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Case Study: Leiomyosarcoma and Disseminated Metastases

Panelists: William 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: Thursday, Aug 23, 2018



Transcript: 

William D. Tap, MD: Maybe we can move on to a second patient. This is a 44-year-old woman who presents with metastatic leiomyosarcoma and a lot of disseminated metastasis within the lung. She started off on treatment with doxorubicin/olaratumab. Maybe we could say for uterine, John, that you may have started with doxorubicin/dacarbazine, or doxorubicin/olaratumab?

Jonathan C. Trent, MD, PhD: Doxorubicin/dacarbazine/olaratumab.

William D. Tap, MD: If they progress on that frontline anthracycline-based regimen, what are some of the options for this patient?

Victor M. Villalobos, MD, PhD: Always clinical trials, for all these patients.

William D. Tap, MD: Always considering clinical trials.

Victor M. Villalobos, MD, PhD: If I have a clinical trial for them, that’s my first step for them, irrespective of everything else. But other than that, gemcitabine and docetaxel work exceedingly well.

Kristen N. Ganjoo, MD: But the Ganjoo regimen works beautifully.

Victor M. Villalobos, MD, PhD: Having trained with Kristen, I have used it before, but I still utilize the day 1, day 8 regimen.

William D. Tap, MD: Some of our Spanish colleagues had a very nice JCO article looking at gemcitabine and dacarbazine.

Victor M. Villalobos, MD, PhD: It’s a very highly tolerable regimen.

William D. Tap, MD: It’s a good regimen. A gemcitabine-based regimen would be something that would be more likely a second-line therapy for you, but what about subsequent lines of therapy? What are our options?

Kristen N. Ganjoo, MD: Dacarbazine for most, even single-agent.

William D. Tap, MD: Single-agent can have activity as well.

Kristen N. Ganjoo, MD: Also pazopanib, going back to it being underutilized, and also trabectedin.

Victor M. Villalobos, MD, PhD: And trabectedin is effective as well. Almost like immunotherapy, there’s a very long tail. We have some patients who are on trabectedin for years, and they can tolerate it even in their 80s. If they have that phenotype of their disease where they get responses with trabectedin, that’s a great outcome for them and they can actually do quite well.

Jonathan C. Trent, MD, PhD: Definitely. We use a lot of trabectedin, and it’s highly effective in this situation. One situation, for instance, is if this patient may have been seen elsewhere and did not get doxorubicin/olaratumab in the frontline setting: perhaps doxorubicin/dacarbazine. Then, I’m seeing them after gemcitabine/docetaxel, after Votrient (pazopanib), and after trabectedin. I would also consider going back to doxorubicin plus olaratumab. If they’re olaratumab-naïve, why not rechallenge them? It could be a different clone that has taken over.

William D. Tap, MD: Sure, rechallenging is an option with a lot of agents.

Victor M. Villalobos, MD, PhD: Particularly in the patients who are alive 4 or 5 years out. They haven’t seen a drug for several years, so I’ll definitely go back to the different drugs.

Jonathan C. Trent, MD, PhD: Yes, and we’re comfortable doing that. We do use dexrazoxane as cardioprotection, or we do use a 72-hour infusion when patients are treated with any doxorubicin so that we have more room under the curve before the risk of cardiomyopathy starts rearing its head.

William D. Tap, MD: What about ifosfamide?

Jonathan C. Trent, MD, PhD: We haven’t mentioned that drug. That’s a go-to drug.

Victor M. Villalobos, MD, PhD: It’s tough to give. I typically give it to an inpatient. For some reason, at that altitude, I have a lot more encephalopathies than most, and so I have a hard time giving it. Frankly, it’s just not that effective for leiomyosarcoma where I think it’s worth the toxicities.

Kristen N. Ganjoo, MD: How about the other ways to give ifosfamide, such as the 14-day continuous infusion for outpatients where they get 1000 mg/m2? We’ve had some good responses with that. But going back to olaratumab, one of the things that has been challenging is if the patient has had a complete dose of Adriamycin in the past but you want to give olaratumab to them, it’s really hard to get insurance authorization of olaratumab with any other chemotherapy because of the lack of data. But hopefully, pretty soon we’ll be able to add it to other chemotherapy drugs because it doesn’t make any sense to me for it to just be lumped in with doxorubicin. That’s one of the challenges.

Victor M. Villalobos, MD, PhD: Right now, I’m looking at gemcitabine/docetaxel plus or minus olaratumab, so we’ll have some data soon.

Kristen N. Ganjoo, MD: Hopefully we’ll have some data.

Jonathan C. Trent, MD, PhD: I have no reservations going back to doxorubicin if the patient has had the 450 mg/m2 requirement.

Kristen N. Ganjoo, MD: That’s what I’ve been doing. I give a couple of doses of doxorubicin with olaratumab, and then I go to maintenance olaratumab. So, at least I have my insurance people’s approval.

