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Evolving Paradigms in STS: Perspectives With Shreyaskumar R. Patel and Jonathan C. Trent, MD

Greg Kennelty
Published Online: Feb 16,2017

Jonathan C. Trent, MD

On October 23, 2015, trabectedin (Yondelis) was approved by the FDA after promising results from the phase III ET743-SAR-3007 trial. Trabectedin is used to treat patients with advanced soft tissue sarcoma, including liposarcoma and leiomyosarcoma subtypes, and specifically those who have previously received chemotherapy that included an anthracycline.
In the open-label, multicenter, phase III SAR-3007 trial, trabectedin reduced the risk of disease progression by 45% versus dacarbazine in patients with advanced soft tissue sarcoma. There was also a slight survival trend with trabectedin, but the results were not significant.
The trial compared trabectedin with dacarbazine in 518 patients with liposarcoma and leiomyosarcoma who previously received an anthracycline-containing regimen followed by at least one additional line of chemotherapy. The protocol required patients to have an ECOG performance status of 0 or 1. The study was conducted at 85 sites in four different countries, but 94% of the patients were enrolled in the United States.
In an exclusive interview with Targeted Oncology, Shreyaskumar R. Patel, MD, professor, Department of Sarcoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, and Jonathan C. Trent, MD, professor of Medicine, co-director, Musculoskeletal Center, Sarcoma Medical Research Program, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, discussed the use of trabectedin and the future of the treatment paradigms in soft tissue sarcoma.

What have been some of the challenges toward evidence-based treatment in soft tissue sarcoma and how is that evolving?


PATEL:  One of the biggest challenges is that this is a rare group of tumors. Of the 1,650,000 or so new cancers diagnosed in the calendar year 2015, soft tissue sarcomas are just under 12,000 cases. As a group of diseases, it's rare. The added complexity is that the soft tissue sarcomas umbrella is comprised of 50 to 75 subtypes of sarcomas.

The three or four of the more common ones tend to be liposarcomas, leiomyosarcomas, and differentiated biomorphic sarcomas, but the list of entities that fall within this group of tumors that we call soft tissue sarcomas is very long. Consequently, what ends up happening is, to try to get level one evidence, you would need a large sample size in a very homogenous population. That's virtually impossible. Compare this to breast cancer, for example, where there are clearly more than 200,000 new cases in a given calendar year. The heterogeneity is a lot less than it is for soft tissue sarcomas. Consequently, it's not impractical.
As a matter of fact, it is standard practice to run between 2000 and 4000 patient clinical trials in the breast cancer population, in a uniform or homogenous population, to obtain the right answers that would constitute that level one evidence. That's virtually impossible in soft tissue sarcomas. You may run into several trials that may show a 10% difference in the primary endpoint in favor of an experimental arm versus the control arm, but the P-value may not be significant because the sample size is small. This is one of the major issues that we run into.
From a statistical standpoint, you really do want larger clinical trials and to get a large number of patients in a reasonable period of time. Of course, "reasonable" as defined by the sponsors and investigators, collectively. You then end up lumping a lot of patients together, and as I typically said, "you make a fruit salad out of the patient population." You mix apples, pears, peaches, and oranges, which makes the data that much less interpretable, if you will. To try to just test the apples, it will take a very, very long time, and that's the major limitation with soft tissue sarcomas.
Is there anything being done about it? I think over the last several years, the international community has come together. There are examples of trials that are run on both sides of the Atlantic, or even extending over to Asia, Australia, and beyond, to try to get behind a given trial that may be of interest to see if we can try to homogenize, if you will, the population as best as we can.

TRENT: The management of sarcoma patients has always been challenging in terms of an evidence-based approach. There are a number of studies, but these clinical trials and other studies tend to be small. They tend to be limited in the focus on specific types of sarcomas. This is not surprising when there"s only 10,000 to 15,000 new patients per year diagnosed with sarcoma in the United States, and there are over 50 different types of sarcoma. It can be really challenging to have robust data and large numbers of patients.

That being said, there have been a number of randomized studies recently that have asked several specific questions. For instance, there was a recent study asking whether the use of gemcitabine/docetaxel was better than using an anthracycline such as doxorubicin in frontline therapy for patients with metastatic sarcoma. The result of that study was that doxorubicin was better tolerated and probably more effective than the combination of gemcitabine/docetaxel. Another study recently led to the approval of pazopanib in the treatment of patients with soft-tissue sarcoma, including liposarcoma and GI stromal tumors. This was based on a phase III study comparing pazopanib to placebo in patients with metastatic sarcoma.
A more recent study looked at the use of trabectedin in patients with liposarcoma or leiomyosarcoma. This subset of patients had metastatic disease, and the patients were randomized to either trabectedin or dacarbazine. The result of the study was superiority of the trabectedin arm.
You can see that there are a number of studies that are enrolling a larger number of patients, some of these in specific histologies such as the trabectedin study, which looked at liposarcomas and leiomyosarcoma.

Shreyaskumar R. Patel, MD

What is the most effective method for a diagnosis and grading soft tissue sarcoma, and how important is molecular genetic testing?


PATEL: The histopathologic diagnosis part of the disease is fairly well standardized. If patients are presenting with a lump or a mass, we will get a biopsy. The tissue is, and should be, analyzed by pathologists with expertise in musculoskeletal pathology. The characteristics of each one of these 50 to 100 different subtypes, depending on how many you're lumping under the umbrella of sarcomas, is reasonably well defined. Pathologists with expertise will not have difficulty in making the diagnosis.

I think the molecular genetics portion of this particular group of sarcomas is a different story. We will slowly, but steadily, be peeling away at some of the smaller subsets. Where there are characteristic translocations, for example, there may be fusion probings that can be identified to try to help from a diagnostic standpoint, assign a specific name to that particular entity.
TRENT: Sarcomas have always been a challenging type of cancer to diagnose and grade. There are 10,000 to 15,000 new sarcoma patients per year in the United States compared with somewhere near 200,000 women diagnosed with breast cancer. This is a very rare disease. To make it more complicated, there are over 50 different types of sarcoma. In any individual type, there may only be several hundred or several thousand cases diagnosed per year in the United States. The rarity of this tumor makes it challenging for pathologists to make the diagnosis and assess the grade of the tumor.
At the University of Miami Sylvester Comprehensive Cancer Center, we have our sarcoma pathologists review all new cases in all new patients that come to our site. I think that the critical first step in understanding how to treat a patient with a sarcoma is making the right diagnosis. I generally recommend have the material reviewed at a sarcoma center by a sarcoma specialty pathologist.

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Evolving Paradigms in STS: Perspectives With Shreyaskumar R. Patel and Jonathan C. Trent, MD
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