J. Dominic Femino, MD, is an associate professor of clinical orthopedic surgery at the Keck School of Medicine of USC and the chief of the USC Musculoskeletal Oncology Center.

Lee Zuckerman, MD, is an orthopaedic surgeon with Keck Medicine of USC

Mark Agulnik, MD, is a medical oncologist with the USC Norris Comprehensive Cancer Center, part of Keck Medicine of USC

Andrew Lim, MD, is a radiation oncologist with Keck Medicine of USC.

In this last episode, experts highlight the key takeaways from the Stand Up to Cancer SARC 032 study (NCT03092323) in soft tissue sarcomas.

Moving the Needle in Undifferentiated Pleomorphic Sarcoma: Conclusions

 OncChats: Moving the Needle in Undifferentiated Pleomorphic Sarcoma

, the following experts highlight key takeaways from the Stand Up to Cancer SARC 032 study (NCT03092323) evaluating pembrolizumab (Keytruda) in patients with soft tissue sarcoma and underscore the importance of multidisciplinary care at specialized sarcoma centers:

, an orthopaedic surgeon with Keck Medicine of USC and chief of the USC Musculoskeletal Oncology Center

, an orthopaedic surgeon with Keck Medicine of USC

, a medical oncologist with the USC Norris Comprehensive Cancer Center, part of Keck Medicine of USC

, a radiation oncologist with Keck Medicine of USC

In conclusion, I’d just like to summarize some of the key points that we learned about today. So, this Stand Up to Cancer SARC 032 study showed a significant improvement in disease-free survival at 2 years with the addition of neoadjuvant and adjuvant pembrolizumab [Keytruda] to preoperative radiation therapy and wide [excision] surgery for high-risk localized UPS of the extremities. And number two, it represents a promising new collaborative treatment strategy for these patients. Number three, this trial exhibits the benefits of multidisciplinary treatment for soft tissue sarcomas and the importance of treatment at specialized sarcoma centers, such as University of Southern California [USC].

I would like to thank the expert panel from the USC Sarcoma Program, Drs Agulnik, Hu, Zuckerman, and Lim, and thank you to 

 for providing the platform to bring the global oncology community together. We hope you have found today’s OncChats informative and helpful for the care of your [patients with] sarcoma. For further information about the USC Sarcoma Program, please contact us through our website and phone number. Thank you very much.

Videos

In this episode, experts highlight the key takeaways from the Stand Up to Cancer SARC 032 study and its clinical implications. 

In this episode, experts discuss the landmark SARC 032 study, highlighting the importance of multidisciplinary collaboration, 

Moving the Needle in Undifferentiated Pleomorphic Sarcoma: Multidisciplinary Collaboration

, the following experts discuss the landmark Stand Up to Cancer SARC 032 study (NCT03092323), highlighting the importance of multidisciplinary collaboration, the significant improvement in disease-free survival with relatively low toxicity, and the potential for expanding this treatment approach to other sarcomas.

Dr Agulnik, this has really been a landmark study for the treatment of undifferentiated pleomorphic sarcoma. Why is it exciting?

It is exciting on so many levels. It would be lost if we didn’t acknowledge how fortunate we are that we work with each other. Because I think we’re somewhat spoiled. As sarcoma specialists, it is amazing that we get to partner, learn from, and collaborate with peers in each discipline, between orthopedic, surgical, and radiation oncology. We have pathology, we have radiology, we have expertise across our nurse practitioners, our PAs, and pharmacy, to really help us manage these patients. I think what this study shows is that you really need that multidisciplinary care. For patients to come through centers that don’t have multidisciplinary care, they potentially can be compromising their care, as highlighted in this study. So, I think it is groundbreaking that you have a study that gets buy in and support, as well as groups that came together—including orthopedic, surgical, radiation, and medical oncology—to collaborate, come up with a concept, and get this concept sent out to the world.

