Adjuvant Therapy.

Most studies have This situation prompted the initiation of a

failed to show a survival multicenter, randomized
benefit from adjuvant chemotherapy for trial sponsored by the American College of
retroperitoneal Surgeons
sarcoma.170-172 Because of the high rates Oncology Group (ACOSOG) comparing
of local recurrence, surgery to surgery
adjuvant radiation therapy has been with preoperative radiation (ACOSOG
proposed for treating microscopic Z9031). Unfortunately,
residual disease following surgical the study was closed prematurely in 2006
resection. However, because of low patient
the optimal technique and timing of accrual. A similar study is now ongoing in
radiation therapy have not Europe, sponsored
been established, and the potential benefits by the Soft Tissue and Bone Sarcoma
of radiation therapy Group (STBSG) of the
must be weighed against the increased risk EORTC.
of treatment-related Current recommendations for radiation
toxic effects. therapy for patients
Radiation treatment of retroperitoneal with retroperitoneal sarcoma at MD
sarcomas is complex Anderson Cancer Center
because tumors are usually large, which are based on disease characteristics at
necessitates large presentation.176 For highrisk
treatment fields close to radiosensitive patients, defined as those with large, high-
structures (e.g., bowel). grade tumors or
Several techniques have been used, recurrent low-grade tumors, preoperative
including preoperative and radiation therapy to a
postoperative external-beam radiation total dose of 50 Gy followed by surgical
therapy, intraoperative resection is considered.
radiation therapy, and brachytherapy.173 Postoperative radiation is discouraged
Preoperative radiation unless the resected tumor
therapy is feasible and well tolerated. Toxic bed is clearly away from dose-limiting
effects may be less structures.
severe with preoperative radiation therapy Treatment of Recurrence. Retroperitoneal
given that the tumor sarcomas recur
borders are definable, the tumor displaces more often than extremity and trunk wall
radiosensitive viscera ones. Retroperitoneal
away from the treatment field, and effective leiomyosarcomas, in addition to recurring
doses of radiation locally in the
may be lower preoperatively.174 tumor bed and metastasizing to the lungs,
Several studies have shown favorable local frequently spread
control rates to the liver. Retroperitoneal sarcomas can
for intermediate- and high-grade also recur diffusely
retroperitoneal sarcoma treated throughout the peritoneal cavity
with preoperative radiation therapy and (sarcomatosis). Resection
complete resection.173 of recurrent retroperitoneal sarcoma is
However, most studies have failed to show similar to resection of
a survival benefit.175
recurrent extremity sarcoma. However, the
likelihood that a
recurrent retroperitoneal sarcoma will be
resectable declines
precipitously with each recurrence. In a
large series of patients
treated at Memorial Sloan-Kettering Cancer
Center, the authors
were able to resect recurrent tumors in 57%
of patients with a
first recurrence but only 20% of patients
with a second recurrence
and 10% of patients with a third
recurrence.68 In up to
25% of patients, well-differentiated
retroperitoneal liposarcoma
recurs in a poorly differentiated form or
recurs with areas of
dedifferentiation. Dedifferentiated
retroperitoneal liposarcoma
is more aggressive than its well-
differentiated precursor and has
a greater propensity for distant metastasis.
Gastrointestinal Sarcoma
Patients with gastrointestinal sarcoma most
often present with
nonspecific gastrointestinal symptoms that
are determined by
the site of the primary tumor. In a series
from Memorial Sloan-
Kettering Cancer Center, early satiety and
dyspepsia were noted
in patients with tumors of the upper
gastrointestinal tract, whereas
tenesmus and changes in bowel habits were
common in patients
with tumors of the lower gastrointestinal
tract.177 In a series of 80
patients with various smooth-muscle tumors
of the gastrointestinal
tract, Chou and colleagues178 identified the
most common presenting
symptoms and signs as gastrointestinal
bleeding (44%),
abdominal mass (38%), and abdominal pain
(21%).
Establishing the diagnosis of a
gastrointestinal sarcoma
preoperatively is often difficult. Radiologic
assessment, including
CT of the abdomen or pelvis, is sometimes
useful to determine
the anatomic location, size, and extent of
disease. Patients
with localized disease frequently present
with a large intraabdominal
mass. However, there is no radiographic
evidence
of regional lymph node metastases, which
would be typical of
an adenocarcinoma of similar size and
anatomic location. In
patients with advanced gastrointestinal
sarcoma, CT may demonstrate
disseminated intra-abdominal masses with
or without
concomitant ascites and invasion of tissue
planes.
