Next Frontiers in Systemic Therapy for Soft Tissue Sarcoma

Cheuh-Chuan Yen; Tom Wei-Wu Chen


Chin Clin Oncol. 2018;7(4) 

In This Article

Abstract and Introduction


Soft tissue sarcoma (STS) is a heterogeneous disease with more than 50 subtypes. Once the disease reached locally advanced or metastatic status, the standard treatment remains to be chemotherapy. Current understanding of the underlying molecular and genomic mechanisms of different histology subtypes have led to encouraging development of new drugs in treating STS. Besides molecular targeted therapy, immunotherapy have also shown promising advancement in solid tumor treatments. This review will be in two parts. The first part will focus on the molecular targeted agents aiming at molecular or genetic alterations that are more specific in STS, including antiangiogenic molecules, plate-derived growth factor receptor alpha (PDGFRA) monoclonal antibody, colony-stimulating factor-1 receptor (CSF-1R), selective inhibitors of nuclear export (SINE), cyclin-dependent kinase 4/6 (CDK 4/6), mdm2, and epigenetic regulators. We also discussed in depth about how current precision medicine influences the treatment paradigm in STS. In the second part, we focus on the landscape of immunotherapy in STS including immune checkpoint inhibitors (ICIs) and the combinations of immunotherapies or with other molecules that could modulate the tumor microenvironment. These included the program cell death-1 receptor and its ligand (PD-1/PD-L1), cytotoxic T lymphocyte associated protein-4 (CTLA-4) and the combination with anti-angiogenic agents that could facilitate the trafficking of T cells. Strategies targeting the tumor-associated antigen NY-ESO-1, which is commonly observed in synovial sarcoma and myxoid round cell liposarcoma, via viral vaccines and adoptive T cells will also be discussed. These new frontiers of treatment that are developed with better insights into sarcoma and immune biology hopefully will change the treatment paradigm of advanced STS in the future.


Soft tissue sarcomas (STSs) accounts for less than 1% of all cancer, but are highly heterogeneous in terms of anatomical location, histology, molecular characteristics and prognosis.[1] Approximately 50% to 60% of cases occur in the extremities. Neoadjuvant and/or adjuvant chemotherapy or radiotherapy can be given, depending on the tumor histological subtype, grade, and margin status.[2,3] A 5-year distant metastasis-free survival of over 60% can be achieved.[4,5] On the other hand, retroperitoneal sarcoma (RS) accounts for 15% of all STSs. Complete surgical resection with a negative margin is hard to achieve mostly because the tumor is deeply seated in the retroperitoneum adjacent to many vital organs, and oftentimes presents as multifocal disease.[6] Local recurrence is the major cause of treatment failure in RS patients, and although retrospective study suggested radiation may play a role in disease control,[7] the result of the prospective clinical trial [Surgery With or Without Radiation Therapy in Untreated Nonmetastatic Retroperitoneal Sarcoma (STRASS); NCT01344018] to understand the role of radiotherapy in improving local control of RS patients is highly anticipated.

For metastatic disease, chemotherapy is still the mainstream therapy. Single agent anthracycline is the standard first-line therapy, with a median overall survival around 12 to 14 months. Combination with ifosfamide may improve response rate but is associated with excessive toxicities.[8] Gemcitabine plus docetaxel may be an alternative option.[9] For the second line treatment, eribulin and trabectedin have demonstrated efficacy in liposarcoma (LPS) and leiomyosarcoma (LMS).[10,11]

Progress of the treatment of advanced STS mainly comes from the understanding of driver oncogenes. Most of the gastrointestinal stromal tumors (GISTs) contained either c-KIT or PDGFRA mutation, which can be effectively inhibited by tyrosine kinase inhibitors (TKIs) such as imatinib, sunitinib or regorafenib ([12–14]). On the other hand, more than 85% of inflammatory myofibroblastic tumors (IMT) harbored kinase fusions involving ALK, ROS1, or PDGFRβ.[15] ALK inhibitor, such as crizotinib, has shown potent efficacy in this disease.[16] Other examples include imatinib or sunitinib for dermatofibrosarcoma protuberans harboring t (17;22) (q22;q13.1) translocation with resultant fusion gene COL1A1-PDGFB,[17] or mTOR inhibitor for perivascular epithelioid cell tumor (PEComa) family with deletion or under-expression of TSC1 or TSC2.[18] The new frontiers of systemic treatments in advanced STS will come from not only the search of driver oncogenes in different STS histology but also the insight of other genomic, epigenetic, and immunological niches in STS. In this review, we will discuss recently identified novel treatments in STS based on different molecular and immune system pathways (Table 1).