Need for Systemic Therapy Remains in Sarcoma

Lisa B. Ercolano, MD

Molecular profiling has paved the way in the sarcoma treatment space by identifying the specific mutations that drive sarcoma growth. With the development of targeted therapies that can attack these mutations, promising results have been seen for patients with sarcoma.

However, while developments have been encouraging, the need for more effective systemic therapies and increased awareness of sarcoma among healthcare providers remains.

“Sarcoma can be a very aggressive disease in general. We definitely want and need to do better in treating our patients and have better systemic therapies available. I think there's been a lot of advances in imaging, in diagnosis, in surgical techniques, and reconstructive techniques, but systemic therapy is what we need better options for,” Lisa B. Ercolano, MD, told Targeted Oncology^TM, in an interview.

In the interview, Ercolano, orthopedic oncologist and chief of musculoskeletal oncology at Allegheny Health Network, discussed the evolving treatment landscape for sarcomas, underscoring the pivotal role of molecular profiling, while addressing the need for more efficacious systemic therapies.

Targeted Oncology: What are some of the advances in determining molecular drivers of the tumor?

Ercolano: We definitely have learned a lot in terms of being able to sequence these tumors and get down to the molecular level. I'd say that that's been most helpful in diagnosis thus far. There's a number of types of bone sarcomas—there's actually hundreds of types of soft tissue sarcomas, and that number keeps getting [bigger and bigger] as we continue to subdivide some of these out. That's where a lot of the molecular work has helped us. Whereas once there used to be an entity called malignant fibrous histiocytoma, that name doesn't even exist anymore for soft tissue sarcomas. Because now we know that that thing is actually many different things that we've been able to parse out. We've been able to do that with an understanding of the molecular differences between these different tumor types. Obviously, the goal is that that can turn into targeted treatments for each of these. That's definitely in the works, that's occurred, we have drugs that target these specific mutations that come about.

Unfortunately, unlike some other types of cancers, we've not really hit the jackpot yet, in terms of finding drugs that drastically improve outcomes. There are some that we think help with prolonging what we call disease-free survival and things like that, but we haven't had any total breakthroughs yet. That speaks to the fact that we need more research and more money to do research, more clinical trials, more resources, in sarcoma, which is hard because it's a rare disease. It kind of gets lumped into the orphan diseases, and doesn't get as much notice or funding as other types of cancers.

Cancer cells, malignant cells, generative ai illustration: © Dr_microbe - stock.adobe.com

What developments have there been with targeted therapies?

There have been a number of drugs, even ones that are used in other cancers that you have probably heard of, like [pembrolizumab] or trabectedin, some of these multiple tyrosine kinase inhibitors, and then immunotherapy drugs. There are a number of them that have been developed and when we identify that they target a mutation in a patient's tumor, we have those as options. The problem again is that we are not seeing years and years of improved survival. We are seeing maybe like months, which as you know, we want more and we want better outcomes than that, obviously. So we are improving, but we are lagging.

What is the standard of care for patients with sarcoma, and how do you think this might evolve over years coming?

Generally speaking, the standard-of-care is variable and it depends on which type of sarcoma and which grade and stage of sarcoma. The details are going to vary depending on where they are on that spectrum, from sort of a lower-risk to a higher-risk disease. But in general, it always starts with diagnosis, so we obtain a diagnosis and then implement a treatment plan. For a soft tissue sarcoma, it’s going to be radiation and surgery. The details of that vary depending on the individual situation. Sometimes chemotherapy is used though, as I had said before, unfortunately, we don't have great systemic therapy for soft tissue sarcomas.

Once we get a patient through their treatment, and hopefully they've recovered well, and their cancer is under good control, we move into a surveillance phase. That's where we monitor patients at regular intervals for typically 10 years or more. Again, those intervals can vary a little bit depending on what the specifics of their disease was.

For bone sarcomas, much of this is the same, with the exception of, for at least some of the more common bone sarcomas, chemotherapy [which] is actually beneficial. Those patients will get chemotherapy and surgery, and then sometimes radiation, but less so than the soft tissue side of things. There's a lot of exceptions. It boils down to the details, but that's kind of the sort of general standard-of-care.

I think the most important thing is for education to get out there and that because of the rarity of this disease, and it's been proven, this isn't just our opinion as orthopedic oncologists, that anyone with a suspicion of a sarcoma needs to be sent to a sarcoma center. Those patients do better. No question. It's not because of anyone's inabilities or being a bad physician. It's simply the care in multidisciplinary care and the nuance of the decision needs to be done by people who do it every day.

What are some of the future directions that you anticipate for diagnosis and treatment of patients with sarcoma?

