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.

, 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?

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

-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.

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.

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

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.

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.

In what population of patients would first-line chemotherapy be most appropriate?

I don't think these decisions are any different for soft tissue sarcomas than most other malignancies. Soft tissue sarcomas is more common in the fifth and sixth decade of life, so most of these patients tend to have a reasonable or a very decent performance status, even when they present with metastatic disease, organ function and performance status is acceptable enough for consideration of front-line systemic therapy. This is unlike some of the other epithelial tumors that may be far more widespread, where patients, either because of organ dysfunction, poor performance status, or just personal choice, would not be candidates for any line of systemic therapy. That proportion happens to be relatively small for the group of patients with soft tissue sarcomas.

In my practice, and in my experience, I think most of these patients with metastatic soft tissue sarcomas will end up going through multiple different lines of chemotherapy, or targeted therapies, or experimental trials, simply because they do tend to maintain and preserve their performance status and organ function for quite a long time.

Frontline chemotherapy is used in a variety of different situations in patients diagnosed with sarcoma. A patient is diagnosed with a primary tumor if the metastatic potential is high such as rhabdomyosarcoma, Ewing"s Sarcoma, desmoplastic small-round-cell tumor, osteosarcoma, these are patients that we initiate on chemotherapy as their frontline surgery, generally even before surgery or radiation therapy. In the metastatic setting, chemotherapy is the mainstay of treatment. These patients may get surgery or radiation at some point in the future, but in the setting of metastatic disease, the primary goal is to use systemic therapy to really control, shrink, hopefully even induce a complete remission for patients with metastatic sarcoma.

Who would be the right patient to receive trabectedin?

Trabectedin recently got approved for patients with metastatic or advanced leiomyosarcomas and liposarcomas. This was based on the way the clinical trial was designed. If you follow the prescribing information, then this would be appropriate for patients with leiomyosarcomas and liposarcomas who have metastatic disease, have advanced incurable disease, and who have failed at least one prior line of therapy that included anthracycline. This is the eligibility criteria for the clinical trial that led to the approval of this drug.

Certain subsets like a patient with myxoid liposarcoma are supposed to have exquisite sensitivity to this drug trabectedin, and if there were issues or contraindications to conventional anthracycline-based therapy, this [trabectedin] certainly can be moved up front in the line of therapy for that particular patient population.

Trabectedin is a new agent that we"re using to treat patients with metastatic or advanced sarcomas, specifically liposarcoma and leiomyosarcoma. Patients with liposarcoma and leiomyosarcoma generally present with primary disease, although many patients present with metastatic disease. Patients who do present with metastatic disease are often treated with an anthracycline combination therapy such as doxorubicin plus dacarbazine or doxorubicin plus ifosfamide. That"s standard frontline therapy for patients with metastatic sarcoma for most types. There are certainly caveats and certainly situations where that"s not the case, but that is the usual course of action.

After an anthracycline-based therapy, patients with metastatic sarcoma are treated with second-line therapy. In the setting of a diagnosis of liposarcoma or leiomyosarcoma, those options are gemcitabine/docetaxel for leiomyosarcoma or trabectedin, which has activity and is now FDA approved for leiomyosarcoma but also for liposarcoma, including dedifferentiated and myxoid liposarcomas.

What important developments have occurred toward improving treatments in leiomyosarcoma?

Leiomyosarcoma, one of the more common subsets of soft tissue sarcomas, has been a focus of attention of at least two large phase III randomized trials recently completed, presented, and to be published soon. One of them would be the Yondelis trabectedin approval for patients with leiomyosarcoma. The other one is a drug called eribulin. Eribulin, similar to trabectedin, was tested in a randomized phase III trial against dacarbazine and the data presented at ASCO last year showed improvement in overall survival. The drug is not yet approved for this indication, but certainly the hope would be that that becomes part of the therapeutic armamentarium for patients specifically with leiomyosarcomas.

