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Frontline Approach in Advanced Sarcomas

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: Monday, Aug 29, 2016


Transcript:

William D. Tap, MD:
But, let’s now move into what we can offer oncologists and say, how do we treat patients with advanced aggressive sarcoma? Let’s focus on metastatic disease. Shreyas, what are some of the things that you consider, and what do you use? What is your first-line therapy? And Damon, I’m going to want to get some insight into pediatric malignancies or sarcomas, as well. But, why don’t you start, Shreyas.

Shreyaskumar Patel, MD: Again, succinctly summarizing what we have been talking about for some time now: I think you look at a host of factors—that is, the patient’s age, performance status, organ function. You look at their social logistics and you look at disease-related factors. Is this the patient who is potentially curable or is their disease something that can be resected and rendered free of gross disease? Those are the patients that we historically have favored the doublet of doxorubicin and ifosfamide, recognizing that it is 6 months with a lot of toxicities, but a higher chance of response. There’s clearly a better progression-free survival, and the possibility of other treatment options, like surgery or radiation, becomes an option.

Take the example of someone who has widespread disease with three or four visceral sites of metastases; then it gets down to the nitty-gritty details of how symptomatic are they. If they’re really symptomatic and the disease is causing problems, then you need a response and an aggressive regimen might make sense. But with those disease sites, if their performance status is relatively good, they’re still working and need to continue to work to maintain insurance–this is what Martee was alluding to earlier. You would try to pick the kinder, gentler treatments that allow them to maintain their normal quality of life and disease control, because we want to turn this into a marathon, not a sprint. So, I think simply stated, from my standpoint, I try to figure out whether this needs to be a marathon or a sprint. Is there a hurry up and get to the finish line objective or is this just something we’ll slowly cruise along and be the tortoise and not the hare, if you will?

William D. Tap, MD: And I think with this idea of Adriamycin, Adriamycin/ifosfamide, and gemcitabine/docetaxel, we’ve had a lot of studies that have emerged within the last few years. Similar approaches, different approaches at your centers? What do you do?

Mark Agulnik, MD: I think it’s identical. I really think you take everything into account, and it really does highlight the fact that experience does make a difference. I also think it’s important that you don’t just have one try. And with so many different drugs, whether a single agent, whether combinations, you do have several lines of therapy. The average patient in most of our practices will see several lines of therapy. I don’t really feel strongly that if your first-line didn’t work, your second-line is necessarily not going to work. I know in some carcinomas, we do feel that way, that your first-line is your best option. I don’t feel that way for our patients here, and so I keep saying to patients, “Set expectations,” because I do think it’s very important. We know what the response rates are to these drugs. You need to say, “Will it be stable disease, will it be a response, what do you anticipate?”, so they know what to anticipate when their scans come in and you’re checking for disease response versus progression. But, I do think there are several lines, and we all could have subtle differences in practice patterns. We could use different doses. But, for the most part, I think that most of us are tending to go to the same drugs in similar orders. It really allows for variability and a lot of options for the patients.

William D. Tap, MD: Maybe before we get to Damon, Martee, talk about metastatic leiomyosarcoma.

Martee L. Hensley, MD: I think, particularly for a uterine leiomyosarcoma, because the number of trials of fixed-dose gemcitabine and docetaxel is fairly robust at this point, I often choose that as my first-line regimen. It comes with its own set of toxicities. I will have some patients tell me that it was more difficult than doxorubicin-based therapy, and then I will have others feel the other way. So, you just counsel patients about what to expect in terms of toxicities.

Very much like Shreyas, a patient with a large disease burden, especially if there is impending organ compromise and you can see the ureteral obstruction coming, that’s a patient for whom I think two-drug therapy is very important. Because, though her quality of life may diminish somewhat from the side effects of drugs, that will be offset by her not needing a ureteral stent or having a large bowel obstruction that makes it impossible to give her further treatment, for example. There are some patients for whom single-drug therapy may be more appropriate and that comes into just the experience of seeing a lot of these diseases and figuring out which treatments are the right fit for each individual patient in some ways.

George D. Demetri, MD: I think this is where we all have to all channel our inner pediatric oncologist, too. Because what we wind up doing is appropriately tapping into the ability to support patients through aggressive treatments, if it’s in their best interest. A localized, large Ewing sarcoma growing rapidly in a 65-year-old, or even a 75-year-old, still could be very curable in that patient. And we want to treat that patient as such. For the other patients, we can do what everybody says: use good medical common sense, work with the patient on preferences and try to be realistic about what the drugs can do, and hope for the best.

