Nomogram Prognostik. Prognostic
nomograms for soft tissue sarcoma have
been introduced for use in patient
counseling, selecting appropriate
surveillance strategies, and selecting
patients for clinical trials.70 One such
nomogram, developed by Kattan and
colleagues at Memorial Sloan-Kettering
Cancer Center, considers age, histology,
grade, location, depth, and
size to determine the likelihood of 12-
year sarcoma-specific survival.70 Two
validation studies using the nomogram
demonstrated good predictive value.71
More recently, the same group of
investigators developed histology
subtype-specific nomograms for patients
with liposarcoma, synovial sarcoma, and
GIST72 and demonstrated that they
were accurate in predicting disease-
specific survival. Other investigators
have just developed a site-specific
nomogram for patients with
retroperitoneal sarcoma, demonstrating
an accurate prediction of survival and
disease recurrence.73 TREATMENT OF
EXTREMITY AND TRUNK WALL
SARCOMA The goals of treatment of
soft tissue sarcoma are to maximize the
likelihood of long-term recurrence-free
survival while minimizing morbidity and
maximizing function. In the past two
decades, a multimodality treatment
approach with optimal sequencing of
treatments for individual patients has
been shown to improve survival.74
Furthermore, patients with soft tissue
sarcoma treated at high-volume centers
have been shown to have improved
survival and functional outcomes.75
Care at such centers is particularly
important for patients with high-risk and
advanced disease. The overall 5-year
survival rate for patients with all stages
of soft tissue sarcoma is 50% to 60%.
For patients with extremity sarcomas, a
multidisciplinary treatment approach has
resulted in local control rates exceeding
90% and 5-year survival rates exceeding
70%. Most patients who die of soft tissue
sarcoma die
of metastatic disease, which becomes
evident within 2 to 3 years of initial
diagnosis in 80% of cases.
Recommendations for evaluation and
treatment of patients presenting with soft
tissue masses are summarized in Table
36-3. Surgery Primary tumors with no
evidence of distant metastasis are
managed with surgery alone or, when
wide pathologic margins cannot be
achieved because of anatomic
constraints and/or the grade is high,
surgery plus radiation therapy. The type
of surgical resection is determined by
several factors, including tumor location,
tumor size, depth of invasion,
involvement of nearby structures, need
for skin grafting or autogenous tissue
reconstruction, and the patient's
performance status. In 1985, the
National Institutes of Health developed a
consensus statement recommending
limb-sparing surgery for most patients
with high-grade extremity sarcomas.76
However, for patients with primary or
recurrent tumors that cannot be grossly
resected with a limb-sparing procedure
and preservation of function (<5% of
patients), amputation remains the
treatment of choice. Margin status after
surgical resection has been shown to be
an independent prognostic factor.77,78
The goal of surgical resection is to
achieve a complete resection because
microscopically positive or grossly
positive resection margins are
associated with increased risk of local
 recurrence and death.79 If an
unexpected positive margin is found on
pathologic examination of the resection
specimen, re-excision should be
performed. In patients with a positive
margin, particularly in patients with
macroscopic residual disease, local
control is unlikely even with the addition
of postoperative radiation therapy.80
Wide Local Excision. The preferred
treatment for extremity sarcomas is wide
local excision that includes resection of
the biopsy site. The goal of wide local
excision is to remove the tumor with
approximately 1 to 2 cm of surrounding
normal soft tissue,77 but narrower
margins may be necessary to preserve
uninvolved critical neurovascular
structures and may be adequate for
patients undergoing radiation therapy.81
Dissection should proceed through
grossly normal tissue planes not abutting
the tumor. Soft tissue sarcomas are
generally surrounded by a zone of
compressed reactive tissue that forms a
pseudocapsule, but this pseudocapsule
should not be used to guide resection
(enucleation). If the tumor is adjacent to
or displacing major neurovascular
structures, these do not need to be
resected, but the adventitia or
perineurium should be removed.1 For
some massive tumors of the extremities,
wide local excision entails a radical or
complete anatomic compartment
resection. Surgical clips should be
placed to delineate the extent of the
resection bed for patients likely to
require postoperative radiation therapy.
