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Gene Barnett, MD, MBA, neurosurgeon and Director of the Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center joins the Cancer Advances podcast to discuss the standard of care for brain metastases. Listen as Dr. Barnett discusses how the traditional surgical approaches for treating patients with brain metastases have evolved and how we are using stereotactic radiosurgery to deliver superior outcomes.

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Stereotactic Radiosurgery in the Treatment Landscape for Brain Metastases

Podcast Transcript

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 I and Sarcoma Programs. Today, I'm happy to be joined by Dr. Gene Barnett, a neurosurgeon in the Cleveland Clinic Neurologic Institute, and director of the Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, is here today to talk to us about stereotactic radiosurgery for treatment of brain metastases. Welcome, Gene.

Gene Barnett, MD, MBA: Thanks, Dale. Happy to be here.

Dale Shepard, MD, PhD: Maybe to start, give us a little bit of an idea of what you do here at Cleveland Clinic.

Gene Barnett, MD, MBA: All right. Well, as you mentioned, I'm a neurosurgeon. I specialize in brain tumors, run the Brain Tumor and Neuro-oncology Center, also run the Gamma Knife Center Here, which is our main platform for cranial radiosurgery.

Dale Shepard, MD, PhD: Very good. So just sort of as a background, give us an idea. Patients come in, they present with brain mets. What are the options for them? What are we able to offer them? And then maybe we can talk about what's best for individual patients. But give us the lay of the land.

Gene Barnett, MD, MBA: Sure. Well, first brain mets are surprisingly common. They actually are the most common brain tumor in adults. And about 20 to 40% of people who get systemic cancers will ultimately get brain metastases. So it's about 10 times more common than the primary brain cancers. The symptoms they present with vary. They may present with neurological problems like progressive weakness, numbness, visual problems, speech defects, trouble with their gait. They may present with a seizure. Very often they'll have no symptoms at all, and these are just picked up on screening. And actually headaches are surprisingly rare. So it's really important that primary care and medical oncologists who are taking care of these patients are really tuned into the possibility of these patients developing brain metastases. And the patients themselves ought to be aware that this is a possibility so that they can report early if they have symptoms, because the options are actually better if we get to these when they're smaller and/or asymptomatic.

Now the options for any type of brain tumor include observation, doing more testing, treating the tumor or the symptom that's causing with drugs, doing something surgical, like needle biopsy, putting a laser probe in it and cooking it, doing a craniotomy to take the tumor out. And then there's the radiation options, which on one extreme are daily low-dose treatments to the whole brain for two or three weeks. And on the other extreme is a single-day targeted radiation treatment where the rest of the head and brain gets almost none. That's called radiosurgery. We use the Gamma Knife here for that. So observation's exceedingly unlikely in these patients, unless there's some question as to whether these brain metastases are something else, in which case, then they may get a short interval scan to remove any doubt.

In terms of further testing, occasionally we will do some further testing to better characterize what's going on, but usually a high resolution MRI scan is all we really need to clinch the diagnosis in the setting of a patient who is known to have a systemic cancer. In terms of drugs, most drugs that are used to treat systemic cancers don't get across the blood-brain barrier very well. And so they're typically not a frontline treatment, although some drugs are getting somewhat better at this. And certainly if the patient is having symptoms, either neurologic symptoms or seizures, then we would treat those medically, typically with steroids if edema is an issue, and then with antiepileptics, if indeed seizures are an issue.

In terms of surgery, the need for needle biopsy or stereotactic brain biopsy is rare. Typically that's reserved where the diagnosis is in doubt. Say they had a remote cancer 10 years ago and have been cancer free for five years, and now we're seeing things that look like brain metastases. That's the kind of situation where we would seriously consider doing a stereotactic brain biopsy.

We usually don't do the laser treatments, the so-called laser interstitial thermal therapy, or LIT, for frontline treatment for these, although craniotomy certainly remains fair game when the diagnosis is in doubt and/or they are sick for mass effect. The radiation options 20 years ago, many or most of these patients would have been treated with the whole brain radiation. But we've learned over time that this has serious neurocognitive consequences down the road, somewhat lessened by hippocampal sparing techniques or the use of the memantine. But still, patients are living longer and they have a longer time to then to develop these white matter changes that are associated with neurologic decline. So stereotactic radiosurgery has really emerged as being the mainstay treatment with brain metastases, either upfront with newly diagnosed metastases or after whole brain radiation, if they've had it, when new ones pop up.

