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Samuel Chao, MD, radiation oncologist in the Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center of Cleveland Clinic Neurological Institute and Cleveland Clinic Cancer Center, joins the Cancer Advances podcast to talk about the work he recently presented at the American Society of Radiation Oncology (ASTRO) 2020 Annual Meeting. Listen as Dr. Chao discusses preliminary results from a recent Cleveland Clinic study that demonstrate that 18F-fluciclovine PET/CT has the potential to distinguish radiation necrosis from tumor progression in brain tumors previously treated with stereotactic radiosurgery (SRS).

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Distinguishing Brain Tumor Progression from Radiation Necrosis

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 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. Sam Chao. Sam is a radiation oncologist in the Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center of the Cleveland Clinic Neurologic Institute and the Cleveland Clinic Cancer Center. He's here today to talk to me about the work he presented recently on distinguishing brain tumor progression from radiation necrosis.

So welcome, Sam. Maybe you can start by telling us a little bit about your role here at Cleveland Clinic.

Samuel Chao, MD: So, thank you, Dale. I am a radiation oncologist here at the Cleveland Clinic. I specialize in brain tumors, which also includes spine tumors as well. My passion is really stereotactic radiosurgery, both in brain tumors, as well as spine. So we have a few studies looking specifically at radiosurgery for brain tumors, as well as radiosurgery for spine tumors.

Dale Shepard, MD, PhD: So, today we're going to talk about this issue of brain tumor progression and radiation necrosis and as someone who has looked at films and talked to patients, this has to be one of the most frustrating things that I come across and never really knowing what's going on, on those scans, so maybe you could tell us a little bit about the study that you presented?

Samuel Chao, MD: Dale, yeah, radiation necrosis is one of those issues that we deal with following stereotactic radiosurgery to the brain. It is a very frustrating thing to diagnose, because we don't really have a lot of good imaging techniques. And when patients do have it, while nowadays we have good treatment options, historically speaking, we don't. And sometimes that gives us reluctance to sometimes provide stereotactic radiosurgery, which we think does a very good job in terms of controlling many brain tumors. In fact, it's considered one of the standard of cares in managing brain tumors. So because there aren't a lot of great options in terms of imaging, we wanted to try to figure out, is there a better way that we can diagnose radiation necrosis? So historically speaking, even just using simple MRI scans or CT scans, we can't really distinguish between the two, so we have to use a little bit more sophisticated imaging.

What we've been using here at the Cleveland Clinic up until more recently is cerebral blood volume with the principle that if you have tumor is going to have elevated blood volume, but if you have radiation necrosis, it should have decreased. Unfortunately that technique only is about 80, no more than 90% accurate. Other techniques like magnetic resonance spectroscopy do offer some help in terms of trying to diagnose between the two, but also adds about 30 minutes to the MRI scan treatment time and it's out of pocket cost for many patients.

So we wanted to create something or find something that could be easily used to diagnose between the two. So historically speaking, PET scans using FDG doesn't do a very good job in terms of distinguishing tumor recurrence versus radiation necrosis, because inflammation from radiation necrosis can also take up FDG. But what has been done historically speaking, is looking at amino acid PET and amino acid PET has a lot of promise in distinguishing between tumor occurrence versus radiation necrosis.

Unfortunately, to create amino acid tracer, that does require a chemistry lab. It can be very expensive to do. Thankfully, Fluciclovine, which is actually used to diagnose metastatic prostate cancer, is one of those amino acid PET tracers. And we thought, well, it is used specifically for prostate cancer, it could be used to try to diagnose between tumor recurrence and radiation necrosis. So we decided that we wanted to do a pilot study, 16 patients here at the Cleveland Clinic, so we approached Blue Earth Diagnostics, which is the company that produces Fluciclovine and we also got some money from the Cleveland Clinic to try to do this study. And so we wanted to do a pilot study looking specifically whether or not we can use Fluciclovine to distinguish between the two.

