assessment of margins and the increased
rate of postoperative
wound complications.112 However,
reconstructive surgical techniques
with advanced tissue transfer procedures
are being used
more often in these high-risk wounds and
reportedly result in
better outcomes. The higher doses generally
required for postoperative
radiation therapy have also been shown to
be associated
with greater long-term functional
impairment.
The only randomized comparison of
preoperative and
postoperative radiation therapy to date was
performed by the
National Cancer Institute of Canada
Clinical Trials–Canadian
Sarcoma Group.113 This trial was designed to
examine complications
and functional outcome. The 190 patients
enrolled from
October 1994 to December 1997 were
randomized to preoperative
radiation therapy (50 Gy) or postoperative
radiation therapy
(66 Gy). With a median follow-up time of
3.3 years, the recurrence
and progression-free survival rates were
similar in the two
groups. However, the incidence of wound
complications was
significantly lower with preoperative
radiation therapy (3% vs.
17%), and the incidence of wound
complications was significantly
higher for tumors of the lower extremity
(43%) than for
those of the upper extremity (5%). 113 Late
radiation toxic effects
(e.g., fibrosis, joint stiffness, and
edema) were more common
with postoperative than preoperative
radiation therapy (48% vs.
32%) because of higher postoperative
radiation doses and larger
treatment field sizes.114
Brachytherapy involves the placement of
multiple radioactive
seeds through catheters inserted in the
tumor resection bed.
The primary benefit of brachytherapy is the
shorter overall treatment
time of 4 to 6 days, compared to the 4 to 6
weeks generally
required for preoperative or postoperative
radiation therapy
regimens. A cost-analysis comparison of
adjuvant brachytherapy
versus adjuvant external-beam irradiation
for soft tissue
sarcomas showed that costs were lower with
brachytherapy.115
Brachytherapy can also be used for
recurrent disease previously
treated with external-beam radiation.
Guidelines established at
Memorial Sloan-Kettering Cancer Center
recommend spacing
the afterloading catheters in 1-cm
increments while leaving a
2-cm margin around the surgical bed. 104 After
adequate wound
healing is confirmed, usually after the
fifth postoperative day,
the catheters are loaded with seeds
containing iridium-192
that deliver 42 to 45 Gy of radiation to
the tumor bed over
4 to 6 days. The primary disadvantage of
brachytherapy is that it
requires significant expertise, extended
inpatient hospital stays,
and bed rest.
IMRT delivers radiation more precisely to
the tumor than
external-beam irradiation while minimizing
the volume of surrounding
tissues exposed to high radiation doses.
The proposed
benefits of preoperative IMRT include
reduced risk of postoperative
wound infections because of minimization of
the dose
to the skin116 and protection of underlying
bone (e.g., femur)
as a result of concave dose distributions. 117
There have been
no prospective randomized trials comparing
the long-term outcomes
following IMRT versus other types of
radiation therapy.
In a retrospective analysis of IMRT,
patients with negative and
positive/close (within 1 mm) margins were
found to have 5-year
local control rates of 94%.118 In addition,
the rates of posttreatment
edema and joint stiffness with IMRT were
lower than the
expected rates with conventional radiation
therapy.
Local toxic effects of radiation therapy
vary according to
radiation dose, field size, and timing
(preoperative or postoperative).
With preoperative radiation therapy, the
most frequent
wound complications are wound dehiscence,
wound necrosis,
persistent drainage, infection, seroma
formation, ulceration,
and cellulitis.113 Postoperative irradiation
of free flaps is often
associated with wound complications, and
patients should
be advised that secondary surgical repair
may be necessary.
Wound complication rates of 13% to 37% have
been reported
for preoperative radiation therapy,
compared to 5% to 20% for
postoperative radiation therapy. 119 If
catheters are loaded after
the fifth postoperative day, rates of wound
complications after
brachytherapy are similar to those after
postoperative radiation
therapy.
