Ewings U: Erin Murphy, MD | The Use of SBRT In Pediatric Solid Tumors

EPISODE THREE: On August 9, 2022, The Little Warrior Foundation + Dr. Erin Murphy of the Cleveland Clinic discussed the use of SBRT in pediatric sarcoma patients. This post contains video, transcript and patient resources.

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Maggie Spada: [00:00:08] Good afternoon, everyone, and welcome to another episode of Ewings U. I am Maggie Spada. I'm one of the co-founders of the Little Warrior Foundation and mom to 11 year old Little Warrior Lucy. Today, we are thrilled to be hearing from Dr. Erin Murphy. Erin Murphy is an associate professor in the Department of Radiation Oncology at the Cleveland Clinic. She completed residency at the Cleveland Clinic and a subsequent fellowship in pediatric radiation oncology at St Jude Children's Research Hospital. She specializes in radiotherapy and radiosurgery for brain tumors and pediatric solid tumors and travels internationally to share her expertise in radiation oncology conferences everywhere. Specifically, the use of SBRT for pediatric patients, which we'll be hearing a lot more about today. In her spare time, Dr. Murphy is also a marathon runner and a wife and mom to three little girls who keep her very busy. Before we kick it over to Dr. Murphy, I just wanted to let everybody know and remind you all that Ewings U is a webinar and podcast production of the Little Warrior Foundation. We are a national childhood cancer foundation with a laser focus on finding a permanent and complete cure for Ewing Sarcoma. We were founded in April of 2020 and have granted out $1 million in high potential therapies for increasing survivorship and decreasing toxicity. We very much so rely on the support of the communities of the big and little warriors who are joining us on this call, and across the country. So we really appreciate all of your community's support to continue our mission so that we can bulldoze to a solution and continue this vital work. Piero, did you want to say a little bit on housekeeping, chat and questions?

Piero Spada: [00:02:09] Yep. Hi, everybody. Thanks for being here and thanks for Dr. Murphy for presenting today. I am Piero Spada, one of the co-founders as well from the Little Warrior Foundation & also Warrior Dad to Lucy, and I had going to be one of your moderators today. And with that, we have a couple of housekeeping items. Number one, the format is going to be pretty straightforward. It'll be roughly 30 to 40 minutes of presentation, followed by 15 to 20 minutes of a Q&A Session. For your questions, simply go to the right hand corner of your zoom screen and use the Q&A box and simply type those in. And then, last but not least, just a reminder we can't answer any personal questions. So no patient specific questions, please. And with that, I'm going to kick it over to Emily before we get on with today's presentation. Thank you.

Emily McFadden: [00:02:54] Great. Thanks, Piero. I just wanted to let everyone know that the session is being recorded and we will make the recording available as well as the transcription on our website within one week on www.littlewarrior.org, and from there you'll find the Ewings U transcripts as well as previous episodes. We're working on our fall programming currently for Ewings U, so if you have any topics that you are eager to hear about, or (for any of the researchers joining us) anything that you're eager to share with the Ewings community, we'd love to hear it. So feel free to drop us a note in the chat functionality or email us at info@Littlewarrior.org and we can see if we can get your topics included into our fall programming. That is it for me. So I'm going to turn it over to Dr. Murphy.

Dr. Murphy: [00:03:55] Thanks so much. Hi everybody. I am delighted to be here. I am a proud supporter of the Little Warrior Foundation and grateful to be here today and kind of share with you about this topic that I'm passionate about. So using SBT and Radiosurgery for Ewing's Sarcoma, I'm a firm believer that it's an awesome tool and it's underutilized in this patient population. I am finding the more I give talks about SBRT for sarcoma that not many people are using this awesome tool. So one of my goals is to get the word out there about this and share important indications because I think it's an awesome tool. I also think all of us together can really help keep the momentum going forward that the Little Warrior Foundation has started. And so I think the benefits of these tools are huge for our younger patients. So both Radiosurgery and SBRT are kind of just different names to call the same thing. So it's very focused, high dose radiation that we can use to aim at and ablate tumors right where they're sitting. So although you hear the terms of radiosurgery or sometimes gamma knife, it's not a surgical procedure. These are noninvasive techniques to kind of oblate or kill tumors right where they're sitting. So some of the several benefits are the fact that it can be given over a 1 to 5 day procedure, which certainly reduces anesthesia needs for smaller patients or patients that may have more claustrophobia or more concerns or anxieties when they're getting these kinds of treatments.

Dr. Murphy: [00:05:55] There's certainly less impact on daily routine and education and a quicker recovery. So again, these tools utilize multiple intersecting beams of radiation to deliver this high dose focused radiation to a very discrete volume. This results in sparing normal tissue with a sharp dose falloff, which we know can be even more important for our younger patients that are still growing and developing. And by getting them this focused high dose radiation, we're actually able to increase the biologic effectiveness of the radiation dose because we're getting it in in a short period of treatments rather than treatments every day, Monday through Friday for six weeks. The indications are many: and include unresectable disease, localized recurrent disease, oligometastatic disease or kind of limited metastases. And what's unique to our younger patients and unique to sarcoma patients is that we also use these tools to consolidate all sites of metastatic disease. So this is very different than the paradigm in adult cancers where you're very limited in the metastases that you treat. Whereas for folks with metastatic Ewing Sarcoma in particular, you want to aggressively treat all their sites of metastatic disease, even when they've already responded to chemotherapy. And using these high dose focused radiation tools is a really good way to get after that. The last line here is that there's extensive availability and clinical experience, but it's mostly in our older patient populations.