Patients diagnosed with metastatic leiomyosarcoma have been difficult to treat over the years. Standard regimens include a combination of an anthracycline such as doxorubicin plus dacarbazine, occasionally doxorubicin plus ifosfamide. Second-line therapy that has been used in the United States includes gemcitabine/docetaxel, and now we have a new agent, trabectedin, that has been proven to be effective in second- and third-line therapy for patients with leiomyosarcoma. This is based on a phase III study where patients with metastatic leiomyosarcoma and liposarcoma were randomized to either trabectedin or a comparator arm of dacarbazine. Trabectedin was found to be superior.

What important developments have occurred toward improving treatment in liposarcoma?

I think both the phase III trials that we just mentioned included patients with liposarcomas and leiomyosarcomas. Yondelis is now approved for use in the United States, as it was for many other parts of the world. Eribulin data, like I said, was presented at ASCO and showed survival advantage, but is not yet approved by the FDA for this indication.

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Shreyaskumar R. Patel, MD and Jonathan C. Trent, MD discussed the use of trabectedin and the future of the treatment paradigms in soft tissue sarcoma.

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

Soft tissue sarcomas (STS) are tumors arising from the mesenchymal cells (

) and occur in fat, joints, muscles, blood vessels, nerves, and deep skin tissue (

According to classification by the World Health Organization (WHO), there are more than 50 histologic subtypes, and although STS are more prevalent than osteosarcomas, they account for only 1% to 2% of all malignancies.

It was estimated that 12,310 people would be diagnosed with STS and 4990 people would die from this cancer in 2016.

New cases of STS account for only 0.7% of all new cancer cases. The heterogeneity and rarity of STS has made evidence-based treatment difficult. As the understanding of tumor biology increases, new approaches to management of STS focus on selectively treating distinct subtypes.

Although the cause of most STS is unknown, known risk factors are associated with the disease.

These include genetic syndromes, radiation, and chemical exposure.

Neurofibromatosis, also known as von Recklinghausen&rsquo;s disease, is an inherited syndrome that increases the cumulative lifetime risk for nerve sheath tumors to 10%. It results from the dysfunction of the NF1 gene. Li-Fraumeni syndrome and hereditary retinoblastoma are also genetic syndromes that are associated with STS and result from germline mutations of tumor suppressor genes, specifically, TP53 and RB1, respectively.

The most common subtype associated with hereditary retinoblastoma is leiomyosarcoma followed by fibrosarcomas.

In a cohort of 963 patients with hereditary retinoblastoma, Kleinerman et al found that 33% of diagnosed STS were leiomyosarcomas.

In addition to genetic syndromes, high-dose radiotherapy increases the risk of secondary STS.

In a 2008 study, Penel et al evaluated 658 patients with STS to determine the frequency of etiologic factors.

Of the patients, 3.3% had radiation-induced STS. The time from primary cancer to secondary STS averaged 10 years.

Results from studies evaluating chemical exposure in association with STS vary.

When correlations are found, they are usually associated with herbicides and chlorophenols. Sex and age are also risk factors for STS. Overall, men have a slightly higher risk for STS than women (1.23:1.00 ratio, respectively), and diagnosis occurs more frequently in patients >55 years, with the mean age at diagnosis being 59 years (

STS are solid tumors and present as a new or growing lump.

The lump is usually painless, and the most common site for STS are the extremities (33%), followed by the trunk (14%) and retroperitoneum (19%).

A total of 8% of STS occur in the head and neck.

When located in the abdomen, STS may obstruct and cause bleeding of the bowels or stomach.

This can present as abdominal pain and blood in stool or vomit.

When a lump is present, imaging tests assist with diagnosis and staging.

Although traditional x-rays can rule out bone tumors and ultrasounds can differentiate between cysts and tumors, magnetic resonance imaging (MRI) is the standard imaging modality for STS, especially STS of the extremities, pelvis, and trunk. Computed tomography (CT) can be used for imaging STS of the retroperitoneum, and chest CT is useful for determining metastasis, since a majority of STS metastasize to the lungs.

Abdominal STS may metastasize to the liver or peritoneum, and lymph node metastases are rare.

Positron emission tomography is also an effective imaging modality, but its cost-effectiveness is undetermined.

Besides imaging tests, biopsy is also required for the diagnosis and grading of STS.