Dale Shepard, MD, PhD: What are some of the, the limitations in ability to use stereotactic radiosurgery?

Gene Barnett, MD, MBA: Well, traditionally, size mattered, that once you got above two centimeters, you had to dial back the dose in order to decrease the risk of adverse radiation events, such as radiation necrosis. Now we've gotten around that by doing what we call two-stage radiosurgery, where we'll give the traditional dose for that particular size, and then to have the patient come back in a month for a boost or what we call a second stage so that they can get a full dose safely at a lower risk of radiation injury if they had given a whole dose upfront. The other limitation is that it doesn't keep new tumors from growing. It just treats what we can see, unlike whole brain radiation. But at the same time, it doesn't carry the baggage of neurocognitive decline that whole brain radiation does. And the fact of the matter is that these days we can treat nearly an unlimited number of brain metastases over time.

Dale Shepard, MD, PhD: What does this look like from a patient perspective in terms of what their experience is as they undergo the treatment and how well they're likely to do? Because I realize that when I see patients in clinic and I tell them they have a lung met or a liver met, they're not nearly as frightened as when I tell them they have a brain met. So how do we reassure patients that... Sometimes it's even hard to get them to get a scan because they don't want to know. How do we decrease that fear and improve that experience for them?

Gene Barnett, MD, MBA: Well, I think that's totally understandable because people understand the brain is who we are and allows us to do what we want to do. Many people know people who've had brain tumors or know of people who've had brain tumors and have not done well. I think the point of reassurance is that they actually do a really good job of controlling brain metastases these days with radiosurgery, to the extent that most people who have brain metastases don't die from them, rather they die of their systemic disease and their brain disease is under control. For the vast majority of brain metastases, the control rate is upwards of 90, 95%. And with the staged technique, the control is typically durable. So I think that giving patients the facts, again, don't want to sugar coat things, but at the same time, giving them the facts that the outcome is actually probably a lot better than they were thinking should be consoling.

Dale Shepard, MD, PhD: From a strictly logistic standpoint, what's the duration of time? How does this look? They come to see you and then they have a procedure. Recovery times, what does that look like for a patient?

Gene Barnett, MD, MBA: Sure. So we typically see the patient either virtually or in person after they've been identified as having brain metastases, and we have an informed consent conversation. The day of surgery, they undergo high-resolution MRI scans of the brain, which are loaded into our planning computer. I then survey the brain to determine what it is that we want to treat as well as nearby structures that we don't want to treat, and compose a plan of different little focal points of radiation, such that in the end, the size, shape, and location of the radiation that's delivered essentially matches the size, shape, and location of each tumor. Sometime after that, we give them some light sedation in the vein. We numb their head up at four points, two in the front and two in back, and there we secure a stereotactic reference frame to their head.

They don't feel sharp pain, because they're numbed up. They will feel some pressure that some people find uncomfortable, but regardless that goes away after five or 10 minutes, and afterwards they shouldn't even feel that it's there. And after the frame's in place, we send them next door to get a specialized stereotactic CT scan. That's also loaded into our planning computer, electronically fused to the MRI scan. I then do some last minute fine tuning. A radiation oncologist then reviews the plan, assigns a dose of radiation to each tumor. The radiation physicist then reviews the plan, makes sure that all the eyes are dotted, T's are crossed, and that the machine is operating properly that day. And then sometime later that day, typically early to mid-afternoon, we then take them across the hall from the room to the treatment room. There, they lie down like on couch, similar to a CAT scan or MRI couch. But that frame that's still on their head is part of a precision positioning system that'll make up to 192 beams of gamma rays, all focused on the spots I picked on the computer to within a fraction of a millimeter.

They then slide into the machine up their lower chest, depending upon the size and location of the tumors, typically about 15 to 20 minutes per tumor. While they're in there, they don't hear, see, smell, feel, taste anything. It's all invisible. They do move around from place to place to place during the treatment. And usually they just listen to the radio on the internet while that's going on. Some people just snooze. While they're in there, we've got several TV cameras on them, a couple of intercoms. People are right outside the door, could be in in a matter of seconds if needed.