Because I think the one other thing, sarcomas tend to be disproportionate for these Lazarus effects, where you go through the genome—this was in the Sunday New York Times a couple of weeks ago—and where you just happen to find that one molecular target, like in the PEComas and an mTOR pathway activation or a TRK fusion. You give them the TRK inhibitor and the thing melts away. That’s the kind of world we’re in right now, where we can’t say, “Oh, that’s going to happen in 9 out of 10 sarcoma patients.” But, even if it happens in 1 out of 10, or even 1 out of 100, it’s made such a huge difference. It would be just a tragedy to overlook that. And I think our pediatric colleagues have always focused on small numbers and the importance of helping small numbers.

William D. Tap, MD: So, Damon, how do you approach pediatric sarcomas, and how is it different than what we’re talking about?

Damon Reed, MD: The combination of doxorubicin and ifosfamide has not shown an overall survival benefit over doxorubicin itself, but that’s with wide ranges of ages, wide ranges of aggressiveness, and wide ranges of the degree of metastatic burden in adult patients. And so, what we’ve heard from everybody on the panel now is that there’s something about it that seems to help some patients. When you’re backed into the corner or when it’s really aggressive, or you really need something to work, we grab both agents. In a patient who has five, six decades to live to meet the median survival for a normal person in our population, there’s no reason to just try one drug. It’s definitely standard to give doxorubicin and ifosfamide for the most common soft tissue sarcomas that we see in pediatrics, namely synovial sarcoma.

Malignant peripheral nerve sheath tumor is another one of the common ones. I notice you left it out, because it is a hard one to figure out where it fits on that chemotherapy-sensitive or chemotherapy-resistant spectrum. But, I must say, in my own personal experience, it’s on the chemotherapy-resistant side of that for sure. So, I really struggle to give doxorubicin and ifosfamide. We shared a patient very recently who made the rounds through; maybe everyone on this panel saw her. But, I think we all recommended not to do chemotherapy for a rather aggressive looking localized tumor. That’s the case for the soft tissue sarcomas.

For rhabdomyosarcoma, I think of it like GIST (gastrointestinal stromal tumor). I would put it in its own bucket. We don’t use doxorubicin and ifosfamide, although both are used in select cases along with a lot of other medications. For the traditional patient that will come with localized disease, vincristine/dactinomycin/cyclophosphamide, a regimen that was worked out before I was born, is still the standard of care and stood the test of time. Cyclophosphamide has a particularly nasty long-term side effect of infertility, especially in boys, and premature ovarian failure. And so, irinotecan has been now accepted as the standard of care. So, a four-drug regimen of vincristine/dactinomycin/cyclophosphamide/irinotecan to spare gonadal toxicity is definitely the standard of care for rhabdomyosarcomas.

Transcript Edited for Clarity
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Transcript:

William D. Tap, MD:
But, let’s now move into what we can offer oncologists and say, how do we treat patients with advanced aggressive sarcoma? Let’s focus on metastatic disease. Shreyas, what are some of the things that you consider, and what do you use? What is your first-line therapy? And Damon, I’m going to want to get some insight into pediatric malignancies or sarcomas, as well. But, why don’t you start, Shreyas.

Shreyaskumar Patel, MD: Again, succinctly summarizing what we have been talking about for some time now: I think you look at a host of factors—that is, the patient’s age, performance status, organ function. You look at their social logistics and you look at disease-related factors. Is this the patient who is potentially curable or is their disease something that can be resected and rendered free of gross disease? Those are the patients that we historically have favored the doublet of doxorubicin and ifosfamide, recognizing that it is 6 months with a lot of toxicities, but a higher chance of response. There’s clearly a better progression-free survival, and the possibility of other treatment options, like surgery or radiation, becomes an option.

Take the example of someone who has widespread disease with three or four visceral sites of metastases; then it gets down to the nitty-gritty details of how symptomatic are they. If they’re really symptomatic and the disease is causing problems, then you need a response and an aggressive regimen might make sense. But with those disease sites, if their performance status is relatively good, they’re still working and need to continue to work to maintain insurance–this is what Martee was alluding to earlier. You would try to pick the kinder, gentler treatments that allow them to maintain their normal quality of life and disease control, because we want to turn this into a marathon, not a sprint. So, I think simply stated, from my standpoint, I try to figure out whether this needs to be a marathon or a sprint. Is there a hurry up and get to the finish line objective or is this just something we’ll slowly cruise along and be the tortoise and not the hare, if you will?

William D. Tap, MD: And I think with this idea of Adriamycin, Adriamycin/ifosfamide, and gemcitabine/docetaxel, we’ve had a lot of studies that have emerged within the last few years. Similar approaches, different approaches at your centers? What do you do?

