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Peri-Operative Therapy for Adult Soft Tissue Sarcoma

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: Wednesday, Jul 25, 2018



Transcript: 

William D. Tap, MD: Let’s take a few quick scenarios. What about a patient who had a 7-cm extremity tumor resected from outside then comes to you with pathology of a sarcoma. How do you look at that patient? What are some of your initial thoughts when you go to a tumor board?

Kristen N. Ganjoo, MD: I think the important thing for that patient would be margins. What are the margins? Are the margins negative? Do we need to go in and resect again? Do we need to use radiation therapy and adjuvant chemotherapy? All of that stuff is important, but the pathology review comes in first for the margins.

Richard F. Riedel, MD: Margins are important. You also need to know the grade of the tumor. For a low-grade well-differentiated liposarcoma that has a positive margin, we may be able to just watch that, as opposed to a high-grade tumor where you’re going to want to perform a tumor bed resection and certainly consider some form of adjuvant therapy.

William D. Tap, MD: I agree. A lot of it is also what the surgeons know going in. Do they know that this was an oncological procedure and did they perform a proper procedure or was this something that they felt was just a benign lesion and took out? Because that reresection could be critical. What about a tumor that involves a 10-cm high-grade extremity lesion? I know there’s a lot of controversy in our field about neoadjuvant therapy versus adjuvant therapy. What do you use? John, why don’t you tell us a little bit about your approach?

Jonathan C. Trent, MD, PhD: At Sylvester Comprehensive Cancer Center, when we see a patient with a particularly larger-than-5-cm high-grade sarcoma, we generally have the approach of multimodality therapy. At tumor board, we discuss chemotherapy, surgery, and radiation. The sequencing is where it’s important to rely on the expertise of the other physicians. For instance, if a tumor is very close to a nerve and another couple of weeks of growth could result in an amputation, you don’t want to do that. Maybe surgery first would be a good approach. But in general, for this specific scenario, we would use preoperative chemotherapy for 2 cycles, reimage with another MRI, decide if it’s stable or responding, and continue with another 2 cycles.

The patient would have preoperative radiation, surgery, and quite likely additional chemotherapy postoperatively for a complete 5 to 6 cycles. Generally, we shoot for 6 cycles of doxorubicin plus ifosfamide. There are limited data, as we all know, on neoadjuvant therapy. But there are pretty good data supporting adjuvant chemotherapy in the setting of a large high-grade sarcoma based on a meta-analysis. And so, what we do is just move a portion of that adjuvant chemotherapy to the preoperative setting. It also helps us understand the sensitivity of the individual patient’s tumor to that chemotherapy, so you can really design a personalized approach.

William D. Tap, MD: Does everyone agree with doxorubicin and ifosfamide?

Kristen N. Ganjoo, MD: It depends on the age of the patient, right? If the patient is older, ifosfamide would be a little bit difficult. I’ve been using Adriamycin with olaratumab neoadjuvantly, even though it’s been approved for the metastatic setting. But for patients over the age of 65, it’s difficult to use ifosfamide.

Victor M. Villalobos, MD, PhD: What are your thoughts about the Italian/Spanish study that came out a couple years ago basically showing equal efficacy of 3 cycles versus 5 cycles of AIM (Adriamycin, ifosfamide, and mesna) in the adjuvant setting? Is it because they’re both equally effective or equally ineffective in the neoadjuvant setting? I think it’s probably more likely that they’re equally effective to a certain degree. But do you need to give 6 cycles, particularly with a drug that has such long-term side effects? Is it worth giving that and actually losing your ability to treat them later on after they metastasize with doxorubicin?

William D. Tap, MD: It’s a tough question because one of the things you’re wondering in that situation is, are you treating for overall survival? My experience sometimes with AIM is you only see your best responses after about 4 cycles of the therapy. It depends what you’re trying to do with the treatment. Are we trying to surgically convert a patient and really shrink it or are we also trying to get to survival? I think it’s important to manage patients’ expectations as well. Rich, how do you approach a patient like this?

Richard F. Riedel, MD: We’ve heard about how John and Kristen use chemotherapy. At Duke, we actually fall on the complete other side of the spectrum. For the scenario that you presented, a large high-grade extremity sarcoma, we would take the tact of neoadjuvant therapy; not chemotherapy, but rather radiation therapy for about 5-and-a-half weeks followed by resection. At least at our institution, the use of adjuvant chemotherapy is used rarely, to be quite honest. With the data that support the use of adjuvant chemotherapy, there’s a suggestion through subgroup analyses that large high-grade extremity sarcomas are the cases that are most likely to benefit.