Then once they're done, we take them out of the machine, back across the hall, remove the frame, put a couple band-aids on their forehead, watch them for half an hour to an hour or so, then they can go home. They take it easy for a day or two. Most people are back to their normal activity for two to three days. Then usually we get them back in two months for a new scan to see how things look in there. If indeed they're going to get a second stage, we have them come back in a month to get that.

Dale Shepard, MD, PhD: So really it's pretty streamlined and patients tolerate that pretty well, which is good to know. And again, good for offering reassurance.

Gene Barnett, MD, MBA: Yeah, we've been doing Gamma Knife since 1997, and I've been doing stereotactic radiosurgery since 1989. So we have it pretty down pat these days.

Dale Shepard, MD, PhD: What are the limitations at this point that could drive this forward? This certainly has been around for a while, but are there anything from an equipment standpoint that might make this more useful as a technique in terms of either efficacy or adverse effects?

Gene Barnett, MD, MBA: Yes. Well, we now have the ability to actually do this without a frame, and can do it with a mask fixation with electronically scanning the patient's head to detect any movement during the treatment. Our Gamma Knife machine has a cone beam CT attached to the front of it, which can actually do a stereotactic CT scan right then and there on the machine. And it allows us to eliminate the frame in some cases, particularly if it's going to be less than an hour treatment, or if we're going to need to fractionate this over three to five days, because again, of the size or location with respect to other critical structures. So that certainly has been in advance in the technology. The other use for stereotactic radiosurgery is with respect to craniotomy for brain metastases.

We know have known since the '90s that if all you do is take out a brain metastasis, more likely than not, it's going to come back. And the pivotal studies back then showed that patients who also got whole brain radiotherapy after craniotomy did better in terms of tumor control than those who did not. But as I mentioned earlier, whole brain radiotherapy carries the baggage of neurocognitive decline.

So not that long ago, probably five, 10 years ago, people started experimenting with doing radiosurgery after craniotomy instead of whole brain radiotherapy. And there results actually were surprisingly good, that indeed it doesn't keep new tumors from growing, but it actually seems to do a good job in terms of sterilizing the surgical bed and preventing recurrence. The one downside to it, however, is that there is a small incidence of about five to 7% of leptomeningeal disease or subdural spread of tumor recurrence afterwards, since those areas don't get sterilized.

And so in the last four or five years or so, people have been looking at doing the radiosurgery before surgically taking out the tumor, so-called neoadjuvant stereotactic radiosurgery, and the results there seem to be at least as good in terms of tumor control and the leptomeningeal disease risk is far, far lower, probably 1 to 2%. So if indeed surgery is contemplated, and from a logistical standpoint, one can work radiosurgery in beforehand, then we try and do that these days. But sometimes you just can't do that, in which case, then we resort to doing the adjuvant or post-craniotomy radiosurgery in those cases. But we've virtually eliminated the need for whole brain radiation in those settings, unless the patient already has known leptomeningeal disease.

Dale Shepard, MD, PhD: So patients sometimes come through and they think that something newer is necessarily better. But as you described, you currently are using 192 beams and you have great localization and can keep patients in the same fixed location to treat them. But questions that sometimes come up are about proton beam in other settings. What role, if any, is there for proton beam in this situation?

Gene Barnett, MD, MBA: So far there's really no clear indication that proton beam is in any way superior for the treatment of brain metastasis than so-called photon beams, which is what we are using with the Gamma Knife and how most other radiosurgery platforms are operating. Certainly there is work going on to try and determine whether there's superiority of one or the other or non-inferiority, but that was going to take some time to answer. There's really no reason to think that protons are really going to be superior for the treatment of these with very rare exceptions.

Dale Shepard, MD, PhD: Are there any particular parts of the brain that are still more difficult to treat than others?

