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Aimee:  Welcome to the Oncology Sound Byte, a podcast produced by the Seattle Cancer Care Alliance designed to offer bite-sized audible oncology education from one of the top cancer treatment centers in the nation. I'm your host, Aimee Martin, a senior physician liaison at the Seattle Cancer Care Alliance, now joined by my new cohost, Dr. Jason Lucas, who serves as the Medical Director of SCCA Issaquah. Welcome, Dr. Lucas.

Dr. Jason Lucas: Thanks, Amy. It's great to be here.

Aimee: We're so glad to have you represent our community oncologists and engage in clinical dialogue with our guests. And speaking of guests, I'd like to introduce Dr. Stephanie Schaub, attending physician and radiation oncologist at SCCA, as well as Dr. Michael Wagner, attending physician and medical oncologist at SCCA, who are here to discuss neoadjuvant therapies in sarcoma cancer.

Welcome to the show.

Dr. Stephanie Schaub: Thank you so much for having us.

Dr. Michael Wagner: Yeah. Thank you. Happy to be here.

Aimee: It's great to have you. I'm going to let Dr. Lucas take it from here and ask our first question.

Dr. Jason Lucas: Well, again, thanks for inviting us to be on. And what I'd like to do as a community oncologist is to open it up to Dr. Wagner and just talk to him initially about what's new and exciting about sarcoma and, given my experience with sarcoma in the past, how have things changed now in the present?

Dr. Michael Wagner: Yeah, absolutely. So, historically, sarcomas have been viewed as extremely difficult to treat, which is still true, but there are many treatment options now that were not available even just a few years ago. And we liked to see people fairly early on. And we have many new clinical trials, then also even FDA-approved drugs that can help people with different sarcoma subtypes. So that's one big change, I think, over the past few years where sarcomas used to be generally just lumped together. Now, we're getting drug approvals more and more specific for subtypes based on the science of what actually drives the different kinds of sarcoma. And we're able to tailor that to really personalize the treatments for specific patients.

And that's really exciting. It's improved outcomes for patients with sarcoma. So, where people would have just a few treatment options a few years ago, now we have many others. And I think we'll talk about that in more detail in a little bit. And then also more specialized care and especially multidisciplinary care and it's great that Dr. Schaub is here and can also give some insight into different ways and benefits of radiation that we can do right now that necessarily wasn't available not too long ago.

Dr. Jason Lucas: Yeah, those are all great points. Dr. Schaub, what do you think? How have things changed for you in your historical perspective up to now with regard to radiation therapy and sarcoma?

Dr. Stephanie Schaub: I agree completely with Dr. Wagner, that this is an incredibly exciting time to be practicing medicine, treating patients with sarcoma. I think one of the most exciting things happening at SCCA with sarcoma is that, for our patients that have a newly diagnosed sarcoma tumor, we have multiple studies right now, investigator-initiated out of the Seattle Cancer Care Alliance for those in a curative setting with neoadjuvant therapy.

And what's beautiful about these trials is they're designed in a way that they work really well for patients that are coming from all across Washington, but also the greater WWAMI and kind of larger region that we serve and treat given this rare disease, because all the actual therapy provided is in a neoadjuvant setting over the course of one to three months. And so it's kind of very easy for patients to be able to get this therapy.

Two trials that we want to highlight today are an immunotherapy and radiation trial with pembrolizumab as well as a targeted therapy and radiation trial with cabozantinib. The immunotherapy and radiation trial is particularly interesting because, with both trials, we're still delivering standard of care, which is radiation for five weeks, followed by surgical resection for these patients with curative sarcomas. But we're trying to ask ourselves, how can we push the needle? How can we figure out how to both increase our chance of not having a sarcoma come back locally in the extremity or wherever the primary tumor is located, but also can these additional therapies that we're adding to our standard of care treatment further decrease the risk of it coming back distantly as well, which continues to be a big problem for many patients with sarcoma.

A big important part with these trials is to see the patients at initial diagnosis so that we can consider them for eligibility. I can hand it back over to Dr. Wagner to talk a bit more about some of the specifics.

Dr. Michael Wagner: Yeah, absolutely. And thank you for that great description. So, as you mentioned, I think it's important again to highlight that, once someone is diagnosed with a sarcoma, it's really critical to be evaluated at a central sarcoma referrals center with multidisciplinary evaluation specifically to see who might be a good candidate for a trial like this or even outside of a clinical trial to really optimize the care that you're receiving.

