clinical review  Ewing’s sarcoma
clinical review
E
wing’s sarcoma (ES) is a rare
malignancy with a strong pe-
diatric predilection, typically
presenting as a bone tumor. ES is the
second most common primary bone
malignancy in patients younger than
age 20 years, following osteosarcoma,
and accounts for approximately 3%
of all malignancies in pediatric pa-
tients.1-3 James Ewing first described
the tumor as an “endothelioma of
bone,” believing that it arose from
the blood vessels of bone tissue.1,3,4
He later described the histopathol-
ogy as small round cells with pale
cytoplasm and small hyperchromatic
nuclei, characterizing the tumor as
an “endothelial myeloma.” Today, the
tumors are described as small, blue,
round-cell tumors and include clas-
sic ES, Askin tumor of the thoracic
wall, and peripheral primitive neuro-
ectodermal tumor (PNET).1
PNETs are highly malignant neo-
plasms, seemingly incompatible with
their pediatric nickname, “peanut
tumors,” and all of these lesions are
included in the ES family of tumors
(ESFT).5,6 ES most commonly occurs
in the second decade of life, and 55%
of the individuals affected are male.6
It is very infrequently diagnosed after
the third decade of life. Patients with
these aggressive neoplasms have a
low survival rate despite treatment
with surgical intervention, chemo-
therapy, and radiation therapy. ES
Ann O. Karosas, B.S.Pharm., BCOP, is Oncology Pharmacist,
Geisinger Medical Center, 100 North Academy Avenue, Danville, PA
17822 (akarosas@geisinger.edu).
The author has declared no potential conflicts of interest.
Ewing’s sarcoma
Ann O. Karosas
Purpose. The current treatments of and
new therapeutic options for the man-
agement of Ewing’s sarcoma (ES) are
reviewed.
Summary. ES is the second most common
primary bone malignancy in pediatric pa-
tients and is numbered among the cancers
that result in the greatest risk of mortal-
ity and morbidity in children and young
adults. Much progress has been made in
the treatment of ES since the disease was
first described in the 1920s. With current
multimodality treatment including che-
motherapy, radiation, and surgery, patients
with localized disease have a long-term
survival rate of approximately 50%. Survival
rates for patients with metastatic disease or
those with early relapse remain poor. New
combinations of cytotoxic agents such as
cyclophosphamide, topotecan, irinotecan,
and temozolomide have shown efficacy
and tolerability in patients with relapsed
or refractory disease. To date, the role of
high-dose chemotherapy supported by
stem cell rescue as a consolidation therapy
for high-risk ES tumors has yet to be con-
usually affects the trunk and long
bones, with the pelvis, ribs, femur,
and humerus being the most com-
mon sites of origination.6 In the
truncal skeleton, the pelvis is most
often affected, then the scapula, ver-
tebrae, ribs, and clavicle. Of the long
bones, ES most commonly affects the
femur, then the humerus, tibia, and
fibula.1,6 This malignancy is charac-
terized by rapid growth and a high
Copyright © 2010, American Society of Health-System Pharma-
cists, Inc. All rights reserved. 1079-2082/10/1001-1599$06.00.
DOI 10.2146/ajhp090526
Am J Health-Syst Pharm—Vol 67 Oct 1, 2010
clusively determined. Much effort is being
invested in treating cancer with targeted
therapies, and the EWS-ETS fusion gene
would likely provide an important tumor-
specific target. Tyrosine kinases (TKs) are
overexpressed in human sarcoma tumors,
and cell lines may serve as potential targets
for new therapies. One TK receptor that is a
promising therapeutic target is insulinlike
growth factor-1 receptor.
Conclusion. Treatments for ES include
surgery, radiation, and cytotoxic regimens,
many of which include vincristine. Treat-
ment for recurrent ES has included topo-
tecan, cyclophosphamide, temozolomide,
and irinotecan. Angiogenesis inhibitors, TK
inhibitors, and bisphosphonates have also
been studied.
Index terms: Antineoplastic agents; Cyclo-
phosphamide; Epidemiology; Irinotecan;
Mechanism of action; Mortality; Pediatrics;
Radiation; Sarcoma; Site of action; Surgery;
Temozolomide; Topotecan; Vincristine
Am J Health-Syst Pharm. 2010; 67:1599-
605
potential to develop metastases, most
commonly in the lungs, bones, and
bone marrow.