Dale Shepard, MD, PhD: So, success?

Samuel Chao, MD: I think so. Yeah, it's still a little bit early on. Okay, we reported this at ASTRO, which is our national meeting for radiation oncology and what we think we are able to see is that if you actually look at the SUV max, it seems to indicate that that more consistent with tumor occurrence and lower SUV max seems to indicate more consistently with radiation necrosis. Now, we still have to accrue a few more patients and we still have to complete our followup studies in order to be sure that that's truly the case, but an early analysis of our results do show some signal.

Dale Shepard, MD, PhD: What kind of timeframe do you think that will be?

Samuel Chao, MD: So I'm hoping that we'll probably get all that information and get a better sense in terms of what promise Fluciclovine have in about six months to a year.

Dale Shepard, MD, PhD: All right, so that's not too far off.

Samuel Chao, MD: No.

Dale Shepard, MD, PhD: When we think about this, is this something that would be most useful or are we looking at metastatic disease or what's the role in a primary tumor like a glioblastoma?

Samuel Chao, MD: That's a great question and I think it's going to hold promise for both. Right now, we're looking specifically at metastatic brain tumors, because we use a lot of stereotactic radiosurgery, and those are the ones that are more prone to developing a radiation necrosis. But eventually, I think that there's going to be some role in terms of using this for gliomas. In fact, there are separate studies from other institutions that are specifically using this particular tracer for the diagnosis of glioma, but I think it will hold promise to also distinguish that from radiation necrosis.

Dale Shepard, MD, PhD: Is it likely that some metastatic tumors will be more or less likely to be... This will be more beneficial, so lung cancers or any particular type of metastatic disease?

Samuel Chao, MD: Well, interestingly enough, we think that it's probably going to hold promise for a lot of different types of primary tumors. I mean, in other words, metastatic tumors with different primaries. So it wouldn't necessarily be specifically for a particular tumor types. I mean, we think that anything that usually grows in the brain usually has relatively rapid growth rate, breast cancer is always sometimes, maybe a little bit slower in terms of growing in the brain, but so far, we think that there is probably some signal. Time will tell, we still need further studies to determine that.

Dale Shepard, MD, PhD: So when you think about the scope of this and what can be affected ultimately, at this point, do we do biopsies to look at whether there's necrosis or progression, and if so, how might this change sort of the way we determine between necrosis and progression?

Samuel Chao, MD: So biopsies are what we consider the gold standard in terms of distinguishing between the two. Unfortunately, we don't want to subject all our patients to biopsies. It is technically morbid, it requires anesthesia, it could delay further treatment. And so, oftentimes what we end up doing is just, we do repeated scans and review at our tumor boards.

But we also want to get at taking care of the patient quickly too. If it turns out to be tumor recurrence, we'd like to try to treat that, perhaps with more radiosurgery if we can. And if it's radiation necrosis, we do have good drugs to take care of radiation necrosis as well. So the hope with this type of study is that if we can catch these patients early on and intervene earlier on, that we can prevent them from becoming symptomatic and we can divert things like biopsies or completely avoid biopsies.

Dale Shepard, MD, PhD: And I can only imagine there's a tremendous amount of patient anxiety related to this?

Samuel Chao, MD: Definitely so. I think patients do become symptomatic. They do have problems from it. They struggle with it. When you see them every couple of months, and sometimes you end up having to shrug your shoulders, because you can't determine between the two, you always try to encourage them to say, "Well yeah, it's probably radiation necrosis, but that concern is always in the back of their heads.

Dale Shepard, MD, PhD: Right. Now, if this becomes successful, how readily available are these scans, either academic centers, community practices, how wide scale would this be in terms of people's ability to get these scans if it ends up being a productive way to follow?

Samuel Chao, MD: I think it's going to take a little bit of time. Right now, the maker, Blue Earth Diagnostics, is interested in the results of our study, because they are rolling into a phase three studies, because they want to try to get this out on the market to be able to use this, to distinguish between the two. They do recognize this to be a big problem. And in fact, the results of our study is going to help drive some of their studies that are forthcoming.