Recent reports demonstrate encouraging
results following radical en bloc resection
with vascular reconstruction in the lower
extremities.82,83 While en bloc
resection with vascular reconstruction
has been associated with increased
rates of postoperative complications,
reported local recurrence and 5-year
survival rates are similar to those for
patients not requiring vessel
resection.84,85 Similarly, studies have
shown acceptable functional outcomes
with resection of the sciatic, tibial, and
peroneal nerves with appropriate
reconstruction and rehabilitation.86 Bone
invasion from extremity soft tissue
sarcoma, which can generally be
identified using high- quality cross-
sectional imaging such as MRI, has been
estimated to occur in about 5% of
patients and is associated with reduced
overall survival.87 In cases of bone
invasion, bone resection is required to
obtain an adequate surgical margin and
to achieve local control. Although tumor
resection and repair of skeletal defects
are possible, the likelihood of
postoperative complications may be
increased, and functional outcomes may
be less favorable. Lin and colleagues88
recently analyzed 55 patients with soft
tissue sarcomas abutting bone and
reported that in the absence of frank
cortical bone penetration, periosteum
was an adequate surgical margin in
patients treated with wide local excision
and radiation. Soft tissue sarcomas
arising in the distal extremities,
particularly the hands and feet, present
unique technical challenges. While
distal-extremity tumors are often
detected at a smaller size (<5 cm) than
proximal-extremity tumors, resection and
reconstruction techniques are often more
complex for distalextremity tumors, and
preoperative planning is critical to obtain
favorable functional outcomes.
Identifying the proximity of the tumor to
underlying critical structures (eg, bone,
 tendon, or
neurovascular structures) using MRI is
essential for surgical planning. In a
reported series of patients with sarcomas
of the hands or feet treated with limited
surgery only, 32% of patients had local
recurrences.89 Preservation of function
and acceptable recurrence rates with
limited surgery and adjuvant radiation
therapy for soft tissue sarcomas of the
distal extremities have been reported.90
For locally advanced tumors, repair of
bone defects, vascular reconstruction,
tendon transfers, and soft tissue
reconstruction using regional or free
flaps have resulted in good functional
outcomes.91 Amputation remains a
reasonable option for patients with soft
tissue sarcomas of the distal extremities
when acceptable oncologic or functional
outcomes cannot be achieved using
available limb salvage techniques. In an
interesting study conducted in Ontario
and Quebec, investigators found patients
expecting a difficult recovery and
patients with uncertain expectations had
worse functional outcomes than patients
anticipating an easy recovery, indicating
that preoperative education including
consultation with rehabilitation services
may optimize outcomes.92 Furthermore,
all patients undergoing resection of
extremity sarcomas should undergo
physical therapy beginning immediately
after surgery and continuing until
maximum function is achieved.1
Locoregional Lymphadenectomy.
Several studies have reported improved
survival for patients with isolated regional
lymph node metastases treated with
radical lymphadenectomy.
27, 63-65 Patients with clinically or
radiologically suspicious regional nodes
should have metastases confirmed
before radical lymphadenectomy. At our
institution, we perform ultrasound-guided
fine-needle aspiration of lymph nodes in
selected patients with suspicious clinical
or radiologic findings. The utility of
sentinel lymph node biopsy has
remained controversial despite the
recognition that several histologic
subtypes of high- grade sarcoma are
known to have a propensity for lymph
node metastasis. However, there have
been no prospective studies of the
sensitivity and specificity of sentinel
lymph node biopsy for such tumors.
Amputation. Amputation is the
treatment of choice for the 5% of patients
with primary or recurrent extremity
tumors whose tumors cannot be grossly
resected with limb-sparing procedures
and preservation of function. Historically,
local excision of large, high-grade soft
tissue sarcomas resulted in local failure
rates of 50% to 70%, even when a
margin of normal tissue around the
tumor was excised; consequently, radical
resection or amputation was
recommended. Today, however, the
addition of radiation therapy to less
radical surgical resection has made limb
salvage possible in most cases. A
comparison of amputation versus limb-
sparing surgery followed by adjuvant
radiation therapy performed by the
National Cancer Institute between 1975
and 1981 demonstrated no significant
difference between the two groups in
local recurrence or overall survival
rate.93 Potter and colleagues49 later
reviewed the entire National Cancer
Institute experience with 123 patients
treated with conservative surgery plus
radiation therapy and 83 treated with
amputation. The local recurrence rate
was significantly higher in the surgery
and adjuvant radiation therapy group:
8% versus 0% in the amputation group.
