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The past, present, and future of cytotoxic chemotherapy and pathway-directed targeted agents for soft tissue sarcoma.
[dedifferentiated liposarcoma]
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
(
MDM
2
)
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
.
Diseases
Validation
Diseases presenting
"and is now approved for use in the sarcomas in many countries"
symptom
dedifferentiated liposarcoma
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