This [study] was done across multiple countries throughout the world. It was also done in its landmark [population]; it was done from patients aged 12 [years] and above and so there is a safety [in knowing that] in this adolescent/young adult population, this somewhat pediatric population, that we could use this to make a substantial difference. What’s most exciting is that it is a substantial difference for our patients. The absolute benefit of disease-free survival [DFS] was about 15%, which is substantial. To move the marker that much with a drug therapy that is relatively nontoxic compared with other therapies we have [is substantial]. We’ve all seen patients who have been treated with adriamycin or doxorubicin, with ifosfamide, or with other therapies that we traditionally use for our [patients with] sarcoma, and we’ve seen here that patients tolerate this therapy better as a whole.

That is certainly very encouraging. To bring something into a setting that is not metastatic, to bring something into a setting where we all collaborate together, where we’ve all made a difference together, is very substantial. It’s very fortunate for us in this community to be able to show that we could collaborate together [to make an] impact and [underscore the] meaning of multidisciplinary care [with regard to] the management of our patients. The patients win in the end because they have improved DFS and their distant disease free[–survival] is also improved with this.

As we follow this study longitudinally, which we will, and it will get presented at other meetings in the future, I anticipate that overall survival will be impacted, as well. We’ll see that ripple effect of this study and hopefully, this will not only be a UPS thing. Hopefully, the study could get replicated, and perhaps [we’ll find] there is a role for this treatment in other types of sarcomas, as well.

In this episode, experts discuss the landmark SARC 032 study, highlighting the importance of multidisciplinary collaboration.

In this episode, experts discuss the impact of neoadjuvant radiation and immunotherapy on surgical planning in patients with soft tissue sarcomas.

Moving the Needle in Undifferentiated Pleomorphic Sarcoma: Impact of Immunotherapy on Surgical Planning

, the following experts discuss the impact of neoadjuvant radiation and immunotherapy on surgical planning, highlighting the importance of specialized sarcoma centers to minimize complications and improve outcomes for patients with soft tissue sarcomas:

So, what are the implications of this study, and having the immunotherapy and radiation therapy? How does that impact your surgical planning?

 It can impact the surgeon in different ways. Partially, let’s talk just about the radiation. Some institutions will do neoadjuvant radiation, as was performed in the study, which is radiation prior to surgery. There are some reasons why they may do surgery intraoperatively or postoperatively. So, there are different options with radiation. With this particular study, we’re going to be doing neoadjuvant [radiation], or prior to surgery. That can take some planning on part of the surgeon if they are not familiar with doing that type of surgery, which we routinely will do here, at University of Southern California, particularly with the importance of getting the patient healed quickly enough so that they don’t have a complication but also can get back on the adjuvant pembrolizumab [Keytruda]. So, it is important to understand, as a surgeon, how to get this patient healed—[for instance,] you may need a plastic surgeon to provide soft tissue coverage, particularly for tumors that you may be resecting a significant amount of skin—and working with those other teams to get the patient on track to get back on their adjuvant therapy afterward. The other difference can be the timing, and based on this study, surgery was performed somewhere between 5 and 9 weeks after radiation was completed. Many institutions and surgeons will perform surgery 4 to 6 weeks after radiation, so adjusting your timing based on this study may be inherent in using this medication.

For patients who have an unplanned surgery and then come to you as a sarcoma expert, how does that affect the treatment plan, and how does it affect the outcome for the patient?

 Yeah, so that’s the difficulty with sarcoma, because it is so rare. Again, this goes back to the importance of being treated by someone who specializes in sarcoma and going to a center that has that multidisciplinary treatment, because when a surgery is performed on a tumor that is not identified by biopsy to be a sarcoma prior to that resection, there can be contamination of the surrounding tissues. If the area is not resected with a margin of normal tissue around the tumor, or the tumor is cut into, then there is likely tumor left behind in the body. This can then be spread locally, typically, but can spread because now you’ve disrupted the normal capsule around that tumor.

