Focused Ultrasound to Open the Blood-Brain Barrier
Neurologist/Neuro-oncologist in Cleveland Clinic’s Rose Ella Burkhardt Brain Tumor & Neuro-Oncology Center, Glen Stevens, DO, PhD, joins the Cancer Advances podcast to talk about the treatment of recurrent glioblastoma. Listen as Dr. Stevens discusses how a study mixing old principles with a new technique may disrupt the BBB, allowing chemotherapy to reach tumor cells.
Focused Ultrasound to Open the Blood-Brain Barrier
Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals, exploring the latest innovative research in clinical advances in the field of oncology. Thank you for joining us for another episode of cancer advances. I'm your host, Dr. Dale Shepard, a medical oncologist here at Cleveland Clinic overseeing our Taussig phase one and sarcoma programs. Today I'm happy to be joined by Dr. Glenn Stevens, a neuro-oncologist in Cleveland Clinic's Rose Ella Burkhardt Brain Tumor and Neuro-oncology Center. Dr. Stevens is also the host of another Cleveland Clinic podcast, Neuro Pathways. Today his on the other side of the microphone is our guest to talk to us about treatment of recurrent glioblastoma. So welcome Glen.
Glen Stevens, DO, PhD: Thanks, Dale. Great to be here. And on the other side of the glass.
Dale Shepard, MD, PhD: Tell us a little bit about your role here at Cleveland Clinic.
Glen Stevens, DO, PhD: So, Dale, I am currently acting as section head of adult neuro-oncology at the Cleveland Clinic. I joined the Cleveland Clinic in 1992, so 30 years. And if I'm not careful, it's going to turn into a career. We currently have five adult neuro-oncologists. We've done some good recruiting in the last year or so. And we actually have a sixth neuro-oncologist starting in June. We're a fully integrated brain tumor center and we have been so for over 25 years. And what that means is that we took neurosurgeons that just did tumor radiation, oncologists that do brain tumor, medical and neuro-oncologists that did brain tumor and we put them in the same cost center.
We live in as you know, in the cancer center and we see all of our patients essentially in the cancer center and we work in an integrative fashion with multidisciplinary clinics. So if a patient comes to see us, they can see the surgeon, the right onc and the med onc at the same time, we also have the benefit of having our own research team. We can integrate through CCF or through the cancer center, but we have our own independent research coordinators, regulatory folks, and nurses to allow us to do phase one, phase two and phase three clinical trials of which we try and do as many as we can.
Dale Shepard, MD, PhD: There you go. You are a very productive group when it comes to research. So we're going to talk a little bit about some of that research. Part of the, we're going to talk about is glioblastoma and looking at ultrasound and blood brain barrier disruption. We'll talk a little bit about that, but a lot of people might be listening that might not necessarily know a lot about neuro-oncology, so maybe we'll start basic. What is glioblastoma?
Glen Stevens, DO, PhD: So glioblastoma Dale is the enemy. The term was coined in around 1924 or so, and then historically for my whole career, we called it glioblastoma multiforme, GBM. Although in 2016, the World Health Organization came out with their newest classification of tumors and they decided to get rid of the term multiforme, but I'm sure that if you went to the computer and Googled anything, you would see the term written as glioblastoma multiforme. The multiforme part really arose from the fact that it was a very heterogeneous type of a tumor. So it seemed very descriptive for it and exactly why they decided to get rid of the multiforme part, I'm not sure. But now we just call it glioblastoma.
Dale Shepard, MD, PhD: Well, I think if we keep it GBM, it confuses the med students as well.
Glen Stevens, DO, PhD: Well, we want to do whatever we can to keep the med students off balance. If you're a connoisseur of all things, neuro-oncologic, the World Health Organization classification for tumors of the central nervous system came up with their newest edition in around December of 2021. So it's pretty fresh, hot off the press and a lot of changes were made. We won't go through those today, but a lot of changes were made that actually impact the diagnosis of GBM, have incorporated more molecular diagnosing, not just phenotype, but phenotype and genotype into it. And it's an ever evolving field, but probably 30 different types of brain tumors that we look at had classification changes and that will continue.