However, survival rates did not differ
between the groups. Several large
single-institution studies have since also
reported favorable local control rates
with conservative resection plus
radiation therapy.94-96 Isolated
Regional Perfusion. Isolated regional
perfusion is a limb-sparing technique in
which a soft tissue sarcoma is perfused
with high concentrations of tumor
necrosis factor-α and melphalan under
hyperthermic conditions. The technique
is generally used for locally advanced,
multifocal, or locally recurrent disease; it
has also served as a palliative treatment
to achieve local control for patients with
distant metastases. Limb perfusion
requires isolating the main artery and
vein of the perfused limb from the
systemic circulation. The anatomic
approach is determined by tumor site:
external iliac vessels are used for thigh
tumors, femoral or popliteal vessels for
calf tumors, and axillary vessels for
upper extremity tumors. The vessels are
dissected, and all collateral vessels are
ligated. The main artery and vein are
then cannulated and connected to a
pump oxygenator similar to that used in
cardiopulmonary bypass. Either a
tourniquet or an Esmarch band is
applied to
the limb to achieve complete vascular
isolation. Chemotherapeutic agents are
then added to the perfusion circuit and
circulated for 90 minutes. Systemic
leakage from the perfused limb is
monitored continuously with 99Tc-
radiolabeled human serum albumin
injected into the perfusate, and
radioactivity above the precordial area is
recorded with a Geiger counter. During
the entire procedure, hyperthermia of the
perfused limb is maintained by external
heating and by warming the perfusate to
40°C. At the end of the procedure, the
limb is washed out, the cannulas are
extracted, and the blood vessels are
repaired. Despite the 40-year history of
using isolated limb perfusion to treat
extremity sarcomas, many questions
about this technique remain to be
answered. The optimal
chemotherapeutic agent in the perfusion
circuit, the benefits of hyperthermia, and
the effectiveness of hyperthermic
perfusion as neoadjuvant or adjuvant
treatment remain to be elucidated.
Studies published to date have involved
heterogeneous patient groups and
various chemotherapeutic agents.
Despite these limitations, response rates
from 18% to 80% and overall 5-year
survival rates from 50% to 70% have
been reported.97-101 However, survival
outcomes following isolated limb
perfusion have not yet been directly
compared with survival outcomes after
more conventional treatment
approaches. In the initial report of
isolated regional perfusion for extremity
sarcomas, published in 1974, McBride
reported results in 79 patients with
extremity sarcomas who had been
treated with isolated limb perfusion
during the previous 14 years.97 All
patients received melphalan and
dactinomycin. The overall 5-year survival
rate was 57%, and only 13 patients had
subsequent amputation for recurrent
disease. Over the next 20 years, isolated
perfusion for treatment of extremity
sarcoma fell out of favor for several
reasons. Most notably, improved survival
and decreased local recurrence rates
could be obtained with less radical
therapy, including conservative surgical
excision combined with radiation to allow
limb sparing in patients who were
previously thought to require amputation.
A 1992 report by Lienard and
colleagues101 renewed interest in
isolated limb perfusion for extremity
tumors. Those investigators reported a
100% response rate among patients with
extremity melanomas and sarcomas
treated with high-dose recombinant
tumor necrosis factor-α plus interferon-γ
and melphalan in an isolated perfusion
circuit. This report led to larger studies
geared specifically to patients with
sarcoma. The largest of these studies,
the European Multicenter Study, was
reported by Eggermont and colleagues
in 1996.99 In that study of 186 patients,
the overall tumor response rate was
82%, and the clinical and pathologic
complete response rate was 29%.
