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Chemotherapeutic Approaches for Locally Advanced STS

Panelists: Williams D. Tap, MD, Memorial Sloan Kettering Cancer Center; Kristen Ganjoo, MD, Stanford University Medical Center; Richard Riedel, MD, Duke Cancer Institute; Jonathan Trent, MD, PhD, Sylvester Comprehensive Cancer Center; Victor Villalobos, MD, PhD, University of Colorado
Published: Friday, Jul 27, 2018


Transcript: 

William D. Tap, MD: We’ve heard what you do, but why do you do it? In other words, John, when you give chemotherapy, are you saying you really want to surgically convert the patient? You want to make sure you get local control? Or are you thinking you are going to improve survival with this patient? How do you approach that? That’s a message we give the patient. But we can also discuss our thought process of why we put patients through what we put them through. I’ll ask each of you that same question.

Jonathan C. Trent, MD, PhD: In medicine, as is always the case, this is a shared decision between us and the patient. Our role is to share with them our experience and our understanding of the published literature. And so, this is the approach that I take in general. A patient with, as you mentioned, a 10-cm high-grade pleomorphic sarcoma has a substantial probability of dying from that sarcoma. That’s generally unacceptable to most of the patients in my practice, so I discuss approaches to minimize the probability of metastasis and death.

The data that we use are what we think are the most reliable data, and those are from the large Italian study where patients received radiation and resection and were randomized to chemotherapy versus no chemotherapy. The same meta-analysis was updated in 2008 and clearly showed an 11% improvement in overall survival and nearly a 15% improvement in local control in patients with high-grade sarcomas, mostly when doxorubicin and ifosfamide were both part of the adjuvant regimen in this setting. This is the rationale for our approach.

William D. Tap, MD: Kristen, do you do the same thing, really focusing on distant relapse-free survival and overall survival with your regimen?

Kristen N. Ganjoo, MD: Absolutely, but I also discuss with my patients that every patient is unique and their goals are unique. I always ask them questions and I tell them the data. I tell them there’s an 11% improvement in survival. I tell them what they have to go through, and they decide. We both decide what’s best for that patient. We’re generally more aggressive, just like John’s approach, and we usually do a lot of chemotherapy neoadjuvantly and adjuvantly.

William D. Tap, MD: It’s interesting because there are nomograms. There’s the SARCULATOR, which is an app that can give you an idea of distant relapse-free survival. But we do question what that percentage is that we can help with the various chemotherapy agents. Rich, it sounds like you would argue the opposite, that we may not know if we’re helping or not.

Richard F. Riedel, MD: John quoted the meta-analysis from 2008. That 2008 meta-analysis importantly included the original 14 studies from the original meta-analysis and 4 additional studies. But the methodology in which they did the analysis actually didn’t mirror the original meta-analysis from the late 1990s. The late 1990s meta-analysis, which did not show a survival benefit, used individualized patient data. The second meta-analysis in 2008 used composite data, and importantly, that second meta-analysis did not include the 450 patients from a large randomized study that showed no benefit for relapse-free or overall survival.

William D. Tap, MD: I do want to point out, too, that about 60% of the pathology was unknown because we had older diagnoses of MFH unknown within that as well.

Victor M. Villalobos, MD, PhD: Intermediate grade as well.

William D. Tap, MD: We also did recently have the Italian study that suggested chemotherapy may have a trend toward survival.

Richard F. Riedel, MD: But to be fair, the inference from that Italian study is not why the study was designed. They were answering a question that it wasn’t powered to ask. But to John and Kristen’s point, I completely agree with the idea of patient shared decision making and having those informed conversations. At least at our institution, our patients will say if you can’t guarantee them that chemotherapy is going to provide a benefit, many of our patients won’t do it.

William D. Tap, MD: It sounds like, chemotherapy aside, the consensus is clearly local control: the importance of making sure that margins are clear, whether or not you need a reresection, and real thoughts about radiation to consolidate especially with higher-grade deeper lesions. These are the types of discussions we have with our patients about the need of chemotherapy. Aptly so, there is going to be input from the DMT [diagnostic management team]. If the surgeon comes back and says we need a little help or we don’t have a window, that may also affect what we decide. But what about a patient who comes in with clearly locally advanced disease? A large pelvic lesion may need a hemipelvectomy if it’s resectable. Is there consensus in approaching that patient?

Victor M. Villalobos, MD, PhD: I imagine not. There are a lot of factors that play into it, right? Clearly, chemotherapy at that point makes more sense to see how they respond, because what you’re trying to do is find out what the biology of this tumor is. If it blows right through chemotherapy, then it doesn’t make sense to do a massive surgery that’s going to be highly morbid and put them through something when 3 months down the road, after they finally get out of the hospital after their huge surgery, they have metastatic disease. What have you gained them?

Those are the cases where the patient and I feel most bothered about whether we should have done that big surgery. And so, find out what the biology is going to behave like, how responsive it’s going to be. If they have a dramatic response, then yes, maybe it’s worth doing a larger resection. It may still recur, particularly in such a high-risk area. But if they want to try to give the benefit of the doubt with getting effective therapy, we should try that out.