I hope we're going to get to the point where the molecular profiling of these tumors and the drugs that we can use to target them is going to improve. We're on sort of the precipice. We've kind of got some of those initial drugs and initial steps, we just haven't figured it out yet completely. While we've got some of the science figured out, we haven't affected outcomes nearly as much as we want. Sarcoma can be a very aggressive disease in general. We definitely want and need to do better in treating our patients and have better systemic therapies available. I think there's been a lot of advances in imaging, in diagnosis, in surgical techniques, and reconstructive techniques, but systemic therapy is what we need better options for. I think it's coming, we just gotta keep pushing the foot on the gas pedal for that.

What is the role of personalized treatment in the treatment of sarcomas?

Each of these [subtypes] are so different. We have tumors that have 1 name and if you take 10 patients with the same diagnosis, the disease can behave quite differently. [While] that's the case probably for all cancers, we see that a lot in sarcoma. If we can continue to learn more about them on an individual basis, we can learn if a sarcoma is going to have a higher chance of metastasizing. That would massively change our abilities to tailor care to that patient in the most effective way. I'd like to say it's around the corner, but I don't know. I think there's potential for that. Again, for rare diseases, it does make you realize those things. The way of the future is not cookie cutter. It's going to be tailored to the individual.

What advances are you excited to see moving forward?

As a surgeon, the technology that's now available to us is really exciting. The use of 3D printing, and custom implants.Iin the past, if you needed some sort of custom item to reconstruct a bone after taking out their cancer, they took months and they weren't great quality. In a fairly short period of time, science and technology has evolved. We see it in all spheres of life and we see how much all of this is advancing. I mean, what's going to happen even with AI is both scary and exciting.

The technology that we now have available to help do surgeries that are first and foremost, oncologically appropriate, meaning cutting out the tumor properly with the least risk of having it return, but also maintaining people's function or optimizing their function. Unfortunately for us, when we take one of these sarcomas out, we're often causing dysfunction. We're taking out important muscles or bones or ligaments but now, I think we're able to do that, and have those patients still be more functional because of technology, because we're able to be more precise, and because what we're able to reconstruct smarter.

What unmet needs still exist in the space?

The most glaring is the lack of systemic therapies. What I mean by that is, if a patient presents with a sarcoma, and it's just localized, we do a good job of taking care of that. We know what to do with that and we're successful. Where we lose effect is when these start to metastasize. We don't have good therapy that treats a patient who has had spread of their cancer. That's the glaring need. We need better systemic therapies for those patients. Again, because I'm the surgeon, I'm always going to focus on that. I think we've made huge strides in our surgical abilities, but that's no reason to stop getting better at the techniques that we have. The varied amounts ranging from implants that we can use to how we can take care of infections that are a common complication and how we can maximize function all needs to come about, but I think, overall, we need funding, we need support to get better at systemic therapy for sarcoma.

Can you discuss some of the ongoing research in sarcoma being done at AHN?

We have a beautiful genomics lab here at AHN, and it's remarkable what they have been able to do in terms of what we're looking at specifically as we're trying to match the tumor sample to cell-free DNA in patients’ blood and serum. What [they have] been able to show is that there's very high concordance between those mutations that are identified in the tumor in the patient's blood. [It is a] much higher concordance than what has been shown before in the literature. The implication of that is that maybe in the future, we can use a blood draw as a way to help diagnose, monitor treatment, and survey for recurrences.

That would be perhaps beneficial in 2 spheres.: Number 1, it would be much easier for the patient. So nowadays, when we see a patient and follow-up, we have multiple scans to get, and there's lots of different follow-ups that they have to do. Maybe we could get all the information we need with a simple blood draw. Secondly, it may be a lot more sensitive. We may know good information through a blood draw way earlier than it would show up on a scan, so it could help both ontologically and just the patient's comfort and day to day life, it could make it easier for them. That's a big project that we have going on that I think could be really fruitful and interesting.

Then we have a number of other projects that are looking at metastatic disease. I know that's not sarcoma, but in my field, we take care of a lot of metastatic disease, which is important largely because patients are living longer with cancer. That's great, but it means that we have to up our abilities to take care of the chronic disease element, which can sometimes present in the skeleton. We're also looking at some projects with our radiation oncologists with different ways to deliver radiation and use MRI as a way to monitor and watch the tumor change during treatment and adjust the treatment to that. We're working on some projects with our radiologists so that we can better define follow-ups for patients. We're doing it enough to be safe, but not too much to cause excess anxiety, which is a real concern sometimes.

I'm also looking at just some patient satisfaction-type projects, because nowadays everything is at your fingertips on your phone, and it is my means of accessing a medical chart. Sometimes I think when you get results on your phone before you have a chance to speak with your doctor, it can cause some more harm. It can cause anxiety, because you don't have someone to review what those results mean. We're trying to figure out just with some patient surveys, what's that experience been for them, what's beneficial, and what's not.