Modern Therapies Expand Options for Soft-Tissue Sarcomas

William D. Tap, MD

Although soft-tissue sarcoma (STS) is seldom diagnosed in adults, the development of several new therapies in recent years for patients with rare subtypes is energizing leaders in the field and underscoring the need for a multidisciplinary approach to care.

Those were among the sentiments that a panel of experts expressed during a recent OncLive Peer Exchange^®. “The idea that there is no effective treatment for sarcoma, or the idea of therapeutic nihilism, really needs to go away, because we are clearly making advances for our patients,” Richard F. Riedel, MD, said.

During the past 6 years, the FDA has approved 4 novel therapies for patients with STS subtypes, such as leiomyosarcoma and synovial sarcoma, who previously had limited therapeutic options (Table). Prior to those approvals, the drug approval activity in STS involved therapies for malignancies classified as gastrointestinal stromal tumors: imatinib (Gleevec) in 2002, sunitinib malate (Sutent) in 2006, and regorafenib (Stivarga) in 2013.^1-3

Many of the new therapies are designed to benefit specific histologies, making treatment selection more complex, Jonathan C. Trent, MD, PhD, noted. “We have to work closely with our pathologists, and we have to use their expertise so that we can leverage all of these exciting new therapies for our patients and look forward to, potentially, some exciting combinations in the future,” he said.

Diagnostic Challenges

The OncLive Peer Exchange^® panelists provided their insights on establishing an accurate diagnosis of STS and discussed the most recent information surrounding treatment of these tumors and the use of modern therapies for advanced disease. They also provided their perspectives on how to apply the latest data to clinical care.Accurate diagnosis of STS poses a significant challenge. Collectively, these tumors constitute approximately 1% of all adult cancers yet are divided into more than 50 subtypes.⁴ “If one were to look in the pathology textbooks, there are over 200 types of soft-tissue sarcomas,” Trent said. They represent different kinds of cancer, he said, with fundamental differences in how they present, their biology and metastatic pattern, and how they are treated.

Table. Recent FDA Drug Approvals for STS Subtypes^1-3

These tumors are also rare. “Benign tumors are 100-fold more common than malignant ones,” Victor Villalobos, MD, PhD, said. This sometimes leads to a false sense of security and, subsequently, an incorrect and potentially harmful treatment approach. To ensure proper treatment, it is essential to accurately determine which sarcoma subtype a patient has. “We need to have an expert pathologist subtype the sarcoma,” Kristen N. Ganjoo, MD, said. “If you don’t have an expert pathologist, the diagnosis is sometimes different than what we actually have.”

The panelists thought that next-generation sequencing could be a helpful diagnostic tool for some patients with sarcomas. “I’ve actually been using next-generation sequencing for about 80% of my high-grade sarcomas—not the low grades—and I have been successful in certain cases to actually change the diagnosis,” Ganjoo said.

In this setting, a change in diagnosis has meaning because there could be very specific treatments for certain subtypes, moderator William D. Tap, MD, explained, noting that a change in diagnosis occurs approximately 15% of the time for patients coming from outside of tertiary care centers.

The panel emphasized the importance of taking a multidisciplinary approach to care and discussing sarcoma cases with colleagues, particularly those experienced with sarcomas. “[Despite being at a sarcoma center], there are a few cases a year of something I’ve still never seen,” Riedel said. Like others on the panel, his institution has a multidisciplinary tumor board to facilitate such discussions.

“With more people in the room, you have hundreds of years of experience between people who have seen these tumors. It really makes care optimal to these patients,” Villalobos added.

Treatment of Adult Soft-Tissue Sarcomas

Because sarcomas are so rare, some community oncologists are likely to see just a handful of such cases, and because these tumors are so challenging to diagnose and treat, even for sarcoma experts, the panel encouraged community oncologists to reach out to sarcoma centers for guidance. “We’re really there to work with [our community oncology colleagues]. The initial diagnosis and initial management of the patient is critical, even when approaching the initial biopsy. Sometimes you have to consider the biopsy within the resection that will be planned, and so this multidisciplinary approach is critical,” Tap emphasized.The panel explained that treatment of adult STS cannot be generalized, because every patient’s case is unique and nuanced. One important issue to work through for larger (>5 cm), high-grade lesions is the sequencing of treatment, which may include chemotherapy, surgery, radiation, and other systemic therapies, such as approved targeted agents or investigational agents in clinical trials.

“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, maybe surgery first would be a good approach,” Trent said. In general, for a high-grade STS that is larger than 5 cm, Trent said his institution would use preoperative chemotherapy for 2 cycles, do another magnetic resonance imaging test, decide whether the tumor is stable or responding, and then continue with 2 more cycles of chemotherapy if appropriate. The patient also would undergo preoperative radiation followed by surgery and then probably additional chemotherapy postoperatively to complete 5 or 6 cycles. Trent’s chemotherapy of choice: usually doxorubicin (Adriamycin) 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, 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,” Trent said.

