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Chemotherapy Regimens for Advanced Soft Tissue Sarcoma

Panelists:Robin L. Jones, MD, MRCP, Royal Marsden Hospital; Shreyaskumar R. Patel, MD, University of Texas MD Anderson Cancer Center; R. Lor Randall, MD, FACS, Huntsman Cancer Institute; Jonathan C. Trent, MD, Sylvester Comprehensive Cancer Center; Brian A. Van Tine, MD, PhD, Siteman Cancer Center; Andrew J. Wagner, MD, PhD, Dana-Farber Cancer Institute
Published: Wednesday, Dec 16, 2015



Transcript:

Brian A. Van Tine, MD, PhD:
I’d like to transition now to what’s going to lead into my favorite thing to talk about, which are clinical trials and the results of clinical trials and really how this landscape may be changing. Since Bob Benjamin came out with Adriamycin trials many, many, many, many years ago, the standard of care really has always been Adriamycin-based.

There was a recent trial presented at ASCO this year looking at metastatic soft tissue, and the field had drifted with certain histologies between starting with gem/tax and starting with Adriamycin, and there were some different beliefs out there. So, somebody went and did a clinical trial of dox versus a gemcitabine-based regimen. Dr. Patel, what are your thoughts on that trial?

Shreyaskumar R. Patel, MD: I think taking a minute before we get into the details of individual trials, it’s probably important to recognize and reiterate for our audience that the stage IV disease for most solid tumors, sarcoma not excluded, remains a challenge.

By definition, this is an incurable tumor. But we all have examples where we have long-term survivors and have succeeded with multi-modality therapy. Resection of metastases is clearly a modality that helps, and we’ll come back to that at some point in time. But, with that, I think the other side of the coin is that these patients are young, they are physically fit, and, more often than not, they do go through multiple different lines of treatment.

That leads into the trial that you asked me to comment on. The English group randomized patients to look at single-agent doxorubicin, which is their standard of care, and compare it to gemcitabine/docetaxel, which is another popular regimen that has come around. For most of us in North America, that’s the default second-line regimen, if you will, unless there are histology-specific reasons to use it front line, like in a gynecologic leiomyosarcoma. And I think their purpose in randomizing to these two regimens was to see if one is clearly superior than the other.

I’m personally not so sure that that was necessarily that important a question to answer, except to say that I think it does generate evidence that, in a select population, for toxicity reasons or patients’ comorbidity reasons, if one chooses to use gemcitabine/docetaxel as a front-line therapy, it compared favorably to doxorubicin when you look at the medians. But, then you start looking at it in more details as they’re commenting on it; the PFS curves are virtually superimposed for quite some time. But beyond 24 months, they start separating out a little bit. And they acknowledge the fact that doxorubicin was a little bit better and, therefore, remains the standard of care.

So, I think every clinical trial gives us valuable information. That said, I don’t think this is necessarily changing anything because whether one uses A first and B later, or B first and A later, doesn’t necessarily make this any more curable. I, personally, would like to think of this in the context of—can we use information to use it as building blocks? If one is a clear winner, can you add something to it and take it to the next level? It’s the only way we’re going to move the needle in terms of higher complete response rates, longer survivals, and so on and so forth.

I think it’s an interesting trial. The two regimens did roughly the same. No reason to necessarily pick one over the other except if you dig deeper into the details. The bigger controversy, as will come up in the trial that you’re going to bring up is, what is really the standard of care? Is it single-agent doxorubicin or is it a doublet? And I think that remains a debate. And I want to make one other point: that we talk about personalized therapy these days as if it’s the next best thing after apple pie. And I think it is in the sense that we have newer molecular ways of personalizing treatment, which we didn’t have before.

But, in a global sense, personalizing therapy is part of the practice of clinical medicine, right? That’s what we were talking about earlier in terms of who would you pick for adjuvant or neoadjuvant chemotherapy? You wouldn’t give it to a stage I or II patient, you would consider it for a stage III. And even there you would add histology, add comorbidities, host-related factors, and so on and so forth. I think personalizing the treatment is clearly, again, another one of these factors that goes in for metastatic disease treatments.

R. Lor Randall, MD, FACS: May I make one—not one point, not to wax philosophic here for a moment, we also need to realize—we all realize—but make the point that by definition, cancer is an unstable genome and is constantly evolving. So what might work today might not work tomorrow because the tumor is continually evolving, and, in and of itself, the clones are heterogeneous.

So, the clone on the lung may be different from the clone on the liver, etc. We’ve seen mixed responses. So, I think moving forward, while the Holy Grail is a cure, it’s really maintenance. And like managing diabetes, we want to get to the goal where we can keep people’s quality of life high and their tumor burden low. But we may not truly be curing a lot of people. But we will be able to maintain them with active, happy lifestyles with continued cancer issues.

Andrew J. Wagner, MD, PhD: An important point that’s not always so clear from the bullets that come out of the clinical trials: often we focus on progression-free survival or overall survival, but it’s also the tolerance of the treatments. So, you could extend life by a few months, but it might be a miserable few months that you’ve added to it.

R. Lor Randall, MD, FACS: Exactly.

Andrew J. Wagner, MD, PhD: So I think really keeping an eye on the toxicities of treatment is important, as well.

Robin L. Jones, MD, MRCP: I think that’s interesting in the context of the doxorubicin versus gemcitabine and docetaxel trial. The gemcitabine and docetaxel arm actually experienced more toxicity, which is, I think, a surprise to a lot of people.