Core needle biopsy is the preferred method because fine needle aspiration does not always provide a sufficient amount of tissue for accurate diagnosis. In cases when the tumor is superficial and smaller than 3 cm, removal of the entire tumor during biopsy may be more practical.

Histologic diagnosis is based on biopsy samples and is classified using the WHO classification of tumors.

Differential diagnosis includes other malignant lesions, desmoids, and benign lesions.

Biopsy samples also provide information for grading.

Two systems are used for grading STS: the French Federation of Cancer Centers (FFCC) and the National Cancer Institute (NCI). Both include 3 tumor characteristics. The NCI system includes tumor histology, location, and necrosis, and the FFCC includes tumor differentiation, mitosis count, and necrosis (

In a study comparing both systems, researchers evaluated 410 patients with STS and found that the FFCC system better predicted tumor mortality and metastasis.

Ancillary diagnostic techniques include molecular genetic testing: immunohistochemistry, cytogenetics, and reverse transcription polymerase chain reaction (RT-PCR).

Molecular genetic testing identifies genetic abnormalities associated with STS subtypes and may also assist with prognosis.

For example, the fusion of the genes PAX3-FKHR or PAX7-FKHR is often expressed in alveolar rhabdomyosarcoma.

The expression of PAX7-FKHR is associated with a 4-year overall survival (OS) rate of 75%, which is much higher than the 3% survival rate associated with the expression of PAX3-FKHR (

= .0015). Synovial sarcoma may express the fusion of SYT-SSX1 or SYT-SSX2.

Some findings support the prognostic value of SYT-SSX fusion, while others invalidate it.

Staging of STS is based on the American Joint Committee on Cancer (AJCC) classification system (

In addition to tumor grade, staging considers the depth and size of tumor, the spread to the lymph nodes, and the presence of metastases.

The average 5-year survival rate for patients with STS is approximately 65%, but this can vary with stage and histology.

When the disease is localized, the 5-year survival rate can be >80% or <20% when the disease has metastasized (

). Prognosis is usually better when STS is located in the extremities compared with the retroperitoneum.

In an epidemiologic study, Corey et al compared 5-year survival of STS subtypes and found that dermatofibrosarcoma had the highest rate of 5-year survival at 92%.

Well-differentiated liposarcoma also had a high 5-year survival rate (84%), whereas dedifferentiated chondrosarcoma had the lowest rate of 5-year survival (19%). Alveolar rhabdomyosarcoma also had a low rate of 5-year survival (20%).

This section covers the Introduction and Epidemiology, Risk Factors, Detection and Diagnosis, and Staging and Prognosis sections of the current Evolving Paradigms in Soft Tissue Sarcoma issue.

Evolving Paradigms in Soft Tissue Sarcoma: Introduction

First-line treatment for STS is surgical resection of the tumor, as well as the surrounding normal tissue, to achieve negative margins.

In the event of positive margins, surgery can be performed again to remove additional tissue as long as tissue function is not compromised.

Zagars et al found that local control rates were better among patients who underwent re-resection, with rates of 85%, 85%, and 82% at 5, 10, and 15 years, respectively.

Local control rates were lower among patients who did not undergo re-resection, with rates of 78%, 73%, and 73%, respectively (

= .03). In rare cases of extremity STS, amputation may be necessary but is avoided whenever possible.

Radiotherapy and chemotherapy may be used as additional treatment strategies, especially for high-grade, deep, or >5 cm tumors.

These treatment approaches can be used together or independently, before surgery to shrink the tumor, and/or after surgery to kill remaining cancer cells. Per guidelines, radiotherapy dose should be administered with best technique to total 50 Gy in 1.8 to 2 Gy fractions.

Radiation techniques include external beam radiation therapy (EBRT), brachytherapy, and proton beam radiation.

The most common radiation technique is EBRT.

During EBRT, radiation dose is administered as high-energy x-rays from outside the body. Intensity modulated radiation therapy (IMRT) is a form of EBRT, but is adjusted to be more specific to the tumor size and shape. This specification reduces the radiation dose to healthy tissue.

In a comparison of conventional EBRT with IMRT, Folkert et al evaluated 319 patients with surgically resected, extremity STS and found that IMRT reduced the risk for local recurrence compared with EBRT.