They'll probably do another one in a few years, but very active field and it really influences in some ways, patient entry into clinical trials. Because if you have to have a certain name of a tumor to go into a trial, you have to fulfill the criteria that we would call that tumor, whether it's a GBM trial or something else. So you really need to be up to date on what the classification of tumors are. Now, the simple answer is you can send them to us and we'll take care of all of that.
Dale Shepard, MD, PhD: I mean, I guess it's probably best from a treatment selection and specificity as well. So much like I treat sarcoma and that's not a disease, it's a collection of diseases, which all behave much, much differently. We can tailor disease treatments much more easily.
Glen Stevens, DO, PhD: Exactly. And I think that, we want to be, have precision and accuracy in everything that we do. All of these things are done because in the old days we'd look underneath the microscope and we would say, well, there's astrocytic cells that are there. There's too many cells. There's some mitosis there. There's vascular proliferation with blood vessels and necrosis, it's a GBM, but we know that your GBM is not necessarily my GBM and the genetic molecular makeup of our tumors may be very different. So we really need to get more precise and patients want precision medicine and they want treatments tailored to them. And I think that's where the field is going. Now, what do we know about GBM? GBM is the most common primary malignant tumor of adults. So we see a lot of it. Incidence is about 3.2 per hundred thousand, median age is around 64 years and average life expectancy, I'm sad to say is somewhere around 15 months to 20 months from diagnosis.
So not what we want it to be. It affects males a little more than females, although there's not huge number discrepancy there. The initial treatment is a surgery, because we need to make a diagnosis. We try and do a surgical resection if we can, as opposed to just a biopsy. The reason that we want to resect if possible is that we want to be able to do all those molecular testings, right? All the next generation sequencing, try and figure things out. And a lot of these molecular tests can help us, not only with what treatments we might want to use, but also prognostically. And that can help patients make an informed decision, how they want to move forward. If the tumor's very deep and we can't do a receptive surgery, then we have all the other tools in our belt here.
We may do something called litt laser interstitial thermotherapy. Litt is a thermotherapy where we essentially cook the tumor. So it allows us to biopsy and then heat it to a certain temperature to kill the tumors that are there. So this is good for deep seated tumors, the thalamic tumors. But again, the biopsy's just giving us a small piece of tissue that we can't do a lot of testing on. After we have tissue, typically patients are treated on the, what we call the stoop regiment based on a study that was published in the England Journal of Medicine, boy back, I think in 05.
Dale Shepard, MD, PhD: Way too long ago.
Glen Stevens, DO, PhD: Yeah. Long time ago. And it looks at the combination of radiation, therapy and chemotherapy and showed that adding chemotherapy to the radiation therapy in the upfront setting, allowed patients to have longer survival. They do approximately six weeks of radiation, given five days a week for six weeks in chemotherapy, we typically use temozolomide, it's given seven days a week.
Over the six weeks we take a one month break, then they get a follow up MRI scan. And if all looks okay, we give them higher doses of the temozolomide in the adjuvant setting for up to six months, given five days out of a 28 day cycle. We also, at that point can discuss with them giving tumor treating fields. Tumor treating fields is one of these different types of treatments where we put on a shaved head, we put a, almost looks like defibrillator pads, and it's giving a low dose electro current to kill cells that are in mitosis. And there's another drug that's also approved, that you're very familiar with called Avastin or bevacizumab. It's a monoclonal antibody directed against VEGF vascular endothelial growth factor and it is used in the recurrence setting. But what we're most interested in is clinical trials for patients.