So one is the Promise study, which is actually already opened that does require biopsy, but we're going to roll into the Revelate study, which is a study that was designed by them. Very similar in terms of our study, maybe a little less radiotracer than what we have used. They're going to use this to try to distinguish between the two kind of using more simple analyses, but also just like how we try to distinguish between the two using our brain tumor report to try to tease out whether or not we think that this is tumor recurrence versus radiation necrosis, we'll have a central truth pattern. So this is more real world use of Fluciclovine and hopefully will yield some positive results.

Dale Shepard, MD, PhD: And when you said that they view this as a big problem, clearly it is in terms of how we distinguish, but talk about numbers. How many patients are we thinking about a year that might have brain metastases, get stereotactic radiation and this comes up, so how many patients a year do you think this becomes an issue? To my sense, it's a big number.

Samuel Chao, MD: Yeah, no, I think it's a huge number. So if you kind of think about how many patients are diagnosed with brain metastases, and we're just focusing on brain metastases alone, there's a lot of other different types of tumor types that we treat with radiosurgery. But focusing on brain metastases alone, there's about 200,000 metastatic brain patients diagnosed each year.

And if you probably think that maybe at least half, if not more are getting radiosurgery and then about anywhere from five to 10% are going to be diagnosed with radiation necrosis, we're talking about tens of thousands of patients, which may be diagnosed with or have to struggle with the issue of radiation necrosis moving forward. We're using more and more stereotactic radiosurgery to treat brain metastases. I think that's becoming more of an established standard. Historically speaking, we used to limit to a few and now, in some cases, we are treating 10 and 15 lesions with radiosurgery, so that's just one we continued to track about the number of patients that we're going to see with this concern of tumor recurrence versus radiation necrosis.

Dale Shepard, MD, PhD: And so, we're certainly making progress in advanced disease, but as we make that progress, you guys have a remarkably busy group, because that progress means that people actually live long enough to get the brain metastasis. So successes yield successes, but also questions, I guess?

Samuel Chao, MD: Oh, absolutely, absolutely. I mean, we're busier, we're using the Gamma more and more, the numbers that we're treating at the Gamma Knife Center continues to increase. It used to be in the 500 range and then more recently was in the 600 range. And now we're going to be hitting towards the 700 and 800 range per year in terms of the number of patients that we treat, so it just gives you an indication in terms of the fact that we're doing a better job in terms of taking care of brain metastases with radiosurgery and so it's increasing its utilization.

Dale Shepard, MD, PhD: And so, if we take a step back and we've been talking about ways to sort of look at response to radiosurgery, you would just mention before about maybe treating up to 10 areas in the brain, what does that look like? What are we looking at now in terms of an ideal patient in terms of size of tumor or number of tumors, how has that changed and kind of where are we now?

Samuel Chao, MD: So, I think that's a great question. One of the issues that, historically speaking, we used to treat maybe two or three or four small brain metastases because, one, when the tumor got bigger, our ability to control the disease with stereotactic radiosurgery wasn't as good. And also, because of the complexities of trying to deliver radiosurgery, historically, it wasn't so easy to treat many, many more. We were really limited by our ability to treat maybe three, no more than four, lesions all together.

And so, what has happened, we have advances in terms of our radio surgical system that allows us to treat many, many more. The planning is much simpler. The planning is much easier. So it's really fast now for us to treat even 10 or 15 lesions without any difficulty. In addition, one of the other important advances is also the fact that for the bigger brain tumors or bigger brain metastases, what we've been doing nowadays is either staging the radiosurgery or doing fractionated radiosurgery.