Dr. Murphy: [00:07:34] So again, the indications for using these tools in our younger patients just in general, can be used for both brain tumors and non brain tumors. In brain tumors, we more commonly use the term SRS for radiosurgery, whereas for outside the brain we use the SBRT or stereotactic body radiation therapy. So again, essentially the same thing where you're using tight immobilization for the treatment, high definition imaging, high dose focused radiation beams to kill tumors or ablate them right where they're sitting. In the world of sarcoma, the most common indications include treating metastases to the spine, treating metastases to the bone outside of the spine, and treating metastases to the lung. So as a brief background, there's certainly limited SBRT data for sarcoma. However, we know that we really need high biologic effective doses of radiation to control sarcoma because in general sarcomas are thought of to be more radioresistant tumors. We also know that patients with limited metastases in the lung and bone are considered curable with aggressive local therapies. However, if you don't treat these metastases, they can usually be fatal. Some of this early data comes from these series that looked at the role of metastatectomy: it essentially moves surgery, which means surgically removing lung metastases. So these come from huge series. This series in particular was looking at both osteosarcoma and soft tissue sarcoma. And you can see that if you remove their lung metastases that folks are living out ten years plus.

Dr. Murphy: [00:09:23] Right. So we still need to do better. But it just really suggests that if you're aggressive with metastatic disease, you can improve survival. And then when we look specifically at the role of treating metastases and Ewing sarcomas. I love this series - it came from the European Union collaborative analysis and this series looked specifically at 120 patients with metastatic Ewings. They had to have metastases (other than lung-only). We know that folks who have lung-only metastases have even better outcomes. And so these folks had to have other metastases besides just lung and they looked at the role of local treatment. So here local treatment could have either be surgery or radiation therapy. And since this was an older study, certainly the role of radiation was more like standard fractionated radiation. We're giving it every day, Monday through Friday for several weeks. And when they looked at local treatment and the impact on three year event free survival (meaning the ability to stop tumors from progressing if they did no local treatment, meaning no surgery, no radiation) the 3-year event free survival was 14%. If you used a local tool to either the primary or the metastases, your event-free survival was essentially double. However, if you used a local tool to both the primary and the metastases, the three year event survival essentially doubles. So this really suggests that you need to be aggressive in looking after folks who have metastatic disease by using these local tools.

Dr. Murphy: [00:11:07] And certainly because SBRT is a local tool, can have significant impact and outcomes in patients with unresectable or metastatic disease. But the initial experience of using SBRT for Ewings and Osteosarcoma came from the Mayo Clinic and was published in 2014. So you'll see here a lot of the data kind of combines Ewing's and osteosarcoma, so it's hard to separate some of this out front and certainly cause calls for us to get a better understanding of histology and disease-specific SBRT, because we know these are very different entities that are treated in different ways, but the data so far still combines these two. So this series included 14 patients with 27 lesions, including both Ewings or osteosarcoma. The median age of patients treated was 24. The median radiation dose is 40 gray, but you can see quite a range. So 30 to 60 gray, over 1 to 10 treatments or fractions is what we call them. This just shows that they were trying to be thoughtful. So they're using a reduction in dose for younger patients or for those getting concurrent therapies, which is really important. And we'll talk more about that. This just shows one example. This was a young kid with actually osteosarcoma metastases to the sacrum. You can see here outlined right here in the left sacrum. And then you can see what their radiation dose lines look like. So this was actually 5000. So a really high dose right there.

Dr. Murphy: [00:12:50] And the normal structures that are important, this is what always limits us as radiation oncologist. So we can give super high doses to these tumors, but we have to be thoughtful about the normal tissues. So we know that the caudal equine, the kind of the bottom of the spinal cord and the nerve roots that sit right in this area saw a pretty high dose. And unfortunately, we need to get a better understanding and better follow-up with patients to understand the impact of these tools on normal tissues, right? Because we don't want to cause morbidity from from our treatments either. And unfortunately, this is an early series. And this patient they did not have follow-up on. So this is kind of the outcomes that they that they were able to publish. So they had two year follow up, which is pretty good. They said local control for definitive lesions was 85%. That means that they were able to stop 85% of these tumors from growing by using this treatment tool. They say definitive lesions (they had they treated both lesions with palliative intent, meaning just for symptom improvement and for definitive intent to try to go for cure). I actually really find that it's hard to differentiate these two in my practice. So I think my intent when I'm using these locally aggressive tools is durable local control. And it makes a lot of sense in folks that are doing well that you want to be aggressive with these tools.