Endoscopy (esophagoduodenoscopy or
colonoscopy) has
become the mainstay for evaluating
symptoms related to the
gastrointestinal tract. For tumors involving
the stomach, upper
endoscopy with endoscopic ultrasonography
and biopsy are
important diagnostic tests used to
distinguish gastrointestinal
sarcoma from adenocarcinoma of the
stomach. This distinction
is clinically significant because the extent of
resection (local
excision versus gastrectomy) and the role of
regional lymphadenectomy
differ for these two conditions. For
gastrointestinal sarcomas,
lymphatic spread is not the primary route of
metastasis;
consequently, lymphadenectomy is not
routinely performed as
part of resection. The general
recommendation for gastrointestinal
sarcoma, based on published data and the
primary pattern of
distant (vs. local) failure, is to resect the
tumor with a 2- to 4-cm
margin of normal tissue. However, some
cases may be technically
challenging because of the tumor’s
anatomic location or
size. For example, for gastric tumors located
near the gastroesophageal
junction, achieving adequate surgical
margins may
not be possible without a total or proximal
subtotal gastrectomy.
Similarly, large leiomyosarcomas arising
from the stomach with
invasion of adjacent organs should be
resected together with the
adjacent involved viscera en bloc.
For sarcomas of the small or large intestine,
segmental
bowel resection is the standard treatment.
For sarcomas of the jejunum, ileum, and
colon, the tumor is excised en bloc with
the involved segment of intestine and its
mesentery; radical
mesenteric lymphadenectomy is not
attempted. For sarcomas
originating in the rectum, the tumor
resection technique is based
on the anatomic location and size of the
tumor. For small, low
rectal lesions, clear margins may be
achievable with a transanal
excision. Large or locally invasive lesions
may require more
extensive operations for complete tumor
extirpation.179,180
Breast Sarcoma
Sarcomas of the breast are rare tumors,
accounting for less than
1% of all breast malignancies and less than
5% of all soft tissue
sarcomas. A variety of histologic subtypes
have been reported
within the breast, including angiosarcoma,
stromal sarcoma,
fibrosarcoma, and malignant fibrous
histiocytoma.
Angiosarcoma of the breast accounts for
about 50% of all
sarcomas of the breast and has increasingly
been associated with
radiation therapy for treatment of primary
breast cancer.10 The
period between radiation therapy and
diagnosis of radiationassociated
breast sarcoma has been reported to range
from 3 to
20 years, with an incidence of 0.3% at 10
years and 0.5% at
15 years.181 In a retrospective study of 55
patients with angiosarcoma
of the breast, patients with radiation-
associated angiosarcoma
were on average 30 years older and were
less likely
to present with distant metastases than
radiation-naive patients.
Clinically, radiation-associated
angiosarcoma of the breast may
occur in the irradiated chest wall after
mastectomy or in the irradiated
breast following segmental resection. The
findings at presentation
of a patient with cutaneous angiosarcoma
often include
an expanding erythematous patch, red
papular eruptions, bluishblack
lesions, or bruise-like discoloration
overlying an area of
induration. Mammography is often
nonspecific, and diagnosis
requires punch or incisional biopsy.
Cystosarcoma phyllodes are generally not
considered to
be sarcomas, because these tumors are
thought to originate from
hormonally responsive stromal cells of the
breast and are usually
benign. In patients with these tumors,
infiltrating tumor
margins, severe stromal overgrowth, atypia,
and cellularity have
all been identified as risk factors for
metastases.182
As with sarcomas at other anatomic sites,
histopathologic
grade and tumor size are important
prognostic factors for sarcomas
of the breast. The likelihood of local
recurrence increases
as tumor size increases; tumors smaller than
5 cm are associated
with better overall survival. Local and
distant recurrences
are more common in patients with high-
grade lesions. Complete
excision with negative margins is the
primary therapy. Simple
mastectomy confers no additional benefit if
complete excision
can be accomplished by segmental
mastectomy. Because of low
rates of regional lymphatic spread, axillary
dissection is not routinely
indicated. Neoadjuvant chemotherapy or
radiation therapy
may be considered for patients with large,
high-risk tumors.
Uterine Sarcoma
Sarcomas account for less than 5% of
uterine malignancies.