Patients who received IMRT were older and were more likely to have received preoperative radiation and to have positive margins and higher tumor grade.

Intraoperative radiation therapy (IORT), another form of EBRT, is administered during surgery after the tumor is removed but before the wound is closed and is usually followed by another radiotherapy technique.

This technique reduces the radiation dose to healthy tissue. In a phase II study, Roeder et al found that 5-year rates of local control, distant control, and OS were 97%, 66%, and 79%, respectively, with the combination of IORT and EBRT.

They concluded that these results compared favorably with previous studies that reported local control rates of 80% to 90%.

Brachytherapy, when radioactive material is placed in the tumor bed, can be dosed at a high-dose rate or low-dose rate.

High-dose radiation is administered in a short time period, while low-dose radiation is administered over several days. Compared with IMRT (median dose 63 Gy), brachytherapy (median dose 45 Gy) had worse local control rates.

Patients receiving IMRT tended to have worse features, such as larger tumors and positive surgical margins. Proton beam radiation uses protons to deliver radiation instead of photons.

This reduces radiation dose to normal tissue. Availability of proton beam radiation therapy is limited and so is the evidence supporting its use.

The timing and dose intensity of radiation can affect clinical outcomes.

Although timing of radiotherapy does not affect survival outcomes and local control, complications differ between preoperative and postoperative dosing. Preoperative dosing is associated with wound complications, and postoperative dosing is associated with long-term side effects, such as fibrosis and joint stiffness.

According to retrospective studies, boosts of postoperative radiation after preoperative radiotherapy do not improve local control and increase the risk of long-term complications compared with preoperative radiotherapy alone.

High-dose therapy, 60 Gy or 66 Gy, is also associated with increased risk of long-term complications.

Holt et al retrospectively evaluated 364 patients with lower extremity STS and found that higher-dose therapy was associated with more bone fractures than lower-dose therapy, at 50 Gy (

The benefit of chemotherapy for the treatment of localized STS is unclear, but chemotherapy is typically used when metastases are present in advanced disease.

In a meta-analysis, Pervaiz et al determined that doxorubicin with ifosfamide in patients with localized STS provided marginal benefits, with an absolute risk reduction in death of 11%.

However, Woll et al found no added benefit with adjuvant chemotherapy.

In this phase III study, they randomized 351 patients with stage II-III STS without metastases to receive adjuvant chemotherapy of doxorubicin with ifosfamide or no chemotherapy.

Relapse-free survival and OS were similar between groups. However, the ifosfamide dose evaluated, 5 g/m2, was lower than the 9 g/m2 dose evaluated by Frustaci et al, who concluded that adjuvant chemotherapy improved survival.

Also, 24% of patients had tumors <5 cm, which are usually not treated with chemotherapy. Woll et al found a slight benefit with adjuvant chemotherapy in an updated meta-analysis (HR 0.86; 95% CI, 0.76-0.97;

Benefits of chemotherapy are more apparent in high-grade, high-risk disease. In a cohort-based analysis, Italiano et al found that adjuvant chemotherapy was significantly associated with improved 5-year metastasis-free survival and OS in patients with grade 3 disease but not in patients with grade 2 STS.

In a comparison of historical matched-control patients and 48 patients treated with doxorubicin, ifosfamide, and dacarbazine, improvements in rates of OS were observed with neoadjuvant chemotherapy in patients with high-grade STS (45% vs 79%, respectively;

An anthracycline-based regimen is standard first-line chemotherapy for advanced STS, specifically doxorubicin.

Doxorubicin may also be combined with ifosfamide, but there is no overwhelming evidence supporting combination therapy over monotherapy. In a meta-analysis of randomized controlled trials, combination therapy with doxorubicin and ifosfamide was associated with higher tumor response rates, but survival outcomes were similar to doxorubicin alone.

In addition, adverse events (AEs) were worse with combination therapy. In cases where&nbsp;tumor response is especially advantageous, combination therapy may be preferred.

As with standard combination therapy, dose-intensified combination therapy does not improve OS. In a phase III trial, Judson et al randomly assigned 455 patients with advanced STS to receive doxorubicin 75 mg/m2 or doxorubicin 75 mg/m2 and 25 mg/m2 with ifosfamide.

