Changing Treatment Landscape in Soft Tissue Sarcoma

Insights From: Victor Villalobos, MD, PhD, University of Colorado School of Medicine; Saketh Guntupalli, MD, University of Colorado School of Medicine; Shreyaskumar R. Patel, MD, University of Texas MD Anderson Cancer Center; Anthony P. Conley, MD, University of Texas MD Anderson Cancer Center


Victor Villalobos, MD, PhD: As you could imagine, in the sarcoma world, there’s always controversy. One of the controversies that we’ve seen, that is more settled now, is choice of therapy in the first-line metastatic setting. There are different schools of thought as far as using a combination of drugs versus single agent drugs. The use of doxorubicin, and ifosfamide, and mesna as a first-line therapy, while it does have a better response rate and a slightly better progression-free survival, there’s no significant difference in the overall survival compared with doxorubicin alone. My approach, previously, before the approval of olaratumab, in the setting where a patient was really not that symptomatic, had been to give single agent doxorubicin. Personally, I would reserve the use of Adriamycin (doxorubicin) and ifosfamide in a patient who is metastatic, where we need to get a response quickly, and they’re quite symptomatic from their cancer. Do you use Adriamycin/ifosfamide at all, in your treatment?

Saketh Guntupalli, MD: Adriamycin/ifosfamide and mesna, of course, is a reasonably toxic regimen. Ifosfamide has to be given inpatient, and there’s so many logistical constraints on using ifosfamide. Generally, for many of the gynecologic cancers, broadly, it has slowly fallen out of favor. We used to use ifosfamide for carcinosarcomas. That’s still standard of care. We’re not disputing that, but we have other regimens that we’ve moved away from. We’re using a lot more single agent Adriamycin, as data have come out for that, simply because of the toxicities of Adriamycin/ifosfamide. They’re pretty impressive. At least in our experience, or my experience, they’re fairly impressive. I think using other doublets though, such as olaratumab, has made the armamentarium that we have for sarcoma treatment much bigger.

Victor Villalobos, MD, PhD: As you know, with the Lancet paper, there was a phase II study with doxorubicin alone versus doxorubicin plus olaratumab. It changed the median overall survival for doxorubicin alone from 14 months to 26 months. If that is confirmed in the phase III study, which has already filled accrual, and hopefully we’ll have data out within the next year-and-a-half, I think that’s going to change our approach, frankly. The big question for that combination is the response rate. If the response rate approaches similar response rates to Adriamycin and ifosfamide, that may be the point where we actually get rid of it. Using Adriamycin/ifosfamide, early on, does affect my ability to treat them differently. There’s no safety data, yet, in combining olaratumab with doxorubicin and ifosfamide, together. We have seen olaratumab in the combination study with doxorubicin. It does slightly increase the risk for cytopenias. And so, you could imagine adding the third drug with ifosfamide. It may be toxic. We don’t know how to treat it safely, yet. But if that is safe, that may also be a very good opportunity, as well, for patients that actually have more aggressive disease. These are changing pretty rapidly. How often do you use gemcitabine and docetaxel in the first-line setting?

Saketh Guntupalli, MD: Well, up until probably about a year ago, I was using it pretty exclusively. Again, this is why collaboration is so important. For most of us, in gynecologic oncology, we were raised in the area of gemcitabine and Taxotere (docetaxel). So, I was using it quite a bit. But as I’ve kind of done more collaboration with you, and have seen more data, we are certainly using more Adriamycin. The point that you brought up is kind of interesting. We have data of gemcitabine/Taxotere versus Adriamycin.  And, we have data of Adriamycin versus olaratumab plus Adriamycin. You shouldn’t do cross-sectional comparisons, because those are 2 separate trials. But I think you raised a really interesting question. Up front, should we be using olaratumab/Adriamycin? We don’t have olaratumab/Adriamycin versus gemcitabine/Taxotere head-to-head data, comparing those 2, to really come up with an answer. But I think that it does raise a lot of compelling questions. I have used olaratumab/Adriamycin, and I have had pretty impressive responses with that. I do think it is obviously a little bit more toxic than single agent Adriamycin. And, I’ll be honest, I don’t think I would be very excited about Adriamycin, ifosfamide, and olaratumab as a triplet. I think that would be quite toxic, as you said, for the reasons of pancytopenia and other issues that come along with adding ifosfamide to an already hard regimen.

Victor Villalobos, MD, PhD: There actually is a clinical trial that is now looking at a gemcitabine and docetaxel combination with olaratumab in both the naive as well as pretreated setting. This study is looking to see if continuation of olaratumab actually benefits patients with different lines of therapy. One of the biggest downsides for using doxorubicin in combination with olaratumab is the fact that we think there’s significant synergy between the 2 drugs. Olaratumab, alone, has a very, very poor response rate, although we do think it has activity as a single agent. One of the patients we share has now been on single agent olaratumab for 30-plus cycles. Before, they had progressed pretty quickly on gemcitabine and docetaxel. So, how we incorporate that into our treatments is going to be really important in the near future, and I think we’re going to have more help to decide that.

Saketh Guntupalli, MD: Definitely.

Transcript Edited for Clarity 
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