Soft Tissue Sarcoma: Decisions Following Progression

Insights From: Victor Villalobos, MD, PhD, University of Colorado School of Medicine; Saketh Guntupalli, MD, University of Colorado School of Medicine; Shreyaskumar R. Patel, MD, University of Texas MD Anderson Cancer Center; Anthony P. Conley, MD, University of Texas MD Anderson Cancer Center


Victor Villalobos, MD, PhD: Dr. Guntupalli, a patient comes in to see you after first-line therapy. Their disease has progressed. What is your approach?

Saketh Guntupalli, MD: The first thing I talk to the patient about is where their disease process stands. Once the sarcoma has come back, particularly, if it’s come back aggressively, cure rates are incredibly low. We talk about progression-free survival. We talk about quality of life. We look at the patient’s performance status. We get excellent imaging. Those things are incredibly important, globally, in the treatment of sarcomas.

After that, if the patient is healthy and is doing well otherwise, we talk a little bit about where we can go from here. The first question I ask myself is, what has this patient gotten? And even before that, we ask them if they are surgically resectable. I think that’s incredibly important. If they’re not, or they’re not interested in surgery, we would look at what they’ve gotten first.

If they’ve gotten an Adriamycin-containing regimen, like olaratumab/Adriamycin or AIM (Adriamycin/ifosfamide/mesna), I would consider using trabectedin next. I would use that because this drug is approved for patients that have already received Adriamycin and have recurred. So, I would consider using trabectedin. I have used trabectedin in about 3 patients, and I’ve gotten more comfortable with the 24-hour intravenous pump that the patients take home. And it’s actually quite easy for patients to adapt to that. And so, that’s probably the next line drug that I would consider if they failed an Adriamycin-containing regimen. If they have not received an Adriamycin-containing regimen, and if they’ve gotten gemcitabine/Taxotere, up front, I would probably consider using an Adriamycin-containing regimen, second-line therapy. Olaratumab/Adriamycin is probably what I would go with.

Victor Villalobos, MD, PhD: Interestingly, most of my patients experience asymptomatic progression. They feel great and they’re doing well. Every time someone progresses, it always brings up the discussion about the goals of care and how it would affect that. But often, the vast majority of my patients are doing so well that we keep going with next therapies. We do this partly because response to one therapy does not dictate how well they’re going to respond to another. While my first-line therapy option is typically doxorubicin plus olaratumab or gemcitabine, if there’s an applicable clinical trial, I would do that. My sequencing typically includes trabectedin, probably, in the third-line setting. That is approved for use in leiomyosarcoma as well as liposarcoma. It works particularly well. In fact, I may even consider doing it sooner in a subtype of liposarcoma called myxoid liposarcoma.

Saketh Guntupalli, MD: Interesting.

Victor Villalobos, MD, PhD: Those have a dramatic response rate. The problem with trabectedin, though, is in managing expectations. That applies to a lot of sarcomas. I don’t quit a drug if it’s not responding. If it’s stabilizing, I think it’s effective.

Saketh Guntupalli, MD: Absolutely.

Victor Villalobos, MD, PhD: The response rate for trabectedin is close to about 6%, but there’s this tail on those overall survival curves and progression-free survival curves. It’s almost like immunotherapy.  You have this 15%, 20% of people that can be on it for years. And so, it’s very common for me to see patients who are being treated for more than a year, or year and a half. We have one patient that was on it for 7 years. They tolerated it well. This gentleman was in his 80s.

Saketh Guntupalli, MD: That’s really, really important. I couldn’t agree with you more. I think stable disease is a reasonable endpoint in sarcoma treatment. As you said, if most patients are truly asymptomatic, and they’ve got a 3-cm mass, or 2- or more 3-cm masses in their abdomen, but we can make them not grow and not affect their life, and not make them symptomatic by giving them drugs that stabilize disease processes such as this, I think that’s a win.

Victor Villalobos, MD, PhD: And, I think that has a large part to do with the biology of sarcomas.

Saketh Guntupalli, MD: Exactly, they’re different.

Victor Villalobos, MD, PhD: How often do you see sarcomas that are 25, 40 cm in the belly, but the patient is relatively asymptomatic? If that was an ovarian cancer or a pancreas cancer…

Saketh Guntupalli, MD: We would take it out.

Victor Villalobos, MD, PhD: That would be the case. They’d be incredibly symptomatic, even from a small mass.

Saketh Guntupalli, MD: Right.

Victor Villalobos, MD, PhD: Patients can tolerate these tumors because they don’t tend to invade as much as they tend to kind of push things out of the way.