But in terms of eligibility for our neoadjuvant studies, we have a few different studies, as you mentioned, and eligibility differs a little bit. But in general, it's for anyone with relatively high-grade tumor who would potentially need to get radiation anyway as part of their care. And again, as you mentioned, the goal of adding the systemic medicines to the radiation is both to increase the effectiveness of the radiation, but also to try and reduce the likelihood of the cancer coming back at some point down the road.

So, really anyone who is newly diagnosed with a sarcoma, I think, should be evaluated. And there's a good chance that they'd be eligible for one of our what we call neoadjuvant or before having surgery clinical trials.

Dr. Jason Lucas: Exactly. And I think from just as a practical standpoint, let's just say I'm the primary oncologist out in Missoula, Montana, what is the best way do you think to make that sort of thing happen?

Dr. Stephanie Schaub: I think with the advent of telehealth as well as the ability to combine many of our visits where we see patients, it's with the orthopedic surgeon or the surgical oncologist or radiation oncologist, as well as a medical oncologist, all at the same visit. We can either coordinate for these visits to be done virtually or in a very kind of patient-friendly fashion where they can come for a single day and be able to leave with a formulated treatment plan.

Dr. Jason Lucas: Well, that'd be amazing. You pointed out, Dr. Schaub, that in the WWAMI region, meaning Alaska, and so from your standpoint, people would come in from Alaska, get all those visits in a single day, head home and consider-- I guess the other question-- could radiation be done up in Alaska or out in Missoula or would they need then to come back to continue the therapy here?

Dr. Stephanie Schaub: So this is a really interesting question. And one of the reasons why I love practicing at University of Washington and Seattle Cancer Care Alliance is that we're a bit spoiled in terms of the radiation types of treatment modalities that we have to offer for patients. We have the traditional x-ray-based radiation therapy that has become incredibly sophisticated in our ability to shrink wrap our high radiation dose lines the way we want to for tumors in all sorts of bodies where sarcomas can appear in as well as via proton therapy, which is a particle-based radiation that really has a nice physics property where it just stops after treating the area that you want to target.

And we found this incredibly helpful for patients that have tumors in particularly challenging areas to treat such as in the spine as well as in the pelvis, because we even have reported patients that have gone on to have children and maintain their fertility, which wouldn't have necessarily been possible with more standard types of radiation.

And the design of the radiation fields, despite having similar types of technology all around the country from the x-ray radiation standpoint, the real design of the radiation field, it's somewhat akin to a surgeon in terms of trying to both treat what you're seeing, but also really having an awareness of the type of tumor, the grade, the degree it could infiltrate or spread into neighboring tissues and how to also best spare the normal tissue so that you really help keep that patient's long-term risk of toxicity low in terms of swelling, lymphedema, fibrosis, wound healing issues. And so it really does require kind of thoughtful consideration and a radiation plan.

And so I do feel that this specific type of tumor can often benefit from being treated by a specialist that does see these types of patients regularly to best tailor and personalize the radiation component of their care.

Dr. Jason Lucas: Well, that certainly makes a lot of sense to me and I'm sure to our listeners as well. And, I guess, one approach certainly could be in certain simpler cases we could conceive of maybe radiation being done at home for these patients. But in certainly in the more complicated cases, and I guess you could ask the question when is sarcoma not complicated, it would probably best be done in a center where a lot of sarcomas are seen, and there's a lot of experience and a lot of knowledge and wisdom in how to approach these kinds of cancers.

Dr. Stephanie Schaub: I agree. We work really closely with our kind of colleagues in different states and locations and try to talk them through specific cases when this comes up and it would cause too much of a hardship to come over here for treatment. And it is a lot of decision-making and a lot of my job is trying to decide which patients it does make sense to come over here as opposed to getting treatment closer to home.

Dr. Jason Lucas: Dr. Wagner, in terms of the therapeutic or the chemotherapeutic and immunotherapeutic approaches, is there anything exciting from your standpoint or specifically very exciting, I would say, in terms of new therapeutic options? I mean, I think all of us in general oncology would say, what's taken the world by storm in the last seven years I suppose, is immunotherapy. And historically, certainly immunotherapy was not effective in sarcoma to my knowledge. But it sounds like we're doing that now here at Seattle Cancer Care Alliance.