Adjuvant Therapy for Locally Advanced Sarcomas

The panelists had differences of opinion regarding adjuvant therapy approaches for locally advanced STS’s. Trent’s approach in favor of a chemotherapeutic regimen using doxorubicin plus ifosfamide was based on data from the Sarcoma Meta-analysis Collaboration, first published in 1997 and updated in 2008.^5,6 The 1997 meta-analysis included 14 trials of doxorubicin-based adjuvant chemotherapy, whereas the 2008 update included 18 trials. In both meta-analyses, use of adjuvant doxorubicin-based chemotherapy improved the time to local and distant recurrence and overall recurrence-free survival. The 1997 meta-analysis just showed a trend toward improved overall survival (OS), but the 2008 meta-analysis showed an OS benefit when ifosfamide was added.^5,6

“The [2008 meta-analysis] clearly showed an 11% improvement in overall survival and a nearly 15% improvement in local control in patients with high-grade sarcomas, mostly when doxorubicin and ifosfamide were both part of the adjuvant regimen in this setting. This is the rationale for our approach,” Trent said.

Riedel pointed out key limitations with the data from these meta-analyses. First, he noted that the analytics differed: “The late 1990s meta-analysis, which did not show a survival benefit, used individualized patient data. The second meta-analysis in 2008 used composite data.” However, he said, the most significant limitation was that the 2008 meta-analysis excluded data from the European Organisation for Research and Treatment of Cancer (EORTC) 62931 trial, a large randomized trial that showed no benefit for relapse-free survival or OS.⁷

Tap also pointed out that 60% of the pathology in these meta-analyses was unknown, adding another limitation.

Riedel said he rarely uses adjuvant chemotherapy at his institution. “For a large high-grade extremity sarcoma, we would take the tack of neoadjuvant therapy—not chemotherapy but, rather, radiation therapy for about 5.5 weeks followed by resection,” he said.

Ganjoo said she uses adjuvant chemotherapy in the locally advanced setting but avoids ifosfamide for older patients because of its toxicity. Instead, she favors combining doxorubicin with olaratumab (Lartruvo), even though this regimen is approved just for patients who are not candidates for curative therapy.⁸ When using radiation, she said, she uses ifosfamide as a radiosensitizer.

She questioned how much response Riedel obtains without use of a radiosensitizer. He replied that it depends on the sarcoma: “Myxoid liposarcomas are extremely sensitive to radiation therapy,” he said. “I don’t think you need chemotherapy for that. With synovial sarcoma, we’ve seen some responses.” He said that he has used full-dose ifosfamide with radiation therapy in select cases, such as for patients with very large tumors and at high risk of developing metastatic disease during the 5 weeks of radiation therapy, adding that such cases are rare.

Although the approach to treatment differed among panelists, they agreed that shared decision making with patients is essential. “Our role is to share with them our experience and our understanding of the published literature,” Trent said. The panel also agreed that the goal, regardless of their adjuvant therapy approach, is to establish local control.

Chemotherapy for Metastatic Sarcomas

As in the locally advanced setting, the treatment approach for metastatic STS varied somewhat among the panelists. In the first line, Ganjoo said, she uses doxorubicin followed by olaratumab, provided patients can tolerate this treatment and have no history of cardiac problems. She said this regimen is the standard of care and that she uses just AIM (Adriamycin [doxorubicin], ifosfamide, and mesna) if a patient is highly symptomatic and the tumor must be shrunk quickly to provide palliation or the patient has a synovial sarcoma. “With other patients in their 60s and 70s who have had bone, liver, and lung disease, we have to have a conversation. Most patients will say, ‘I do not want ifosfamide.’ Especially if they’re older than 65, you’ll get a lot of [adverse] effects,” she said.

Trent suggested that, despite its toxicity, doxorubicin plus ifosfamide is an acceptable frontline regimen in the metastatic setting. He said he uses this more aggressive treatment approach if he thinks he can move a patient into an oligometastatic situation. “Long-term survival at 10 years may be as high as 20% in the adult rhabdomyosarcoma patients. These are the patients who respond to chemotherapy and are able to go on to some type of consolidative, localized, oligometastatic resection,” he said. Even in patients with widely metastatic disease, in which resection does not appear possible, he thought AIM could make resection possible and lead to a complete response in some cases. “In my practice, I try to give doxorubicin plus ifosfamide plus olaratumab because I think that gives the best chance for an individual patient,” he said, explaining that this is done as part of a clinical trial and not as an off-label treatment.

Villalobos disagreed regarding the addition of ifosfamide for most patients, because it more than doubles the toxicity. “I think tolerability is of massive importance to a lot of my patients,” he said. Nevertheless, he acknowledged that patients with sarcoma are a heterogeneous group with different tolerability thresholds. Despite not favoring AIM for most patients, he said he uses it when he thinks it can get a patient to resection. “In a situation where surgery really is not feasible, going more gently with a drug that can actually increase overall survival may be more effective,” he said.