Uterine sarcomas have been classified into
four histologic subgroups:
uterine leiomyosarcoma, endometrial
stromal sarcoma,
malignant mixed mullerian tumor
(carcinosarcoma), and undifferentiated
endometrial sarcoma. Five-year overall
survival
rates for patients with uterine sarcoma are
30% to 50%.183 Total
abdominal hysterectomy (TAH)
recommended for localized
disease. Bilateral salpingo-oophorectomy is
mandatory only
in endometrial stromal sarcoma. Because
uterine sarcomas are
rare, the benefits of adjuvant therapy (e.g.,
chemotherapy, hormonal
therapy) have not been adequately
evaluated. Pelvic postoperative
irradiation has been studied instead in a
randomized
fashion. The results of such study have been
reported, showing
no benefit in survival in favor of radiation
therapy.184
Uterine leiomyosarcomas are smooth-
muscle tumors and
account for 35% to 40% of uterine
sarcomas. Leiomyosarcoma
can affect women in their twenties, although
it is more commonly
diagnosed between 50 and 60 years of age.
Standard
treatment is TAH with or without ovarian
preservation depending
on the patient’s wishes and menopausal
status. Lymph node
metastasis is present in less than 5% of
patients at diagnosis, and
lymphadenectomy is not recommended.
Adjuvant pelvic radiation
therapy can be considered for selected high-
risk patients.
Adjuvant chemotherapy is controversial.
Gemcitabine plus
docetaxel has been noted to be well
tolerated and highly active,
with a response rate of 53% in patients with
unresectable uterine
leiomyosarcoma.127 Doxorubicin and
trabectedin have also
demonstrated activity when used as first- or
second-line therapy.
Endometrial stromal sarcomas account for
is approximately
7% to 10% of uterine sarcomas. Mitotic
count is used to classify
endometrial stromal sarcomas as low grade
(<10 mitoses
per 10 high-power fields) or high-grade
(>10 mitoses per 10
high-power fields). In general, low-grade
tumors demonstrate
an indolent clinical course, while high-grade
tumors are more
aggressive with a poorer prognosis. Unlike
other uterine sarcomas
subtypes, endometrial stromal sarcomas
express progesterone
receptors and have been found to be
responsive to
hormonal manipulation as an adjuvant
therapy or for treatment
of recurrent disease.185,186 Surgical
treatment for these tumors
includes TAH and bilateral salpingo-
oophorectomy in premenopausal
women; postoperative hormone replacement
therapy is
contraindicated.187 Recurrent or advanced
disease may respond
to antiestrogen therapy. Tamoxifen is not
recommended because
it may be proestrogenic in this setting.
Malignant mixed mullerian tumor accounts
for 50% of
uterine sarcomas and arises predominantly
in postmenopausal
women. This tumor is regarded as epithelial
and is treated not
with agents typically used to treat sarcoma
but with agents used
to treat ovarian and endometrial cancers.
Undifferentiated endometrial sarcoma is an
aggressive
malignancy that does not express estrogen
or progesterone
receptors. It is associated with a poor
prognosis even in patients
presenting with localized disease. TAH with
or without preservation
of the ovaries is recommended;
postoperative pelvic
radiation therapy may also be administered.
Systemic agents for
other soft tissue sarcomas are used for
recurrent and/or metastatic
disease.
GASTROINTESTINAL STROMAL
TUMORS
GISTs, which account for the majority of
gastrointestinal
sarcomas, have distinctive molecular
features that have been
characterized over the last decade. These
tumors share phenotypic
similarities with the intestinal pacemaker
cells known
as the interstitial cells of Cajal188;
interstitial cells of Cajal and
GIST cells express the hematopoietic
progenitor cell marker
CD34 and the growth factor receptor c-
Kit.189 Expression of the
c-Kit gene protein product, CD117, has
emerged as an important
defining feature of GISTs. Using these
diagnostic criteria,
the incidence of GIST has been estimated to
be 6 to 15 cases
per million individuals per year.190-192
Until recently, systemic treatment for
patients with unresectable or metastatic
GIST was
of little benefit because these tumors were
resistant to conventional
chemotherapy. Since the recognition that
KIT activation
occurs in most GISTs, KIT inhibition has
emerged as the primary
treatment modality along with surgery.
Approximately 80% of GISTs have a
mutation in the gene
encoding the KIT receptor tyrosine kinase,
and 5% to 10% have
a mutation in the gene encoding the related
PDGFRA receptor
tyrosine kinase; such mutations result in the
expression of
mutant proteins with constitutive tyrosine
kinase activity.1 The
remaining GISTs do not have a detectable
mutation, but lack of
a mutation does not preclude a diagnosis of
GIST if the tumor
is morphologically typical of GIST. The
presence and type of
KIT (exon 11 or exon 9) or PDGFRA (exon
18) mutation has
been found to predict tumor response to
imatinib. In a phase II
trial, patients with KIT exon 11 mutations
had better response
rates (83.5% vs. 47.8%) and survival than
those with KIT exon 9
mutations or those without KIT or PDGFRA
mutation.193 These
findings have subsequently been confirmed
in two additional
phase III trials conducted by the EORTC–
Italian Sarcoma
Group–Australasian Gastrointestinal Trials
Group (EORTC-
62005).194,195
The most common locations for GISTs are
the stomach
(60%) and small intestine (30%), but GISTs
can arise anywhere
along the gastrointestinal tract.196 Gastric
GISTs have been
shown to be associated with a more
favorable prognosis than
GISTs at other sites.197 GISTs are most
commonly diagnosed
by upper endoscopy and/or CT of the
abdomen as an incidental
finding in an asymptomatic patient or in a
patient being evaluated
for symptoms of early satiety, abdominal
pain, or gastrointestinal
bleeding. GIST most frequently
metastasizes to the liver
and/or abdominal cavity.