Long-term (chronic) effects of radiation
therapy (those
occurring >1 year after completion of
therapy) are generally
related to fibrosis/contractures,
lymphedema, neurologic injury,
osteitis, and fractures, all of which can
cause substantial functional
impairment.119 Variables associated with
poorer functional
outcome after radiation therapy include
larger tumors, higher
doses of radiation (>63 Gy), longer
radiation fields (>35 cm),
poor radiation technique, neural sacrifice,
postoperative fractures,
and wound complications.114,120 Additionally,
complications of
any kind are less likely after treatment
for upper extremity sarcoma
than after treatment for lower extremity
sarcoma.112,113
Definitive radiation therapy that delivers
maximal-tissuetolerance
doses of radiation may be appropriate for
selected
patients with unresectable soft tissue
sarcomas. In a study of
112 patients with unresectable soft tissue
sarcomas, tumor size
and radiation dose were found to influence
local control and survival.
121 The local control rate was 51% for tumors
smaller than
5 cm and 9% for tumors larger than 10 cm,
and patients who
received at least 64 Gy had better local
control and survival.
Systemic Therapy
Despite improvements in local control
rates, metastasis and
death remain significant problems for
patients with high-risk
soft tissue sarcomas. Patients considered
at high risk of death
from sarcoma include those presenting with
metastatic disease,
localized sarcomas at nonextremity sites,
or sarcomas of intermediate-
or high-grade histology larger than 5
cm.58,104
Standard Chemotherapy. For most patients
with sarcoma,
results of conventional chemotherapy
regimens have been poor.
The chemosensitivity of soft tissue sarcoma
varies by histologic
subtype.29 Synovial sarcoma, myxoid/round
cell liposarcoma,
and uterine leiomyosarcoma are sensitive to
chemotherapy,122
whereas pleomorphic liposarcoma,
myxofibrosarcoma, epithelioid
sarcoma, leiomyosarcoma, MPNSTs,
angiosarcoma, and
desmoplastic round cell tumors have
intermediate sensitivity to
chemotherapy. Relatively chemoresistant
histologic subtypes
include clear cell sarcoma, endometrial
stromal sarcoma, alveolar
soft part sarcoma, and extraskeletal myxoid
chondrosarcoma.
Considering the variability of responses by
histologic subtype,
it is not surprising that clinical trials
of standard chemotherapy,
which often include heterogeneous
populations with respect to
tumor grade and histology, have
demonstrated no overall survival
benefit.
Doxorubicin and ifosfamide are the two most
active agents
against soft tissue sarcoma, with
consistently reported response
rates of 20% or greater and positive dose-
response curves.123,124
The European guidelines recommend
doxorubicin 75 mg/m2
every 3 weeks as first-line treatment for
advanced disease.29
Treatment duration is based on response,
but a maximum of six
cycles is generally recommended because of
the risk of cumulative
cardiotoxicity. Ifosfamide is the
recommended second-line
treatment and is recommended for first-line
treatment in patients with cardiac
morbidity. The standard dose of ifosfamide
is 9
to 10 g/m2; however, single-institution
series using higher-dose
regimens (>10 g/m2) or standard-dose
ifosfamide combined
with doxorubicin have shown response rates
of 20% to 60%.124
Synovial sarcomas have been shown to be
particularly sensitive
to ifosfamide. Ifosfamide-associated toxic
effects include
hemorrhagic cystitis, neurotoxicity, and
renal tubular acidosis.
Historically, combination therapy with
doxorubicin plus ifosfamide,
dacarbazine, or both has resulted in
increased response
rates but no improvement in overall
survival.125 Dacarbazine as
a single agent has also demonstrated
activity in clinical trials.
Over the past decade, several additional
chemotherapeutic
agents, including gemcitabine, taxanes, and
trabectedin, have
been noted to be active against soft tissue
sarcomas. Gemcitabine
as a single agent was reported to produce
responses in 18% of
patients with advanced sarcoma.126
Gemcitabine combined with
docetaxel has been reported to produce
response rates as high as
53% in patients with uterine
leiomyosarcoma.126,127 Gemcitabine
combined with vinorelbine has also been
associated with clinical
benefit in patients with advanced
sarcomas.128 The taxanes
(docetaxel and paclitaxel) have been found
to be active against
angiosarcomas, particularly of the face and
scalp, likely because
of their potent antiangiogenic effects. 129,130
Novel Chemotherapeutic Agents.