William D. Tap, MD: Rich, do you agree? Are those the patients you use chemotherapy and multimodality therapy in?

Richard F. Riedel, MD: You can’t cure a patient without surgery, and if you’re dealing with disease that’s locally advanced, that would preclude the ability to do surgery, or that surgery would be particularly morbid in, then I think in those situations you should use everything at your disposal to try to give the patient a favorable outcome. That’s a different scenario than the patient in whom it’s clearly easily resectable or more easily resectable.

William D. Tap, MD: And is there a consensus in what you would use in that situation? Jonathan, I know you’re going to say AIM, right?

Kristen N. Ganjoo, MD: I agree with Jonathan.

William D. Tap, MD: I would too.

Kristen N. Ganjoo, MD: Definitely AIM.

Victor M. Villalobos, MD, PhD: If you want a response, you give AIM. But I think as important as, if not more important than, when to do something is when not to do something. Going away from sarcomas and more into desmoids, not touching it up front may be better than going through a massive surgery. We see a lot of that, where someone should probably not have undergone something that they went through because it is probably not beneficial to them or maybe even harmful to them.

William D. Tap, MD: I agree, and I’m a big fan of AIM, especially when I need quick palliation for symptoms or if we’re really trying to surgically convert patients.

Victor M. Villalobos, MD, PhD: I agree.

William D. Tap, MD: I do think that’s our best regimen if the patient can tolerate it to get things to shrink.

Jonathan C. Trent, MD, PhD: I have a couple of comments. Supporting the use of doxorubicin plus ifosfamide is the randomized study by Ian Judson, and it has been published now, but it was previously presented at ASCO. It clearly showed a doubling in response rate for the patients who were randomized to doxorubicin plus ifosfamide and a significant prolongation for progression-free survival by about 3 months, also with a trend toward an improvement in overall survival. I thought that was pertinent to this conversation. And then, the comment about desmoid tumors opens a whole new can of worms. It’s a different tumor, and we don’t resect them.

Our surgeons generally don’t resect desmoid tumors, particularly if they’re infiltrating. Very small ones, maybe. But the data in the pazopanib study that was presented at ASCO this year were fascinating because not only is it effective—and sorafenib is also effective, we know—with almost a 40% response rate in a disease where response rates are rare, but there was also approximately a 20% spontaneous regression rate for the patients who were randomized to placebo. We all see these spontaneous regressions, but that was a little higher than I expected.

William D. Tap, MD: No, it’s true, and it shows the complexity of the disease. We also think about when we engage our community oncologists. What care is done at the tertiary care center? What care is done in the community? How do we interface? These are just complicated patients. We’re using intense chemotherapy regimens. We need to maintain intensity, we need to keep people on track. Also having that discussion with their local oncologist is critical.

Transcript Edited for Clarity

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Transcript: 

William D. Tap, MD: We’ve heard what you do, but why do you do it? In other words, John, when you give chemotherapy, are you saying you really want to surgically convert the patient? You want to make sure you get local control? Or are you thinking you are going to improve survival with this patient? How do you approach that? That’s a message we give the patient. But we can also discuss our thought process of why we put patients through what we put them through. I’ll ask each of you that same question.

Jonathan C. Trent, MD, PhD: In medicine, as is always the case, this is a shared decision between us and the patient. Our role is to share with them our experience and our understanding of the published literature. And so, this is the approach that I take in general. A patient with, as you mentioned, a 10-cm high-grade pleomorphic sarcoma has a substantial probability of dying from that sarcoma. That’s generally unacceptable to most of the patients in my practice, so I discuss approaches to minimize the probability of metastasis and death.

The data that we use are what we think are the most reliable data, and those are from the large Italian study where patients received radiation and resection and were randomized to chemotherapy versus no chemotherapy. The same meta-analysis was updated in 2008 and clearly showed an 11% improvement in overall survival and nearly a 15% improvement in local control in patients with high-grade sarcomas, mostly when doxorubicin and ifosfamide were both part of the adjuvant regimen in this setting. This is the rationale for our approach.

William D. Tap, MD: Kristen, do you do the same thing, really focusing on distant relapse-free survival and overall survival with your regimen?

Kristen N. Ganjoo, MD: Absolutely, but I also discuss with my patients that every patient is unique and their goals are unique. I always ask them questions and I tell them the data. I tell them there’s an 11% improvement in survival. I tell them what they have to go through, and they decide. We both decide what’s best for that patient. We’re generally more aggressive, just like John’s approach, and we usually do a lot of chemotherapy neoadjuvantly and adjuvantly.

William D. Tap, MD: It’s interesting because there are nomograms. There’s the SARCULATOR, which is an app that can give you an idea of distant relapse-free survival. But we do question what that percentage is that we can help with the various chemotherapy agents. Rich, it sounds like you would argue the opposite, that we may not know if we’re helping or not.

Richard F. Riedel, MD: John quoted the meta-analysis from 2008. That 2008 meta-analysis importantly included the original 14 studies from the original meta-analysis and 4 additional studies. But the methodology in which they did the analysis actually didn’t mirror the original meta-analysis from the late 1990s. The late 1990s meta-analysis, which did not show a survival benefit, used individualized patient data. The second meta-analysis in 2008 used composite data, and importantly, that second meta-analysis did not include the 450 patients from a large randomized study that showed no benefit for relapse-free or overall survival.

