William D. Tap, MD: Are there different approaches? I always think about metastatic disease as running a marathon. We need the right pace and the right course. Sometimes you need to sprint. Sometimes you need more intense regimens for whatever reason, and I think it’s always a struggle. What is it that we would start off with?

Kristen N. Ganjoo, MD: I think one of the other things for AIM—ifosfamide, mesna, and Adriamycin (doxorubicin)—is that the only time I use it in the metastatic setting is if there are a lot of symptoms, obviously, and I need to shrink it quickly to get the symptoms out. But otherwise, the standard of care right now is Adriamycin if patients can tolerate it, if they don’t have any cardiac history, and then olaratumab. That’s the standard of care. And then we use subsequent therapies. Most of my patients with metastatic disease get 6 or 7 lines of therapy, but it just depends on how you sequence them.

Jonathan C. Trent, MD, PhD: I might just push back a little bit.

William D. Tap, MD: We’re setting you up for that.

Jonathan C. Trent, MD, PhD: Doxorubicin is clearly the most active drug in frontline therapy for metastatic sarcoma, and I’m speaking just in general. Of course, every patient is an individual and we make decisions based on individual situations. But as Bill mentioned, there is survival advantage in doxorubicin plus ifosfamide, seemingly. It may not be statistically significant in studies, but it’s an acceptable frontline regimen in the metastatic setting. Doxorubicin/olaratumab is also an acceptable regimen in the frontline setting, with a survival benefit from the study. And so, when we see a patient with metastatic disease, we look at the patient not as that there’s a 90% chance they’re not going to survive this; we look at the patient as that there’s a 10% chance they may live more than 10 years.

Kristen N. Ganjoo, MD: That’s exactly what I thought.

Jonathan C. Trent, MD, PhD: If you look at most of the sarcoma subtypes, long-term survival at 10 years may be as high as 20% in the adult rhabdomyosarcoma patients. These are the patients who respond to chemotherapy and are able to go on to some type of consolidative, localized, oligometastatic resection. When we see these patients, just like what you do, we treat aggressively. We treat with doxorubicin/ifosfamide. If the patient is eligible for the trial, we use doxorubicin plus ifosfamide plus olaratumab, with the idea of getting the best response possible. And then, if the patient is able to get into an oligometastatic situation, we have lung nodules resected and liver lesions resected or ablated if we’re able to render the patient completely NED for metastatic disease.

Victor M. Villalobos, MD, PhD: But for patients with widely metastatic disease, where resection is not possible, would you give AIM at any point?

Jonathan C. Trent, MD, PhD: Absolutely. Resection may be possible with a complete response in the majority of the areas.

Victor M. Villalobos, MD, PhD: I think I disagree because the addition of ifosfamide to Adriamycin more than doubles the toxicity. It is a very, very difficult regimen. I think tolerability is of massive importance to a lot of my patients as well. Now, that being said, sarcoma patients are a very heterogeneous group of patients, right? You have patients in their teens and you have patients in their 80s. Clearly that plays a major role, but I think it depends largely on what the patient feels. I have given metastatic patients AIM if we think that we can get them to surgery to resect. But I think in a situation where surgery really is not feasible, going more gently with a drug that can actually increase overall survival may be more effective.

Jonathan C. Trent, MD, PhD: I agree completely.

Kristen N. Ganjoo, MD: I agree with you, John, on one point. If I have a synovial sarcoma, they will definitely get ifosfamide/Adriamycin even if they have metastatic disease, even if they have bone disease. That is the one group of patients who will always get ifosfamide. But with the other patients in their 60s and 70s who have had bone, liver, and lung disease, and all those things, we have to have a conversation. Most patients will say, “I do not want ifosfamide.” Especially if they’re older than 65, you’ll get a lot of side effects. But I do agree on that one point.

Jonathan C. Trent, MD, PhD: I’m agreeing with you completely. This is a long conversation that I have with patients, and we’re talking about metastatic patients. If you look at the retrospective reviews with all of their biases, there are patients with metastatic disease who are long-term survivors.

Kristen N. Ganjoo, MD: Yes, I agree.

Jonathan C. Trent, MD, PhD: There are data in the surgical literature and data in the interventional radiology literature that those patients who are going to live longer with those procedures are the ones who are responding to chemotherapy. I choose the regimen that has the highest probability of response, in order to offer those consolidative procedures. It’s also supported, to some degree, by the doxorubicin plus ifosfamide versus doxorubicin study. The PFS was statistically higher with the combination, the response rate was doubled with the combination, and the overall survival was 9% higher for the patients who got the combination. We’re talking overall survival. Although the P value fell a little short, the trend is there.

Richard F. Riedel, MD: To use your logic, the doxorubicin/olaratumab study improved response rates and improved progression-free survival but had a massive improvement in overall survival. That wasn’t the 2 months that we’ve seen with doxorubicin/ifosfamide, but instead 11.8 months. In your clinic, who do you give olaratumab to, if anybody?

Jonathan C. Trent, MD, PhD: I try to give it to any patient I’m giving doxorubicin to. In my opinion, the doxorubicin/olaratumab combination has replaced doxorubicin. I don’t use single-agent doxorubicin anymore. I think you said that yesterday in your education session.

Richard F. Riedel, MD: Yes, I did.

Jonathan C. Trent, MD, PhD: Doxorubicin/olaratumab has not been compared head-to-head to doxorubicin/ifosfamide, so there’s a little bit of a gray area as to which one is superior. You can’t compare the 2 studies. So, in my practice, I try to give doxorubicin plus ifosfamide plus olaratumab because I think that gives the best chance for an individual patient.

Richard F. Riedel, MD: As part of a clinical trial or off label?

Jonathan C. Trent, MD, PhD: As part of a clinical trial if the patient is eligible. If not, then it’s an off-label discussion.

Transcript Edited for Clarity