Radiologic Assessment
FDG-PET has been reported to be useful for
preoperative
staging of GISTs because it may reveal
early metastases and
establish baseline metabolic activity. PET
has been shown
to be highly sensitive in detecting early
response to imatinib
treatment and in predicting long-term
response in patients with
metastatic GIST. If PET is to be used for
monitoring response to
therapy, baseline PET should be performed
before initiation of
treatment. Because PET is still not widely
available and because
PET fails to detect some lesions because of
poor glucose uptake,
new CT-based criteria for detection of GIST
and for predicting
prognosis of GIST have also been
proposed.198
Management of Localized Disease
Complete surgical resection with negative
margins is the recommended
treatment for localized GISTs. Extended
anatomic
resection and lymphadenectomy are not
required. Resection
of even locally advanced tumors is
associated with improved
survival.199 The 5-year survival rate for all
patients with GISTs
ranges from 20% to 44%, and the 5-year
survival rate for
patients with completely excised early-stage
tumors is up to
75%.199 An analysis of 200 patients by
DeMatteo and colleagues
found a disease-specific survival rate of
54% for patients with
grossly complete resection of primary
GIST, and the median
survival duration for patients with
metastatic disease was only
20 months.57
As for other soft tissue sarcomas, tumor size
has consistently
been identified as an important prognostic
factor for
GIST. Mitotic activity has also been
identified as an important
prognostic factor and is generally
categorized as fewer than
5, 5 to 10, or more than 10 mitoses per high-
power field. The
National Institutes of Health200 and the
Armed Forces Institute
of Pathology196 have proposed prognostic
criteria for risk
stratification of surgically treated, localized
primary GIST.
Both groups take into account tumor size
and mitotic count; the
Armed Forces Institute of Pathology also
includes tumor site as
a prognostic variable. Accurate risk
stratification is essential for
selecting patients most likely to benefit
from adjuvant treatment.
Management of Locally Advanced or
Metastatic Disease
Treatment with imatinib mesylate (Gleevec,
ST1571), a selective
inhibitor of the KIT protein tyrosine kinase,
has resulted in
impressive clinical responses in a large
percentage of patients
with unresectable or metastatic GISTs. On
the basis of the initial
results in a single patient with metastatic
GIST, the EORTC Soft
Tissue and Bone Sarcoma Group initiated a
phase I study to
test the safety and efficacy of imatinib.201
In that study, 53% of
patients with GISTs had confirmed partial
responses; investigators
concluded that imatinib is safe and effective
against this
disease.201 A multicenter, international trial
of imatinib for GIST
was begun in July 2000 at four treatment
centers: Dana-Farber
Cancer Institute, Oregon Health Sciences
University, Fox Chase
Cancer Center, and University Hospital of
Helsinki, Finland.202
A total of 147 patients with unresectable or
metastatic GISTs
were randomized to 400 or 600 mg of
imatinib daily for up to
24 months. Objective response was
demonstrated in 79 patients
(54%); all had partial responses, and there
was no significant
difference in response rate between imatinib
doses.203 Fourteen
percent of patients experienced disease
progression. The toxicity
profile was acceptable; the predominant
effects were gastrointestinal
effects (diarrhea, nausea), periorbital
edema, muscle
cramps, and fatigue. However, 21% of
patients experienced
serious (grade 3 or 4) adverse events,
including gastrointestinal
bleeding in 5% of patients, most likely
related to the rapid tumor
response of mural lesions.
A phase III randomized Intergroup trial was
simultaneously
performed to assess the clinical activity of
imatinib at
two dose levels for patients with
unresectable or metastatic
GIST expressing the c-Kit tyrosine
kinase.204 From December
15, 2000, through September 1, 2001, 746
patients were
accrued and randomized to low-dose (400
mg/d) or high-dose
(800 mg/d) imatinib. The primary endpoint
of the trial was survival.