William D. Tap, MD: I do want to point out, too, that about 60% of the pathology was unknown because we had older diagnoses of MFH unknown within that as well.

Victor M. Villalobos, MD, PhD: Intermediate grade as well.

William D. Tap, MD: We also did recently have the Italian study that suggested chemotherapy may have a trend toward survival.

Richard F. Riedel, MD: But to be fair, the inference from that Italian study is not why the study was designed. They were answering a question that it wasn’t powered to ask. But to John and Kristen’s point, I completely agree with the idea of patient shared decision making and having those informed conversations. At least at our institution, our patients will say if you can’t guarantee them that chemotherapy is going to provide a benefit, many of our patients won’t do it.

William D. Tap, MD: It sounds like, chemotherapy aside, the consensus is clearly local control: the importance of making sure that margins are clear, whether or not you need a reresection, and real thoughts about radiation to consolidate especially with higher-grade deeper lesions. These are the types of discussions we have with our patients about the need of chemotherapy. Aptly so, there is going to be input from the DMT [diagnostic management team]. If the surgeon comes back and says we need a little help or we don’t have a window, that may also affect what we decide. But what about a patient who comes in with clearly locally advanced disease? A large pelvic lesion may need a hemipelvectomy if it’s resectable. Is there consensus in approaching that patient?

Victor M. Villalobos, MD, PhD: I imagine not. There are a lot of factors that play into it, right? Clearly, chemotherapy at that point makes more sense to see how they respond, because what you’re trying to do is find out what the biology of this tumor is. If it blows right through chemotherapy, then it doesn’t make sense to do a massive surgery that’s going to be highly morbid and put them through something when 3 months down the road, after they finally get out of the hospital after their huge surgery, they have metastatic disease. What have you gained them?

Those are the cases where the patient and I feel most bothered about whether we should have done that big surgery. And so, find out what the biology is going to behave like, how responsive it’s going to be. If they have a dramatic response, then yes, maybe it’s worth doing a larger resection. It may still recur, particularly in such a high-risk area. But if they want to try to give the benefit of the doubt with getting effective therapy, we should try that out.

William D. Tap, MD: Rich, do you agree? Are those the patients you use chemotherapy and multimodality therapy in?

Richard F. Riedel, MD: You can’t cure a patient without surgery, and if you’re dealing with disease that’s locally advanced, that would preclude the ability to do surgery, or that surgery would be particularly morbid in, then I think in those situations you should use everything at your disposal to try to give the patient a favorable outcome. That’s a different scenario than the patient in whom it’s clearly easily resectable or more easily resectable.

William D. Tap, MD: And is there a consensus in what you would use in that situation? Jonathan, I know you’re going to say AIM, right?

Kristen N. Ganjoo, MD: I agree with Jonathan.

William D. Tap, MD: I would too.

Kristen N. Ganjoo, MD: Definitely AIM.

Victor M. Villalobos, MD, PhD: If you want a response, you give AIM. But I think as important as, if not more important than, when to do something is when not to do something. Going away from sarcomas and more into desmoids, not touching it up front may be better than going through a massive surgery. We see a lot of that, where someone should probably not have undergone something that they went through because it is probably not beneficial to them or maybe even harmful to them.

William D. Tap, MD: I agree, and I’m a big fan of AIM, especially when I need quick palliation for symptoms or if we’re really trying to surgically convert patients.

Victor M. Villalobos, MD, PhD: I agree.

William D. Tap, MD: I do think that’s our best regimen if the patient can tolerate it to get things to shrink.

Jonathan C. Trent, MD, PhD: I have a couple of comments. Supporting the use of doxorubicin plus ifosfamide is the randomized study by Ian Judson, and it has been published now, but it was previously presented at ASCO. It clearly showed a doubling in response rate for the patients who were randomized to doxorubicin plus ifosfamide and a significant prolongation for progression-free survival by about 3 months, also with a trend toward an improvement in overall survival. I thought that was pertinent to this conversation. And then, the comment about desmoid tumors opens a whole new can of worms. It’s a different tumor, and we don’t resect them.

Our surgeons generally don’t resect desmoid tumors, particularly if they’re infiltrating. Very small ones, maybe. But the data in the pazopanib study that was presented at ASCO this year were fascinating because not only is it effective—and sorafenib is also effective, we know—with almost a 40% response rate in a disease where response rates are rare, but there was also approximately a 20% spontaneous regression rate for the patients who were randomized to placebo. We all see these spontaneous regressions, but that was a little higher than I expected.

William D. Tap, MD: No, it’s true, and it shows the complexity of the disease. We also think about when we engage our community oncologists. What care is done at the tertiary care center? What care is done in the community? How do we interface? These are just complicated patients. We’re using intense chemotherapy regimens. We need to maintain intensity, we need to keep people on track. Also having that discussion with their local oncologist is critical.

Transcript Edited for Clarity
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