Trabectedin, a marinederived
alkaloid that binds DNA, affecting
transcription and
inducing the formation of DNA double-strand
breaks, has
shown benefit in the treatment of advanced
soft tissue sarcomas,
particularly leiomyosarcoma, myxoid
liposarcoma, and
other translocation-related sarcomas.131
Trabectedin is generally
well tolerated but can be associated with
prolonged and severe
neutropenia, thrombocytopenia, and hepatic
toxic effects.
Palifosfamide is a stabilized formulation
of the active
metabolite of ifosfamide that has been
reported to be better tolerated
than ifosfamide.132 Early trials have
suggested antitumor
activity comparable or superior to that of
ifosfamide without
nephrotoxicity.
Targeted Therapies. Several targeted agents
are being investigated
for the treatment of soft tissue sarcomas.
Among these are
tyrosine kinase inhibitors (e.g., imatinib,
sunitinib, sorafenib,
and dasatinib) that have been developed and
approved for treatment
of GIST. Clinical data accumulated in phase
II trials also
support the use of tyrosine kinase
inhibitors (e.g., imatinib,
sorafenib, and sunitinib) in the management
of other advanced
sarcomas.125 Anti–vascular endothelial growth
factor antibodies
such as bevacizumab have demonstrated
activity in patients
with metastatic or unresectable
angiosarcoma, solitary fibrous
tumor, and epithelioid
hemangioendothelioma.133 Pazopanib is
an oral angiogenesis inhibitor that targets
vascular endothelial
growth factor receptors, platelet-derived
growth factor receptor
(PDGFR), and c-kit. In a recent phase III
study, pazopanib
showed efficacy against placebo in second
or further line of
therapy in patients with advanced soft
tissue sarcoma.134 Inhibitors
of the mammalian target of rapamycin
pathway, including
temsirolimus, everolimus, and
ridaforolimus, have also shown
activity against some soft tissue sarcomas
(i.e., PEComas).135
Benefits of Systemic Therapy. The use of
adjuvant and
neoadjuvant chemotherapy for soft tissue
sarcomas remains
controversial. More than a dozen individual
randomized trials
of adjuvant chemotherapy have failed to
demonstrate improvement
in disease-free or overall survival for
patients with soft
tissue sarcoma. However, several
limitations of these individual
trials
may explain the lack of observed
improvement. First, the
chemotherapy regimens used were suboptimal,
consisting of
single-agent therapy (most commonly with
doxorubicin) and
insufficiently intensive dosing schedules.
Second, the patient
groups were not large enough to reveal
clinically significant differences
in survival rates. Finally, most studies
included patients
at low risk of metastasis and death, namely
those with small
(<5 cm) and low-grade tumors.
The Sarcoma Meta-Analysis Collaboration
analyzed
1568 patients from 14 trials of
doxorubicin-based adjuvant
chemotherapy to evaluate the effect of
adjuvant chemotherapy
on localized, resectable soft tissue
sarcomas.136 At a median
follow-up time of 9.4 years, doxorubicin-
based chemotherapy
significantly improved the time to local
and distant recurrence
and recurrence-free survival rates.