And I think that if we're talking life expectancies of what we just mentioned, we should be talking about clinical trials. And our goal is to have a clinical trial for every patient if we can. If you go to the NCCN guidelines and you look at what are the treatment recommendations for GBM, you'll see written in the NNC CCN guidelines, look at clinical trials. So I think we'll probably transition to that in a minute, but that's really the crux of where we need to go. Why are these tumors so difficult to treat multiple reasons? But a few of them include the infiltrative nature. They're very infiltrative tumors, they are not surgically curable. We still recommend a maximal safe resection. But if it's in an area that we're going to certainly hurt somebody, doesn't make sense to do surgery, but it does allow us to do next gen sequencing.
So that's good. The tumor heterogeneity that we mentioned with the multi formality issue to it, we've blocked everything individually, right? We blocked this pathway, that pathway, all the second messenger pathways with individual drugs, this isn't Gleevec, we can't just give a drug and give a magical cure here. It'll just find a different pathway. And of course, what we're going to discuss here mostly today is the blood brain barrier. It's there for a purpose, right? It wants to keep things out of the brain. And most of the drugs we use, or you would use to treat sarcoma, aren't going to go to the brain because the drugs are too large. They've got the wrong charge particle. The lipidicity is not correct. There's a lot of reasons we want to keep things out the brain. So those drugs don't get into the brain. So things that may work really great outside the brain, can't get it into the brain. So we need to look at things that allow us to get something into the brain.
Dale Shepard, MD, PhD: So we're going to talk about ultrasound as a way to get things into the brain. Is that correct? Yes. Can you give us a brief history of this because this has been a challenge for a long time, this blood brain barrier, and there have been a number of attempts to disrupt that blood brain barrier and get therapies across? What has been kind of the primary reason those have failed in the past?
Glen Stevens, DO, PhD: Yeah. So I'll mention a couple of things. One is that, many years ago we ran a blood brain barrier program here for primary CNS lymphoma. And what we did is we used mannitol and the blood brain barriers formed by very tight junctions between the endothelial cells and essentially is the Berlin Wall that's up there and we need to open that wall up. Maybe we need Reagan, to tear down that wall.
Dale Shepard, MD, PhD: Yeah, there we go.
Glen Stevens, DO, PhD: Yeah. We used mannitol to try and disrupt the barrier. Now we do know naturally things disrupt the barrier. When we do an MRI scan on somebody and we give them gadolinium and we see gadolinium enhancing in a glioblastoma. The reason that it enhances or the gadolinium gets into the brain, is because the tumor causes significant brain edema or swelling and that opens the blood brain barrier and it allows the gadolinium to get in and we can see it in the brain. But when we were looking at primary CNS lymphoma, we looked at it as a very chemo sensitive tumor, and we wanted to try and decrease the amount of radiation we're giving patients. So we are giving mannitol inter-arterially. So we are putting catheters into the brain, and then we're giving the mannitol under general anesthesia to open the blood brain and then give them high doses of methotrexate entirely to try and treat the tumor.
But as you can imagine, a very invasive procedure, patients would be treated monthly for a year and we would have to inject in one of the four major arteries, twice during each month cycle. So it's a very invasive procedure. We could potentially get mannitol only, but again, doesn't seem to work as well. And part of the negative of just doing this focal opening of the barrier, is it allows all other things to get in and the patients are on other medications. Then they may go into the brain and cause a negative consequence or problem. And then how do you shut the barrier? Well, one drug we know that can shut the barrier is steroids. So we have to be very careful with steroid use, because we use too much steroid, it can actually close the barrier and make it more difficult to give drugs.
Of course, we mentioned Avastin earlier, Avastin, very good at closing the barrier. So there have been a number of other drugs that have been looked at over time, bradykinin and analogs and various types of things, but nothing has really been shown to be very fruitful. So ultrasound been around for a long time, back in the forties, they looked at focus ultrasound a little bit different than what we're using. We'll talk about two things here. We'll talk about high frequency, which is ablative and heat and low frequency, which is what we use, which is non-thermal. And what happened historically is that they want to use thermal therapy to treat brain tumors. We thought let's just cook the tumors sort of, as I mentioned with the laser interstitial thermotherapy and the fundamental principle of focus ultrasound is really analogous to a magnifying glass.