Dr. Murphy: [00:14:21] And so "durable local control" is the intent that I think makes the most sense. The two failures were in folks who had osteosarcoma lesions treated with a 30 gray & three fraction dose regimen. They saw very acceptable acute toxicity. So just grade two toxicity: toxicities are graded on a 1 to 5 scale. And so grade two is usually managed very conservatively. However, they did see significant late toxicity in three patients. And again, this is great that they shared with us their early series, right? So that we could all learn from this. So it's nothing against that. They had these outcomes. Someone has to, at some point, you have to take some kind of a risk and try these tools. Right? And so this was early-on experience. And so one patient had a three sacral plexopathy, meaning they had impact on their nerve roots when they received pretty significant dose of 60 gray in ten fractions sometime after receiving their initial up front conventional radiation. So for us as radiation oncologists, we always have to think about how much dose this area had received before and what's the time interval from the prior radiation, because that can really impact what you can get in safely. Another patient had a grade three myonecrosis, which means almost kind of dead muscle tissue. You can see that example is down here. So they treated this right iliac metastasis

Dr. Murphy: [00:15:51] you can see right here, this orange shaded color correlates with this orange right here. And that's the 5000 centigray that was given in just five treatments, that was given with concurrent gemcitabine, which we know can be a radiation sensitizing. Which is great, right? It might make the radiation more powerful, but also can have some more impact on the normal tissues. You can see in their follow up -so this is the muscle tissue all around that bone area that was treated- with significant inflammation. And then they also had a grade three avascular necrosis of the femoral head, which is the top of the hip that then went on to fracture in the patient who had a significant dose as well. You know lots to learn from this early experience. There have been now prospective sarcoma trials incorporating SBRT into their regimens. One of the early ones was a Children's Oncology Group study, which was investigating the role of an IGF-1 receptor antibody. So patients were randomized to receive that antibody or not. And these patients, (this has been close to accrual not published yet) these patients as part of their treatment paradigm receive 40 gray in five fractions to all bony metastatic sites that were less than five centimeters on initial studies. Folks can present with widespread metastases sometimes, right? So this can be a number of lesions that then you're going to want to consolidate or add radiation to try to stop those areas from coming back. And this dose right here,

Dr. Murphy: [00:17:34] this 40 gray in five fractions, I highlighted it right? Because this just came from that series of 14 patients from the Mayo Clinic. And that was just their median dose. So it was a good dose to start off with. But again, this is the dose already being used on prospective studies. So I think us as a group of radiation oncologists need to come up with/figure out, is this the right dose for that? Right. You can see here how they did their target dosing and they did a little bit of higher dose to where they could see the tumor and then a little bit lower dose in an area there to treat any microscopic disease. The other prospective trial that incorporated SBRT was a phase two trial of SBRT for sarcoma bone metastatic sites done by these three institutions. So they were not including patients with rhabdomyosarcoma and there including patients older than three and less than 40. These patients had to have limited metastases, so just 1 to 5 sites of spine or non spine bone metastases. And they had size cut offs as well. For these folks, they held the chemotherapy for two weeks. The dose that they use for all of these sites was, again, 40 gray in five fractions. This data has been published. So this was their early results. So 14 patients, 37 lesions, but all treated in the same way.

Dr. Murphy: [00:19:04] So they all got the 40 gray in five fractions. So after a median follow up of about seven months, the progression free survival was six months. Which states, for the median time that they did not progress was about half of a year. When they looked at local control  -- so they looked at local control by both the patient and by the lesions, since there were more lesions. The local control was quite awesome. So 89% by patient, 95% by lesion treated. They also found this significant and I think important finding. Although this data is early it again suggests the importance of treating all metastatic sites. So when they say "consolidation of metastatic sites", that means so eight patients had all of their sites treated with SBRT and six of them did not. And here you can see significant difference to progression free survival. So nine versus about four months and even an impact on overall survival for these patients. They report a very reasonable toxicity as well. So two patients experienced grade three toxicity. One had osteonecrosis that went on to fracture and then one patient had esophagitis during treatment but then was treated. So this is some other published data. So this was a phase two study, which was essentially a review combined from the UCSF and St Jude experience. So this included a total of 55 patients and 107 lesions that were treated. You can see so they in general were treating just all metastatic solid tumors.

Dr. Murphy: [00:20:53] But in this box, you can see here that the majority of patients that they treated with SBRT were sarcoma patients. The majority of them had recurrent disease. And the majority had multiple metastatic sites. And I highlighted this box here again, they kind of divided the intent. (I think that this is hard to do I feel like in a clinical scenario). So what it means is if someone if you're treating them just for symptom improvement, you may not be as aggressive with the dose. And that's what they may be calling the palliative treatments versus the definitive. You can see here the use of a wide range of SBRT regimens. These patients were not treated with the same regimens. So they receive 25 to 40 gray over those five sessions. And for when patients had larger lesions they treated them, they divided up the dose a little bit more. So it was 40 gray over eight sessions altogether. Just when things are bigger, you want to be a little bit more thoughtful about the surrounding normal tissue so some of you might divide it down more. And these are their results so far. So you can see probably about median progression free survival is about six months as well. What was interesting is they did a deep dive into looking at radiographic response and then pattern of failure. So I think we could learn a lot from this.

Dr. Murphy: [00:22:22] So when they looked at the radiographic response by a special RECIST criteria, the rate of a good response (so whether it was stable disease or up to a complete response) when you're treating lesions in the bone, it's better than when you're treating lesions in the soft tissue. So you can see here 91% versus 77% and the duration of the response in the bone was longer than for soft tissue disease. And we can see this in our own series & across other tumor sites. So with in the bone, it may be easier to kind of delineate and easier to be generous with your clinical target value when you're including microscopic disease. Whereas in the soft tissue, it might be harder to see and you may need to add more of a margin for microscopic disease. Or it might be because it's soft tissue adjacent to the bone might be pressing and closer to normal structures. So it can be many kind of reasons that might go into the fact to why we're not seeing responses as good in soft tissue targets. They also looked at symptom response, and you can see that two thirds of patients who presented with symptoms improved with a duration of about four months. They had no significant acute toxicity. They did have two late grade three toxicities. Again, we're seeing that if you're treating weight bearing bones like the radius or the femoral head, you may see a higher risk of necrosis and then perhaps fracture.