Preliminary toxicity data from 325 patients
revealed a
23% incidence of grade 3 or 4 adverse
events, including nausea
and vomiting, gastrointestinal bleeding,
abdominal pain, edema,
fatigue, and rash.
In February 2002, the U.S. Food and Drug
Administration
approved imatinib for treatment of GIST
based on the results of
these promising clinical trials. Both the
Intergroup trial mentioned
in the preceding paragraph and a separate
phase III trial
compared the efficacy of low-dose (400
mg/d) and high-dose
(800 mg/d) imatinib in patients with
metastatic or unresectable
GISTs.205,206 Both studies showed
equivalent response rates and
overall survival for the two doses but
increased toxicity for the
800-mg/d dose. Current recommendations
include consideration
of dose escalation to 800 mg/d for patients
who experience disease
progression at a dose of 400 mg/d and for
patients with
advanced GIST and KIT exon 9
mutations.1,207
The optimal duration of imatinib treatment,
the duration
of benefit from imatinib, and the long-term
toxicity of imatinib have not been
established. When feasible, imatinib should
be
continued in the absence of disease
progression. A randomized
trial reported worse median progression-free
survival in patients
who stopped imatinib after 1 year than in
patients who continued
beyond 1 year (progression-free survival of
6 months vs.
18 months).208 Less than 4% of patients
with GISTs have experienced
serious adverse events with imatinib. Mild
gastrointestinal
toxicity is the most frequently reported
adverse event, but
gastrointestinal tract hemorrhage,
presumably from rapid tumor
necrosis, has also been reported. Thus, all
patients with GISTs
treated on clinical protocols should be
evaluated and followed
by a team of medical professionals that
includes a surgeon.
Many patients with GIST develop resistance
to imatinib.
Primary resistance is defined as clinical
progression that develops
during the first 6 months of treatment and is
most commonly
seen in patients with KIT exon 9 mutation,
PDGFRA exon 18
mutation, or no mutations.209 Secondary
resistance is defined as
progression that develops more than 6
months after the start of
treatment in a patient with an initial
response.210 Imatinib resistance
should be managed by either dose escalation
or transition
to treatment with sunitinib.1
In 2006, sunitinib malate (SU11248, Sutent,
Pfizer)
emerged as an alternative systemic
treatment for patients unable
to tolerate imatinib and patients with
imatinib-refractory GIST.
Sunitinib is a tyrosine kinase inhibitor that
targets multiple
kinases, including the vascular endothelial
growth factor receptors,
PDGFRA, KIT, and FLt3. Sunitinib has
both antiangiogenic
and antiproliferative activity. In a phase III
randomized
placebo-controlled trial, sunitinib was
associated with a significant
improvement in median time to progression resistance are currently being investigated.
(27.3 weeks Surgery has been
vs. 6.4 weeks with placebo) in patients with shown to be beneficial for selected patients
imatinib-resistant with isolated disease
GIST.131 In addition, sunitinib therapy was progression during imatinib therapy.216-
well tolerated; diarrhea, 219 Surgical resection of
fatigue, and nausea were the most common residual metastatic disease responding to
adverse effects. imatinib-sensitive
Sunitinib has also been associated with GIST has also been shown to result in
hand-foot skin reaction, progression-free survival
hypertension, cardiotoxicity, and in 70% to 96% of patients with imatinib- or
hypothyroidism.211-213 In 2006, sunitinib-sensitive
sunitinib was approved by the U.S. Food GISTs.218-220 The optimal timing of
and Drug Administration surgery in relation to imatinib
for treatment of patients with resistance or therapy for patients with metastatic disease
intolerance to remains to be determined. It is not possible
imatinib. to compare outcomes for patients
Other tyrosine kinase inhibitors are in treated with kinase inhibitors alone and
development, many patients treated with
of which target more than one family of kinase inhibitors plus surgical resection
protein kinases.214 outside the context of
Among these are sorafenib, dasatinib, and randomized trials given the heterogeneity of
nilotinib, which patients and biases
are actively being investigated for the associated with selection of patients for
treatment of imatinib-resistant surgical resection.
GIST.215 Everolimus (RAD001) and
protein kinase C
are being investigated as agents that may
maximize the extent
and duration of response to imatinib by
blocking potential pathways
of resistance.
Multidisciplinary Treatment
Although imatinib has improved survival of
patients with
advanced GIST, most patients with
advanced GIST are not
cured with imatinib. Some patients develop
secondary resistance
to imatinib with one or more sites of disease
progression after
6 months of clinical response (Fig. 36-10A
[before imatinib],
Fig. 36-10B [after imatinib]). The
mechanisms of imatinib