What that does for us is it makes our surgery more extensive, so I have to usually, based on preoperative MRI or CAT scan or something, as well as discussion with the surgeon who performed the surgery, decide where the tumor was and what they did during surgery. And now, I have to resect—not just where the tumor was, but I have to take out the area where the surgeon operated, which may be much more extensive than what we would normally need to do if I saw this patient primarily. That, again, can impact both the radiation treatment, whether you need a plastic surgeon, etc. Ultimately, there are multiple studies that show that if a biopsy were performed in certain ways that we would be concerned about, we may not be able to perform that limb salvage surgery. The importance of having the surgery initially done at a sarcoma center is vital for these patients.

The good thing about this study, and this does not preclude a proper surgery done initially, is that we have another treatment so these patients who may have had an excisional biopsy, where the tumor was taken out, or taken out in pieces at another institution, ideally, this medication now helps decrease the risk of local recurrence as well as metastatic spread in these patients.

Check back tomorrow for the next episode in this series.

In this episode, experts discuss the surgical approach to soft tissue sarcomas.

Moving the Needle in Undifferentiated Pleomorphic Sarcoma: Surgical Oncology Goals

, the following experts discuss the surgical approach to soft tissue sarcomas, emphasizing the importance of multidisciplinary care, precise biopsy techniques, achieving negative margins, and the advancements in limb salvage procedures that have minimized the need for amputation:

Dr Zuckerman, you are an orthopedic surgical oncologist, and surgery remains a primary curative approach for soft tissue sarcomas. What are your primary technical goals of surgery when you treat these patients with undifferentiated pleomorphic sarcoma of the extremities?

 Yes, thank you for the question. Taking care of a patient with sarcoma starts when you initially see them, so I’m going to focus a little bit on that, and part of that is the importance of being taken care at a sarcoma center where you have this multidisciplinary approach, especially for these newer treatments. But on the evaluation of a patient, someone who comes into your office who has a soft tissue mass that’s more than 3 cm or deep to the fascia, regardless of size, deserves some form of advanced imaging to help with your diagnosis and to plan your biopsy. The biopsy itself can be extremely important, and whether that’s done by a surgeon or by an interventional radiologist, it should be done under the supervision of the surgeon who’s going to do the resection, because in many cases, the biopsy tract is considered contaminated and we’re going to resect it at the time of surgery. It can also matter for when the patient is getting preoperative radiation, for planning of how we’re going to take this out and what type of reconstruction techniques we’re going to make.

Once the biopsy is performed, it’s also very important to have a pathologist at your institution who can identify that this is a UPS so that [patients] can get on the proper treatment. Once they’ve undergone their neoadjuvant therapy, we’re going to want to do a resection of the tumor that involves negative margins. What that means is we want to see on the pathology that there is normal tissue between the edge of the tumor and the edge of the specimen. [The question of how] much of a margin is debatable. Ideally, we’re getting at least a couple of mm, as wide a margin as possible. But when we’re performing limb salvage surgery, these tumors may be pressed up against a blood vessel or a nerve, so we may be taking a very minimal margin, or sometimes what some people call a planned positive margin, which is really when we’re resecting a thin layer, such as the adventitia off a vessel or the epineurium off a nerve, and that’s going to be our margin. We do that when the tumor is pressing up against these structures, but we can still perform limb salvage for the surgery. And so, from the initial evaluation of the patient to the final surgery where we’re performing this, there are many complicated steps that we have to take in order to hopefully provide cure for these patients.

 And are you able to salvage the limb most of the time, or does this involve an amputation?

At this point, [most] of the time we’re able to save someone’s arm or leg. [That is a] question that goes with the surgeon also, because we always can offer an amputation, but that’s a discussion with the surgeon of what the patient prefers and different factors with it. For the most part, someone who specializes in sarcoma can save the person’s extremity the majority of the time. At this point in my career, I perform very few amputations. Even if the tumor involves certain blood vessels or certain nerves, there are methods to save the patient’s limb. The function may not be as ideal, obviously, if we have to sacrifice a nerve, but the techniques that we’ve developed over the past several years really make limb salvage the standard surgical option for these tumors.