Dr. Michael Wagner: Yeah, absolutely. So actually one of the clinical trials that we're talking about combining radiation with systemic medicines is an immunotherapy study. So it's combining immune checkpoint inhibitor with radiation and we think that, or at least we hope, that will increase the long-term benefit from the radiation.

But even for people who have metastatic disease or disease that spread to other parts of their body, immunotherapies just like you said, at least recently weren't thought to be very effective against sarcomas, but we're now learning that there are certain sarcoma subtypes and certain types of immunotherapy that actually do have good activity in sarcoma.

And specifically, it looks like a type of sarcoma called undifferentiated pleomorphic sarcoma seems to be responsive to the checkpoint inhibitors, that type of immunotherapy that, like you said, sort of took the oncology world by storm where those are now used for so many different types of cancers. And it seems like those are effective against that particular subtype of sarcoma.

There's also, it looks like, a subset of angiosarcoma. So patients with certain angiosarcoma could benefit from the same therapies. And then also even other types of immunotherapies, specifically cell therapies, where we can actually take the T-cells from a patient, modify them to try and make them recognize the cancer cells and then put them back into the patient.

And there are a few different clinical trials now that have been ongoing and their initial results have been incredibly promising for at least two different types of sarcomas. And one of them is synovial sarcoma and the other is myxoid/round cell liposarcoma where those types of therapies are probably going to revolutionize the way those particular subtypes of sarcoma are treated in the future.

And we're still learning more. So we're hopefully going to be able to figure out why some of these other sarcoma subtypes aren't really responsive to immunotherapies and potentially even develop combinations that might open up immunotherapies for even more patients.

Dr. Jason Lucas: Wow. That's fascinating. So you're saying immunotherapy plus something else to somehow assist somewhat similar to this idea that radiation therapy can increase the PD-L1 positivity and therefore sensitize tumors to immunotherapy.

Dr. Michael Wagner: Right. Exactly. So similar ideas and there are a few different studies that have been done and also that are ongoing. So we actually recently finished a trial looking at immunotherapy combined with more standard chemotherapies and at least those early results seemed promising. And we have more trials in the pipeline both with immunotherapy alone, but also in combinations, both for those subtypes that I specifically mentioned before, but also trying to enhance just the immune checkpoint inhibition alone. Because even though we're seeing activity in those particular subtypes, it's not quite to the level that you see in a cancer like melanoma, where treatment has almost exclusively been replaced by immunotherapies.

Dr. Jason Lucas: And correct me if I'm wrong, but my experience early on in immunotherapy was I looked a lot at tumor mutational burden. That doesn't seem to be a driver of sensitivity in sarcoma, does it?

Dr. Michael Wagner: Yeah, that's a good and very interesting point. So It certainly doesn't hurt to have a high tumor mutation burden. But we've seen patients actually have responses where even outside of a trial, when we just give it on a compassionate use basis. We've had patients have really excellent responses and through all the mutation testing and PD-L1 staining that we don't actually find it clear reason for why.

So there's something, and there must be some marker out there that we just don't know yet to identify who might truly benefit from immunotherapies. But we certainly have seen some patients have responses even if we don't have a clear molecular reason for why their tumors in particular would be susceptible to those sorts of treatments.

Dr. Jason Lucas: Well, immunotherapy just got another boost. Now, you can give it to everybody at any time, or at least later in the stage of disease in terms of compassionate use, as you're mentioning. I mean, that's something conceivable, especially if we don't know why it works in some people.

Dr. Michael Wagner: Yeah. I mean, understanding that there are still the risks of side effects, but...

Dr. Jason Lucas: Of course, yeah. Of course.

Dr. Michael Wagner: I certainly would be willing to try in someone who's otherwise doing well and understands the risks.

Dr. Jason Lucas: Exactly. Dr. Schaub, I think you were going to make a point there, but it got cut off.

Dr. Stephanie Schaub: Oh, I was just going to tie in that you pointed out very well that radiation is one of the many ways in which people are currently interested in investigating to try to make immunotherapy work better. And we don't know all the answers in terms of why some responders are excellent and others allude that kind of responses that we're wishing to see. But we're learning more and more in terms of the role of radiation as well as the dose that we deliver per fraction of radiation and how sometimes giving a sweet spot kind of Goldilocks between a certain amount actually can induce the immune response. But actually if you give too much or too little, it may actually down-regulate the immune response. And these are all things that we're further learning and understanding.