So you take a magnifying glass and you want to carve your girlfriend's initials in the wood. You take the beams of sun and you bring, I always tell patients this and they look at me like, where am I from? And you want to carve their initials into the wood, it's the same thing. You take the focus beam ultrasound and you put it through a series of arrays and it can thermally heat up and cook an area. But as you can imagine, back in the forties, when they did this, where do you think all that energy's going? Right on the skull right? So people would have a lot of burns and those types things, and it was very hard to penetrate the bone and some individuals, their skull is thicker than other individuals. So you'd get a lot of attenuation of the beam for the focus ultrasound.
So a lot of problems in the forties, although there was a lot of interest and it kind of died away a little bit. And then they said, well, let's just do a craniotomy. Let's just put a big hold in the brain and do the focus ultrasound. Well, that works. You can do that, but then people have a big craniotomy and they weren't so excited about that, otherwise. If you're going to do a craniotomy, then why not just go in and resect the tumor at that point. So patients, as they usually do vote with their feet and their feet said, I'm not going to do that. They're moving in the other direction. So the real big development was MRI and MRI allowed us precision and accuracy, allowed us to be able to target lesions and could use real time thermal monitoring in an MRI machine.
So that's the beauty of the MRI, is you can do the scan, you get perfect anatomy, you can see exactly where you're treating. So when you're doing targeting for your X, Y, and Z coordinates, you can go exactly where you want to go and you can treat very small lesions or you can treat big lesions and you can do real time thermography in an MRI. And then they came out with multi-channel arrays and transducers for focused ultrasound. So you can have targets or beams coming in from multiple areas. So you can dissipate the heat and you're not causing it so much. And we started to understand better whose skull is too thick or whose skull isn't too thick. I suspect you'd have a problem. This is what-
Dale Shepard, MD, PhD: I'd thank you.
Glen Stevens, DO, PhD: Well, this is what I hear about you, very thickheaded. So, they'll do CTs and if people have too thick a skull, then they may not be able to do it. Or if they've had a lot of surgery or hardware or those types of things, they may not be able to do the treatment. But in 2016, the FDA approved high frequency focused ultrasound, this thermal treatment for tremor. So we do a lot of this at the Cleveland Clinic and it's usually done on the same day that we do our treatments, done in the same machine, uses a different transducer, because there's high hours low, but a lot of every part of it is the same. And we normally would do a case because we have to give them chemo afterwards, which we'll get into. So we kind of bump them till later in the day. But it's a great thing to see with treating tremor in these patients, because it's a very obvious thing, right?
Someone's got a hand that's shaking quite a bit, they're awake and alert. They're in the MRI. They can give them low doses of ultrasound, lower heat doses and give a mild ablation and they can then test people, have them do an arced circle or writing or finger pointing and they can see, hey, I really think I'm where I should be. And my tremor is attenuated a certain amount. So now I can give him the full dose and I can cause an ablative lesion. So we have been doing that for the last few years. So it was a natural transition for us because 80% of the procedure is similar type of things that we're doing. We just had to get a different transducer. And the company inside tech asked us if we'd be interested in looking at doing LIFU or low intensity focused ultrasound to open the blood brain barrier. So for all the things mentioned to you earlier about what a problem it is, this is a real interest to us.
Dale Shepard, MD, PhD: What kind of timeframe from a treatment standpoint, how long is a person in MRI actually getting treated?
Glen Stevens, DO, PhD: Yeah, so it's a good question. And one of the negatives of the high frequency ultrasound is that patients are being treated for tremor. So we really can't give them medications because we don't want to give them sedatives or medications that are going to affect their tremor. One of the benefits of the low intensity is that we can give them medication for their tremor. And everybody likes a little bit of medication if you're going to be in an MRI for a long time. But the trial that we're doing is a phase one clinical trial. And as you know, a phase one clinical trial is really a safety trial, it's not an efficacy trial, although everybody wants to know about efficacy, but it's really a safety trial and it's for recurrent GBM. So these are people that have gone through the radiation, gone through the chemotherapy and have recurrence and we're treating them in the recurrence setting and it takes place in neuroradiology. And what happens is a patient shows up about 06:30 in the morning. I know it's early.
