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Chemotherapy Sensitivity in Soft Tissue Sarcoma

Panelists:William D. Tap, MD, Memorial Sloan Kettering Cancer Center; Mark Agulnik, MD, Feinberg School of Medicine;George D. Demetri, MD, Dana-Farber Cancer Center;Martee L. Hensley, MD, Memorial Sloan Kettering Cancer Center; Shreyaskumar Patel, MD, The University of Texas MD Anderson Cancer Center;Damon Reed, MD, Moffitt Cancer Center
Published Online: Tuesday, Aug 23, 2016



Transcript:

William D. Tap, MD:
One of the things I want to get back to is this comment that sarcoma is a chemotherapy-insensitive disease. I’m sure we can talk about, and we will, some diseases that are chemotherapy-insensitive. But what’s your thought on that, that myth or that statement?

Mark Agulnik, MD: I think the patients are all told it.

Damon Reed, MD: Heterogeneity comes up again though, right? Sometimes it is, sometimes it’s not.

Martee L. Hensley, MD: In uterine leiomyosarcoma, there are objective response rates. For first-line therapy, the objective response rates to doxorubicin-based treatment or gemcitabine/docetaxel is probably really about one-third of patients with clinical trial–defined partial responses. Some are with complete responses; some are with really prolonged duration. And then even in the second-line, we will see responses because there’s not a lot of cross-reactivity. And those kind of numbers are really quite similar to the objective response rates you see in other solid tumors, but superior to some. So, I think cytotoxics can work in certain histologies.

Mark Agulnik, MD: I also think we speak two languages. So, we discuss response and we’re discussing medical response. If you told the patient their tumor shrunk by 19%, you’d say by medical terms, you didn’t respond. Every patient is going to say this is a response. And so, I think when we quote numbers, we’re really using this RECIST criteria, which is meaningless to patients. But, certainly, we’ve all seen patients that have had very good outcomes from these drugs, and we’ve seen patients that haven’t. But, certainly, there’s a role to use them.

Shreyaskumar Patel, MD: Part of the misconception, I guess, in terms of patients coming in either reading the Internet or being told locally that this is a chemotherapy-insensitive disease, gets back to the sample size. If someone has just treated two patients with what we may feel is suboptimal therapy and the patients didn’t respond, yet had the toxicity, it’s only human that they carry the impression, “Oh yeah, in my experience, it doesn’t work at all.” And I think that perpetuates. So, I think these are the things that we tend to correct and say, “Well, there are responses that happen in 1 out of 3 patients or 3 out of 10 patients,” or whatever. We can get it to the reality with numbers, if you will, that no, we’re not necessarily being overtly optimistic that 100% of patients are going to respond. But there is a fraction that will respond. And the question is, are you willing to give it a try? And we are.

William D. Tap, MD: Yes. And building off these points, that stability is often a victory with these diseases. So, if you don’t see these tumors shrink away, if you can really shut them down, put them into a period of quiescence, that can really be a positive outcome for some of our patients.

George D. Demetri, MD: I also think it’s the difference between dealing with a typically younger patient population. Not even necessarily adolescents and young adults, but our median age of metastatic patients in our clinic is probably in the late 50s, early 60s. In many of our carcinoma clinics, it’s upwards of 70 years. And those 20 years make a difference in terms of what patients’ preferences are, what patients are able physiologically to put up with, and frankly what they want to put up with. Because they have a lot more to live for. So, controlling disease is a positive benefit to a lot of our middle-aged and younger patients. We appreciate that.

William D. Tap, MD: Yes, I agree.