Dose-intensified combination therapy was associated with better progression free survival (PFS; 7.4 vs 4.6 months, respectively) and overall response compared with doxorubicin alone, but it did not improve OS. It was also associated with greater rates of AEs, especially leucopenia, febrile neutropenia, anemia, and thrombocytopenia. The authors suggested dose-intensified combination therapy when the treatment goal is tumor shrinkage.

Second-line chemotherapies for STS include ifosfamide alone, gemcitabine with or without docetaxel, and dacarbazine with or without gemcitabine, although evidence of efficacy is limited.

As a second-line therapy, ifosfamide is administered to patients who have not previously progressed on ifosfamide or is administered at a higher dose in patients who previously received a standard dose. Gemcitabine has demonstrated efficacy in angiosarcoma and leiomyosarcoma as a single agent, although combination therapy may be more effective. In a phase II trial, Maki et al randomized 122 patients with STS to receive gemcitabine alone or with docetaxel and found that PFS and OS were better with combination therapy than monotherapy (PFS at 6.2 vs 3 months; OS at 17.9 vs 11.5 months, respectively), although toxicity was greater.

Pautier et al, however, found similar survival outcomes between single-agent and combination therapy in a phase II study evaluating patients with leiomyosarcomas, specifically.

The combination of dacarbazine with gemcitabine also improves survival outcomes compared with dacarbazine alone.

In a phase II study, Garcia del Muro et al randomly assigned 113 patients with advanced STS to receive dacarbazine alone or with gemcitabine.

OS was 16.8 months with combination therapy and 8.2 months with monotherapy (

= .014). PFS and objective response rates (ORRs) were also significantly different in favor of combination therapy. A systematic review performed by Sharma et al also demonstrated improved PFS with combination therapy.

The 3-month PFS rate was 54.2% with combination therapy and 35.2% with monotherapy.

Trabectedin, originally derived from a marine compound, binds the minor groove of DNA and disrupts the cell cycle, which inhibits cell proliferation.

Trabectedin is approved in Europe and was also approved in the United States in October 2015

for the treatment of liposarcoma and leiomyosarcoma in patients who previously received anthracycline-based chemotherapy, although it can also be used in other subtypes.

Trabectedin received US FDA approval on the basis of a phase III clinical trial involving 518 patients with metastatic or recurrent leiomyosarcoma or liposarcoma.

Participants were randomly assigned to receive either trabectedin or dacarbazine. The patients receiving trabectedin experienced a PFS of about 4.2 months compared with only 1.5 months in patients assigned to dacarbazine (HR 0.55;

<.001). An interim analysis of OS showed a 13% reduction in risk of death in the trabectedin arm compared with dacarbazine (

The most common grade 3 to 4 AEs were myelosuppression and transient elevation of transaminases in the trabectedin arm.

In an expanded access program, Samuels et al evaluated 807 patients with advanced STS who received trabectedin. Half of the patients had disease progression and the remaining half had a complete response (CR), partial response (PR), or stable disease (SD). ORRs were higher in patients with leiomyosarcomas or liposarcomas than in patients with other STS (5.7% vs 7.5% vs 4.0%, respectively). Leiomyosarcomas and liposarcomas (L-sarcomas) were also associated with better OS (16.2 vs 8.4 months, L-sarcomas vs other STS, respectively). The most common AEs were nausea, vomiting, constipation, increased liver enzymes, anemia, and neutropenia.

In separate retrospective studies, researchers found that fatigue and myelosuppression were reasons for discontinuation of trabectedin after 1 year of therapy.

In a study by Blay et al, trabectedin and doxorubicin-based chemotherapy did not demonstrate efficacy in translocation-related sarcomas.

Trabectedin is recommended at a dose of 1.5 mg/m

given as an intravenous infusion over the course of 24 hours every 21 days until disease progression or unacceptable toxicity.

It is recommended that patients taking trabectedin have a normal bilirubin and aspartate aminotransferase and alanine aminotransferase levels of &le;2.5 times the upper limit of normal.