Dr. Murphy: [00:24:02] And then there was one patient who had pneumonitis. I was actually really interested in looking at our series to see what was the rate of fracture in folks with weight bearing bones. So we presented this probably at two ASTROs ago and we looked at those patients who had SBRT to weight bearing to the upper and lower extremities, and we saw no, no increased risk of fracture, which is great and that was already at two year follow ups. So it's nice to see that. It's hard to say what may make some patients at higher risk for fracture versus others,but it certainly can be one of the potential downsides of doing this focused high dose radiation. Although we didn't see a significant -we didn't see any -in our patients (knocking on wood? on my wooden desk right now). But just something important to keep in mind and be thoughtful about. This just demonstrates how they analyzed local failure. It's helpful information to see. So what you're looking at here: so the recurrent tumor, so the tumor that had progressed. And this is the 95% isadose line. So essentially what's in green was the prior target. So you can see here something that was called directly in field is directly in the field. So you can see the entire recurrent lesion within the area that was treated. Something marginal has this range of 20 to 80% of the recurrent lesion within that treated value.

Dr. Murphy: [00:25:39] Then something considered out of field has less than 20% of this kind of recurrent lesion was within this prior green field. So just helpful & across all series, we try to be consistent in our verbiage, right, so that we can compare and contrast our studies and call things "in-field", "marginal", and "out of field" in a similar manner. So this was how they looked at their pattern of failure. They had 25% local failure at one year, which means 75% were controlled. When we looked at pattern of failure, so most of the patients, half of the patients failed right in-field. This certainly may speak to are we not giving enough dose? Should we consider something different as far as concurrent therapies just to try to get more impact from our treatments? And then I thought, so what's interesting here is that you can see, so this is the cumulative incidence of local failure. So soft tissue is this lighter gray color and you can see a significant higher risk of local failure when soft tissue targets are treated as compared to bone targets. I also find this interesting --I think we see the same across our series--for the 13 local failures that were not in field, the majority had paraspinal disease extension, which means they had soft tissue component extension. Which I think suggests we need to be a little bit thoughtful about the coverage that we're doing for when there's soft tissue, extensive disease.

Dr. Murphy: [00:27:22] I'll share with you our own experience and kind of what we've learned from it so far. So at this point, we've treated over 140 lesions and probably about 50 plus patients using SBRT for folks with sarcoma. I really wanted to try to take advantage of the fact that we've looked after many patients and get a sense of "can we learn anything about SBRT dose or fractionation and try to see if we can do better, & have a better understanding of what dose is really needed?" Again, since the dose that we're using comes from a small retrospective series. So what I did, in trying to think about this, is the histology of sarcoma in general is quite varied. And so I tried to group our series into those that were more radiosensitive, which includes all small round blue cell sarcomas like Ewing Sarcoma, rhabdomyosarcoma and desmoplastic small round cell tumors, and then those that were radioresistant, like osteosarcoma or synovial sarcoma. And at the last time we analyzed this, the follow-up was about ten months. What I think is important to kind of pull out and discuss here is that the median time from development of recurrence for metastatic disease to actually using SBRT, that's over a year. I really believe that these tools should be considered earlier in the treatment course. The folks that we're looking after were heavily pretreated with multiple chemotherapy regimens, multiple prior treatments in general.

Dr. Murphy: [00:29:09] The more folks are treated, the more maybe resistant their disease comes to our treatments. So this is our series starting back several years ago. And so we initially started off more conservative, because it was a brand new tool & at this point in time SBRT had been used commonly in the adult settings to the bone metastases to the spine, and to treat early stage lung cancer. So treating non-spine bone metastases was a very new paradigm several years ago. And so we started off with a lower dose, trying to make sure we did no harm and then eventually got our comfort level went up as we saw that folks were tolerating this quite well. And so the median dose that we used here was 30 gray in four fractions, but again, quite a range. You can see here that the majority of lesions that we treated were within the bone. We did treat a large number of lung metastases. So again, we were starting out early. So treating these bone metastasis at kind of a general lower dose, thirty gray in five fractions. We were already comfortable treating primary lung cancer with this kind of dose level and treated one  liver metastases. And our results  - I'll highlight here looking at 1 year local control. So 1 yr local control was just under 70%, when you look at all and again, this is using some patients getting lower doses than we use now,

Dr. Murphy: [00:30:49] but it really allowed us to ask that question on the impact of dose. So when we looked, we didn't see any difference for radiosensitive versus radioresistant when we looked across local control in general. We perform this Receiver Operating Characteristic curve to determine the optimal biologically effective dose using an alpha-beta ratio of three gray. So there's various alpha-beta ratios that are associated with the sensitivity or resistance of a disease to radiation. So in general, sarcomas are thought of being more resistant and that's why a lower number, this alpha-beta of 3 gy is used and we found a significant cutoff. So we found a significant advantage to this biologic effective dose of at least greater than or equal to 95 gy, which essentially was equivalent to at least 35 gray in five fractions for five fraction regimens. And again, SBRT and Radiosurgery can be given over 1 to 5 sessions in general. So that just could be different doses can be can be seen in different regimens. But when you look at a way to calculate across dose fractionation it's this biologic effective dose. So again so when we looked at one year local control using that cutoff, you can see a significant difference, 75% versus 46% ability to stop these tumors from growing. We saw that the split for radiosensitive tumors also had a significant difference.