However, the absolute benefit
in overall survival was only 4%, which was
not significant
(P = .12). In a subset analysis, patients
with extremity tumors
had a 7% benefit in terms of overall
survival (P = .029).136
After this meta-analysis, randomized
controlled trials of
more contemporary anthracycline/ifosfamide
dosing combinations
with relatively small numbers of patients
have yielded
conflicting results. In an Italian
cooperative trial, adjuvant chemotherapy
improved median disease-free and overall
survival
times in patients with high-risk extremity
soft tissue sarcomas.137
In that study, 104 patients with high-grade
tumors 5 cm or larger
were randomized to definitive surgery or
surgery plus adjuvant
chemotherapy consisting of epirubicin (60
mg/m2/d on days 1
and 2) and ifosfamide (1.8 g/m2/d on days 1
through 5) for five
cycles. With a median follow-up time of
almost 5 years, diseasefree
survival times were 16 months in the
surgery-alone group
and 48 months in the combined-treatment
group (P = .04), and
median overall survival times were 46
months in the surgeryalone
group and 75 months in the combined-
treatment group
(P = .03).137 However, several years later,
the surgery-alone
and combined-treatment groups had
equivalent relapse rates and
deaths, which resulted in statistically
similar overall survival.138
In an effort to further assess the role of
chemotherapy
in patients with stage III extremity
sarcoma, a cohort analysis
of the combined databases of The University
of Texas MD
Anderson Cancer Center and Memorial Sloan-
Kettering Cancer
Center was performed. Data on 674 patients
with stage III
extremity sarcoma who received either
preoperative or postoperative
doxorubicin-based chemotherapy were
reviewed. The
5-year disease-specific survival rate was
61%.139 Cox regression
analysis showed a time-varying effect of
chemotherapy
with an associated benefit during the first
year while receiving
chemotherapy. However, the clinical
benefits of chemotherapy
in patients with stage III sarcomas were
not sustained beyond
1 year. Grobmyer and colleagues compared
the outcomes of
patients treated at two institutions (1990–
2001) with surgery
only or surgery plus preoperative
chemotherapy containing
doxorubicin and ifosfamide. In this
analysis, chemotherapy was
associated with an improvement in the 3-
year disease-specific
survival rate that was most pronounced in
patients with tumors
larger than 10 cm (62% for surgery alone
vs. 83% for neoadjuvant
chemotherapy and surgery).140
More recently, the European Organization
for Research
and Treatment of Cancer (EORTC) completed a
phase III randomized
study (trial EORTC-62931; conducted from
1995
through 2003) comparing surgery alone
versus surgery plus
adjuvant ifosfamide (5 g/m2) plus
doxorubicin (75 mg/m2)
with growth factor support (lenograstim)
every 21 days for five cycles in 351
patients with resected grade II or III soft
tissue
sarcoma at any site. The estimated relapse-
free survival rate
was 52% in both arms, and the overall
survival rate was better
in the control arm (69% vs. 64%). 141 Although
most individual
studies are underpowered, data from all of
these studies suggest
that chemotherapy regimens that incorporate
ifosfamide may
provide some disease-free survival benefit
but do not improve
long-term overall survival for the majority
of patients with soft
tissue sarcoma.
In 2008, two updates to the 1997 Sarcoma
Meta-Analysis
Collaboration were published.142,143 O’Connor
and colleagues
included all of the trials in the original
meta-analysis and added
data from four additional trials, for a
total of 18 trials with 2170
patients.142 The results showed a benefit of
chemotherapy in
terms of disease-free survival at 5 years
and recurrence-free
survival at 10 years but again failed to
demonstrate a benefit in
terms of long-term overall survival. The
second update, by Pervaiz
and colleagues, which did not include the
EORTC-62931
trial, showed that adjuvant chemotherapy
was associated with
a significant decrease in the risk of death
(hazard ratio, 0.77;
P = .01).143
Because the evidence regarding adjuvant
systemic therapy
for stage III soft tissue sarcoma is
inconclusive, considerable
variation still exists in treatment
recommendations even though
patients with large, stage II or stage III
soft tissue sarcomas are
at high risk for recurrence and metastasis.
Chemotherapy may
be considered to downstage large tumors to
enable limb-sparing
procedures, particularly for tumors known
to be chemosensitive.
It is likely that subsets of high-risk
patients with extremity
soft tissue sarcoma defined on the basis of
tumor size or histology
derive significant benefit from systemic
chemotherapy. For
example, retrospective cohort analyses have
noted a diseasespecific
survival benefit in patients with large,
high-grade liposarcomas
and synovial sarcomas of the extremity
treated with
ifosfamide plus doxorubicin versus no
chemotherapy.144