Eribulin, like trabectedin, is derived from a marine compound.

Eribulin stops cell proliferation by inhibiting the movement of microtubules, and has also demonstrated improved efficacy in liposarcoma and leiomyosarcoma when compared with other forms of STS. In a phase II study, Schöffski et al evaluated 128 patients with either adipocytic sarcoma, leiomyosarcoma, synovial sarcoma, or other sarcomas treated with eribulin 1.4 mg/m2 on days 1 and 8 every 3 weeks. The adipocytic sarcoma and leiomyosarcoma groups met the primary endpoint, and the 12-week PFS was 46.9% and 31.6%, respectively. Common grade 3 to 4 treatment-emergent AEs included neutropenia and leucopenia.

Eribulin was approved in January 2016 for patients with unresectable or metastatic liposarcoma who have received a prior anthracycline-based chemotherapy regimen.

The results were based on a phase III study by Sch&ouml;ffski et al in which eribulin was compared with dacarbazine.

Among 143 patients with liposarcoma, the OS was 15.6 months with eribulin compared with 8.4 months with dacarbazine.

In 452 patients with liposarcoma and leiomyosarcoma, patients receiving eribu&shy;lin had an OS of 13.5 months compared with dacarbazine (11.5 months), but the difference was not significant (HR, 0.77;

PFS was also not significantly different between the 2 groups. Grade &ge;3 AEs were more common in the eribulin group than the dacarbazine group. &nbsp;

Olaratumab, a platelet-derived PDGFR-alpha antagonist, was granted accelerated approval by the US FDA for the treatment of unresectable, advanced STS when given in combination with doxorubicin in October 2016.

Approval was also recommended by the European Medicines Agency's Committee for Medicinal Products for Human Use in September 2016.

The phase II trial that led to its approval showed a 48% reduction in the risk of death over doxorubicin monotherapy (HR, 0.52;

OS was improved with the combination compared with doxorubicin (26.5 vs 14.7 months, respectively). PFS and ORR were also increased with the combination.

AEs were more frequent in the trial with the combination versus with doxorubicin alone. The AEs more frequently seen with the combination included neutropenia, mucositis, nausea, vomiting, and diarrhea. Grade 3 or higher febrile neutropenia was noticed in 13% of patients in the combination arm and in 14% of patients in the doxorubicin monotherapy arm.

Olaratumab is administered at 15 mg/kg intravenously over 60 minutes on days 1 and 8 of a 21-day cycle, with doxorubicin also given for the first 8 cycles.

It is recommended for patients with a histologic subtype for which an anthracycline-containing regimen is appropriate, and for patients whose tumors are not amenable to surgery or radiotherapy. Treatment with olaratumab and an anthracycline are also recommended in the frontline setting for metastatic or recurrent disease in a number of subtypes.

The agent had been granted fast track and breakthrough therapy designations and a priority review status from the FDA prior to its accelerated approval.

The phase III ANNOUNCE confirmation trial to verify the benefits of olaratumumab plus doxorubicin is ongoing and has already been fully accrued.

Pazopanib, a second-line therapy, is an oral multitargeted tyrosine kinase receptor inhibitor and is approved to treat patients with non-adipocytic and non-GIST STS.

Specifically, pazopanib targets VEGF 1-3, fibroblast growth factor receptor 1 and 3, PDGF a and b, and KIT selectivity. In the phase III PALETTE trial, van der Graaf et al randomized 369 patients with advanced STS to receive pazopanib or placebo.

Pazopanib significantly improved PFS compared with placebo (4.6 vs 1.6 months, respectively; P <.0001). No differences in OS were found, and the majority of patients had SD. Only 6% of patients had a PR. In the same group of patients, Coens et al found that pazopanib did not improve or worsen health-related quality of life.

The most common AEs with pazopanib were fatigue, diarrhea, nausea, weight loss, and hypertension.

Using data from the PALETTE trial and a phase II trial, Kasper et al determined that 22% of patients were long-term responders and survivors with pazopanib.

of 18 months. A total of 12 patients (3.5%) were treated with pazopanib for >2 years, and favorable prognostic factors included good performance status, low or intermediate tumor grading, and normal hemoglobin level at baseline.