Check back tomorrow for the next episode in the series.

In this episode, experts shed light on the surgical approach to soft tissue sarcomas.

Experts discuss the potential of radiation therapy to enhance immune response in soft tissue sarcomas.

Moving the Needle in Undifferentiated Pleomorphic Sarcoma: Radiation Oncology and Immune Stimulation

OncChats: Moving the Needle in Undifferentiated Pleomorphic Sarcoma

, the following experts discuss the potential of radiation therapy to enhance immune response in soft tissue sarcomas, exploring how dose fractionation and emerging techniques like spatially fractionated radiotherapy (SFRT) may optimize immunostimulation in combination with immunotherapy:

, an orthopaedic surgeon with Keck Medicine of USC and chief of the USC Musculoskeletal Oncology Center 

, an orthopaedic surgeon with Keck Medicine of USC 

, a medical oncologist with the USC Norris Comprehensive Cancer Center, part of Keck Medicine of USC 

I want to move on to some of the radiation oncology issues. Dr Lim, radiation therapy has traditionally been used for the treatment of soft tissue sarcomas, but now, with the addition of immunotherapy, what are the potential mechanisms for radiation therapy–induced immune stimulation for these patients?

It’s really important to know that we’re still unraveling the intricacies of this interaction, and what we’ve seen is that radiation can play both an immunostimulant effect as well as [an] immunosuppressant [effect]. The balance between these 2 states depends on a lot of variables. Focusing on the immunostimulatory side, we can really identify a few key mechanisms. First off, we have immunogenic cell death, so when radiation goes in and kills a cancer cell, it can release danger signals like tumor-associated antigens, thereby alerting the immune system to the presence of dying cells. Then, secondly, radiation has been shown to alter the tumor microenvironment, really increasing the expression of MHC class I [molecules], as well as death receptors on the tumor cells. So there are just a couple of mechanisms that are currently being investigated as being the underlying mechanism of radiation stimulation of the immune system.

 Does the radiation dose fractionation influence the cooperative activity of radiation with immune checkpoint blockade?

You’re absolutely right. Dose fractionation can play a significant role in determining whether radiation is immunostimulant or immunosuppressive. Standard fractionation, which has been the standard of care for sarcomas for decades and used in Stand Up to Cancer SARC 032, can independently kill the cancer cell. But interestingly, what we’re finding is that standard fractionation may actually have an immunosuppressive effect overall, decreasing tumor CD8 T cells and increasing CD4 T regulatory cells. So, we know that 50 Gy in 20 fractions kills the cancer cells, but now some early preclinical studies have [suggested] that it has a more immunosuppressant effect.

So traditionally, for soft tissue sarcomas, we’ve used 50 Gy in 25 fractions. Because this study was conducted during COVID-19, there were a few patients who received hypofractionation of their radiation with their immunotherapy. Could this possibly improve the outcomes using hypofractionation?

 Absolutely. In some studies, we’ve showed that both hypofractionation, so very high doses per session as well as very low doses of radiation, may be the future if our goal is immunostimulation. So interestingly, very low doses of radiation have been associated with increasing antitumoral immunity. Here, at the University of Southern California, we’re actually the lead investigators of a radiation technique called SFRT, which is spatially fractionated radiotherapy, and this may be the future of immunostimulation. SFRT has the ability to deliver high doses in some areas of the tumor, therefore, killing the cancer cell and releasing these tumor-associated antigens, as well as other areas of the tumor may receive low doses, activating the immune system.

In this episode, experts discuss the potential of radiation therapy to enhance immune response in soft tissue sarcomas.

In this episode, experts discuss the rationale behind the combined treatment in the Stand Up to Cancer SARC 032 trial done in patients with undifferentiated pleomorphic sarcoma.