Dr. Murphy: [00:32:30] And here for radioresistant lesions, the split was not significant. But you can see here, there's certainly a trend looking at a benefit to a higher dose versus the lower dose cutoff. It's really cool, that we looked at, I thought - was looking at this neutrophil lymphocyte ratio. So we found that this ratio that can be commonly found from a common CBC was a significant predictor of both survival and local control in the setting of SBRT for lung cancer. So totally different disease. But we certainly think that SBRT in general can cause a significant kind of inflammatory reaction that the patient's own immune system might recognize and it might help fight that cancer. So we looked at our patients and we looked at the simple CBC that was available pre and post SBRT and at time of progression of last follow up, and we found several variables were significantly detrimental to survival. So a higher ANC before SBRT, a higher neutrophil to lymphocyte ratio before SBRT, a higher neutrophil lymphocyte ratio after SBRT - and then we also found - so that when you look at those "had local progression" you can see that in general there was an increase in this neutrophil lymphocyte ratio at time of progression as compared to the pre and post SBRT numbers. And so this is just fact finding, hypothesis generating. And so we've developed a prospective trial now thanks in part to the funding from the Little Warrior Foundation, where we're going to be looking after patients with SBRT and checking they're just basic CBCS and also doing a deeper dive into other inflammatory markers and immune markers to see how SBRT may impact patients' immune system and then eventually see if we can incorporate immunotherapies or that kind of thing.

Dr. Murphy: [00:34:39] So it's really going to help us understand what would be an ideal timing to perhaps incorporate those immunotherapies and which patients in particular might have even more of a benefit. So we're really excited about that and hopefully we'll be enrolling patients soon. I'm going to skip this because I see the time is already 235. This is just our spine experience. I will highlight this here. So this is looking across several retrospective series of doing spine radiosurgery for patients with metastatic sarcoma. So in these series, these patients only had metastases to the spine. And in general, when you do spine radiosurgery, it's more commonly done in just one treatment. That's why you see kind of different doses here. When you look at local control across all these series, I've treated a wide variety of sarcoma diagnoses. You can see pretty decent local control 96%, 76%, 75%, etc. except in these two series that we're using a lower dose for their treatment. So it really speaks to how important getting in the right dose is, but doing that safely. So these EQD2s are just another way of kind of looking at the impact of dose.

Dr. Murphy: [00:36:00] So they're the "Equivalent Dose" as if it was given at two gray per fraction looking at different alpha beta ratios. You can see here in general, if you do 16 gray in one fraction or one treatment, you can see that the equivalent doses are about half what you get if you do 24 gray in a single fraction. Certainly we know if you're doing 24 gray in a single fraction, there can be more toxicity or more side effects. So you have to be very thoughtful about when you're trying to increase the dose for these sarcoma patients to make sure that it's safe. That's why oftentimes we do a fractionated regimen or divide it up over five sessions so that we can get in these high doses, but do it more safely, more thoughtfully for the normal tissues. Also I think what's very useful we've now have CTV recommendations for how to do your volumes for non spine, bone metastases, SBRT. And so essentially it's going to be important to add at a margin in the bone of up to one centimeter depending on kind of which high definition imaging you have available. Obviously, if you don't have high definition imaging, you want to be more thoughtful and you might be more generous about the margins that you're incorporating to make sure you're treating microscopic disease as well. Certainly, as we kept hinting at before, that if you have the soft tissue expansion, you can be really thoughtful about adding a margin to your treatment value also to make sure you're getting after microscopic disease.

Dr. Murphy: [00:37:41] I highlight just two examples here. As I said that when you're doing non-spine-bone met SBRT its newer. It's got to be really thoughtful about the normal tissues that you're contouring to make sure that we give that information to our planners to say, all right, here's normal tissues, here's the target, and make sure you can push the dose away from those normal tissues. So just an example. If you're treating someone with an iliac bone metastases, OAR means organs at risk. You want to be really thoughtful about contouring the bowel that's close by, & contouring the strip of skin to really push the dose in and away from those more critical structures. I highlight one other example below. So this is someone with a metastases to a rib and you have to be really careful. So when a patient is on the table being treated and they're breathing, this target may move. So an ITV is an internal target volume which essentially incorporates that motion into your target or into your planning. So just we have to be really thoughtful about when we're treating non spine bone maets because they can be all over the body. So you've got to be really thoughtful about the normal tissues that you're drawing out and pushing the dose away from. So Ewings SBRT: What lessons have we learned so far? So certainly can be a challenging patient population to look after.