Dale Shepard, MD, PhD: It's early.
Glen Stevens, DO, PhD: And on the initial trial that we had, we had to shave the head for patients. Now like everything, things start to progress forward and they don't have to have a shaved head now, they can have short hair, but we would shave their head. We would give them some versed and some morphine. So they're a little bit lighter. And then we have to affix a head frame to them. So we essentially bolt a head frame to them because we have to have something that is stereotactic in space. That's not moving so that even though we're not lesioning a tiny area, we can't have something moving. It has to be fixed. So we bolt a head frame to them, but once the frame's on, it's very comfortable and then we have to place a bladder around them.
So we put on this silicone bladder that goes around the head, that will then connect to the transducer and be filled with water. And the benefit of that is that it dissipates any heat. With the low frequency, it's not a big issue. We still generate heat with the ultrasound, but not like the high frequency people, but it's hooked up to a multi array transducer to give the ultrasound through various areas. And they're then in the MRI machine and they're there, usually about four hours, but it depends on what we're treating. So they'll get an MRI first with the transducer on, we'll have had MRIs previously and drew out the target, it's probably not going to change, but we treat what's called the leading edge or the flare part of it, we also treat the enhancing part, but we want to treat this the highest percentage area that has tumor.
And when we first started doing the clinical trial, we could only treat about 30 CCs. And then as the trial progressed and it was safe, we could treat a larger volume. So by the end, we were able to treat 110 CCs, which is a pretty big area of individuals. And what we do is, we do individual sonication. So we can treat, if we had 110 CCs, we can only treat small areas at a time. Now hopefully as the software and hardware develop, and I'm, I'm thinking hopefully in a year from now, we'll be able to treat much larger areas at a single time, which I think will decrease our time in half or maybe even a fourth, which will then make it a lot easier to do and a lot better for patients. But we do a sonication where in real time it takes about 90 seconds.
We can give a certain amount of energy and we can see visually on the MRI scan, the disruption that is taking place. We can actually see the changes in real time and we can do what's called T2 star imaging. And we can see the changes on the imaging in patients. So, 90 seconds, two CCs at a time, 110 CCS, you can do the math and figure out how long it's taking. So it's a long time that people are in the scanner, but you know what? In the phase one clinical trial, which is we finished the last patient a couple of weeks ago, their sixth treatment. There was one patient that wasn't able to complete the time period.
Dale Shepard, MD, PhD: And I guess, was there an escalation phase where you, you mentioned you were doing larger volumes, were you also altering the energy?
Glen Stevens, DO, PhD: Yeah. So that's a really good question. And I think that there are parameters of how we can give the energy and how much energy, because the concern is also too much energy. Maybe we cause too much internal change and maybe we actually, we're going to cause some lesions. So I would say that, so there were parameters and yes, we did change the energy as we went, but obviously we're within the confines of how far we could go. And sometimes if you're, you learn a lot of things. If you're neurosurgical cavity, it can be a bit of a sinkhole. You may need more energy to be able to cause cavitation to open the barrier. So a lot of things were learned as we went through.
Dale Shepard, MD, PhD: And so I guess considering it's a phase one safety trial, I'll ask the obvious question, which is any early word on efficacy.
Glen Stevens, DO, PhD: So I'll start by saying that safe looks good, right? Looks safe. We had no bleeding issues. One of our concern is would people have some bleeding related problems from the procedure? We did not see that at our site and we'll see when all the data comes out and published, but my understanding was not an issue. And we didn't see significant neurologic symptoms related to the treatment in a negative way. So that's good.
Dale Shepard, MD, PhD: Or as you mentioned, things like concomitant medications, crossing blood brain barrier, things like that.
