Advances in Gamma Knife Treatment for Brain Metastases

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals exploring the latest innovative research and clinical advances in the field of oncology.

Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Sheppard, a Medical Oncologist and Co-Director of the Sarcoma Program at Cleveland Clinic.

Today, I'm happy to be joined again by Dr. Sam Chao, Associate Director of the Gamma Knife Center at Cleveland Clinic. He was previously a guest on this podcast to discuss the evolution of Gamma Knife technology and to discuss radiation necrosis, and those episodes are still available for you to listen to.

He's here today to talk about the use of Gamma Knife^® for brain metastasis. Welcome back.

Samuel Chao, MD: Thank you.

Dale Shepard, MD, PhD: So remind us a little bit about what you do here at Cleveland Clinic.

Samuel Chao, MD: Certainly. So I'm a radiation oncologist in the Department of Radiation Oncology at the Cleveland Clinic.

I focus mainly on CNS brain tumors as well as spine tumors. My primary focus is actually radiosurgery, as well as stereotactic body radiation therapy, to treat spine tumors as well.

Dale Shepard, MD, PhD: We're going to talk about Gamma Knife^®, and we have had a previous episode, we kind of covered part of this, but let's just kind of go through.

Remind us, what exactly is that?

Samuel Chao, MD: So the Gamma Knife^® is a machine that actually delivers radiosurgery. So it's actually dedicated specifically to treat brain tumors, which makes it unique in the sense that it has a nice throughput specifically for patients with brain tumors and allows us to treat functional disorders as well.

The way that the machine works is 192 beams of radiation, all focused on a single point, to be able to target disease and also can lesion in the brain.

Historically speaking, it used to be primarily frame-based, but nowadays, with updated technologies it can be done with a mask, which increases patient comfort and allows us to fractionate the radiosurgery if we need to.

Dale Shepard, MD, PhD: Okay. And I guess just for people not familiar with that frame versus mask, what is the purpose of that? Because a lot of people might be listening and not exactly familiar with technically how this works.

Samuel Chao, MD: So obviously, we're going to target something accurately and precisely in the brain, we need to be sure that the patient is not going to be moving during treatment.

So historically speaking, and ever since the '50s and the '60s when the Gamma Knife^® was originally developed, a frame was oftentimes used, which it requires two pins in the front, two pins in the back, and a frame that's affixed to the patient's head.

Because of improved technologies that allows us to localize using, for example, cone beam CT, so this is getting a CT scan before the treatment, now we can use something that's a little bit more flexible, like a mask. And this mask is a thermoplastic mask that has warmed up in the oven, goes over the face, as it cools down and hardens, it prevents the head from moving too much.

But obviously, the lineman is not going to be accurate every time we set the patient up. So we get a CT scan, realign them, and then deliver the treatment.

The machine also has tracking capabilities in case the patient does move during treatment, so that we still can ensure a very accurate and reliable treatment.

Dale Shepard, MD, PhD: All right, excellent. Tell us a little bit about the types of tumors that are most amenable to doing Gamma Knife^®.

Samuel Chao, MD: So the ideal candidates, or ideal tumors, for Gamma Knife^® radiosurgery are tumors that are fairly focused. They don't infiltrate into the brain too much, so that includes brain metastases, for instance.

It can include other benign tumors like meningiomas, pituitary adenomas, vestibular schwannomas. And we can also use the Gamma Knife^® to lesion within the brain.

So there is actually a painful disorder called trigeminal neuralgia, and we can target the nerve itself and we can even treat tremors by targeting within the thalamus.

Dale Shepard, MD, PhD: And when we think about size of tumors, how large a tumor can you treat?

Samuel Chao, MD: Great question. So typically speaking, conventional wisdom would be to say we wouldn't want to treat anything greater than four centimeters.

However, we've developed techniques, particularly with staged radiosurgery, where we can even treat even upwards of about six centimeters. Because what we do is we try to "stage it," meaning that we give a little bit of radiation, allow the brain to recover, give a little bit of radiation, allow the brain to recover, and then deliver the final treatment.

Dale Shepard, MD, PhD: And so instead of the traditional single treatment, it's a series of treatment over what period of time?

