SLIDES & TRANSCRIPTS
Monday, June 17

Primary Management of Soft Tissue Sarcomas: Current Approaches and Challeges

Samuel Singer, MD

The challenges, I think, can be considered in three broad categories: Can we develop and improve systems of sarcoma classification and prognostication based on molecular genetic methods, NMR spectroscopic methods, so that we can select out those patients at highest risk in an objective fashion? Can we understand the molecular mechanisms in sarcoma oncogenesis, leading to novel therapy such as c-kit and GIST and PPAR-gamma ligands in liposarcoma, which is still an evolving story? Finally, can we improve local and systemic therapy by improving the way we select patients for adjuvant therapy?

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Clearly, for the optimal management of sarcoma, histologic classifications. It is extremely important. We have to know the histologic type of the sarcoma, since that influences the type of surgery and extent of surgery that the surgeon will perform. We clearly need sufficient biopsy material, whether it is multiple cores or small, incisional biopsy, to determine that. It is a multidisciplinary team approach that is important to these patients. We can all agree on the gains of avoiding local recurrence, preservation of limb or organ function, reducing morbidity and improving survival in these patients.

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In terms of histologic distribution, in the extremity, liposarcoma and myxofibrosarcoma are the most common type, with the myxoid round cell subtype most common in the extremity location. For the retroperitoneal, liposarcomas account for the majority of these tumors, with leiomyosarcomas under those, and other liposarcomas in the retroperitoneum, most are the well-diff, de-diff subtype. In the viscera, they are largely accounted for by GI stromal sarcomas, with the unique expression of kit.

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In terms of the diagnostic evaluation, the MRI or the CT of the primary allows the surgeon to determine the size, the extent of muscle or organ involvement, and the relation to neurovascular structures. This is clearly very important in helping define the procedure.

A chest CT or chest x-ray for lung metastasis in the future -- I think we will see arising more molecular imaging technologies, such as new techniques in PET scanning, molecular profiling, and NMR biochemical patterns, that will help us further hone the diagnostic strategies with relatively non-invasive techniques.

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The treatment plan that a surgeon designs is largely tailored to a lesion's predictive pattern of local growth and the risk and site of distant metastasis. The extent of the surgery locally largely depends on the size and histologic type of the tumor and the anatomical relation to major neurovascular bundles. The question a surgeon needs to ask is, can you reduce loss of function by the use of neoadjuvant or adjuvant chemotherapy or radiotherapy and to choose that type of therapy, whether it be neoadjuvant or adjuvant therapy, is really dependent upon the histologic type, grade, and size of the tumor at present.

We really need, though, to develop molecular and biochemical markers of risk of recurrence and response to therapy, so that we can better tailor the therapy to the individual patient.

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In terms of the therapeutic advances and the local treatment of sarcoma, in the 1970s, most patients -- over 50 percent -- were treated with amputations and those who did have wide excision alone, there was a 20 to 30 percent local recurrence rate. In the next decade, we saw the introduction of multi-modality therapy with 90 percent of patients having limb-sparing surgery and, in those who were treated with wide excision and radiotherapy, many series had about a 10 to 15 percent local recurrence rate.

The adjuvant chemotherapy trials in this decade largely showed improved local control with no improvement in overall survival. In the 1990s, we saw a further optimization of various applications of adjuvant therapy, particularly the randomized brachytherapy trial carried out at Memorial, as well as the randomized external beam radiotherapy carried out at the NCI.

In addition, we also saw advances in soft tissue reconstructive technologies with using soft tissue transfer, free flaps, and the ability to reconstruct nerve and other tissues.

I think in the next decade you will see the introduction of molecular targeted therapy, which we have begun to see with GIST, and also molecular targeted selection of adjuvant therapy.

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So, when should brachytherapy be utilized? This is a typical patient who presented with a lesion, a seven-centimeter lesion that was shelved out from the antecubital fossa. It was synovial sarcoma. It was treated with a wide excision with implantation of brachytherapy and a free tissue transfer for limb preservation that continues to be disease-free out to seven years, and has excellent limb function.

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The question is, a key trial which addressed the use of brachytherapy was designed by Dr. Brennan back in 1982, accrued patients over a 10-year period. In that trial, 164 patients with completely resected extremity and superficial trunk sarcoma were stratified by size, grade, depth, and site and intraoperatively randomized to either brachytherapy or observation.