ES is often underdiagnosed. One
of the earliest symptoms is mild pain
at the tumor site, but as the tumor
grows, the pain increases in intensity
and necessitates therapy with analge-
sics.1,6 Pain is often followed by the
appearance of a palpable mass, which
may be tender and inflamed. Tumor
1599
 clinical review  Ewing’s sarcoma
growth eventually leads to a pal-
pable or visible inflammation of the
affected site. If the tumor is in the
pelvis or involves the spinal column,
paresthesias or interference with
normal bladder and bowel func-
tion may be present. Most often,
these tumors arise from bone, and
in some cases, pathological fracture
secondary to minor trauma can
be the hallmark sign that initiates
medical intervention. Rarely, these
tumors will arise from soft tissue
and are then labeled extraosseous or
extraskeletal ES (EES). The most fre-
quent sites of EES are the chest wall,
lower extremities, and the paraver-
tebral region. Less frequently, the
tumor occurs in the pelvis and hip
region and the retroperitoneum.6
Tumor bulk may be indiscernible
for a long period of time if these
tumors are deep seated, resulting in
large tumor volume at diagnosis and
a subsequent poorer prognosis. It is
not uncommon for teenage patients
who are physically active to have
their pain attributed to bone growth
or to injuries resulting from sports
or daily activity before the diagnosis
of ES is made.2
Biology and pathology
Recent advances in molecular
pathology have greatly enhanced
practitioners’ ability to classify and
differentiate these round-cell tu-
mors. Immunohistochemical analy-
sis, along with molecular analysis
for chromosomal abnormalities, is
necessary to distinguish the histology
of ES from that of other small, blue,
round-cell tumors of childhood,
such as non-Hodgkin’s lymphoma,
rhabdomyosarcoma, retinoblastoma,
and neuroblastoma. The transloca-
tion t(11;22)(q24;q12) is the most
common translocation diagnostic for
ES and is present in approximately
85% of ES cases.1,6 This is a trans-
location involving chromosomes
11 and 22, which fuse portions of
the EWS gene on 22q12 with the
FLI1 gene on 11q24, thus creating a
1600 Am J Health-Syst Pharm—Vol 67 Oct 1, 2010
novel fusion gene (EWS-FLI1) with
oncogenic properties. Using reverse
transcriptase polymerase chain reac-
tion (RT-PCR) and fluorescence in
situ hybridization, the presence of
this translocation has been found
to correlate with high expression
of the cell surface sialoglycoprotein
CD99mic2.1 Although overexpression
of CD99mic2 is not diagnostic for this
disease because of its presence in
normal tissues, overexpression of this
transmembrane protein may offer
a potential target for drug therapy.
Lymphomas are periodic acid–Schiff
(PAS) negative and reticulin positive,
whereas ESs are PAS positive (due to
intracellular glycogen) and reticulin
negative.1,6
Epidemiology
Caucasians have the highest rate
of ES, while Asians and African
Americans rarely develop this dis-
ease.1,6 Its peak age of occurrence is
15 years, slightly lower than that for
osteogenic sarcoma, which has a peak
age of 19 years old. In addition, there
is no second peak of occurrence in
the eighth decade of life, as is seen
with osteogenic sarcoma. ES affects
approximately 250–400 patients
in the United States each year, and
80% of these cases occur before
age 18 years.7 There is, however, an
increasing number of adults over
the age of 30 being diagnosed with
this disease. The oldest person at ES
diagnosis was a 77-year-old woman
who sought care for a painful left
inguinal mass.8 EES was confirmed
by the presence of the EWS-FLI1
detected by RT-PCR.
Prognosis
The key prognostic factor in ES is
the presence or absence of metastatic
disease, and while 80% of patients
have clinically localized disease, sub-
clinical metastases are assumed to be
present in nearly all patients.3,6 Overt
metastatic disease becomes evident
in weeks to months in patients who
do not receive adequate treatment.
Symptoms, including fever, malaise,
weight loss, and anemia, are pres-
ent in 10–20% of patients and are
thought to be due to circulating
cytokines, which are the direct result
of a large tumor volume. For patients
with localized disease, those with ex-
tremity lesions tend to have a better
prognosis than do patients with axial
primary lesions (e.g., involving ribs,
clavicle, pelvis, spine, scalp, skull, or
sternum), mainly because the latter
tumors cannot be surgically removed
with adequate negative margins.3,9
Primary pelvic disease, age greater
than 12 years, and an elevated serum
lactic dehydrogenase level are typi-
cally unfavorable prognostic indica-
tors.3,4 An elevated lactic dehydroge-
nase level, along with an interval of
less than three months between the
onset of symptoms and diagnosis,
is exponentially related to decreased
survival and may be a predictor of
metastatic disease.3 Primary sites of
metastasis are the lungs, bones, and
bone marrow. Lung metastasis alone
is not necessarily a negative prog-
nostic indicator, and approximately
30% of patients with pulmonary
metastasis alone will have prolonged
survival, compared with only 10% of
patients with bone or bone marrow
involvement.9
Chemotherapy
Regardless of whether metastatic
disease is identified during the initial
staging and patient workup, treat-
ment of ES should include chemo-
therapy and either radiation therapy
or surgery or both.1,6,10 Before the
use of multiagent chemotherapy, the
long-term survival rate of ES was less
than 10%, even though these tumors
were known to be extremely sensi-
tive to radiation.1,6 Currently, most
clinical centers performing intensive
chemotherapy report long-term
survival rates of 50–70%, suggest-
ing that ES is sensitive to traditional
chemotherapy.1,3,6 The current cy-
totoxic armamentarium includes
doxorubicin, cyclophosphamide,

vincristine, ifosfamide, etoposide,
and dactinomycin.