Dr. Murphy: [00:39:06] A lot of the folks that we see have had multiple prior therapies, so you want to be really thoughtful about that. And their disease may be more resistant. The folks that we look after rarely have limited metastases, but again, I hope you're seeing that there's a significant advantage to consolidate all sites of metastases. So again, this is a very different paradigm than SBRT in adult patients with metastatic cancer. We're certainly seeing that durable local control is possible. We know that SBRT can be well tolerated as long as we're thoughtful about the concurrent therapies that were given and the total cumulative dose if they've seen prior radiation. I think we do not know yet ideal dose or fractionation schemes. I think we're getting a better understanding. But prospective studies are needed and certainly I think it's really important to highlight here that a multidisciplinary team is critical to identify appropriate patients and to incorporate these aggressive local treatments into the overall treatment plan. And just a quick thank you to all of my awesome partners. So it really takes a team to be able to deliver these high dose focused radiation treatments appropriately and safely. So I have a lot of radiation oncology partners who are awesome. And then it's really important to highlight the role of physicists and therapists that are so important to deliver these treatments safely. And then my awesome pediatric oncology team as well. And a special thanks to the Little Warrior Foundation. I'm happy to take any questions.

Piero Spada: [00:40:46] Thank you for that, Dr. Murphy. I'm sure grateful that we have that recording chock-full of information. I was taking notes like crazy, and I'll definitely be looking back at this one for sure. We have several questions here, but I thought first we'd start off with a general question. In your own experience, I think starting in, what was it, 2014 at Cleveland Clinic looking at SBRT for sarcoma patients as a whole . .  are you able to parcel out which subtypes are better candidates for SBRT like Ewing's vs Osteo? Because sometimes we talk about one being more sensitive than another sarcoma type. Is that playing out in the SBRT?

Dr. Murphy: [00:41:23] I think it's a great question. I don't think that one benefits more than the other. I think just we have to be very thoughtful when we're applying these tools. I think in particular, we know that for osteosarcoma, radiation isn't even thought about for upfront treatment. So often when I'm seeing younger folks with metastatic osteosarcoma, they've never even met a radiation oncologist before. And those are certainly settings where someone has limited disease and you're going to want to be as aggressive as possible with the doses that you're using, right? So you might need to push dose more for patients who have osteosarcoma just because in general it might be more radioresistant. So it's not that it's not that the tool is better for one diagnosis versus the other. You just have to be thoughtful about how you can use the tool for the specific diagnosis.

Piero Spada: [00:42:24] And do we understand- I guess this takes us back to more conventional radiotherapy IMRT- why one sarcoma type would respond to radiotherapy and the other wouldn't? Is there that biological response, like understanding that at all? Is that

Dr. Murphy: [00:42:41] understood? So it's not understood well, to be honest with you. And also even within one histology group, there might be a variety of sensitivities to radiation and SBRT as well. You know, these these tumors are always trying to outsmart us. And sometimes we don't know why someone might have a much better response than others. And I think that's why we're learning more and more about the molecular makeup of these tumors and how we can eventually, we can hopefully, get to the point where we can be more patient specific with our treatments. Right now, I mean, you guys know it well. We apply these same old treatment regimens to to everybody. Right. And so hopefully that's certainly an area where we need to learn more so that we can be really patient specific, disease specific. But really the ultimate goal is patient specific for our treatments.

Piero Spada: [00:43:42] Okay. All right. Thanks for that. I got to hand it off to Emily for another question.

Emily McFadden: [00:43:48] All right. Thanks, Piero. We can always count on Lance Mosby for some great questions at Ewings U. So he asked: "when used for consolidating metastatic disease, can the multiple locations be treated at the same time? So say four sites, but each each treated for the same 1 to 5 day period? Or do these have to be done in a series over a more extended period?"

Dr. Murphy: [00:44:16] That is a great question, Lance. So the way I've been looking after folks who need multiple sites treated is I want to be really thoughtful about their time in the clinic. And also, though, you've got to be thoughtful about time on the treatment table. So when you're doing these treatments, each treatment might take 15 to 30 minutes. Right. And so you don't want to keep someone on the treatment table for too long. That would just be burdensome to the patient because our tables unfortunately are not comfortable. But I'm able to look after, treat, about three lesions. Four lesions might be pushing it, but treat about three lesions at a time. And the way I've looked at for folks that I'm consolidating multiple areas is I'll do the planning session for a few sites, get those treatments started, and then while they're on treatment for those sites, do a planning session for the next three or so sites so that I can kind of keep it going and get them done in just a few, maybe just a few weeks. Another thing that you can do is you can actually treat like two or three sites one day and then intersperse, treating two or three different sites the next day and kind of then treat every other day and get done over two weeks.

Dr. Murphy: [00:45:31] So there's multiple ways to kind of think through it. But I've been really, really impressed by my younger patients and their ability to tolerate these treatments and procedures. It's amazing how well they do with it with really little side effects. And that's why I'm such a big proponent of doing SBRT when I see these folks who've gone through so much already and then they're able to get through these treatments like hop on and off the table, I see them for their visits, make sure they're doing okay. They got nothing going, no new symptoms or side effects and just can go about their day. And that's in folks that are treated to multiple areas. Right. So I've been really impressed and really happy to see that - that these tools are not significantly impacting folks' quality of life. So it's nice that they can get these treatments done in just a few sessions and go about their life.

Piero Spada: [00:46:35] Thanks, Dr. Murphy. The next question kind of building off of that. So we talked about why SBRT might be good for those that have oligometastatic disease. But what about for those that present with overtly metastatic disease? What is the upper limit in terms of the number of sites that you can treat with SBRT? And then the flipside of that is what what do we do for those patients that have overtly metastatic disease? Does SBRT play a role in that treatment at all?