But also for patients with sarcoma, we often use radiation in a setting of when the immunotherapy may be working for most sites of disease. But if there's one progressive area, we can always consider local control of that area for patients on either more traditional targeted or chemotherapies or immunotherapies. And I do think that over time, we're just seeing a lot more multimodality types of approaches to helping these patients live longer and with a nice quality of life.

Dr. Jason Lucas: I think that's a great point. One other question maybe before we take this out is, from at least my experience with this, is that pathology means everything. And do you feel like in both of your experiences, that pathology needs to be re-evaluated before patients come here just to make certain that the diagnosis of some of these rare tumors is really what we think it is?

Dr. Michael Wagner: Yes, that's an excellent point. And I would absolutely agree that I think having a sarcoma specialist pathologist is critical. And specifically for the reason that you mentioned to actually confirm the diagnosis, because these are such rare tumors. It's actually surprisingly common for our pathologists to, in some way, modify the diagnosis. So in some cases that can be as simple as just changing the grade of the tumor, which might actually have an impact on the therapy planning. So a tumor that is originally felt to be a low-grade or intermediate-grade tumor that's then converted after the sarcoma pathology reviewed to a high-grade tumor that actually would affect the treatment decisions.

And in more rare cases, we'll actually see sometimes that the diagnosis changes. So either from one subtype of sarcoma to another, which again can have treatment effects. So especially because there are now drugs that are approved specifically for certain subtypes. And then also, even sometimes I've seen cases go both ways where either someone was diagnosed as a different type of cancer on the outside that then here was reinterpreted as a sarcoma and vice versa where we think that someone has a sarcoma, but then when our pathologists finalize the read, it turns out to be a carcinoma of some sort or even a melanoma, which again obviously drastically changes the treatment planning.

Dr. Jason Lucas: Yeah, that's major change. So I think what I'm hearing, at least in the big picture from patients who were in the WWAMI region or close by, definitely if they're looking, if they have a sarcoma or an oncologist believes they have a patient with a sarcoma, have the pathology re-evaluated by us as sort of a first things first. And then if it is indeed sarcoma, send those patients to us at SCCA early, probably before any therapy gets started. So at least we can weigh in in terms of what things can be done right off the bat, as opposed to after first or two or three doses of standard chemotherapy. Is that kind of about where you see things?

Dr. Michael Wagner: Yeah, absolutely. With, I think one tweak where I'd say we can do all of that in parallel where a patient can be set up to see a medical oncologist and radiation oncologist and surgeon if needed. And at the same time, our pathologists would review the pathology ideally before the patient sees us, but while those appointments are getting set up,

Dr. Jason Lucas: Dr. Schaub, any last words?

Dr. Stephanie Schaub: No, I completely agree with all your conclusions. I think my final consideration would be if there's any concern that you are seeing a mass that could be a sarcoma, having all thought-out biopsy by a center that is very well-practiced and kind of not violating any tissue plans that may be un-involved is very important when the tissue is obtained.

Because we still know that despite our best efforts, that if non-oncologic type of procedures happen for these tumors, they can not be at a much higher risk of coming back locally. And we always want to just try to maximize our chance of curing and controlling this as much as possible. So we're always happy to see them early on and get them started on their diagnostic workup. Many patients we see actually still do not have a biopsy yet. And our either orthopedic surgeons or surgical oncologists help to coordinate and figure out the best way in which to handle this.

Dr. Jason Lucas: That's amazing. I agree with everything you said. I was just thinking about a time when I had a man with a sarcoma in his arm and it was difficult to find an orthopedic oncologist. And that was even in the context of being in Seattle. So I can imagine in other places, it's more difficult to find someone who specializes in this very narrow field of orthopedics

Dr. Michael Wagner: Absolutely. I will say we have a couple of great orthopedic oncologists here at SCCA. So, hopefully, if that situation comes up again, we can certainly plug any of those patients in.

Dr. Jason Lucas: That sounds good. Well, I really want to thank you two for coming on today and I think this is going to be very helpful for the folks here in Seattle and farther afield as well.

Aimee: I want to make sure to just thank my co-host, Dr. Lucas, who provided great perspective, had some great questions to ask our guests and sarcoma specialists, doctors Shelby and Wagner, for joining us today, along with our listeners for tuning in to the Oncology Sound Byte.  

To hear more, subscribe to the Oncology Sound Byte in your favorite podcast app. And to receive updates on our future podcast episodes along with other news out of SCCA, go to SeattleCCA.org/providerblog, and click subscribe. Until next time. Thanks for listening and take good care.