kind of reverse of how things typically have been. We do all these things for patients with glioblastoma, this high-grade glioma, because they're more common and all rightfully so. But we make so much more impact any way you want to measure it for low-grade gliomas compared to high-grade gliomas, and they're not benign tumors. You know, we still see patients where that's kind of what they've been told and sort of that's mindframe, and they're absolutely not. They do inevitably progress. And so, the way we want to really kick the can down the road and delay that progression, it makes a big difference, is one of the most impactful, you know, surgeries we do as neurosurgeons is on low grade patients, it can double survival, for example. And when you think about the type of numbers we're talking about here, that's a really major impact. And so, I think just being really serious and aggressive about the way we think about these tumors rather than sort of considering them just sort of slowly, kind of trickling along tumor. You know, we see these patients all the time and know that, but that may not be the impression out in the community as much.

Dr. Andrew Wilner: Well, it's really exciting for me as a neurologist to hear about the progress that's being made and the progress that is going to be made shortly in the treatment of low-grade glioma. So, Drs. Dixit, Tate, and Templer, thank you all very much for this informative discussion.

Dr. Jessica W. Templer: Thank you.

Dr. Karan Dixit: Thanks for having us.

Dr. Matthew Tate: Thank you.

Dr. Andrew Wilner: To refer your patient or for more information, head to our website at BreakThroughsforPhysicians.NM.Org/Neuro to get connected with one of our providers. And that wraps up this episode of Better Edge, a Northwestern Medicine Podcast for physicians. I'm your host, Dr. Andrew Wilner. Thank you for listening.