The individual rarity of the many subtypes of
soft tissue sarcomas has historically mandated an empiric approach to systemic
therapy.
Doxorubicin, first reported to have activity in
sarcomas 40 years ago, remains the generalizable first-line treatment of choice for many subtypes, with no other
drug or combination having shown an overall-survival advantage. Other
cytotoxic agents, such as
paclitaxel for
angiosarcoma or
gemcitabine with
docetaxel for
leiomyosarcoma, are commonly used for certain histologic subtypes based on relatively small studies.
Trabectedin, particularly active against
leiomyosarcoma and
myxoid liposarcoma, is approved in many countries worldwide but not yet in the United States or Australia. Newer
cytotoxic agents, including
ifosfamide derivatives, are in current phase III testing. Although advances is systemic
therapy of
soft-tissue sarcomas have been hampered by their
biologic heterogeneity, this diversity also serves as fertile ground for discovery and validation of targetable molecular drivers. The most notable success in this regard has been the development of small molecule
therapies for
gastrointestinal stromal tumors. Other targets of recent interest include mouse double minute 2 homolog (MDM2) in
dedifferentiated liposarcoma and
anaplastic lymphoma kinase (ALK) in inflammatory myofibroblastic
tumor. Molecular
therapies that have shown activity in diverse
sarcoma populations include
mammalian target of rapamycin (
mTOR) inhibitors and
vascular endothelial growth factor (
VEGF-R) inhibitors. Among the latter,
pazopanib demonstrated a progression-free survival over placebo in prior-treated patients with advanced
sarcoma, and is now approved for use in the
sarcomas in many countries. Efforts to understand the key molecular aberrations in any particular
tumor continue towards a goal of individualized
sarcoma therapy.