Dr. Will Meador (Host): Welcome to Better Edge, a Northwestern Medicine podcast for physicians. I'm your host, Dr. Will Meador, Associate Professor of Neurology at the University of Alabama at Birmingham. Today, we have a panel discussion looking at glioblastoma current and future treatments. And joining us for that discussion today, we have Dr. Roger Stupp, who is Chief of Neuro-Oncology in the Department of Neurology and the Paul C. Bucy Professor of Neurological Surgery at Northwestern Medicine; and Dr. Rimas Lukas, who is Vice Chair of Outpatient Neurology and Professor of Neuro-Oncology and Hospital Neurology at Northwestern Medicine. Thank you both for joining us today.

Dr. Roger Stupp: Our pleasure.

Dr. Rimas Lukas: Thank you for having us.

Host: And Dr. Stupp, we'll start with you. So, glioblastoma remains one of the most aggressive and therapeutically resistant cancers that we treat. Thinking about it from a biological and clinical standpoint, what makes this disease so uniquely difficult to manage?

Dr. Roger Stupp: I think its location, its location in the brain, its repercussions on function, complications that you get, like seizures. But then, also, the brain is protected by the blood-brain barrier. So, any treatment for CNS disease has additional challenges of drug distribution.

Dr. Rimas Lukas: Yeah, I think I agree fully with Roger. And the other, I think element that I would add is that this is a highly infiltrative tumor. So, it's really interwoven with the functioning brain. And it's something that's not a solid ball with little fingers sticking in, but independent cancer cells that are surrounded by all the normal milieu.

Dr. Roger Stupp: Which gives you the answer for the next question you may or may not have is for treatment, the fact that it is infiltrative. So, any local treatment, surgery, radiation can only treat what is safe to resect or treat and what you can see. But always, we see the tips of the iceberg. And the iceberg underneath is more challenging to access, to treat. And we are really dependent on treatment that the body itself could help take care of the tumor as well.

Host: And especially considering how hard it is for someone to hear that they have glioblastoma, knowing how difficult it is to treat, as we just discussed. Dr. Lukas, how is it crucial or so important for interprofessional collaboration between neurology, neurosurgery, and neuro-oncology to manage individuals through this care pathway?

Dr. Rimas Lukas: Well, I think that this is a field that is not great for a lone wolf. So, this is not something where an individual, as a physician can just sit by themselves and not interact with the other key team members. So, it's highly multidisciplinary. You know, I'm lucky because I sit there in the same room as my neurosurgery colleagues. I have my neuroradiology colleagues right across the hall. We're all interacting on a very regular basis with regards to tumor board, the discussions with the neuropathologist, the neuroradiologist, other neuro-oncology colleagues like Dr. Stupp. So if I have a question, I can sit there and ask him in, you know, quasi real-time.

I think that colocalization in that collaborative approach is really what plays a big role in improving outcomes for patients. So, people do better when all the different parts of the puzzle are together, or all the different moving parts are going in the same direction.

Dr. Roger Stupp: You mentioned difficult. I would say if you're at Northwestern Medicine and the Malnati Brain Tumor Institute getting your care, we are so integrated—that makes us different. We sit together, we are in multiple departments, a little more administrative meetings to go, but we interact. We interact with neuroradiology who's sitting there in the room with them. I had already two calls today with neuropathology fully integrated. We have five, six outstanding neuropathologists plus outstanding fellows. There's a permanent interaction. So for us, it's one, and it should not matter. And the patient who comes can see on the same day the neurosurgeon, one or two neuro-oncologists and the person taking care of epilepsy, we have our social worker that is integrated. So, it's really a pragmatic way, patient is centered, and we are all around there to really go for the best care.

Host: Yeah, that sounds fantastic. Dr. Lukas, thinking about the early course of an individual who's being evaluated for glioblastoma, are there opportunities that are maybe missed early on to identify the diagnosis or to get to effective treatment more quickly in cases that you've seen that maybe could have benefited them as it relates to their outcome long-term?

Dr. Rimas Lukas: Yeah. I think that, for me, you know, we operate in an environment where we're able to oftentimes get to the diagnosis quickly. I like combining the diagnostic work with the therapeutic management. And so, the first surgical intervention is the perfect example of that where most of the time there is not a need for a diagnostic biopsy followed by a surgery. You can combine everything into one with a goal of really maximally removing as much tumor as possible.

And then, I think that close integration that we were talking about previously allows for rapidly going to that next step. So, not burning up time and energy doing things that may be inadequately productive while not treating a malignant brain tumor. So, it's nice for us to be able, you know, move from point A to point B very quickly in an orchestrated manner. So, I think that that's one specific place.

And I think the integration of clinical trials early on is also going to be an opportunity that, you know, ideally is not missed. So, we're always kind of constantly thinking about that. So whether it's before the surgery, which is going to be a limited clinical trial set of opportunities shortly after surgery, before we start radiation or, you know, in that post-radiation phase, those are all time points in which we may be able to augment our standard of care treatments.