Dr. Murphy: [00:47:02] Yeah. So that's that's a really great question. So I often feel like we partner with our awesome oncology team who gives us systemic therapies, right? And so when someone has metastatic disease, it's so important that they're getting some kind of therapy that goes throughout their whole body. And then my tools can be a local tool, right? So certainly in all of these patients with metastatic disease, the chemotherapy systemic agents are so important. And as far as when someone has widespread disease so what's really interesting is that phase two SBRT one trial from multiple institutions that treated all their patients forty gray/ five fractions, they did have only limit it to five and under. But if we go way back to that initial European Union's collaborative analysis and remember when they were looking at the impact of local treatments, whether it was surgery or radiation therapy, on the event free survival. And when you when you treated local treatment to all sites of disease, there are significant advantage to event free survival. And we're also seeing these overall survival suggestions from more modern data. Right. But when you dive deep into the data from that European collaborative analysis, certainly folks who had just one side of metastatic disease did better than if you had many. But they didn't find a significant difference in the benefit of local treatment for two up to ten metastases. So that shows you've got to be aggressive. It sounds like a lot of treatments, but it makes a lot of sense to be aggressive. So you're right, sometimes we can't treat everything because it could just be too burdensome, because you have to be really thoughtful about impact on marrow, impact on normal tissues. And then those settings where you can't treat everything just because of safety, you prioritize the areas that would be at higher risk for growing or those that may not have responded well to chemotherapy or those that are in critical areas that if they did grow, could cause neurologic deficits. So then you have to go back to, okay, what how should we prioritize these lesions? That's a great question.

Emily McFadden: [00:49:20] Next, we have a question from one of your colleagues, Dr. Pete. Dr. Anderson asks, "Would it be possible to use alpha emitters with SBRT to cause double trouble or double strand breaks in metastases?"

Dr. Murphy: [00:49:39] Great question, Dr. Pete. So anything can be thoughtfully done if we think about doing something prospective like that. So I think as you see that we need to do better with local control if we can't get enough dose. So it's a settings where if we can't get in that at least 35 grade or five fractions that at least that greater than 95 gray biologic effective dose or we need to do something more. . . And I actually so this is where I was thinking a lot with our awesome colleague, Dr. Isilon, who does cryotherapy. So I was talking to him recently, and want to sit down more with him about in those sites that we need to be more aggressive with our local impact that are close to normal critical structures: Can we combine our tool? Where we can be really tight and carve our Dose way around critical structures? Perhaps we would use cryo as a boost within the middle or that kind of thing. So it's really partnering other kind of local tools or other concurrent therapies at the same time. As you know so we have a unique experience looking at concurrent Pazopanib, right, which we know that these kind of tyrosine kinase inhibitors may cause more toxicity combined with radiation. So you want to be really thoughtful. We've actually looked back at our series and there's this suggestion of even overall survival advantage if you're using that kind of therapy concurrent with SBRT. So just figuring out the right ways to enhance our tools and do it safely. But I think there's many potential ways to do that.

Piero Spada: [00:51:20] Thanks for that. Dr. Murphy. The next question kind of dovetails off of the CBC results, the correlates that you presented there. I'm really curious to know, too: why would having high ANCs prior to SBRT and conversely high NT/LR ratios (which basically says you're having high ANC and/or low lymphocytes). Why does that correlate to a worse prognosis and outcome?

Dr. Murphy: [00:51:45] Yeah, so I think that's a great question. And I think unfortunately why I said that was just kind of fact finding and hypothesis generating. so that was just retrospective series. And so the timing of collecting that CBC data was anywhere between like one week to a couple of months before. And vice versa afterwards. So it was kind of peri-SBRT but not done in a prospective setting where we can really understand the impact. And those levels are so impacted by chemotherapy. And so certainly we can see that chemotherapy may be impacting those. And so on our trial, we want our folks to be still getting standard of care treatments. And we're not going to take them off of certain chemotherapy regimens just so that we can understand what is the exact experience of or impact of SVR and the immune system, because we want it to be a real world experience. Right? We're not going to take kids off of their systemic agents while they're getting SBRT because they still need those.We're treating them for metastases. And so we're going look at it and kind of divide it up into chemotherapies that are more impactful on CBC, that kind of thing. So is it more myelosuppressive versus less suppressive, and then prospectively collect that information. It's going to be done like a week before the last day or within one week after and then in follow up so that we can really get a true sense of those levels. So it's hard to say. We can't really correlate. I can't really answer that yet. But one day.

Piero Spada: [00:53:25] Too many confounding variables at this point.

Maggie Spada: [00:53:28] Can I jump in and ask a question? I recently saw this actually on some of the Ewing sarcoma message boards where a lot of the patient families seek out advice and input. And I think I know what your answer would be, but I think it'd be powerful to have you state it. When someone has a wonderful response to chemotherapy. Let's say they had lung metastases or a small metastases elsewhere bony met - But it responds on imaging nearly to to complete remission. Would it be your advice to still approach local control aggressively? Because we often see people saying they don't --  they don't really want to go for it. No one wants to do radiation. As much as we love you, Dr. Murphy. No one wants to go get radiation. And so I guess what would your your messaging be when someone has a great response to front line chemotherapy?