Samuel Chao, MD: Typically, over a month.

Dale Shepard, MD, PhD: And really, by doing the stage procedure, is it more to because there's risk of treating the entire tumor at the same time, or you're trying to spare the area you're doing by saving normal brain around it?

Samuel Chao, MD: A little bit of both. So when we do the staged radiosurgery, we're dialing down the dose a bit so that we can be protective of the surrounding brain, and then we give a little bit of time for the brain recover.

What has happened as a consequence of doing that type of technique is that sometimes the brain tumor will actually shrink, which means that as the brain tumor shrinks, there's going to be less surrounding brain that's eventually going to see radiation. So it does allow for that as well.

Dale Shepard, MD, PhD: Are there particular types of tumors? You mentioned of course benign conditions as well. Within cancers, are there certain cancers that are more or less amenable to Gamma Knife^®?

Samuel Chao, MD: So nowadays, we treat all sorts of brain metastases, so it doesn't really matter histology specific. Quite frankly, when we start looking into treating brain metastases, they were really, for the most part, histology agnostic, meaning that it didn't really matter what we would treat.

One of the things that we had previously excluded from a treatment standpoint was small cell lung cancer, for instance. And the reason being was the thought that there was just such a high propensity to spread to the brain, that whole brain radiation was a better approach, and that these tumors are also radiation-sensitive, so therefore you don't really need a big hammer like radiosurgery to treat those lesions.

It turns out that patients actually do really well from radiosurgery to small cell lung cancer, that there isn't a tremendous propensity for distant brain failure as a consequence of doing stereotactic array of surgery alone for small cell lung cancer. And so nowadays, we've been doing more small cell lung cancer, for instance.

Dale Shepard, MD, PhD: Where's the point from a number of different metastatic lesions, where's the break point where you think whole brain radiation versus a series of Gamma Knife^®?

Samuel Chao, MD: That's a great question, and historically speaking, it had been even up to four, and that anything more than four, we would've just done whole brain radiation.

Now there's a lot of studies that indicate radiosurgery is for patients even upwards of 10 brain metastases, and even upwards of 15 to 20 brain metastases.

So nowadays, we're treating more and more, and even up to patients with 20 brain metastases, we may offer radiosurgery alone.

Dale Shepard, MD, PhD: Yeah, and so I guess an important question would be is, is this something that's sort of widely adopted in multiple centers? If somebody has brain metastases, when would somebody need to be treated at a center that specializes in this?

Samuel Chao, MD: So a lot of the issues in terms of the number of brain metastases also has to do with the technologies that are involved to treat these brain metastases.

Nowadays, radiosurgery is becoming more commonplace, even in the community setting. The linear accelerators that are used to treat any other indication with radiation can be adapted to treat brain metastases.

However, as we get to beyond four brain metastases, oftentimes these technologies become a bit more complicated to utilize. And so, especially when we're talking about higher numbers, let's say five, 10, 15, it may be more facile to actually treat on a brain-dedicated radiosurgical platform like the Gamma Knife^®.

The Gamma Knife^® is nice in the sense that it keeps track of what we treat. So we don't have to say, "Well, was that treated before or was that not treated?" and accidentally double dose the treatment, for instance. It prevents us from doing that.

Dale Shepard, MD, PhD: And I'm guessing there's probably some comfort level of the radiation oncologist in terms of what they're treating and how they're treating if they're in a community setting not doing this as often.

Samuel Chao, MD: Absolutely. One of the things that we also do with our Gamma Knife^® center is that we work together with the neurosurgeon to deliver the radiosurgery, and that certainly increases the level of safety and ensuring that where we are treating with the Gamma Knife^® radiosurgery is going to be safe.

And if they do develop toxicities, that we have ways of managing that with the help of the neurosurgeon.

Dale Shepard, MD, PhD: And I guess that brings to mind the question about location. Are there locations that you have to avoid if there's a tumor in a certain region of the brain? Is this limiting?

Samuel Chao, MD: There are certain limitations in terms of radiosurgery. So the primary limitation is going to be proximity to critical structures. And the one that really is a little bit more tricky in terms of location is going to be near the optic nerve and chiasm.