Glen Stevens, DO, PhD: Yeah. So one of the keys is patients couldn't be on a bunch of steroid. And I think two milligrams was the lowest dose of steroids they can beyond which is a pretty low dose of steroids, but we did not have to escalate steroids on any of our patients. We did not get cerebral edema as a side effect of the treatment, which was very encouraging and helpful. And we didn't have progressive neurologic symptoms afterwards, which was very helpful as well. I'll just tell you, because you asked me nicely, the goal was to treat with six cycles of carboplatin and you've used carboplatin quite a bit in your time. That's a lot right to do that. There were sites, there were only a handful of sites that were doing the study, a group in Israel, a group in Toronto and a group in Korea.
And I think two others in the states were doing the study, but I can tell you that we got so excited with the last patient that we treated and you can't take much from a single patient, but I tell you, it helped us all get up in the morning. And this patient has a recurrent glioblastoma, was able to do the full six cycles. I was talking to his wife at the sixth treatment and she told, I said, how do you do after the fifth cycle? And she said, well, we went to Disney World with the kids and we walked, we were there for five days, walked about 40 miles in the five days. So we did pretty good.
Dale Shepard, MD, PhD: Pretty good.
Glen Stevens, DO, PhD: That was there. But the great thing about it was that he was able to get through the six cycles, didn't have a problem. Neurologically, completely intact and his tumor significantly shrunk. Now I would say that was not the usual situation for most of the patients and our goal is to stop it from growing. But one of the things that we get excited about clinical trials is even if trials turn out to be negative trials, and this will clearly go to new phase trials, there are always individuals within the clinical trial that it turns out to be a really good treatment for. And it just allows people to do something that they couldn't have done. This is something that he never would've done and maybe if we just gave IV carboplatin afterwards, the barriers open, he would've done as well, but six months of treatment and his tumor was smaller than it started, where the average efficacy for a recurrent GBM trial response rate is 15%.
It's a pretty slow number, with progression at four months. So here we are six months out when we did the last treatment and his tumor was smaller. So again, I think that this is a technology that's really more a proof of principle and we'll get more interesting drugs to give as we go along, but looks like it's pretty safe. If we can cut down the treatment time, make it a little more tolerable for patients or also looking at trying to do a frameless based system. So there's less of that than something that we're all excited about.
Dale Shepard, MD, PhD: Wow. Well, it sounds like you've stumbled into something here that old principles, new techniques that look pretty promising.
Glen Stevens, DO, PhD: Yeah, we're excited. We're actually with the same company, going to be starting a new trial in GBM patients where we, and this is really starting to get out there now, but using something called five ALA. ALA is, I would say it, but we won't be able to spell it on there, alpha-linolenic acid, but it is a drug that is used in neurosurgery to light up GBM, it's taken into the GBM and you can fluoresce it so you can see where it is. And you can use photo dynamic therapy to sort of affect the oxygenation and kill cells, it's used in dermatologic. But there's also some preliminary data to look at using sonication. To take this ALA that's in GBM patients and it can then through sonication kill the GBM cells. So we're just through the IRB and hopefully we'll be putting our first patient on trial in the next month or so.
Dale Shepard, MD, PhD: Well, Glen, somehow you've managed to take a really bad disease and tell us about some new therapies that give us some hope so well done.
Glen Stevens, DO, PhD: Well, I like your term and hope is what it is, right? I mean, we all know what it is, but we need to do better than we're doing. And the only way we're going to do that is trials. So those of you listening out there, just encourage you to look at clinical trials for your patients. We're happy to see them. If they're somewhere close to where you are that are doing clinical trials for this or other cancers, don't be afraid of it. It just allows your patients access to things that they're not normally going to get and for them it may be the right thing.
Dale Shepard, MD, PhD: It's outstanding. Thanks for being with us.
Glen Stevens, DO, PhD: Dale. I really appreciate it. It's great being on the other side, I think I yapped way too much and I apologize for that.
Dale Shepard, MD, PhD: Oh, no worries is great information.
Glen Stevens, DO, PhD: Thanks man.
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