Damon Reed, MD: Another source that says chemotherapy doesn’t work… It might be a quick conversation about a stage III patient, maybe a 6-cm high-grade tumor. And they’re talking to the surgeon and the surgeon says, “Let’s do surgery appropriately.” And maybe we would—maybe we wouldn’t, depending on some additional factors—recommend chemotherapy. But, when they hear that, “Oh, we didn’t do chemotherapy at that point,” but then the recurrence comes back, they carry with them that chemotherapy doesn’t work. And so, when we made our pathway for how we deal with things, if someone is a stage III patient with high-grade, greater than 5-cm soft tissue sarcoma, even localized, we ask that they be referred to the medical oncologist to have a discussion of systemic therapy that they might need for neoadjuvant or just to hear another perspective, or for down the road.

William D. Tap, MD: I love that you use the word systemic, too, because we always talk about chemotherapy-insensitive. But it’s why it’s so important to get the correct diagnoses, even if we’re stratifying into a different sarcoma subtype. Because not only do we have chemotherapy, we have a plethora of targeted therapies and other therapies that we can offer patients. So, there are very few patients, if any patients, where you come in and would ever say, “I don’t have something for you.” We definitely know of certain subtypes that are very chemotherapy-sensitive—synovial sarcoma, the round cell component, and myxoid round cell. Are there ones that you think about as chemotherapy-insensitive? Are there ones where you’d say, “I want to look directly into a clinical trial or targeted therapy?”

Shreyaskumar Patel, MD: Clearly, there are histologies where we would not recommend any of the drugs that we would talk about as part of the standard of care: alveolar soft part sarcoma, clear-cell sarcoma, GIST—when it used to be called GI leiomyosarcoma. These are the absolute examples. And then there are gradations. There are other histologies, like an extraskeletal myxoid chondrosarcoma or epithelioid sarcoma, that are very marginally sensitive. And there better be a very good reason for us to recommend systemic therapy incorporated into a patient’s treatment plan where local therapy is a real option. And then there are the sensitive ones like you said. There are the small cell ones that we share with the pediatric oncology colleagues and the myxoid liposarcomas, angiosarcomas, and synovial sarcomas, where the threshold for us to recommend systemic therapy would be much higher because we can make an impact. We can downstage the tumor and that may well open up other options for the patient.

George D. Demetri, MD: And the wisdom of what Shreyas just said is really important. And whenever we have our CME events and people go to our meetings, that’s around the time where you start to see people’s eyes glaze over and they go, “I’m never going to remember this. And in the next patient to see, how do we get that information across?” And I think the simple thing is because that was a bunch of polysyllabic peculiar pathology diagnoses, and I appreciate that.

William D. Tap, MD: Just like that tongue twister.

George D. Demetri, MD: Exactly. And that’s why I think it’s this collaboration between the academic centers and our field, even more than in standard practice, that we have to support the people in the community. And hopefully we can make ourselves open, that we are there to support their practice, and support the best patient care.

Mark Agulnik, MD: And I do think for patients with these rare diagnoses, they don’t necessarily need a clinical trial. Are they ideal for a clinical trial? Sure. Is every single person able to travel or do a clinical trial? Absolutely not. Is there a clinical trial locally that they’re able to hop onto? Probably not. And so, I do think it is our responsibility, as well, to look at the best data that we have. And often, whether it’s one or two patients that were treated on a phase I and there’s a signal of activity—and we’re excited about it—or whether or not there’s a very small phase II, I think it is our responsibility to get that information back to the local oncologists. Because there are drugs that are on the market that you can use off-label for several of these tumors that may or may not have an effect, but certainly may have a better toxicity profile. And patients need something. And if they can’t get a clinical trial, then it is our responsibility to provide that for them, as well.

Martee L. Hensley, MD: Maybe an example of that would be malignant PEComa (perivascular epithelioid cell tumor). It is weird and rare, but we have a rational treatment even though it wasn’t rationally designed for it. But it’s a fit for the disease, and it’s in the NCCN guidelines. You wouldn’t have to get your treatment in a major academic medical center, and yet, you could still get the right treatment for the disease.