Shreyaskumar R. Patel, MD: I was going to make exactly the same point. That I think, surprise, surprise, doxorubicin came out to be a better-tolerated regimen in the hands of our English colleagues. Can you believe that?
                                                                                                                                                                                                                                                                                                                

Transcript Edited for Clarity

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Transcript:

Brian A. Van Tine, MD, PhD:
I’d like to transition now to what’s going to lead into my favorite thing to talk about, which are clinical trials and the results of clinical trials and really how this landscape may be changing. Since Bob Benjamin came out with Adriamycin trials many, many, many, many years ago, the standard of care really has always been Adriamycin-based.

There was a recent trial presented at ASCO this year looking at metastatic soft tissue, and the field had drifted with certain histologies between starting with gem/tax and starting with Adriamycin, and there were some different beliefs out there. So, somebody went and did a clinical trial of dox versus a gemcitabine-based regimen. Dr. Patel, what are your thoughts on that trial?

Shreyaskumar R. Patel, MD: I think taking a minute before we get into the details of individual trials, it’s probably important to recognize and reiterate for our audience that the stage IV disease for most solid tumors, sarcoma not excluded, remains a challenge.

By definition, this is an incurable tumor. But we all have examples where we have long-term survivors and have succeeded with multi-modality therapy. Resection of metastases is clearly a modality that helps, and we’ll come back to that at some point in time. But, with that, I think the other side of the coin is that these patients are young, they are physically fit, and, more often than not, they do go through multiple different lines of treatment.

That leads into the trial that you asked me to comment on. The English group randomized patients to look at single-agent doxorubicin, which is their standard of care, and compare it to gemcitabine/docetaxel, which is another popular regimen that has come around. For most of us in North America, that’s the default second-line regimen, if you will, unless there are histology-specific reasons to use it front line, like in a gynecologic leiomyosarcoma. And I think their purpose in randomizing to these two regimens was to see if one is clearly superior than the other.

I’m personally not so sure that that was necessarily that important a question to answer, except to say that I think it does generate evidence that, in a select population, for toxicity reasons or patients’ comorbidity reasons, if one chooses to use gemcitabine/docetaxel as a front-line therapy, it compared favorably to doxorubicin when you look at the medians. But, then you start looking at it in more details as they’re commenting on it; the PFS curves are virtually superimposed for quite some time. But beyond 24 months, they start separating out a little bit. And they acknowledge the fact that doxorubicin was a little bit better and, therefore, remains the standard of care.

So, I think every clinical trial gives us valuable information. That said, I don’t think this is necessarily changing anything because whether one uses A first and B later, or B first and A later, doesn’t necessarily make this any more curable. I, personally, would like to think of this in the context of—can we use information to use it as building blocks? If one is a clear winner, can you add something to it and take it to the next level? It’s the only way we’re going to move the needle in terms of higher complete response rates, longer survivals, and so on and so forth.

I think it’s an interesting trial. The two regimens did roughly the same. No reason to necessarily pick one over the other except if you dig deeper into the details. The bigger controversy, as will come up in the trial that you’re going to bring up is, what is really the standard of care? Is it single-agent doxorubicin or is it a doublet? And I think that remains a debate. And I want to make one other point: that we talk about personalized therapy these days as if it’s the next best thing after apple pie. And I think it is in the sense that we have newer molecular ways of personalizing treatment, which we didn’t have before.

But, in a global sense, personalizing therapy is part of the practice of clinical medicine, right? That’s what we were talking about earlier in terms of who would you pick for adjuvant or neoadjuvant chemotherapy? You wouldn’t give it to a stage I or II patient, you would consider it for a stage III. And even there you would add histology, add comorbidities, host-related factors, and so on and so forth. I think personalizing the treatment is clearly, again, another one of these factors that goes in for metastatic disease treatments.

R. Lor Randall, MD, FACS: May I make one—not one point, not to wax philosophic here for a moment, we also need to realize—we all realize—but make the point that by definition, cancer is an unstable genome and is constantly evolving. So what might work today might not work tomorrow because the tumor is continually evolving, and, in and of itself, the clones are heterogeneous.

So, the clone on the lung may be different from the clone on the liver, etc. We’ve seen mixed responses. So, I think moving forward, while the Holy Grail is a cure, it’s really maintenance. And like managing diabetes, we want to get to the goal where we can keep people’s quality of life high and their tumor burden low. But we may not truly be curing a lot of people. But we will be able to maintain them with active, happy lifestyles with continued cancer issues.

Andrew J. Wagner, MD, PhD: An important point that’s not always so clear from the bullets that come out of the clinical trials: often we focus on progression-free survival or overall survival, but it’s also the tolerance of the treatments. So, you could extend life by a few months, but it might be a miserable few months that you’ve added to it.

R. Lor Randall, MD, FACS: Exactly.

Andrew J. Wagner, MD, PhD: So I think really keeping an eye on the toxicities of treatment is important, as well.

Robin L. Jones, MD, MRCP: I think that’s interesting in the context of the doxorubicin versus gemcitabine and docetaxel trial. The gemcitabine and docetaxel arm actually experienced more toxicity, which is, I think, a surprise to a lot of people.

Shreyaskumar R. Patel, MD: I was going to make exactly the same point. That I think, surprise, surprise, doxorubicin came out to be a better-tolerated regimen in the hands of our English colleagues. Can you believe that?
                                                                                                                                                                                                                                                                                                                

Transcript Edited for Clarity
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Online CME Activities
TitleExpiration DateCME Credits
Moving Forward From the Status Quo for the Treatment of Soft Tissue Sarcoma: Key Questions & New Answers to Optimize OutcomesAug 16, 20181.5
Clinical Interchange™: Moving Forward From the Status Quo for the Treatment of Soft Tissue Sarcoma: Key Questions and New Answers to Optimize OutcomesOct 31, 20182.0
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