Richard F. Riedel, MD: The data suggest the benefit of olaratumab is from longer exposure with doxorubicin.

Kristen N. Ganjoo, MD: Right, but if they had had 450 mg/m2, then I’m comfortable giving another 2 cycles at 150 mg/m2 of that.

Richard F. Riedel, MD: Typically, if I see somebody who has had an anthracycline, if they’ve had 450 mg/m2 I’ll actually push them to the 600 mg/m2 and then transition.

Jonathan C. Trent, MD, PhD: I would say to just do the ECHO. I have a patient who has had 1600 mg/m2 doxorubicin and has no cardiomyopathy at all. It’s idiosyncratic; not everybody’s going to get it. I would not let a potential or theoretical problem stop me from treating a patient who needs therapy. But the ifosfamide data—and this is a subset analysis—are not that active in nonuterine leiomyosarcoma. In uterine disease, there’s some activity.

William D. Tap, MD: That’s the point. In primary bone leiomyosarcoma, although very rarely, there’s some activity. I agree.

Richard F. Riedel, MD: I was just going to say that. We heard about gemcitabine-based regimens, trabectedin, dacarbazine, and pazopanib.

William D. Tap, MD: What about eribulin?

Richard F. Riedel, MD: It’s off-label, but I think at least in the phase III study where eribulin was compared to dacarbazine, which was thought to be an active comparator, it had similar outcomes.

Jonathan C. Trent, MD, PhD: It’s as active as dacarbazine.

Victor M. Villalobos, MD, PhD: I wouldn’t say it’s inactive.

Richard F. Riedel, MD: If you’re going to consider dacarbazine, then I think you should consider it after eribulin. The challenge, at least at our institution, is off-label use. The insurance companies are becoming increasingly stringent in wanting to know with pazopanib, have you had prior chemotherapy for eribulin? What is the histology?

William D. Tap, MD: Right. We’re getting very specific on that.

Kristen N. Ganjoo, MD: There’s another thing. With the leiomyosarcomas—this part I agree with Richard on in terms of immunotherapy with ipilimumab and nivolumab—this is the group that I wouldn’t give immunotherapy to off-trial just because in the past, they haven’t really responded.  

William D. Tap, MD: Clearly, with the single-agent checkpoint inhibitors, there were a few extra responses to the combination. But everything is generally sensitive to checkpoint inhibition. There’s a lot of work we need to do to understand that, and there are a lot of ongoing studies.

Transcript Edited for Clarity 

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Transcript: 

William D. Tap, MD: Maybe we can move on to a second patient. This is a 44-year-old woman who presents with metastatic leiomyosarcoma and a lot of disseminated metastasis within the lung. She started off on treatment with doxorubicin/olaratumab. Maybe we could say for uterine, John, that you may have started with doxorubicin/dacarbazine, or doxorubicin/olaratumab?

Jonathan C. Trent, MD, PhD: Doxorubicin/dacarbazine/olaratumab.

William D. Tap, MD: If they progress on that frontline anthracycline-based regimen, what are some of the options for this patient?

Victor M. Villalobos, MD, PhD: Always clinical trials, for all these patients.

William D. Tap, MD: Always considering clinical trials.

Victor M. Villalobos, MD, PhD: If I have a clinical trial for them, that’s my first step for them, irrespective of everything else. But other than that, gemcitabine and docetaxel work exceedingly well.

Kristen N. Ganjoo, MD: But the Ganjoo regimen works beautifully.

Victor M. Villalobos, MD, PhD: Having trained with Kristen, I have used it before, but I still utilize the day 1, day 8 regimen.

William D. Tap, MD: Some of our Spanish colleagues had a very nice JCO article looking at gemcitabine and dacarbazine.

Victor M. Villalobos, MD, PhD: It’s a very highly tolerable regimen.

William D. Tap, MD: It’s a good regimen. A gemcitabine-based regimen would be something that would be more likely a second-line therapy for you, but what about subsequent lines of therapy? What are our options?

Kristen N. Ganjoo, MD: Dacarbazine for most, even single-agent.

William D. Tap, MD: Single-agent can have activity as well.

Kristen N. Ganjoo, MD: Also pazopanib, going back to it being underutilized, and also trabectedin.

Victor M. Villalobos, MD, PhD: And trabectedin is effective as well. Almost like immunotherapy, there’s a very long tail. We have some patients who are on trabectedin for years, and they can tolerate it even in their 80s. If they have that phenotype of their disease where they get responses with trabectedin, that’s a great outcome for them and they can actually do quite well.

Jonathan C. Trent, MD, PhD: Definitely. We use a lot of trabectedin, and it’s highly effective in this situation. One situation, for instance, is if this patient may have been seen elsewhere and did not get doxorubicin/olaratumab in the frontline setting: perhaps doxorubicin/dacarbazine. Then, I’m seeing them after gemcitabine/docetaxel, after Votrient (pazopanib), and after trabectedin. I would also consider going back to doxorubicin plus olaratumab. If they’re olaratumab-naïve, why not rechallenge them? It could be a different clone that has taken over.