Dr. Murphy: [00:54:27] So it's a great question and it's certainly hard in the lungs. The lung is a different scenario. So for us to do focus high dose SBRT, you need to see something to aim it. So in the setting of a complete response in the lung. Great. That's awesome. Right. And those are the folks that we want to keep a close eye on. So where we do lung SBRT is in the setting of folks who had had prior whole lung radiation as their consolidation tool for lung metastases. And they have a local progression, or I use it in the setting of folks who have not had prior whole lung irradiation, but they've been followed and then they have limited progression in the lungs and it makes sense to aim at that. And and I don't think it burns a bridge. I think that if it ever became important to get full lung, you could do it after that as well. So the lung is a separate situation because we need to see something to aim at. We're not going to aim at just a hole in the lung based on prior imaging. But the bone soft tissue is very different. So even the prospective study so was not a question of randomizing folks with Ewing Sarcoma on the COG trial randomizing them to get SBRT or not.

Dr. Murphy: [00:55:52] It was more kind of a feasibility. So. Folks are called to get SBRT to all initial sites of metastatic disease that are less than five centimeters in size, regardless of response. So you're still getting after it. You're still getting after it. And we really believe that why it makes sense to target these areas is that might be the areas where they're most likely to fail. So and it's much easier to get after it up front when there's the least amount of microscopic disease. Right. And when they're not having symptoms from that. Right. But it's also so important then that if someone has these awesome responses and they're not having symptoms, it's on us to use our tools in a thoughtful manner. But we're not going to cause symptoms, right? Because folks are doing great. Why would you want to do something that could cause symptoms? Right. So I think that that tool is very important to be used as a consolidated tool, even in the setting of really good responses. If you want to be aggressive with their local issues.

Emily McFadden: [00:57:02] Thank you. I had one more question come in that I think is important for patients that are geographically dispersed and do not have access to someone like you. How can a very good local radiation oncologist best leverage your expertise, this research and the experience of others who may have many more sarcoma research expertises?. So how can local oncologists get involved?

Dr. Murphy: [00:57:38] Yep. Yep. It can be hard sometimes, but it comes up almost every day. So I've been thinking a lot about this, and I think there's a couple a couple of ways to do this so both in a bigger picture and then a one on one patient. So in the bigger picture, I want to reach out and get some combined experiences combined with other folks who do do more SBRT, like we do to get together, set up some symposium or sit down and talk, whether it's virtual or in person, and combine our data so that we can ask questions. Sometimes it's hard to pull out of retrospective data, but with rare tumors, sometimes it's the best you can do. I think it's a really important setting to then combine combine all of our data and ask some of these important questions about toxicity dose,  what's the best concurrent therapy regimen? Who's the patients that might benefit best from this? Right. So we need to do that on a bigger scale. And in that same setting with folks that have more experience, we need to develop guidelines that we can share with the community about how to target these, what the indications, what dose to use, what toxicity be aware of, what normal tissues to counter. So that's the bigger - that's something that we need to do as a bigger group and have that information available for others that may not be as comfortable about it to use these tools. And then at a patient specific level. So Doctor Pete and I and a bunch of our pediatric oncology colleagues look after a lot of folks who are from out of town.

Dr. Murphy: [00:59:19] It's important. I actually had a colleague recently reach out who was asked to kind of give a talk about looking after patients from out of the state. We're now - they're having more and more restrictions on us - which is really hard when we just want to help folks. Right. So there's second opinions. There's second opinion programs that are set up that always has a fee. And that might be where we would reach out to like Little Warrior Foundation or other foundations to see if they would support so that folks can have have that expertise available to them. But for us, we're just very happy to reach out to their local doctors, kind of talk through what their comfort levels are. The blessing is we actually look after a lot of folks from out of town so we can meet them and do virtual consults and then bring them here for the treatment planning session to meet them in person and then bring them back for their one week of treatment. That's what's also so cool is although we don't want to force folks to travel, if these kind of treatments are not locally available, the blessing is it's done in the week and then we can follow people locally. They don't have to come back. They can send us images and we can have virtual follow ups. And so we do a lot of that. And that's allowed us to extend our tools to to wider reaching success.

Emily McFadden: [01:00:41] Great. And I know we are we are at time. But there was an important plug in the chat box for the National Ewings Tumor Board, which is an effort that Dr. Trucco, some of your colleagues and others are spearheading, and something that Little Warrior wants to make sure everyone's aware of. So we'll include some information and follow up to this for that tumor board, because that could be a great option for remote folks.

Dr. Murphy: [01:01:11] Awesome

Maggie Spada: [01:01:13] Thank you so much, Dr. Murphy. There's more questions in here, and I know that we could stay and talk with you forever, but you've got plenty of patients to give back to. Thank you guys all for joining. Dr. Murphy, the information was awesome. On a personal note, we adore you and love you and thank you for taking such good care of our Little Warrior and so many others that we've come to know in the Ewing sarcoma community. To everyone listening and on the call today, we will see you back again in September. Please be sure to subscribe to our Ewings U emails. You can do that by going to littlewarrior.org And navigating to the Ewings U tab on the website. Also follow us on Instagram and Facebook as we always post about our next speaker that way as well. Finally, we have a phrase here, a little warrior that we feel embodies our fight in honor of and in memory of so many little and big warriors who have faced this cancer. It's how we sign off on all of our communications, both internally and externally. So while I know most of you are muted, the four of us will say it together a little. (It swords up, Dr. Murphy). So on a count of three, everyone. One, two, three.

Dr. Murphy: [01:02:29] Swords Up!