William D. Tap, MD: I think this is a great segue, because what we’re really saying is you really have to understand the disease you’re facing. You have to really think about the goals of the treatment. You really have to think, is this a localized disease or a metastatic disease? And you have to think about using local control even with patients with metastatic disease. And then there are all these kind of caveats, and these rare aspects of rare diseases.

Transcript Edited for Clarity

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Transcript:

William D. Tap, MD:
One of the things I want to get back to is this comment that sarcoma is a chemotherapy-insensitive disease. I’m sure we can talk about, and we will, some diseases that are chemotherapy-insensitive. But what’s your thought on that, that myth or that statement?

Mark Agulnik, MD: I think the patients are all told it.

Damon Reed, MD: Heterogeneity comes up again though, right? Sometimes it is, sometimes it’s not.

Martee L. Hensley, MD: In uterine leiomyosarcoma, there are objective response rates. For first-line therapy, the objective response rates to doxorubicin-based treatment or gemcitabine/docetaxel is probably really about one-third of patients with clinical trial–defined partial responses. Some are with complete responses; some are with really prolonged duration. And then even in the second-line, we will see responses because there’s not a lot of cross-reactivity. And those kind of numbers are really quite similar to the objective response rates you see in other solid tumors, but superior to some. So, I think cytotoxics can work in certain histologies.

Mark Agulnik, MD: I also think we speak two languages. So, we discuss response and we’re discussing medical response. If you told the patient their tumor shrunk by 19%, you’d say by medical terms, you didn’t respond. Every patient is going to say this is a response. And so, I think when we quote numbers, we’re really using this RECIST criteria, which is meaningless to patients. But, certainly, we’ve all seen patients that have had very good outcomes from these drugs, and we’ve seen patients that haven’t. But, certainly, there’s a role to use them.

Shreyaskumar Patel, MD: Part of the misconception, I guess, in terms of patients coming in either reading the Internet or being told locally that this is a chemotherapy-insensitive disease, gets back to the sample size. If someone has just treated two patients with what we may feel is suboptimal therapy and the patients didn’t respond, yet had the toxicity, it’s only human that they carry the impression, “Oh yeah, in my experience, it doesn’t work at all.” And I think that perpetuates. So, I think these are the things that we tend to correct and say, “Well, there are responses that happen in 1 out of 3 patients or 3 out of 10 patients,” or whatever. We can get it to the reality with numbers, if you will, that no, we’re not necessarily being overtly optimistic that 100% of patients are going to respond. But there is a fraction that will respond. And the question is, are you willing to give it a try? And we are.

William D. Tap, MD: Yes. And building off these points, that stability is often a victory with these diseases. So, if you don’t see these tumors shrink away, if you can really shut them down, put them into a period of quiescence, that can really be a positive outcome for some of our patients.

George D. Demetri, MD: I also think it’s the difference between dealing with a typically younger patient population. Not even necessarily adolescents and young adults, but our median age of metastatic patients in our clinic is probably in the late 50s, early 60s. In many of our carcinoma clinics, it’s upwards of 70 years. And those 20 years make a difference in terms of what patients’ preferences are, what patients are able physiologically to put up with, and frankly what they want to put up with. Because they have a lot more to live for. So, controlling disease is a positive benefit to a lot of our middle-aged and younger patients. We appreciate that.

William D. Tap, MD: Yes, I agree.

Damon Reed, MD: Another source that says chemotherapy doesn’t work… It might be a quick conversation about a stage III patient, maybe a 6-cm high-grade tumor. And they’re talking to the surgeon and the surgeon says, “Let’s do surgery appropriately.” And maybe we would—maybe we wouldn’t, depending on some additional factors—recommend chemotherapy. But, when they hear that, “Oh, we didn’t do chemotherapy at that point,” but then the recurrence comes back, they carry with them that chemotherapy doesn’t work. And so, when we made our pathway for how we deal with things, if someone is a stage III patient with high-grade, greater than 5-cm soft tissue sarcoma, even localized, we ask that they be referred to the medical oncologist to have a discussion of systemic therapy that they might need for neoadjuvant or just to hear another perspective, or for down the road.