This section covers the Current Treatment Strategies section of the current Evolving Paradigms in Soft Tissue Sarcoma issue.

Evolving Paradigms in Soft Tissue Sarcoma: Current Treatment Strategies

Cytotoxic chemotherapy is still one of the mainstays of treatment for patients with STS, yet several emerging agents are being investigated in STS and are making a difference in the treatment paradigm.

Aldoxorubicin is a prodrug of doxorubicin.

When administered intravenously, aldoxorubicin binds to albumin, which accumulates&nbsp;at solid tumors due to their high metabolic rate. In the acidic environment of the tumor, aldoxorubicin becomes the active drug, doxorubicin. This mechanism of delivery reduces the risk for cardiotoxicity, which is associated with doxorubicin. In the phase IIb trial, Chawla et al randomly assigned 83 patients with unresectable STS to receive aldoxorubicin 350 mg/m2 every 3 weeks and 40 patients to receive doxorubicin 75 mg/m2 every 3 weeks.

PFS was significantly longer with aldoxorubicin than doxorubicin (5.7 vs 2.8 months; P = .018). Common AEs included neutropenia, anemia, nausea, and mucositis. Aldoxorubicin was not associated with reduced left ventricular ejection fraction.

A new drug application is planned for aldoxorubicin as a second-line treatment for patients with relapsed STS, based on results from the phase III trial. Pre-NDA meetings have been arranged with the US FDA to discuss the application.

In the phase III trial, 433 patients with metastatic, locally advanced or unresectable STS who had not responded to or had progressed following a systemic regimen of non-adjuvant chemotherapy were randomized 1:1 to either aldoxorubicin or investigator&rsquo;s choice of chemotherapy regimens. The manufacturer reported that in 312 STS patients, aldoxorubicin demonstrated a significantly significant difference in PFS (

Aldoxorubicin showed a 38% reduction in risk of progression (HR, 0.62; 95% CI, 0.44-0.88). Overall, aldoxorubicin showed an improvement over investigator&rsquo;s choice of chemotherapy, but it did not reach statistical significance (HR, 0.81; 95% CI, 0.64-1.06;

= .012). AEs were similar to those noted in the phase IIb trial.

Evofosfamide, a DNA-alkylating agent also known as TH-302, is a prodrug that is activated in hypoxic environments. Because solid tumors have hypoxic regions, evofosfamide is more selective for tumor cells.

In a phase II study, 91 patients with advanced STS received evofosfamide 300 mg/m2 on days 1 and 8 and doxorubicin 75 mg/m2 on day 1 of each 21-day cycle.

Chawla et al found that PFS was 6.5 months. OS was 21.5 months, and 34% of patients had a PR. The study authors concluded that outcomes compared favorably with historical outcomes.&nbsp;

In the phase III SARC-021 trial by Tap et al, evofosfamide plus doxorubicin was compared with doxorubicin alone in patients with locally advanced unresectable or metastatic STS.

The authors concluded that the combination did not improve OS rates compared with doxorubicin alone (18.4 vs 19.0 months). The most common grade 3 to 5 AEs included anemia, neutropenia, and leucopenia. AEs led to death in 2.6% of patients in the combination arm and in 1% of patients in the doxorubicin alone arm.

Immunotherapy is increasingly being explored in STS, but has not yet been incorporated into standard practice.

Many researchers and ongoing trials are currently exploring the role of immunotherapy in the treatment of STS.

Pembrolizumab is one of the PD-1 inhibitors currently being investigated in sarcomas. In the phase II SARC-028 trial, pembrolizumab was studied both in pretreated patients with soft tissue and bone sarcomas.

Patients were treated with 200 mg of pembrolizumab every 3 weeks. Among the STS group, the ORR was 19% and the 4-month PFS rate was 44%. Common side effects included immune-related adrenal insufficiency, diarrhea, and acute interstitial nephritis.

Responses to pembrolizumab were greatest among patients with undifferentiated pleomorphic sarcoma. Among the 9 evaluable patients, the ORR was 44% including 4 patients with a PR and 3 patients with SD. As of 8 weeks, the PFS was 67%.