The optic nerve and chiasm can see only a certain amount of radiation. For the most part, as long as there is a little bit of separation, we could do radiosurgery on those, but we may have to do it more in the fractionated way to be a bit safer about it.

The brainstem is another location that a lot of folks out in the region and the community, and even some academic centers, may be a little bit concerned about. Certainly, if one develops radiation necrosis within the brainstem, you can be very, very symptomatic from it.

So what we do do is that we go down on the radiation dose, and in some cases, especially for the larger brain metastases that are in the brainstem, we may even stage the radiosurgery just to be a little bit safer about it, or fractionated too.

Dale Shepard, MD, PhD: You mentioned about working with neurosurgery related to toxicities. What are some of the short-term and long-term toxicities that patients might experience?

Samuel Chao, MD: Yeah, so there can be some transient edema that can cause neurological symptoms. The one thing that we worry most about is seizures. So oftentimes, these patients are put on steroids after completion of radiation to minimize that swelling that could potentially lead to seizures.

With the advent of immunotherapy, and we recognize that patients are undergoing immunotherapy at the same time as us doing radiosurgery, we don't necessarily want to put them on high doses of steroids. So what we do is that we may limit the dose, maybe no more than four milligrams daily of dexamethasone, and then titrate them off of it afterwards. So that doesn't interact too much with the immunotherapy.

In some cases, we may offer using some sort of anti-seizure medication lasting about 10 days to 14 days to minimize that seizure risk if we don't want to put them on steroids. So that's going to be the main acute toxicity from radiosurgery.

The main long-term toxicity of radiosurgery is going to be radiation necrosis, and that can be managed in a number of different ways. Typically speaking, steroids are often effective enough to take care of radiation necrosis, but there are some cases where we have to do something more than steroids alone. And we could use drugs like Avastin or bevacizumab to take care of radiation necrosis is very, very effective.

But as I mentioned, one of the important parts of having a neurosurgery partnership is that sometimes surgery may be considered to take care of radiation necrosis, especially if the diagnosis is uncertain. In which case, they may do a traditional surgery or craniotomy to remove the area of necrosis.

But there is also another procedure called laser interstitial thermal therapy, or LIT, where we actually stick a laser probe, burn off the dead tissue, and that's also very effective in terms of taking care of radiation necrosis. So it's very essential for us to have that partnership with the neurosurgeon.

Dale Shepard, MD, PhD: So just to elaborate on the radiation necrosis part, because that's something that has historically been problematic. Traditional MRIs, kind of hard to differentiate progression versus radiation necrosis sometimes. So I guess a little aside, where are we with that ability to determine if something's radiation necrosis or not?

Samuel Chao, MD: Yeah, that's still such a moving target. We've been trying to strategize with other imaging techniques, particularly in the form of nuclear medicine PET scans.

Things are still kind of equivocal in terms of is anything really a homerun in terms of distinguishing tumor versus radiation necrosis. And part of the problem is that inflammation can also cause PET to light up with a traditional FDG PET, but could also with other tracers light up too.

Some of the other things that we're working on is MR Fingerprinting. So we have a current study looking specifically at MR Fingerprinting that appears to be promising, but obviously more studies are needed.

There are other ways of using the MRI scan in terms of just looking at delayed contrast assessment and seeing if that could pan out in terms of distinguishing tumor versus radiation necrosis. Not routinely used here because it does take a long time to be able to do that in terms of imaging time, but certainly something for us to consider moving forward in the future.

Dale Shepard, MD, PhD: So that sounds like it's going to be an upcoming podcast.

Samuel Chao, MD: Upcoming podcast. More to come.

Dale Shepard, MD, PhD: More to come. So what is being done in terms, if anything, about combining systemic therapies?

You mentioned before, as people of course might be on an immunotherapy or targeted therapy and develop brain mets and need treatment. Is there anything being done to use drugs as radio sensitizers to improve the ability to do Gamma Knife®, or what does that look like?

Samuel Chao, MD: Yeah, there's a lot of different interests in terms of trying to strategize how to better take care of brain metastasis. By itself, with radiosurgery, our outcomes in terms of tumor control is quite good, is on the order 80 to 90%. But if there's anything that we could do to make that better, certainly we'd like to look into it.