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In this trial, which Dr. Brennan has now updated as of June 2001, it shows an improved local disease-free survival in the group treated with brachytherapy; but this did not reach statistical significance in the overall patient population.

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However, in the high-grade extremity group and superficial trunk group, there was a statistically significant improved local recurrence disease-free survival -- 90 percent at five years compared to the non-treatment arm, which only had a 65 percent disease-free survival at five years, showing the efficacy of use of brachytherapy in the extremity.

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However, despite this large difference in the local recurrence rate, there was no difference in overall survival now with long-term follow-up showing that, even if these patients did recur, they were able to be salvaged with subsequent surgery, and it did not impact on their overall survival. This trial shows that a targeted radiotherapy which is perhaps more targeted than external beam in the high-grade group is effective at local control and may even suggest as well that we might be able to target our external beam radiotherapy more than we presently do now. Furthermore, it shows that brachytherapy was not of particular use for the low-grade tumor.

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So, what is the role of external beam radiotherapy in sarcoma management? This is a patient with a large tumor in the biceps femoris, got a wide incision, complete resection, clean but close resection margins on the sciatic nerve, and was treated with post-op adjuvant radiotherapy. He is a long-term survivor after seven years with excellent function and is an active runner.

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What is the impact of post-operative external beam radiation therapy in extremity sarcoma? Well, in NCI's prospective randomized trial, this was best addressed by comparing limb-sparing surgery to limb-sparing surgery with post-operative external beam radiotherapy.

The high-grade group was all treated with post-op chemo and randomized to either external beam radiotherapy or no treatment.

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In the group that was treated -- in the high-grade group which was treated with limb-sparing surgery alone and post-operative chemotherapy -- there was a 22 percent local recurrence rate. In the group that was treated with radiotherapy, there were no local recurrences in this group and, despite the 22 percent difference in local recurrence rate, there was no difference in overall survival suggesting that this increased incidence of local recurrence, again, did not impact on overall survival.

The other issue here is, you can take this trial and say that external beam radiotherapy should therefore be used in all patients with high-grade tumors, because it can effectively improve local control. On the other hand, you can look at the 78 percent of patients who were treated with limb-sparing surgery alone and never recurred.

The question really is, can we pick out those patients who don't need the adjuvant radiation therapy, who don't need to have the morbidity or the cost of that therapy?

One way, if you go back over the series and looked at the margin status, in those patients who they achieved a greater than one-centimeter margin, there were no local recurrences. So, one way to do that might be on the margin status.

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From the same trial, this looks at the low-grade group of extremity sarcomas. Again, in the limb-sparing alone group, there was a 36 percent incidence of local recurrence, which was similar to the incidence seen in the Memorial brachytherapy trial.

If you added radiotherapy to this limb-sparing surgery group, you could reduce the recurrence rate to five percent.

Again, in spite of reduction of as much as 22 percent local recurrence, no difference in overall survival. In the group that achieved a greater than one-centimeter margin, there were no local recurrences in the group that was treated with limb-sparing surgery alone.

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Do all cases of limb-sparing surgery require radiotherapy for good local control? This is a particular patient where I think it is useful to use surgery alone. This is a six-centimeter superficial tumor, superficial to the fascia. You can take the deep fascia as part of your resection and perform a good one- to two-centimeter margin excision with a clean resection, primary closure. This patient had no local recurrence, yet died of systemic disease three years later.

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We have our own series of function-sparing surgery without radiotherapy for sarcoma, which was carried out at the Brigham, with 77 patients treated with limb-sparing surgery without radiotherapy with a median follow-up of 126 months.

The 10-year actual local control rate was seven percent in the series. In those patients where less than a one-centimeter margin was achieved, there was a 13 percent local recurrence. There was no local recurrence, similar to the NCI series, in those that achieved a greater than one-centimeter margin. There was a trend for the high-grade tumors to have a higher local recurrence rate than the low-grade tumors, but this did not reach statistical significance.

Clearly, I think there is a role for limb-sparing surgery, in that we tend to overuse radiotherapy in our management of these patients. If we could select out a group based on careful criteria, this would be quite useful for reducing morbidity in these patients.