We know that there have been recent published data—John quoted the meta-analysis—showing improvement in local and distant recurrence-free survival, a trend toward overall survival. More recent randomized data showed absolutely no improvement for relapse-free or overall survival. I think it’s still an area that’s controversial, but it’s certainly not wrong to consider it. I think it’s certainly very reasonable to consider it, but I think it’s also reasonable to consider radiation therapy for improving local control with primary resection.

Kristen N. Ganjoo, MD: How much response do you get with radiation therapy without any radiosensitizers? Because we use ifosfamide with radiation. Even with low doses of ifosfamide, we’ve seen 99% necrosis in some of these tumors without neoadjuvant chemotherapy.

Richard F. Riedel, MD: I think it depends on the histology. Myxoid liposarcomas are extremely sensitive to radiation therapy. I don’t think you need chemotherapy for that.

Kristen N. Ganjoo, MD: That’s right.

Richard F. Riedel, MD: With synovial sarcoma, we’ve seen some responses. I can’t say that we’ve seen 99% necrosis routinely. I have used full-dose ifosfamide with radiation therapy in a situation where someone had a very large tumor and I was worried about the interval development of distant metastatic disease during the 5 weeks of trying to give radiation therapy. But that’s a fairly uncommon scenario.

Victor M. Villalobos, MD, PhD: I think the difficulty in general, and why there is some controversy, is that they’re not great. If it was a massive difference, everyone would be doing it. There would be no controversy. But the problem is these are very toxic drugs and they don’t cause a dramatic change. There is a difference between age. If you have a 45-year-old patient with young kids, they’re much more likely to accept significant toxicity to try and have some increased benefit versus if you have a 78-year-old patient who is more likely to say, “You know what, this really toxic drug combination may not be for me.” I always try and frame that with the patient and say, “Look, here are the data. I can’t make a decision for you.” This is not osteosarcoma, where there’s a really a dramatic difference between the 2. To a large degree, it becomes a judgment call.

William D. Tap, MD: It’s interesting because we have 4 experts with 4 different opinions; not so differing, but with different approaches. Who’s right? Who’s wrong? You can have a community oncologist who may only see a handful of sarcoma patients.

Transcript Edited for Clarity 

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Transcript: 

William D. Tap, MD: Let’s take a few quick scenarios. What about a patient who had a 7-cm extremity tumor resected from outside then comes to you with pathology of a sarcoma. How do you look at that patient? What are some of your initial thoughts when you go to a tumor board?

Kristen N. Ganjoo, MD: I think the important thing for that patient would be margins. What are the margins? Are the margins negative? Do we need to go in and resect again? Do we need to use radiation therapy and adjuvant chemotherapy? All of that stuff is important, but the pathology review comes in first for the margins.

Richard F. Riedel, MD: Margins are important. You also need to know the grade of the tumor. For a low-grade well-differentiated liposarcoma that has a positive margin, we may be able to just watch that, as opposed to a high-grade tumor where you’re going to want to perform a tumor bed resection and certainly consider some form of adjuvant therapy.

William D. Tap, MD: I agree. A lot of it is also what the surgeons know going in. Do they know that this was an oncological procedure and did they perform a proper procedure or was this something that they felt was just a benign lesion and took out? Because that reresection could be critical. What about a tumor that involves a 10-cm high-grade extremity lesion? I know there’s a lot of controversy in our field about neoadjuvant therapy versus adjuvant therapy. What do you use? John, why don’t you tell us a little bit about your approach?

Jonathan C. Trent, MD, PhD: At Sylvester Comprehensive Cancer Center, when we see a patient with a particularly larger-than-5-cm high-grade sarcoma, we generally have the approach of multimodality therapy. At tumor board, we discuss chemotherapy, surgery, and radiation. The sequencing is where it’s important to rely on the expertise of the other physicians. For instance, if a tumor is very close to a nerve and another couple of weeks of growth could result in an amputation, you don’t want to do that. Maybe surgery first would be a good approach. But in general, for this specific scenario, we would use preoperative chemotherapy for 2 cycles, reimage with another MRI, decide if it’s stable or responding, and continue with another 2 cycles.