William D. Tap, MD: Sure, rechallenging is an option with a lot of agents.

Victor M. Villalobos, MD, PhD: Particularly in the patients who are alive 4 or 5 years out. They haven’t seen a drug for several years, so I’ll definitely go back to the different drugs.

Jonathan C. Trent, MD, PhD: Yes, and we’re comfortable doing that. We do use dexrazoxane as cardioprotection, or we do use a 72-hour infusion when patients are treated with any doxorubicin so that we have more room under the curve before the risk of cardiomyopathy starts rearing its head.

William D. Tap, MD: What about ifosfamide?

Jonathan C. Trent, MD, PhD: We haven’t mentioned that drug. That’s a go-to drug.

Victor M. Villalobos, MD, PhD: It’s tough to give. I typically give it to an inpatient. For some reason, at that altitude, I have a lot more encephalopathies than most, and so I have a hard time giving it. Frankly, it’s just not that effective for leiomyosarcoma where I think it’s worth the toxicities.

Kristen N. Ganjoo, MD: How about the other ways to give ifosfamide, such as the 14-day continuous infusion for outpatients where they get 1000 mg/m2? We’ve had some good responses with that. But going back to olaratumab, one of the things that has been challenging is if the patient has had a complete dose of Adriamycin in the past but you want to give olaratumab to them, it’s really hard to get insurance authorization of olaratumab with any other chemotherapy because of the lack of data. But hopefully, pretty soon we’ll be able to add it to other chemotherapy drugs because it doesn’t make any sense to me for it to just be lumped in with doxorubicin. That’s one of the challenges.

Victor M. Villalobos, MD, PhD: Right now, I’m looking at gemcitabine/docetaxel plus or minus olaratumab, so we’ll have some data soon.

Kristen N. Ganjoo, MD: Hopefully we’ll have some data.

Jonathan C. Trent, MD, PhD: I have no reservations going back to doxorubicin if the patient has had the 450 mg/m2 requirement.

Kristen N. Ganjoo, MD: That’s what I’ve been doing. I give a couple of doses of doxorubicin with olaratumab, and then I go to maintenance olaratumab. So, at least I have my insurance people’s approval.

Richard F. Riedel, MD: The data suggest the benefit of olaratumab is from longer exposure with doxorubicin.

Kristen N. Ganjoo, MD: Right, but if they had had 450 mg/m2, then I’m comfortable giving another 2 cycles at 150 mg/m2 of that.

Richard F. Riedel, MD: Typically, if I see somebody who has had an anthracycline, if they’ve had 450 mg/m2 I’ll actually push them to the 600 mg/m2 and then transition.

Jonathan C. Trent, MD, PhD: I would say to just do the ECHO. I have a patient who has had 1600 mg/m2 doxorubicin and has no cardiomyopathy at all. It’s idiosyncratic; not everybody’s going to get it. I would not let a potential or theoretical problem stop me from treating a patient who needs therapy. But the ifosfamide data—and this is a subset analysis—are not that active in nonuterine leiomyosarcoma. In uterine disease, there’s some activity.

William D. Tap, MD: That’s the point. In primary bone leiomyosarcoma, although very rarely, there’s some activity. I agree.

Richard F. Riedel, MD: I was just going to say that. We heard about gemcitabine-based regimens, trabectedin, dacarbazine, and pazopanib.

William D. Tap, MD: What about eribulin?

Richard F. Riedel, MD: It’s off-label, but I think at least in the phase III study where eribulin was compared to dacarbazine, which was thought to be an active comparator, it had similar outcomes.

Jonathan C. Trent, MD, PhD: It’s as active as dacarbazine.

Victor M. Villalobos, MD, PhD: I wouldn’t say it’s inactive.

Richard F. Riedel, MD: If you’re going to consider dacarbazine, then I think you should consider it after eribulin. The challenge, at least at our institution, is off-label use. The insurance companies are becoming increasingly stringent in wanting to know with pazopanib, have you had prior chemotherapy for eribulin? What is the histology?

William D. Tap, MD: Right. We’re getting very specific on that.

Kristen N. Ganjoo, MD: There’s another thing. With the leiomyosarcomas—this part I agree with Richard on in terms of immunotherapy with ipilimumab and nivolumab—this is the group that I wouldn’t give immunotherapy to off-trial just because in the past, they haven’t really responded.  

William D. Tap, MD: Clearly, with the single-agent checkpoint inhibitors, there were a few extra responses to the combination. But everything is generally sensitive to checkpoint inhibition. There’s a lot of work we need to do to understand that, and there are a lot of ongoing studies.

Transcript Edited for Clarity 
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