Brian A. Van Tine, MD, PhD: I think this really allows for a quick transition to the surgical management of, say, primary localized tumors. So, if you could briefly discuss that, I think it would be useful.

R. Lor Randall, MD, FACS: Without getting into too much detail, the small, lower-grade lesions, for the most part, are influenced by the nuances of anatomic location. But for the smaller, lower-grade lesions, I think most people agree that wide local excision is simply the standard of care with important surveillance locally and systemically. For the more aggressive lesions, particularly as they get bigger, we have to roll in adjuvant modalities or neoadjuvant modalities, and radiotherapy is a cornerstone of that.

Most centers, in my opinion, having trained when we did it post operatively, are now moving towards neoadjuvant or preoperative radiotherapy for a variety of reasons I won’t get into right now, but I’m happy to come back to later. And then, obviously, neoadjuvant chemotherapy use to cyto-reduce is also a very important point. But we also know that the margin matters. We need our colleagues to work together to get that tumor out.

Brian A. Van Tine, MD, PhD: You can never over stress the importance of surgery and radiation in the treatment of our disease. I think they’re just invaluable modalities. But I think what the real moving target is, and what I’d like to spend most of the rest of our time today talking about, is our standard-of-care chemotherapy and everything that’s evolving.

Because this field, for the first time in a very long time actually, has an influx of potential new drugs that are going to very quickly start changing the landscape of how the nonsurgeons approach the tumors. Jonathan, why don’t we let you lead off with a discussion of your approach, and we can all chime in, for chemotherapy in advanced soft tissue sarcoma.

Jonathan C. Trent, MD: Our approach is, really, first to evaluate the patient fully, discuss the patient at a multidisciplinary tumor board, and if this is termed an advanced soft tissue sarcoma, then we’re in the situation where this is either metastatic or locally advanced—locally advanced meaning that at the current point in time, the oncologic resection that would be needed is not appropriate or not acceptable to the patient in terms of morbidity.

So, then, in order to transition a locally advanced or unresectable tumor to one that could be resected, we consider alternative therapies to try to get to that point in terms of tumor shrinkage. That could be chemotherapy. That could be preoperative chemotherapy. In certain circumstances, that could be a targeted therapy. But the goal really—to get from an advanced to a resectable situation—requires tumor reduction in size. And so our approach in that situation is to do whatever we can do optimally to get to resection. And that’s generally, for the usual or the common unclassified pleomorphic sarcomas, leiomyosarcomas, certain liposarcomas, to use preoperative chemotherapy, preoperative radiation, and try to get to a situation where an operation that is appropriate and acceptable to the patient, can be performed.

We spend a lot of time within the medical oncology group discussing which chemotherapy to use, and our general approach is the one that we believe is most effective for that patient because we’re looking for cytoreduction and decreasing the tumor size. So, we’ll choose the regimen that we believe has the highest response rate in terms of reduction in size. That’s our general approach.

We also use that opportunity to administer chemotherapy to treat micrometastatic disease, as well as to improve local control rates. And so preoperative chemotherapy for many sarcoma types is standard at our center. There are certain histologies where we don’t use preoperative chemotherapy, in some of the tumors that are chemoresistant and some of the chondrosarcomas, unless it’s in the context of a clinical trial.

Brian A. Van Tine, MD, PhD: I think you’re absolutely right. I think this is one of the reasons that people like you are involved very early on in helping us decide what to do with who because you actually have to treat the patient also and their very specific kind of sarcoma, and it’s not a one-size-fits-all anymore.

So, it’s kind of a moving target, and it’s evolving and we’re learning. And then everything gets very complicated by the fact our tumors like to fibrose and not change in size. So, that’s one of the things where I think we, as a field, are very comfortable with that concept. But then everybody outside gets very uncomfortable. If chemo’s not working and things aren’t getting smaller, they may just be fibrotic.

Andrew J. Wagner, MD, PhD: Certainly, one of the big challenges, as Jon was just saying, is that different tumors behave differently. So, having a good knowledge of the expected behavior is important in terms of response to chemotherapy or even radiation therapy. But then, what’s even trickier, is that for a given tumor type, it’s still quite variable as to what the response is, and you don’t often know until the tumor is removed in the neoadjuvant setting, for example, whether or not there was a treatment response.

I agree with the use of neoadjuvant radiation therapy and neoadjuvant chemotherapy. The chemotherapy piece, the important question we like to ask the surgeons is, will it help you more if we shrink this tumor? The radiation is really important for tumors to help with margins and local control, but the problem sometimes with giving neoadjuvant chemotherapy is that you can introduce toxicity and, in some cases, it’s not effective and the tumor worsens, instead of reducing in size. And so, it could instead compromise the ability to resect the tumor. Again, it’s a very important thing to discuss in a multidisciplinary setting to say …

R. Lor Randall, MD, FACS: It really is discretionary.

Andrew J. Wagner, MD, PhD: Yeah, what’s the risk associated with this, as well as what are the chances of this benefiting the patient?

Robin L. Jones, MD, MRCP: I think that that’s the crucial thing—that it needs to be a very careful, thoughtful, decision regarding the use of neoadjuvant chemotherapy. The evidence base is limited for both neoadjuvant and adjuvant chemotherapy, and we have to be aware of that and have to make the patients and their families aware of that fact, particularly in the context of the long-term side effects of the chemotherapy drugs that are used.

I think you’re right; it needs to be a very thoughtful decision regarding the histological subtype, regarding the surgical management of the patient, if the tumor is downstaged. Will that change the operation that’s done? We know that some subtypes are very chemosensitive; others are very chemoresistant. And it needs to be a very, very thoughtful discussion.

Brian A. Van Tine, MD, PhD: Lor, as a surgeon, can I get your brief thoughts on either regional hyperthermia therapy or isolated limb perfusion therapies, some of which are more classical and not used as much. What are your thoughts on those?

R. Lor Randall, MD, FACS: I maintain healthy skepticism. I respect those treatments. I don’t generally advocate for them because of their issues with associated toxicities to the limb and potentially even systemically. But, I also want to make sure that the message is that, in the context of a clinical trial or in the context of something where there might only be ablative options, those modalities do have a role.

Robin L. Jones, MD, MRCP: Yeah, I agree.

Andrew J. Wagner, MD, PhD: There aren’t many centers that do them either, so it’s another challenge. As we talked about patients traveling quite a distance to get their care, that adds another layer of complexity where there aren’t many centers that do either one of those treatments.

Transcript Edited for Clarity