Dr. Roger Stupp: If I can add to the reference to the research, our research team is an integral part. So, going from the lab to where we see the patients is five minutes, it's in the same building or just across the bridge. We bring ideas from the lab all the way to the clinic, but also questions that we see in the clinic that go back to the lab. We have weekly meetings among the different disciplines and also from the bench and the bedside people. So, that really ultimately moves the needle and ultimately helps the patient.

Host: And Dr. Stupp, kind of continuing in that vein of thinking, you know, almost 20 years ago, the Stupp protocol was developed from that research effort that you just described and is really kind of the central element of the management of glioblastoma. Looking back on that time, what do you think was the key insight that led to radiation therapy plus temozolomide becoming the standard of care?

Dr. Roger Stupp: Well, it was game-changing because it started integrating the different disciplines. Before, it was the surgeon first then came to radiation-oncologist. And if a patient was maybe still asking for more, a neuro-oncologist was consulted. Again, everybody around the table. It started with working together between disciplines. At the time, it was neurosurgery, radiation-oncologist, and myself. But again, already lab people integrated, we could find biomarkers and so on. And it really changed the field from being, "Oh, we don't want to do any harm," and being very negative to, "Okay, we can do something. What did it change? It changed paradigms." Treating in the upfront setting, not waiting until the tumor is multi-resistant and the patient is so symptomatic that he will not have the strength to withstand more treatment and fight. He will not live long enough for a novel treatment to even have an impact.

So, that's what it did. Now, to be honest, it's just the first building stone, the fundamental. It's nothing to write home about and to be so proud of. It's just less bad than it was before. But I think there is, for many young people, a hope they will see this video to actually get motivated. There is still the bar to be put higher up. But we have patients who live not months, but years now. And we didn't see that before.

Host: And until there's those trainees in the future and future physicians develop a new management, we still use this protocol today. And how has it evolved over time, Dr. Stupp?

Dr. Roger Stupp: It hasn't evolved much, I would say, to my big chagrin. We even use it when we should not use it because we don't have a better treatment for the unmethylated ones. We tried that, withholding temozolomide where temozolomide has marginal effect at best. But many of the novel treatments we have tried, even the ones we were most, excited, like bevacizumab or immune checkpoint inhibitors, when we put them to test in a phase III trial, it did not show a benefit.

That's the other lesson you need to put your ideas to test. There is way too many treatments out there that are recommended on the internet, but have never been put to test. I didn't invent temozolomide, but I took it instead of having an opinion to test. And we have new treatments like tumor-treating fields, same thing. We had believers and non-believers. And then, you had the people like Dr. Lukas, myself, and many others who put it to test. It doesn't matter what we believe, we need what we need to know. We need to learn from each patient we treat.

Host: And Dr. Lukas, so there's been a lot of advancement in neurology and medicine in general over the last 20 years, including advances in technology, supportive care. Despite this, we really see that survival gains for glioblastoma improvements have been fairly modest, as it relates to the treatment options we have available. From your perspective, what has held the field back the most in that regard?

Dr. Rimas Lukas: That's a tough question. You know, I think we have had modest gains. So if you look at the population level, you'll see that there has been sort of an incremental improvement in survival over time, over slow decades, but certainly not enough.

I think, for us, it's just a very difficult disease to treat. And, you know, I mentioned one of the elements earlier that it's a disease that's interwoven with a lot of functional or relatively functional brain. It is a disease that is extremely heterogeneous at the cellular level. And this is not spatial heterogeneity, meaning area A versus area B versus area C is different, but all integrated and, you know, adjacent to one another and intermingled, which makes it tough to treat.

So even if we figure out the target in tumor cell A and B, tumor cell C may still be resistant to it. It is a disease that has a tremendous amount of mobility in a very delicate organ system. So, it's different than many other solid tumors where you have a little bit of invasion adjacent to the primary mass. But then, they really cause their problems when they get into the bloodstream and can figure out how to travel long distances. Here, it can travel long distances within the brain itself without needing to touch on the vasculature or anything else. No need to ride on any other structure. So, I think all those elements make it a very difficult disease to treat.

And then, I guess, finally, I would also highlight that it's within a very immunosuppressed microenvironment. And the brain itself is set up in such a way that it's supposed to be immunosuppressed, right, in comparison to other organ systems where the immune system has, you know, more free reign. And so, the tumor is able to hijack those same existing pathways and processes, and then just augment them, make them much more aggressively immunosuppressive. So, we have a large number of barriers to go after. And then, one of the problems that we have is that we go after one of them, which is the appropriate thing within the scientific setting to say, "Hey, does this seem to have some validity? Is this thing able to be tolerated?" Et cetera.

But as Dr. Stupp alluded to earlier, it's that multidisciplinary element that really makes us successful thus far. And it's probably going to have to be something multifaceted that we're using to treat it. So, I doubt there's going to be like a single silver bullet. We're going to need a whole armamentarium.

Host: And, Dr. Lukas, coming back to something you commented on earlier at diagnosis, thinking about early trial enrollment, what does the current clinical trial landscape look like for patients who've recently been diagnosed with glioblastoma? And why should clinicians really think about that early on in their clinical course?