The patient would have preoperative radiation, surgery, and quite likely additional chemotherapy postoperatively for a complete 5 to 6 cycles. Generally, we shoot for 6 cycles of doxorubicin plus ifosfamide. There are limited data, as we all know, on neoadjuvant therapy. But there are pretty good data supporting adjuvant chemotherapy in the setting of a large high-grade sarcoma based on a meta-analysis. And so, what we do is just move a portion of that adjuvant chemotherapy to the preoperative setting. It also helps us understand the sensitivity of the individual patient’s tumor to that chemotherapy, so you can really design a personalized approach.

William D. Tap, MD: Does everyone agree with doxorubicin and ifosfamide?

Kristen N. Ganjoo, MD: It depends on the age of the patient, right? If the patient is older, ifosfamide would be a little bit difficult. I’ve been using Adriamycin with olaratumab neoadjuvantly, even though it’s been approved for the metastatic setting. But for patients over the age of 65, it’s difficult to use ifosfamide.

Victor M. Villalobos, MD, PhD: What are your thoughts about the Italian/Spanish study that came out a couple years ago basically showing equal efficacy of 3 cycles versus 5 cycles of AIM (Adriamycin, ifosfamide, and mesna) in the adjuvant setting? Is it because they’re both equally effective or equally ineffective in the neoadjuvant setting? I think it’s probably more likely that they’re equally effective to a certain degree. But do you need to give 6 cycles, particularly with a drug that has such long-term side effects? Is it worth giving that and actually losing your ability to treat them later on after they metastasize with doxorubicin?

William D. Tap, MD: It’s a tough question because one of the things you’re wondering in that situation is, are you treating for overall survival? My experience sometimes with AIM is you only see your best responses after about 4 cycles of the therapy. It depends what you’re trying to do with the treatment. Are we trying to surgically convert a patient and really shrink it or are we also trying to get to survival? I think it’s important to manage patients’ expectations as well. Rich, how do you approach a patient like this?

Richard F. Riedel, MD: We’ve heard about how John and Kristen use chemotherapy. At Duke, we actually fall on the complete other side of the spectrum. For the scenario that you presented, a large high-grade extremity sarcoma, we would take the tact of neoadjuvant therapy; not chemotherapy, but rather radiation therapy for about 5-and-a-half weeks followed by resection. At least at our institution, the use of adjuvant chemotherapy is used rarely, to be quite honest. With the data that support the use of adjuvant chemotherapy, there’s a suggestion through subgroup analyses that large high-grade extremity sarcomas are the cases that are most likely to benefit.

We know that there have been recent published data—John quoted the meta-analysis—showing improvement in local and distant recurrence-free survival, a trend toward overall survival. More recent randomized data showed absolutely no improvement for relapse-free or overall survival. I think it’s still an area that’s controversial, but it’s certainly not wrong to consider it. I think it’s certainly very reasonable to consider it, but I think it’s also reasonable to consider radiation therapy for improving local control with primary resection.

Kristen N. Ganjoo, MD: How much response do you get with radiation therapy without any radiosensitizers? Because we use ifosfamide with radiation. Even with low doses of ifosfamide, we’ve seen 99% necrosis in some of these tumors without neoadjuvant chemotherapy.

Richard F. Riedel, MD: I think it depends on the histology. Myxoid liposarcomas are extremely sensitive to radiation therapy. I don’t think you need chemotherapy for that.

Kristen N. Ganjoo, MD: That’s right.

Richard F. Riedel, MD: With synovial sarcoma, we’ve seen some responses. I can’t say that we’ve seen 99% necrosis routinely. I have used full-dose ifosfamide with radiation therapy in a situation where someone had a very large tumor and I was worried about the interval development of distant metastatic disease during the 5 weeks of trying to give radiation therapy. But that’s a fairly uncommon scenario.

Victor M. Villalobos, MD, PhD: I think the difficulty in general, and why there is some controversy, is that they’re not great. If it was a massive difference, everyone would be doing it. There would be no controversy. But the problem is these are very toxic drugs and they don’t cause a dramatic change. There is a difference between age. If you have a 45-year-old patient with young kids, they’re much more likely to accept significant toxicity to try and have some increased benefit versus if you have a 78-year-old patient who is more likely to say, “You know what, this really toxic drug combination may not be for me.” I always try and frame that with the patient and say, “Look, here are the data. I can’t make a decision for you.” This is not osteosarcoma, where there’s a really a dramatic difference between the 2. To a large degree, it becomes a judgment call.

William D. Tap, MD: It’s interesting because we have 4 experts with 4 different opinions; not so differing, but with different approaches. Who’s right? Who’s wrong? You can have a community oncologist who may only see a handful of sarcoma patients.

Transcript Edited for Clarity 
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