Historically speaking, and this is even in the 2010s era, we had a lot of concerns about systemic therapies and concurrent chemotherapies as increasing toxicity risks. So oftentimes, a lot of patients we would strategize with the medical oncologist to say, "Well, hold off on the systemic therapy for a few days before and then after the radiosurgery."

It turns out, when we did some studies looking specifically at concurrent delivery of a lot of those therapies, we didn't really see increased toxicities in terms of radiation necrosis. So, for example, concurrent chemotherapies doesn't seem to increase the risk of radiation necrosis. Certainly, hormonal therapies doesn't increase the risk of radiation necrosis.

There are drugs, particularly TKIs, that can slightly increase the risk of radiation necrosis. But if you also look in terms of how it influences tumor control, it actually improves tumor control as well. So we wouldn't necessarily say stop those drugs because we do see some benefit.

Immunotherapy is a little bit of a hit or miss. Certainly, it can increase the risk of radiation necrosis just by how it works, but again, it also increases the rate of control within the brain. And so certainly, we don't necessarily want to stop that.

The one drug that is starting to pan out to be maybe a little bit risky in terms of concurrent deliver is these new antibody conjugate therapies, like sacituzumab, for instance. And so certainly, we have a little bit of reluctance. I think more studies need to be done in terms of how much does it increase the risk of radiation necrosis versus how much benefit it delivers. But that's one thing that we probably would want to stop before we do the radiosurgery, at the very least.

Dale Shepard, MD, PhD: You mentioned your neurosurgery colleagues. How does one decide, if you have two new brain mets, decide whether to do Gamma Knife^® radiosurgery or traditional surgery?

What are the criteria? How do you sort through one or the other?

Samuel Chao, MD: Yeah, so that's usually a multidisciplinary discussion in terms of the comfort level to do radiosurgery nowadays. For the most part, if we can do radiosurgery, we'll try to do radiosurgery because we'll always have surgery as a salvage option.

Neurosurgeons are going to decide on surgery based on size and location and current symptoms. So, for example, if you're talking about a large, large brain metastasis, oftentimes we may want to consider doing surgery on that to alleviate the mass effect as well as to improve symptoms.

And one strategy that we have done here, and we do have a study looking specifically at this, is to do what we call neoadjuvant radiosurgery. So we do the radiosurgery and then we excise the tumor because we always know that even once we remove the tumor, that bed is going to be at risk of recurrence, and hopefully by doing it neoadjuvantly, we can prevent that recurrence. It also has some benefit in terms of reducing the rate of radiation necrosis or leptomeningeal spread, comparative to doing the radiosurgery afterwards. So there's certainly one strategy if we do decide to do surgery.

The neurosurgeon may also decide to do surgery if we don't really have a clear diagnosis. So, in other words, there's a mass in the brain, patient has a very remote history of a cancer, hard to say whether or not this is a metastasis versus a glioma, for instance. And so, they would undergo surgery to help decide between the two.

Dale Shepard, MD, PhD: You sort of alluded to before that a lot of radiation oncology is about the equipment and what you're able to do.

What's new and exciting from a technology standpoint? Ablated image, use of AI... What's swirling around is going to be the next new plateau in making this better?

Samuel Chao, MD: Yeah, so we recently upgraded one of our machines to the Gamma Knife^® Spree, and it really is an advance in terms of updating the computing power of the system. And hopefully, as Electa continues to develop new tools, it will be integrated into that machine.

Certainly, we are strategizing with other potential equipment moving forward in the future. We are certainly looking at improving technologies within our Department of Radiation Oncology, and perhaps some of that can be used to treat with the Gamma Knife® system or some other system as well.

So we're looking into all of that.

Dale Shepard, MD, PhD: Excellent. Well, certainly as we treat people longer with systemic therapies, there are more and more brain metastases and so fantastic to have great ways to treat that.

Samuel Chao, MD: Mm-hmm.

Dale Shepard, MD, PhD: Appreciate you giving us some good insights today.

Samuel Chao, MD: I appreciate it.

Dale Shepard, MD, PhD: Thanks for being with us.

Samuel Chao, MD: Great. Thank you.

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