Dr. Rimas Lukas: Well, I'll start with the last question first. So, as Roger had mentioned a little while ago, you know, using temozolomide in the upfront setting was a game-changer, in part because it was in the upfront setting, right? It's not waiting until disease progression. And it's in that space that we've had the most obvious successes in treating this disease. And so, there's a rationale that we may have our future successes in that same place as well.

And so in turn, thinking about really taking advantage of that specific time period when the tumor isn't as far afield, hopefully, and the tumor isn't as heterogeneous, and maybe that immuno environment is not as immunosuppressed might be the places where we're going to see those biggest gains.

Now, the clinical trial landscape, I think, has shifted in that direction over the past handful of years. So when I was doing my training, it felt as if every clinical trial was for multiply progressive disease. And they all turned out to be negative trials. And now, we're shifting more and more to upfront studies, although I'd say it's a very heterogeneous basket right now, which I think is a good thing. So, it's not, you know, all the same idea repeated ad nauseum. I think there's a variety of different approaches, which, you know, hopefully something will shake out in a favorable manner if we look enough directions wisely.

Host: And Dr. Stupp, what gives you the most optimism right now thinking about glioblastoma research or clinical care?

Dr. Roger Stupp: So, let me go back just what you had before when we have said, "Oh, it's all modest." I think that's the wrong way to look at it. You know, it's incremental improvement, but I can change that modesty to something completely different. When I started and in the randomized trial with radiation first, and then temozolomide may be at a recurrence, we had a two-year survival rate of 10%. So, one in 10. At the end of this trial, with the combination, it's one in four. We have a biomarker, so neuropathology, biology understanding. And we are one in two alive at two years. So, that changes the numbers.

And I think what I want to get there, what you say, what's going to come for the future, we have now way better sophistication with neuropathology being present to identify rare drivers, that's maybe only 5% or 10% of the patients, but we can identify them investing in looking much deeper and finding out who are the ones who would individually benefit from intervention A or B, rather than have one fits-it-all. So, there is a lot of progress there, and that's the basis on how we can work.

But for Dr. Lukas and myself to work, we need to have the pathology. We need to have the pathology done the right way, and that's in the upfront setting. And I would really encourage any patient who listen to that or family members. The first steps are much more important than the steps when it comes back. When it comes back, sometimes we also need to know when not to treat that's difficult to accept, but let's put it in when we can gain most.

Host: Yeah. And Dr. Lukas, we heard some about this earlier, but maybe kind of expanding upon it a bit. What makes Northwestern particularly well-positioned to help lead the next major shift in glioblastoma care?

Dr. Rimas Lukas: I think we have a very well-rounded group of clinicians and researchers who enjoy interacting with each other who are able to bounce ideas off one another who are able to eviscerate somebody's idea if they think it's not that good. And I think the environment is one in which there is that tremendous amount of collegiality that allows those type of open discussions. And then, we're comfortable testing those ideas, right? So as Dr. Stupp had mentioned, you know, a little bit earlier, we don't want to just take something verbatim. We want to be able to say, "Okay, I believe in this. Let me put it to the test," and then design our studies in a way that if it's a bad idea, that kills it. And if it's a good idea, then we can kind of go on further. And even if it turns out to be ineffective, to hopefully have learned a lot during that process.

Now, I think, the rest of our team are really key components to what makes us successful. So, we are very lucky to have phenomenal neurosurgeons who are great clinicians and great scientists. We have the neuropathologist whom you've heard reference to a few times who are really at the top of their game with the ability to conduct the most sophisticated molecular testing of the tumors and then also, more importantly, be able to interpret those results. So, people such as ourselves, as the clinicians, seeing patients in the clinic, we need to be able to make sense of all of this data that's coming in and that's constantly evolving and what we know now is different than six months ago.

And then, in addition to that, we have fantastic radiation-oncologists, excellent neuroradiologist, so all the different team members. And I think it's even further augmented by, you know, tumor-related epilepsy, et cetera. So, I think we have just a really well-rounded group exploring a number of different avenues that may be hopefully successful.

Dr. Roger Stupp: And let me just add to that. And we have outstanding nurses, APNs, cares. We don't only deliver treatment, but we deliver care. We have a social worker integrated. All that is also thanks to philanthropy that makes us exist as we are that we have a little less of the daily financial pressure that we can allow certain things to take the time. So, I would also thank them at this opportunity.

And lastly, it's not only us. We work with a network across continents, across the United States of other centers of excellence. We collaborate, we exchange, we call each other when we want more advice. So, this is really an effort of people on a mission.

Host: Well, it definitely sounds like patients are in very good hands at your center and are well taken care of, and really have the opportunity to participate in clinical trials and cutting-edge therapies. So, it's great to hear from both of you today. Dr. Lukas, Dr. Stupp, thank you for joining us.

To refer your patient or for more information, head on over to our website at breakthroughsforphysicians.nm.org/neurosciences to get connected with one of our providers. And that wraps up this episode of Better Edge, a Northwestern Medicine Podcast for physicians.

Dr. Roger Stupp: Thank you.

Dr. Rimas Lukas: Thank you very much for having us.