Moving the Needle in Undifferentiated Pleomorphic Sarcoma: Trial Design and Key Data

, the following experts discuss the rationale behind the Stand Up to Cancer SARC 032 trial (NCT03092323), which examines combining pembrolizumab (Keytruda) with surgery and radiation to prevent metastatic disease in patients with high-risk stage III undifferentiated pleomorphic sarcoma (UPS) and improve survival outcomes without significantly increasing adverse effects (AEs):

What is the rationale behind the combined treatment [examined in the] Stand Up to Cancer SARC 032 [trial]?

I think there are some absolutes that we are all confident [about] and we all know. Some of them are that for stage III soft tissue sarcomas, it is standard to treat these patients, especially in the extremities and the limb girdles, with surgery and radiation. We know that when we counsel our patients—[those] who are at very high risk for metastatic disease in the future—we have to quote numbers. I think as the tumors get larger in size, and as the grade of the tumor increases, we know that the risk could be over 50%, and that’s historically what we talked to them about.

I think Dr Hu and I would easily say that the majority of our career is spent treating patients with metastatic disease and doing clinical trials for these patients. What we’re trying to do for most of those [cases] is offset the survival curves and try to improve upon the survival of those with metastatic disease. What’s groundbreaking about a trial like this is that we’re not trying to offset a situation that already exists. What we’re trying to do is prevent a situation. So, here is a time when we’re looking at patients who are at high risk for metastatic disease, and what we’re trying to do is see whether we could decrease the risk of the metastatic disease forming and improve outcomes that way as opposed to treating disease that already develops.

When we’re looking at these situations, what we need to figure out is, what are new therapies that will help prevent disease formation vs what are new therapies that will help treat metastatic disease? When we go back and look at some of the work that we’ve done previously, specifically looking at SARC 028 [NCT02301039,] which was a study using immunotherapy [in the form of] pembrolizumab [Keytruda] in patients with a wide variety of soft tissue sarcomas who had metastatic disease, we saw that for patients with undifferentiated pleomorphic sarcoma, they had a response rate that was close to about one-quarter of all patients; I think it was about 23%. When we look at the dedifferentiated liposarcoma and pleomorphic sarcoma, we did see a response rate that was about 1 in 10 patients. So, when we look at those 2 cohorts of patients, it becomes very interesting to see whether we could offset the risk of metastatic disease and improve survival and incorporate pembrolizumab in the neoadjuvant therapy as well as the adjuvant therapy of now patients with stage III disease instead of stage IV disease.

Dr Agulnik, can you go over the AEs of the study?

Yes, definitely. I think what happens is, that anytime you’re going to introduce something new, you really want to see what impact it has on new symptomatology as well as what impact it has on the treatments that you’re already offering. Does the addition of pembrolizumab cause increased AEs related to the therapies [patients are] already getting? That would be related to radiation or surgery. If we look at [effects] like wound infection and wound dehiscence, it looks very similar when you look at the grade 1, 2, and 3 toxicities associated with the control arm that received radiation and surgery alone vs the group that got the experimental treatment, which was the pembrolizumab, surgery, and radiation. That’s the first thing that you have to check off and say when you counsel patients, that it’s very encouraging that the treatments did not increase AEs related to other therapies, and therefore, from that perspective, it is felt to be safe.

Then, we start to [question,] what are the AEs of pembrolizumab in this [specific] group? That should be no different than the AEs of pembrolizumab in the general population. What we did see was an increased amount of grade 3 anemia, increased grade 3 colitis, increased grade 3 hypothyroidism, and increased grade 3 dyspnea; those were all felt to be AEs related to pembrolizumab. They’re not uncommon AEs. There was nothing new that was discovered with this. For drugs that are currently FDA approved, you always want to make sure that you’re not unmasking something that has not previously been reported and there’s nothing in this study that would indicate that. Most of the AEs are grade 1 and grade 2. So those would be [effects] that would be relatively easy to treat, relatively easy to manage, and ones that should not affect patients’ abilities to perform their activities [associated with] daily living. There were very few grade 3 AEs, which is encouraging, and very few, if any, grade 4 toxicities that are likely unrelated to the treatments that were being given.