Gene Barnett, MD, MBA: Well, the brainstem is kind of the Manhattan of the brain in terms of functional density, whereas you can get away with some swelling and edema up in the cerebral hemispheres or even out in the cerebellar hemispheres, that isn't as well tolerated in the brainstem. So we have to dial the dose down from what we would actually like to give for a given size, but we still can do the staging that I talked about. So ultimately the patient can wind up getting a full dose with minimal risk of an adverse radiation effect.

Dale Shepard, MD, PhD: What are we looking into in terms of systemic therapies in combination with stereotactic radiosurgery? You mentioned that you treat the given areas that you know about, but it doesn't really minimize your risk for additional lesions developing. So are we doing things in terms of adding systemic therapies?

Gene Barnett, MD, MBA: So as you're probably aware, Dale, that there are new agents that do cross the blood-brain barrier and have shown some efficacy in treating brain metastases. Now, most of the data that I've seen actually suggests that the combination of radiosurgery with those agents is superior in terms of tumor control than either one of these by themselves. So I think there's actually synergy with these new agents, and still the opportunity for a medical oncologist and the radiosurgery teams to work hand in hand to get better control of these tumors for their patients.

Dale Shepard, MD, PhD: So much like you talked about radiation and surgery and sort of how you sequence those. What are the current thoughts about sequencing a systemic therapy with stereotactic radiosurgery?

Gene Barnett, MD, MBA: So typically, radiosurgery does not get in the way of the patient going on either conventional chemotherapy or some of these new targeted therapies, immunotherapies, whatever. The only real limitation that we have is that we normally give a short course of steroids after doing radiosurgery to minimize the risk of early swelling and seizure, because there is a slight risk of that in the first week after radiosurgery, unless you use the steroids, which of course that's a no-no with immunotherapy. We all know that that can decrease the efficacy. So in those cases, we forego the steroids and put them on a short course, about two weeks’ worth. And that seems to work quite well, both in terms of prophylaxis against seizure, but also not getting in the way of the immunotherapy. So from our standpoint, the medical oncologist can do whatever he or she wants in terms of administering the medical therapy, irrespective of whether they're going to get Gamma Knife and when they're going to get Gamma Knife.

Dale Shepard, MD, PhD: So we have a center here that has a tremendous amount of experience doing this. And my question would be what are the particular things we do here differently, you think do better? What's the type of patient that really should come here to get evaluated, to be perhaps treated here compared to other places?

Gene Barnett, MD, MBA: Well again, we've been doing this for a very long time. I've been doing this for a very long time. We have a very experienced team. I think we are as experienced as just about anybody else out there. In fact, our expertise is recognized such that we're one of a handful of centers around the world that are authorized by the manufacturer of the Gamma Knife to teach physicians, surgeons, radiation oncologists, medical oncologists, how to do Gamma Knife radiosurgery. In fact, we have a course going this week, as we speak.

Dale Shepard, MD, PhD: When you think about the progress we've made, what do you think is going to be the next leap? What's a gap, or where should we be thinking about directing our energies to make this even better?

Gene Barnett, MD, MBA: Well, I think in the end, better drugs, drugs that produce control without even having to do radiosurgery. I know that might put me out of business, but if there are safe, effective drugs that are well tolerated, then so be it. There's always other things besides pre-metastases that we can and treat with radiosurgery and probably will be for the foreseeable future. I think basically, radiosurgery technology, as you said, has been around. For now, it's mature. I don't really think it's going to get any better. It does the job. So far, any effort to come up with radiosensitizerers for radiosurgery have really not come up with any benefit. So I think in terms of radiosurgery, we're at a high point, and you get more drugs, more development with our team in medical oncology to work together, to get control of this all too common problem.

Dale Shepard, MD, PhD: Well, Gene, I appreciate your insights today. I appreciate your help for our patients and appreciate you being here with us today.

Gene Barnett, MD, MBA: Dale, thanks for the opportunity.

Dale Shepard, MD, PhD: This concludes this episode of Cancer Advances. You'll find additional podcast episodes on our website, clevelandclinic.org/canceradvancespodcast. Subscribe to the podcast on iTunes, Google Play, Spotify, SoundCloud, or wherever you listen to podcasts. And don't forget you can access real time updates from Cleveland Clinic's Cancer Center experts on our Consult QD website at consultqd.clevelandclinic.org/cancer. Thank you for listening. Please join us again soon.

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