William D. Tap, MD: I love that you use the word systemic, too, because we always talk about chemotherapy-insensitive. But it’s why it’s so important to get the correct diagnoses, even if we’re stratifying into a different sarcoma subtype. Because not only do we have chemotherapy, we have a plethora of targeted therapies and other therapies that we can offer patients. So, there are very few patients, if any patients, where you come in and would ever say, “I don’t have something for you.” We definitely know of certain subtypes that are very chemotherapy-sensitive—synovial sarcoma, the round cell component, and myxoid round cell. Are there ones that you think about as chemotherapy-insensitive? Are there ones where you’d say, “I want to look directly into a clinical trial or targeted therapy?”

Shreyaskumar Patel, MD: Clearly, there are histologies where we would not recommend any of the drugs that we would talk about as part of the standard of care: alveolar soft part sarcoma, clear-cell sarcoma, GIST—when it used to be called GI leiomyosarcoma. These are the absolute examples. And then there are gradations. There are other histologies, like an extraskeletal myxoid chondrosarcoma or epithelioid sarcoma, that are very marginally sensitive. And there better be a very good reason for us to recommend systemic therapy incorporated into a patient’s treatment plan where local therapy is a real option. And then there are the sensitive ones like you said. There are the small cell ones that we share with the pediatric oncology colleagues and the myxoid liposarcomas, angiosarcomas, and synovial sarcomas, where the threshold for us to recommend systemic therapy would be much higher because we can make an impact. We can downstage the tumor and that may well open up other options for the patient.

George D. Demetri, MD: And the wisdom of what Shreyas just said is really important. And whenever we have our CME events and people go to our meetings, that’s around the time where you start to see people’s eyes glaze over and they go, “I’m never going to remember this. And in the next patient to see, how do we get that information across?” And I think the simple thing is because that was a bunch of polysyllabic peculiar pathology diagnoses, and I appreciate that.

William D. Tap, MD: Just like that tongue twister.

George D. Demetri, MD: Exactly. And that’s why I think it’s this collaboration between the academic centers and our field, even more than in standard practice, that we have to support the people in the community. And hopefully we can make ourselves open, that we are there to support their practice, and support the best patient care.

Mark Agulnik, MD: And I do think for patients with these rare diagnoses, they don’t necessarily need a clinical trial. Are they ideal for a clinical trial? Sure. Is every single person able to travel or do a clinical trial? Absolutely not. Is there a clinical trial locally that they’re able to hop onto? Probably not. And so, I do think it is our responsibility, as well, to look at the best data that we have. And often, whether it’s one or two patients that were treated on a phase I and there’s a signal of activity—and we’re excited about it—or whether or not there’s a very small phase II, I think it is our responsibility to get that information back to the local oncologists. Because there are drugs that are on the market that you can use off-label for several of these tumors that may or may not have an effect, but certainly may have a better toxicity profile. And patients need something. And if they can’t get a clinical trial, then it is our responsibility to provide that for them, as well.

Martee L. Hensley, MD: Maybe an example of that would be malignant PEComa (perivascular epithelioid cell tumor). It is weird and rare, but we have a rational treatment even though it wasn’t rationally designed for it. But it’s a fit for the disease, and it’s in the NCCN guidelines. You wouldn’t have to get your treatment in a major academic medical center, and yet, you could still get the right treatment for the disease.

William D. Tap, MD: I think this is a great segue, because what we’re really saying is you really have to understand the disease you’re facing. You have to really think about the goals of the treatment. You really have to think, is this a localized disease or a metastatic disease? And you have to think about using local control even with patients with metastatic disease. And then there are all these kind of caveats, and these rare aspects of rare diseases.

Transcript Edited for Clarity
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