The panel also discussed gemcitabine-based regimens. “In the United States, gemcitabine [Gemzar]/docetaxel [Taxotere] is very popular,” Tap said. He noted that in the GeDDis study, which compared gemcitabine/docetaxel with doxorubicin, the outcomes between regimens were similar.⁹ This led the investigators to conclude that doxorubicin should remain the standard first-line treatment for most patients with advanced unresectable or metastatic STS’s.⁹ However, Tap said, the study grossly underdosed gemcitabine at times, which might have led to some bias.

Villalobos said he administers a gemcitabine-based regimen in the frontline if a patient has heart disease or the toxicities of a doxorubicin-based regimen are problematic. Ganjoo agreed with that approach and said another important consideration is dosing. In the GeDDis study, patients in the gemcitabine arm received intravenous (IV) gemcitabine 675 mg/m² on days 1 and 8 and IV docetaxel 75 mg/m² on day 8 every 3 weeks.⁹ Ganjoo said she gives both drugs every 2 weeks instead. “The dose of gemcitabine is 1500 mg/m², and docetaxel is 50 mg/m². We have really good responses,” she said. Villalobos cautioned that docetaxel can be quite toxic at higher doses, such as 100 mg/m², which was used in some studies. At these doses, patients can develop a lot of edema and neuropathy, he warned.

Other Therapies for Sarcomas

In 2012, the FDA approved pazopanib (Votrient) for advanced sarcoma, except liposarcoma and gastrointestinal tumors, in patients who had received previous chemotherapy. Pazopanib is an oral tyrosine kinase inhibitor that targets VEGF receptors.

Approval was based on the results of the phase III PALETTE trial, which was conducted in collaboration with the EORTC.¹⁰ The study included patients with >20 subtypes of sarcoma and showed improved progression-free survival (PFS) with pazopanib versus placebo (4.6 months versus 1.6 months, respectively). Although there was a trend toward an OS benefit with pazopanib, the result did not reach statistical significance.¹⁰

Riedel said he will consider pazopanib in the third-line setting or beyond. “I will typically have an anthracycline-based regimen in the frontline and a gemcitabine-based regimen in the second-line setting,” he said, acknowledging that this is a bit of an oversimplification, because each patient is different.

Trent said he sometimes uses pazopanib in earlier lines. “We use it in second-line therapy for synovial sarcoma. We don’t use gemcitabine/docetaxel [in that setting because] our patients with synovial sarcoma in retrospective series are resistant to that regimen,” he said. He also said he sometimes uses pazopanib as a frontline therapy, such as for solitary fibrous tumor and for extraskeletal myxoid chondrosarcoma. “It may be reasonable for alveolar soft part sarcoma, too,” he added.

Newer chemotherapeutic agents approved for sarcoma include trabectedin (Yondelis) and eribulin mesylate (Halaven). Trabectedin was approved in October 2015 based on the phase III ET743-SAR-3007 trial for patients with metastatic or unresectable liposarcoma and leiomyosarcoma who received previous anthracycline-based chemotherapy, and eribulin was approved in January 2016 as a treatment for patients with metastatic or unresectable liposarcoma following prior treatment with an anthracycline-based chemotherapy. “For leiomyosarcomas, I will use trabectedin prior to pazopanib,” Riedel said.

Immunotherapy

The panel briefly touched on immunotherapies, particularly the combination of nivolumab (Opdivo), a PD-1 inhibitor, and ipilimumab (Yervoy), a CTLA-4 inhibitor. This is an area where data are just starting to emerge.

“I’ve been using a lot of immunotherapy over the past year based on the Alliance trial with ipilimumab/nivolumab versus nivolumab. I’ve had some very good responses, some CRs [complete responses], and some really good patients-coming-out-of-hospice responses, but I still have to figure out which patients those are,” Ganjoo said.

In the Alliance trial, confirmed responses were observed in 6 of 38 patients (16%) in the ipilimumab/nivolumab arm versus 2 of 38 patients (5%) in the nivolumab arm.¹¹ A similar response rate was observed in the SARC028 trial, which assessed single-agent pembrolizumab (Keytruda).¹² After a median follow-up of 17.8 months, 7 of 40 patients with STS’s (18%) had an objective response. This included 4 of 10 patients (40%) with undifferentiated pleomorphic sarcoma, 2 of 10 (20%) with liposarcoma, and 1 of 10 (10%) with synovial sarcoma.¹²

It is unclear which patients will respond to certain immunotherapies, because those markers have not been determined yet; thus, many of the panelists agreed that immunotherapies should be given just as part of a clinical trial. However, Villalobos suggested that because single-agent immunotherapies such as pembrolizumab, atezolizumab (Tecentriq), and other PD-1/PD-L1 inhibitors are very tolerable therapies, they may be worthwhile trying off-label, such as if there is no appropriate clinical trial for the patient.

References

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10. van der Graaf WT, Blay JY, Chawla SP, et al; EORTC Soft Tissue and Bone Sarcoma Group; PALETTE study group. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2012;379(9829):1879-1886. doi:10.1016/ S0140-6736(12)60651-5.
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