Saketh Guntupalli, MD: Particularly in the lung, as well. The most common site of metastatic disease in leiomyosarcomas of the uterus is the lung. You can have 3 or 4 masses in the lung, but be walking around, doing your daily chores, and not really be affected by it. As long as we can keep it stable, particularly in an asymptomatic patient, this is a win in sarcomas.

Victor Villalobos, MD, PhD: Going back to trabectedin, I think one of the primary things that we see that can be challenging with the use of that drug is how we give it. At our institution, we have take-home pumps. They’ll go home with a pump. They have to have a port in place, and they will actually get disconnected after a 24-hour infusion. There is a slight risk of causing extravasation. It’s something we need to educate the patients about. They need to let us know if that happens. Interestingly, we have seen, not infrequently, elevation in liver enzymes. Usually, that does not raise as much concern. In my case, it often responds quite well with dose reduction. It can be treated easily, and it usually resolves on its own. But I can see why people that don’t have as much experience with that medication have some concerns about it. In your case, you’ve used it a couple of times. What have your experiences been with trabectedin?

Saketh Guntupalli, MD: Overall, they’ve been pretty good. I personally had some apprehension about sending a patient home with a 24-hour pump. I’m a surgeon, so I’m a control freak. I like to know what’s happening, and I like the idea of a patient getting chemotherapy in an infusion center where people can monitor them. So, that took a little bit of getting used to. But after I had the first patient do it and it seemed to work well, I became much more comfortable with it.

I think it’s important to note, for trabectedin, elevations in LFTs [liver function tests] is also something that we saw. We watch the patient. We make sure they’re not asymptomatic. We’ll get a right upper quadrant ultrasound to make sure things are not getting out of hand. We’ll do things to kind of watch that. We may do some dose reductions, and such. But overall, I think patients have done OK on it. It does cause some fatigue, and there’s some mild myelosuppression with it. So, you’ve got to watch all of those things. I think just doing the things that we would do for any patient on chemotherapy, which is just watching them judiciously and having them communicate with us when they’re having symptoms, is key.

Victor Villalobos, MD, PhD: The point I’d like to make for general practitioners is that this is not a commonly used drug. That’s why it’s so important to talk with one of your local sarcoma experts who uses this drug frequently. I think we’ve treated over 100 patients with trabectedin. We have a lot of experience with it. So, if there are any questions, we’re always happy to discuss the different side effect profiles and what to expect. That way, someone is not stopping therapy just because the LFTs doubled, which can be scary. I think that’s really important.

Saketh Guntupalli, MD: As the sarcoma expert, what do you do in the third-line setting for patients that have recurred after some of the drugs that we had talked about before? What would you offer that patient?

Victor Villalobos, MD, PhD: It largely depends on the pathology, right? That’s why it’s so important to have expert pathologists.

Saketh Guntupalli, MD: Absolutely.

Victor Villalobos, MD, PhD: There are so many different subtypes that can respond so differently to different therapies. Take myxoid liposarcoma. That’s an example where one wouldn’t necessarily use gemcitabine/docetaxel, early on. I would use trabectedin, first off. There are even clinical trials for that. It can block certain pathways that are being activated by the translocation. I think that’s why it’s so incredibly important for a patient to be seen at an academic center, just to see what new options there are. The field is changing dramatically every month, and there are new targets coming along. There’s new research and it’s actively changing. Because there are so many super small tumor types that have very simple mutations or translocations that might be targetable in the field of liposarcoma, dedifferentiated and well differentiated, there’s been a lot of progress made with targeting different aberrations, such as CDK4 [cyclin-dependent kinase 4] amplifications with a drug like palbociclib, a CDK4 inhibitor. There has also been progress in targeting the MDM2 [mouse double minute-2 homolog] amplification with a drug like idasanutlin, which can block the interaction. These are such complicated cases because there’s so much data out there. It’s hard to expect someone that sees 1 or 2 of these a year to know, in depth, what is available and what’s coming.

Saketh Guntupalli, MD: Absolutely.

Victor Villalobos, MD, PhD: That’s why it’s so important to know your local sarcoma expert and develop a relationship with him/her. I can’t tell you how many of my colleagues in the community will just say, “I’ve got a patient. What should we do next?” And I say, “First, we have these trial options. You should think about these. If not, this is what I recommend.” We’re a resource. We have the benefit of seeing hundreds of patients a year. We have all of the up-to-date data and trials available. The same thing happens with you, right? You can’t expect a gynecologist to be doing these large surgeries on these major tumors. I’m sure you work very closely with them?

Saketh Guntupalli, MD: Absolutely. I agree with your points regarding the importance of collaboration with sarcoma experts. Ultimately, we’re all here to help patients.

Transcript Edited for Clarity 
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