And so, as a whole, the AE profile is very safe for patients. The counseling that has to happen for patients—and Dr Hu and I do this all the time—is [focused on] the AEs of immunotherapy. Treatment with pembrolizumab is similar to other immunotherapies we give, and we really know how to manage and control the AEs and watch patients carefully over time to make sure that we catch things quickly so that we could offset AEs getting worse.

In this episode, experts discuss the rationale behind the combined treatment in the Stand Up to Cancer SARC 032 trial.

Experts experts discuss the latest advancements in the multimodal treatment of undifferentiated pleomorphic sarcoma of the extremities, including the role of immunotherapy, radiation, and surgery in improving patient outcomes.

Moving the Needle in Undifferentiated Pleomorphic Sarcoma: Overview of Paradigm

, experts discuss the latest advancements in the multimodal treatment of undifferentiated pleomorphic sarcoma (UPS) of the extremities, including the role of immunotherapy, radiation, and surgery in improving patient outcomes.

 OncChats, brought to you by the University of Southern California [USC] Sarcoma Program at the Keck School of Medicine and Norris Cancer Center. We’re thrilled to have you join us as we dive into the latest updates in the multispecialty treatment of undifferentiated pleomorphic sarcoma of the extremities. 

In this [series], we’ll be exploring cutting-edge insights, innovative treatment strategies, and the collaborative approach that’s shaping the future of care for this complex and rare condition. Whether you’re a healthcare professional or simply interested in learning more, we hope you find this discussion informative and impactful.

My name is J. Dominic Femino, MD, and I will serve as your moderator today. I am an associate professor of clinical orthopedic surgery at the Keck School of Medicine of USC and the chief of the USC Musculoskeletal Oncology Center. Our expert panelists for today’s discussion are sarcoma specialists from medical oncology, radiation oncology, and orthopedic surgery—all of the USC Sarcoma Program. I will ask them to please introduce themselves.

Yes, thank you, and thanks for having me. I am a professor of clinical medicine in the Department of Medicine at Keck Medicine of USC, and I am a sarcoma specialist.

I’m Dr Lee Zuckerman. I’m an associate professor of orthopedic surgery, specializing in orthopedic oncology with a focus on sarcoma with limb salvage.

Hi, nice to meet you. Thanks for having me. I’m an assistant professor of radiation oncology and a sarcoma specialist.

Thank you. I’d like to give you an overview of our topic today. Undifferentiated pleomorphic sarcoma, or UPS, is a type of high-grade malignant soft tissue tumor that’s characterized by significant cellular pleomorphism and the absence of a specific line of differentiation. Historically known as malignant fibrous histiocytoma, it is now classified as undifferentiated pleomorphic sarcoma. UPS typically presents as a rapidly growing mass, often located in the extremities or retroperitoneum. It is known for its aggressive behavior with a high propensity for local recurrence and distant metastases. The diagnosis of UPS is one of exclusion, made after ruling out other specific types of sarcomas through histologic assessment, immunohistochemistry, and molecular genetic studies.

Recently, immunotherapy, radiation therapy, and surgery are emerging as a growing and promising combination for the treatment of UPS of the extremities. Pembrolizumab [Keytruda], an anti–PD-1 immune checkpoint inhibitor, has shown efficacy in various malignancies, including soft tissue sarcomas. The Stand Up to Cancer Sarcoma Alliance for Research through Collaboration [SARC] 032 trial demonstrated that the addition of pembrolizumab to preoperative radiotherapy and surgery significantly improved disease-free survival in patients with stage III UPS of the extremities compared with radiation and surgery alone.

The multimodal approach addresses both local and systemic disease control, offering a comprehensive treatment strategy for stage III UPS of the extremities. The combination of pembrolizumab, radiotherapy, and surgery represents a significant advancement in the management of this aggressive sarcoma subtype.

In this episode, experts discuss the latest advancements in the multimodal treatment of undifferentiated pleomorphic sarcoma of the extremities.

J. Dominic Femino, MD

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