Among patients with leiomyosarcoma, none experienced a response, yet 6 patients had SD. The PFS rate at 8 weeks was 50%. Patients with synovial sarcoma experienced a PFS of 30%. Only 1 patient in this population experienced a PR and 2 had SD.  &nbsp;

Nivolumab, another PD-1 inhibitor, was also tested in 20 patients with metastatic STS and 3 patients with bone sarcomas. In the trial by Paoluzzi et al, patients received 3 mg/kg of nivolumab intravenously every 2 weeks with or without additional pazopanib at 800 mg daily.

Overall, clinical benefit was observed in 39% of the patients. Three patients experienced a PR, including 1 patient with proximal epithelioid sarcoma who also received pazopanib. Mixed responses were noted in 2 patients with STS and 4 patients with STS experienced SD. The most common side effects included grade 1 to 2 liver function transaminase elevation, especially among patients receiving the combination regimen, and grade 3 to 4 toxicities included elevated liver function transaminase levels, pneumonitis, colitis, and anemia.

An ongoing phase II trial is currently exploring combining nivolumab with or without the CTLA-4 inhibitor ipilimumab in patients with metastatic unresectable STS or bone sarcoma.

PD-L1 expression has shown potential in other tumor types to be predictive of responses to PD-1 inhibitors, such as pembrolizumab and nivolumab. In STS, PD-1 positive lymphocytes and PD-L1 expression could be used as a prognostic indicator, and has shown a correlation with reduced OS and event-free survival rates.

Testing patients for PD-L1 expression could be used to help select which patients would benefit more from treatment with a PD-1 inhibitor. Further, in the trial by Paoluzzi et al, the highest expression of PD-L1 was observed in those who experienced a PR.

Targets of therapy with activity in soft tissue sarcoma are depicted in

STS express factors for angiogenesis, such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF).

Such factors are required for the development of sarcomas. Activation of proto-oncogenes also aid in the development of sarcomas. The inhibition of tyrosine kinase receptors disrupts cell signaling and has demonstrated clinical benefit in gastrointestinal stromal tumors (GIST) with imatinib and sunitinib and in STS with pazopanib. Although imatinib and sunitinib are effective in GIST, they have not demonstrated activity in STS as a whole.

Sorafenib, an inhibitor of VEGF, is also not effective for STS.

Anlotinib is a multitarget RTK inhibitor, and in a phase II study in China, the progression-free response at 12 weeks was 57.23% and the median PFS was 5.63 months.

Anlotinib was particularly effective in patients with synovial sarcoma and alveolar soft part sarcoma. The most common grade 3 to 4 AEs included hypertension, pneumothorax, and thyroid hypofunction.

Regorafenib is a multikinase inhibitor, and in a phase II study, Mir et al found that regorafenib may have antitumor activity in non-adipocytic STS.

In 57 patients with leiomyosarcoma and 53 patients with other STS, regorafenib significantly improved PFS compared with placebo (4.0 vs 1.9 months, P = .017; 4.6 vs 1.0 months, P= .002, respectively).

At 6 months, rates of OS were better with regorafenib than placebo among patients with leiomyosarcoma (87% vs 75.9%, respectively; P = .013). In synovial sarcoma, regorafenib showed improved PFS over placebo (5.6 vs 1.0 months, respectively;

Whereas in adipocytic STS, PFS was better with placebo compared with regorafenib (1.7 vs 1.1 months, respectively). Improvements in OS rates were not deemed clinically relevant in the trial though due to crossover.

Mammalian target of rapamycin (mTOR), a kinase, participates in a pathway often deregulated in cancers.

This section covers the Emerging Cytotoxic Agents, Current and Emerging Targets, and Emerging Therapies for Specific Histologies sections of the current Evolving Paradigms in Soft Tissue Sarcoma issue.

Soft Tissue Sarcoma

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

Evolving Paradigms in Soft Tissue Sarcoma: Introduction

Evolving Paradigms in Soft Tissue Sarcoma: Current Treatment Strategies

Evolving Paradigms in Soft Tissue Sarcoma: Current and Emerging Targets

Evolving Paradigms in Soft Tissue Sarcoma: Conclusion and References

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