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Here we review the current state of multimodality treatment of LPS and highlight opportunities for future
advancements in LPS management.

Local therapies - surgical resection and radiation therapy
For patients with primary localized LPS, surgery with complete gross tumor resection (R0/R1 margins)
remains the definitive management and only potential curative treatment. However, local recurrence rates
are high (> 80%) [53,54] . Radiation therapy (RT) and/or chemotherapy can be used as adjuncts to reduce local
and distant recurrence risk for those with dedifferentiated, myxoid/round cell, or pleomorphic LPS.

Systemic therapies
Cytotoxic therapies
WDLPS and DDLPS are relatively chemoresistent [1,2,55] , with response rates in the literature reported as low
[53]
[56]
as ≤ 12% and as high as 21% [Table 1]. Thus, in the primary or recurrent resectable setting, systemic
therapy has not been frequently used and there is no consensus regarding their use in the neoadjuvant or
adjuvant setting. For those with unresectable or metastatic LPS, cytotoxic chemotherapy is the standard of
care [4,57] . Myxoid/round cell LPS is considered to be relatively chemosensitive and thus chemotherapy may
be considered for those patients with resectable disease in the neoadjuvant or adjuvant as well as in the
[58]
unresectable or metastatic settings . The role of systemic therapy for pleomorphic LPS is less well defined
[58]
although a number of retrospective studies suggest a degree of chemosensitivity in the metastatic setting .
Despite the differences in chemosensitivity, in the first line, anthracycline (typically doxorubicin), often in
combination with ifosfamide, is the standard systemic therapy. Second-line systemic therapy options that are
[65]
used frequently include trabectedin [59-61] , eribulin [60,62-64] and gemcitabine/docetaxel . Other regimens with
activity in soft tissue sarcomas are used infrequently, include gemcitabine, and dacarbazine monotherapies
[58]
as well as combination of gemcitabine/dacarbazine . Though trabectedin and eribulin are both approved
for the treatment of all liposarcomas, trabectedin has much higher response in MRCLS and eribulin leads to
longer progression free survival benefit in pleomorphic LPS.

Investigational therapies - targeted therapies
For patients who have failed standard of care systemic therapies, there are a number of investigational
[66]
therapies that may be considered including targeted agents and immunotherapies alone or in combination
with other therapies [41,67,68] . Amplification of the CDK4 oncogene as well as MDM2 are seen in > 90% of
WDLPS/DDLPS. Small molecule inhibitors targeting CDK4/6 (palbociclib) and MDM2, are being evaluated
in ongoing studies, either alone or in combination with chemotherapy. These trials are enrolling patients
with WDLPS/DDLPS [58,69] .

Pazopanib, a tyrosine kinase inhibitor approved for use in second/third-line and beyond in non-adipocytic
soft tissue sarcoma, has limited activity in LPS subtypes [68,69] . Olaratumab is a recombinant human
immunoglobulin G (IgG) monoclonal antibody that binds PDGFRa and blocks receptor activation and has
shown improved overall survival in a randomized phase Ib/II study for all soft tissue sarcoma subtypes,
[58]
when given in combination with doxorubicin compared to doxorubicin alone , but the recently released
phase III data did not validate these results. Selenixor (XPO-1 inhibitor) and PPARy agonists are also under
investigation for advanced LPS.

Investigational therapies - immunotherapy
In recent decades, major advances have been made in cancer therapy through the use of immune checkpoint
blockade - with the FDA approval of therapies targeting the CTLA-4 and PD-1 across multiple cancer types
[70]
and cancer care continuum in the metastatic and adjuvant settings . Current FDA approvals for immune
checkpoint blockade therapies are limited to cancer types characterized by high mutational burden such