What I mean by staging is that we would treat them and then bringing them back about a month later and re challenging that area just like a booster shot, like you would with a vaccine, give a little bit extra radiation to maximize control. And our ability when we do that, our ability to control the disease is just as good as even the smaller ones. Or we can also fractionate, which means to deliver the radiosurgery, but deliver the radiosurgery over three to five fractions. So certainly we're not as limited in terms of size as we used to be. And at the same time, we're not as limited by number as we used to be.

Dale Shepard, MD, PhD: Yes, those are both really, really important points, because oftentimes people may still have the perception that it has to be a small tumor or a limited number, so it's great you elaborate on that. Where are the gaps? So where do we need to get better with stereotactic surgery for brain, either in terms of delivery, choice of patients, evaluation of necrosis versus progression? Where do we need to go?

Samuel Chao, MD: So, one, I think, upfront, we need to be able to see whether or not someone's going to be at risk of radiation necrosis or not. And that allows us just to be a little bit more proactive in terms of taking care of them, even try to offer maybe medications and drugs that may be designed or developed in the future to try to prevent things like radiation necrosis, so that's one avenue that we should embark on.

Another avenue is that not every patient is the same. So, we're treating beyond 10 or more brain metastases, some are going to do extremely well by doing that type of treatment, some patients are not going to do very well. Or we have no way of predicting whether or not they're going to recur so often and so frequently that we should be offering something like whole brain radiation upfront. So trying to better triage these patients in terms of whether or not this is going to be a good candidate, they're high risk for developing new brain metastases, so those are the ones that we should probably do something more like whole brain radiation versus, even though we treat 10, maybe we'll get good control for months or even years and so therefore those are better patients for stereotactic radiosurgery, and people are making some algorithms to determine between the two.

I think what's going to be the most important is really understanding what systemic therapy can do in terms of managing brain metastases. There's a number of agents that are out there, they're getting better, they're also crossing the blood brain barrier and they're controlling disease better in the brain, for example, ALK+ lung cancer. The first-generation drugs didn't cross the blood brain barrier very well, so we still had a very strong role for doing radiosurgery, but the second generation and beyond do a better job.

Samuel Chao, MD: And so, often than not, we may see a few small brain metastases. We may not necessarily want to jump in right away in terms of doing radiosurgery. We may want to consider using some of these systemic therapies to take care of the brain metastases. But by the same token, while immunotherapy is becoming more and more popular and can potentially control disease within the brain, trying to decide between whether or not what we're seeing in terms of follow-up imaging, pseudo progression versus true progression, where we have to do something like radiosurgery could be difficult. So strategies to try to diagnose between the two are going to be necessary as well.

Dale Shepard, MD, PhD: Do you see the use of systemic therapy as being systemic therapy or radiosurgery, or do you see it as a radiosensitive role or maybe a little of both?

Samuel Chao, MD: Maybe a little bit of both. So, there might be patients where they may have a few big dominant lesions, but a lot of small lesions. We may not necessarily want to treat all the little small lesions with radiosurgery. Let's take care of the big dominant lesions and if we have good systemic therapy that can cross the blood brain barrier, take care of the rest with that type of therapy. Or, if we have patient with multiple, multiple brain metastases, we may go up front in terms of taking care of them with radiosurgery, but we want to prevent them from recurring and then using systemic therapy in that situation to try to prevent recurrences in the brain is another way of optimizing their management.

Dale Shepard, MD, PhD: Well, thank you very much for your insight today. Do you have any additional comments?

Samuel Chao, MD: With the use of something like Fluciclovine, trying to get a better sense in terms of diagnosing tumor recurrence or radiation necrosis, I hope that we won't shy away from using stereotactic radiosurgery. We know that's a very, very effective type of therapy. And so, by giving us a little extra comfort, being able to diagnose radiation necrosis better, we have better treatments now available that we can potentially be more aggressive about using radiosurgery for our patients.

Dale Shepard, MD, PhD: Well, thank you very much. Appreciate you being with us today.

Samuel Chao, MD: Great. Thank you, Dale.

Dale Shepard, MD, PhD: This concludes this episode of Cancer Advances. You will 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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