Mark Agulnik, MD: I think it’s identical. I really think you take everything into account, and it really does highlight the fact that experience does make a difference. I also think it’s important that you don’t just have one try. And with so many different drugs, whether a single agent, whether combinations, you do have several lines of therapy. The average patient in most of our practices will see several lines of therapy. I don’t really feel strongly that if your first-line didn’t work, your second-line is necessarily not going to work. I know in some carcinomas, we do feel that way, that your first-line is your best option. I don’t feel that way for our patients here, and so I keep saying to patients, “Set expectations,” because I do think it’s very important. We know what the response rates are to these drugs. You need to say, “Will it be stable disease, will it be a response, what do you anticipate?”, so they know what to anticipate when their scans come in and you’re checking for disease response versus progression. But, I do think there are several lines, and we all could have subtle differences in practice patterns. We could use different doses. But, for the most part, I think that most of us are tending to go to the same drugs in similar orders. It really allows for variability and a lot of options for the patients.

William D. Tap, MD: Maybe before we get to Damon, Martee, talk about metastatic leiomyosarcoma.

Martee L. Hensley, MD: I think, particularly for a uterine leiomyosarcoma, because the number of trials of fixed-dose gemcitabine and docetaxel is fairly robust at this point, I often choose that as my first-line regimen. It comes with its own set of toxicities. I will have some patients tell me that it was more difficult than doxorubicin-based therapy, and then I will have others feel the other way. So, you just counsel patients about what to expect in terms of toxicities.

Very much like Shreyas, a patient with a large disease burden, especially if there is impending organ compromise and you can see the ureteral obstruction coming, that’s a patient for whom I think two-drug therapy is very important. Because, though her quality of life may diminish somewhat from the side effects of drugs, that will be offset by her not needing a ureteral stent or having a large bowel obstruction that makes it impossible to give her further treatment, for example. There are some patients for whom single-drug therapy may be more appropriate and that comes into just the experience of seeing a lot of these diseases and figuring out which treatments are the right fit for each individual patient in some ways.

George D. Demetri, MD: I think this is where we all have to all channel our inner pediatric oncologist, too. Because what we wind up doing is appropriately tapping into the ability to support patients through aggressive treatments, if it’s in their best interest. A localized, large Ewing sarcoma growing rapidly in a 65-year-old, or even a 75-year-old, still could be very curable in that patient. And we want to treat that patient as such. For the other patients, we can do what everybody says: use good medical common sense, work with the patient on preferences and try to be realistic about what the drugs can do, and hope for the best.

Because I think the one other thing, sarcomas tend to be disproportionate for these Lazarus effects, where you go through the genome—this was in the Sunday New York Times a couple of weeks ago—and where you just happen to find that one molecular target, like in the PEComas and an mTOR pathway activation or a TRK fusion. You give them the TRK inhibitor and the thing melts away. That’s the kind of world we’re in right now, where we can’t say, “Oh, that’s going to happen in 9 out of 10 sarcoma patients.” But, even if it happens in 1 out of 10, or even 1 out of 100, it’s made such a huge difference. It would be just a tragedy to overlook that. And I think our pediatric colleagues have always focused on small numbers and the importance of helping small numbers.

William D. Tap, MD: So, Damon, how do you approach pediatric sarcomas, and how is it different than what we’re talking about?

Damon Reed, MD: The combination of doxorubicin and ifosfamide has not shown an overall survival benefit over doxorubicin itself, but that’s with wide ranges of ages, wide ranges of aggressiveness, and wide ranges of the degree of metastatic burden in adult patients. And so, what we’ve heard from everybody on the panel now is that there’s something about it that seems to help some patients. When you’re backed into the corner or when it’s really aggressive, or you really need something to work, we grab both agents. In a patient who has five, six decades to live to meet the median survival for a normal person in our population, there’s no reason to just try one drug. It’s definitely standard to give doxorubicin and ifosfamide for the most common soft tissue sarcomas that we see in pediatrics, namely synovial sarcoma.

Malignant peripheral nerve sheath tumor is another one of the common ones. I notice you left it out, because it is a hard one to figure out where it fits on that chemotherapy-sensitive or chemotherapy-resistant spectrum. But, I must say, in my own personal experience, it’s on the chemotherapy-resistant side of that for sure. So, I really struggle to give doxorubicin and ifosfamide. We shared a patient very recently who made the rounds through; maybe everyone on this panel saw her. But, I think we all recommended not to do chemotherapy for a rather aggressive looking localized tumor. That’s the case for the soft tissue sarcomas.

For rhabdomyosarcoma, I think of it like GIST (gastrointestinal stromal tumor). I would put it in its own bucket. We don’t use doxorubicin and ifosfamide, although both are used in select cases along with a lot of other medications. For the traditional patient that will come with localized disease, vincristine/dactinomycin/cyclophosphamide, a regimen that was worked out before I was born, is still the standard of care and stood the test of time. Cyclophosphamide has a particularly nasty long-term side effect of infertility, especially in boys, and premature ovarian failure. And so, irinotecan has been now accepted as the standard of care. So, a four-drug regimen of vincristine/dactinomycin/cyclophosphamide/irinotecan to spare gonadal toxicity is definitely the standard of care for rhabdomyosarcomas.

Transcript Edited for Clarity
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