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One way to carry this out, we would need to have very careful assessment of the type of procedure. Surgeons talk about procedures in terms of marginal, wide, and radical amputation; but more important, what is the pathological margin that you actually achieve with this procedure? We need to develop better technology for determining margin assessment, determine the true microscopically positive margin. The type of margin is important, whether you have a leather-bound fascia or whether it is just a cuff of muscle or fat, and the size of the margin. So, we need to develop better technologies for margin assessment if we want to plan to design trials to predict those patients who could be treated with surgery alone and don't need adjuvant therapy.

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One interesting proposal might be to look, for example, at invasiveness in adhesive genes, that may affect both local and distant recurrence.

The matrix metalloproteinases, such as collagenases and stromelysins -- these degrade the extracellular matrix components and could make a tumor more likely to invade locally.

One could look at the various modulators of these metalloproteinases, whether they be inhibitors or stimulators, and look at these genes in molecular profiling to determine whether a tumor had a propensity for local recurrence of not. You could look at collagens and laminin. In sarcomas where that had abundant matrix, those may put up barriers to subsequent tumor invasion and there may be less incidence of local recurrence in these patients. This is a potential idea for the development of molecular parameters that would correlate with the risk of local occurrence.

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In terms of identifying molecular patterns that might predict response or resistance to adjuvant therapy, that would help us select patients, one could look at checkpoint genes that act to arrest the cell cycle, either due to DNA damage, incomplete DNA replication or mitotic spindle cell disruption. If you have loss of a checkpoint gene, you might get proliferation even in the presence of unrepaired DNA and this may increase the tumor's response to adjuvant radiotherapy or adjuvant therapy of any type. On the other hand, if you had loss of a mitotic spindle checkpoint gene, the tumor cells could become more aneuploid and resistant to adjuvant therapy.

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Finally, can one develop molecular NMR biochemical markers of apoptosis? This sort of is a quantitative measure of response to adjuvant therapy. If we can understand the basic apoptotic pathways, can we design -- that should be able to predict response to radiation or chemotherapy based on interfering with the process of apoptosis?

There is already data suggesting varying levels of bcl-2, for example, in synovial sarcoma, particularly in the spindle cell regions of that tumor.
Other papers have shown that this bcl-2, that there is a lack of bcl-2 phosphorylation and that this may correlate with the resistance of these tumors to chemotherapy.

One could assess for both pro-apoptotic response genes -- TNF, TNFR, Bax, Bad and caspase family proteases -- or anti-apoptotic resistance genes, and then use this pattern to subsequently select patients who would be potentially resistant or responsive to therapy.

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In terms of our current approach to extremity and truncal sarcoma summarized -- for the subcutaneous or intramuscular small, less-than-five-centimeter high-grade sarcoma or any size low-grade sarcoma -- one should consider surgery alone with adequate wide margin excision.

We need to develop new protocols that would define these criteria to a greater degree. If you have a patient with a close-margin, extramuscular involvement or previous excisional biopsy, then oftentimes you may want to add radiotherapy to the local treatment in those patients.

In terms of a large, high-grade extremity or truncal tumor, there is a great deal of controversy in the treatment of these lesions. It would depend on which institution you are treated at, the exact sequence and combination of therapies you would obtain. Size is clearly continuous variable.

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You can identify various cut-offs of five, eight, and 10, at which point you would think the risk sufficient for potential metastatic disease that you would want to incorporate neoadjuvant chemotherapy into your protocol, for example, for the large, greater-than-10-centimeter high-grade lesion.

The advantage of giving the chemo upfront for that particular high-risk case might be that you could assess those people who are going to progress and not have to go through the toxicity of further chemotherapy. We really need to define clearly the benefit of all this adjuvant therapy and clearly define randomized trials, similar to what has been done with external beam and brachytherapy in those randomized trials.

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In terms of future challenges in the management of sarcoma, we really need to develop clinical, molecular and biochemical markers that predict local or distant recurrence, and then use these markers to identify those patients who need adjuvant therapy and those that are unlikely to benefit from the therapy. We need to then identify the molecular biochemical markers that predict therapeutic response.

Again, in those patients who are resistant to therapy, either you would avoid it or you could develop a target treatment that could overcome this resistance. I think if we could achieve these goals, it would be a major step forward in the primary management of soft tissue sarcoma. Thank you very much.

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