Although all of the study participants
were reported to initially be candidates
for amputation, the rate of limb salvage
following isolated limb perfusion was
82%.99 Subsequent studies have shown
high local response and limb salvage
rates and acceptable local and
systemic toxic effects.102 However,
results in the United States have been
inferior to those reported in Europe. In a
study by Fraker and colleagues, the
complete response rate was 26%, and
an additional 30% of patients had a
partial response. Fourteen patients
(32%) underwent amputation for
progressive tumors, while the remaining
30 patients (68%) were able to undergo
limb-sparing surgery after isolated limb
perfusion.100 The inferior results in the
US- based studies are thought to be due
to patient selection biases and the
degree of treatment before limb
perfusion. Radiation Therapy Radiation
therapy is part of the standard treatment
for highgrade extremity and trunk wall
soft tissue sarcomas either in the pre- or
postoperative setting. Patients with low-
grade tumors or small, superficial high-
grade tumors that have been resected
with adequate margins may safely avoid
radiation therapy. The evidence
supporting adjuvant radiation therapy for
patients eligible for conservative surgical
resection comes from two randomized
trials103,104 and three large single-
institution reports.105-107 In a
randomized trial by the National Cancer
Institute, 91 patients with high-grade
extremity tumors were treated with limb-
sparing surgery followed by
chemotherapy alone or radiation therapy
plus chemotherapy. The 10-year local
control rate was 98% for patients
receiving radiation therapy compared
with 70% for those not receiving
radiation therapy (P = .0001).103
Similarly, in a randomized trial from
Memorial Sloan-Kettering Cancer
Center, 164 patients underwent
conservative surgery followed by
observation or brachytherapy. For
patients with high-grade tumors, the 5-
year local control rate was 66% in the
observation group and 89% in the
brachytherapy group (P = .003).104 For
patients with low-grade tumors, no
significant difference was observed
between treatment groups.108 Until
recently, the standard treatment
guidelines required radiation therapy
after surgery for all patients with
intermediate- or high-grade tumors of
any size. However, small tumors (≤5 cm)
have not generally been associated with
local recurrence, and radiation therapy
for such tumors may not be
necessary.104 In a series of 174
patients reported by Geer and
colleagues, postoperative radiation
therapy did not improve 5-year local
recurrence or overall survival rates for
patients with small soft tissue sarcomas.
109 Karakousis and colleagues reported
a 5-year local recurrence rate of 6% for
80 patients with extremity sarcomas
treated with wide local excision and
observation, a rate similar to that for the
64 patients who underwent resection
with narrower surgical margins and
postoperative radiation therapy.110 The
optimal mode of radiation therapy
(external-beam radiation therapy,
brachytherapy, or intensity-modulated
radiation therapy [IMRT]) and timing of
radiation therapy (preoperative,
intraoperative, or postoperative) have yet
to be defined. External-beam radiation
therapy can be delivered using photons
or particle beams (electrons, protons,
pions, or neutrons). Conventional
fractionation is usually 1.8 to 2 Gy per
day. CT is an integral part of radiation
therapy, used to define the gross tumor
volume and to estimate the margin of
tissue at risk for microscopic tumor
involvement. The optimal radiation
margin is not well defined: a margin of 5
to 7 cm is standard, but some centers
advocate wider margins for tumors larger
than 15 cm. At most institutions, the
typical preoperative dose is 50 Gy given
in 25 fractions, and resection is
performed 4 to 8 weeks after completion
of radiation therapy to allow acute
radiation changes to subside.
Postoperative radiation therapy planning
is based on tumor site, tumor grade,
surgical margins, and institutional
preferences. The entire surgical scar and
drain sites should be included in the field
so that a near-full dose can be
administered to the superficial skin.
Metallic clips placed in the tumor bed
during surgery can help define the limits
of the resection and aid in radiation
therapy planning. Doses of 60 to 70 Gy
are usually necessary for postoperative
treatment. No consensus exists on the
optimal sequence of radiation therapy
and surgery. The available data come
largely from single-institution,
nonrandomized studies. Proponents of
preoperative radiation therapy note that
multidisciplinary planning with radiation
oncologists, medical oncologists, and
surgeons is easier early in the course of
therapy. In addition, for some
radiosensitive histologic subtypes, such
as myxoid liposarcoma,
preoperative radiation therapy may
shrink the tumor, facilitating resection
with negative margins. Furthermore, a
tissue bed undisturbed by resection has
better tissue oxygenation and can be
successfully treated with lower doses of
radiation. In addition, Nielsen and
colleagues111 demonstrated that
preoperative radiation fields are smaller
than postoperative radiation fields and
that the average number of joints
included in the field is lower with
preoperative than postoperative radiation
therapy, which may result in improved
functional outcome. Critics of
preoperative radiation therapy cite the
difficulty of pathologic 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 (eg, 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 (eg, 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. 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 patientswith
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. 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 (eg, 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 (eg, 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 (ie,
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.