In 1962, Sutow and Sullivan 11
and Pinkel12 separately described the
use of cyclophosphamide for ES. In
1972, Hustu et al.13 reported that 10
of 15 patients with localized ES had
prolonged disease-free survival using
a combination of vincristine and cy-
clophosphamide administered over
one to two years. In 1974, Rosen et
al.14 treated 12 previously untreated
children with a confirmed histologi-
cal diagnosis of clinically localized
ES with vincristine, dactinomycin,
cyclophosphamide, and doxorubicin
(VACD). The authors reported long-
term survival with no evidence of
recurrent tumor, metastatic tumor,
or central nervous system disease for
up to 37 months.
This early research led to the First
Intergroup Ewing’s Sarcoma Study
(IESS-I), which established the supe-
riority of adding doxorubicin to the
regimens.15 The Second Intergroup
Ewing’s Sarcoma Study (IESS-II)
examined the effects of dose inten-
sity of doxorubicin and proved the
superiority of escalated over moder-
ate doses of doxorubicin in five-year
survival of patients with localized
ES (63% versus 35%) and the rate
of relapse-free survival (55% versus
23%).16
In Europe, similar relapse-free
survival rates (55%) were seen in the
Cooperative Ewing’s Sarcoma Study
(CESS)-81, which also demonstrated
that tumor volume was highly pre-
dictive of prognosis.17 The estimated
relapse-free-survival rates were 80%
for patients with small tumors (<100
mL) and 31% for patients with larger
tumors. The estimated disease-free
survival rate for all patients at five
years was 55%. In CESS-86, ifos-
famide was compared with cyclo-
phosphamide, randomizing low-risk
patients (tumor volume of <100
mL) to VACD and high-risk patients
(tumor volume of ≥100 mL, centrally
located tumors, or both) to vincris-
tine, dactinomycin, ifosfamide, and
clinical review  Ewing’s sarcoma
doxorubicin.18 Ten-year event-free
survival rates were similar between
the standard-risk group (52%) and
the high-risk group (51%), suggest-
ing that ifosfamide had usefulness in
high-risk patients with ES.
The Pediatric Oncology Group–
Children’s Cancer Group study
INT-0091 randomized patients to re-
ceive either VACD alone or VACD plus
ifosfamide and etoposide (VACD-IE),
prompted by Phase II study results
achieved with VACD-IE.19,20 In pa-
tients with no evidence of metastatic
disease, the VACD group achieved a
five-year survival rate of 54%, while
the VACD-IE group had a five-year
survival rate of 69%. These results
led to the adoption of VACD-IE as
the gold standard for the treatment
of localized ES.21 For patients with
ES and metastases at the time of
diagnosis, the addition of etoposide
and ifosfamide to standard therapy
did not improve event-free or overall
survival.22
Investigators from St. Jude Chil-
dren’s Research Hospital enrolled
pediatric patients in the high-risk
sarcoma (HIRISA) trials, HIRISA1
and HIRISA2.23 They hypothesized
that intensive, concomitant admin-
istration of vincristine, doxorubicin,
cyclophosphamide, ifosfamide, and
etoposide within a defined period
(29 weeks, compared with 49 weeks
in INT-0091) would reduce drug
resistance and kill more tumor cells,
resulting in improved survival. The
HIRISA2 study was conducted be-
cause patients in the HIRISA1 study
were unable to complete the therapy
within the specified time because of
significant hematologic and nonhe-
matologic toxicities. The main differ-
ence between the two studies was the
delay in local control (radiotherapy
with or without surgery). Local con-
trol began during week 9 in HIRISA1
and during week 16 in HIRISA2.
Seven of 13 patients in HIRISA2
completed therapy within the speci-
fied time, though the regimen was
associated with significant myelosup-
Am J Health-Syst Pharm—Vol 67 Oct 1, 2010
pression and grade 3 or 4 mucositis
requiring total parenteral nutrition.
Both the five-year survival and five-
year event-free survival estimates
were 45%, demonstrating that dose
intensification of alkylator-based che-
motherapy in patients with high-risk
sarcoma is associated with appreciable
toxicities and marginal benefits.
Children’s Oncology Group pro-
tocol AEWS 0031 investigated in-
terval compression of the five-drug
North American standard (vincris-
tine, doxorubicin, and cyclophos-
phamide alternating with ifosfamide
plus etoposide) administered every
two weeks versus every three weeks.24
Preliminary results of this study re-
vealed that patients treated every two
weeks had a superior four-year event-
free survival rate (76% versus 65%,
p = 0.029) and four-year overall sur-
vival rate (91% versus 85%, p = 0.026)
compared with the group receiving
standard therapy. The chemotherapy
trials are summarized in Table 1.
Bone marrow transplantation
By the 1980s, it became apparent
that despite a steady improvement
in overall response with multimodal
therapy, including the intensive
chemotherapy regimens described
above, there was a subset of patients
at high risk for treatment failure. Few
patients who had metastatic disease
or extensive but unresectable local-
ized disease, primarily lesions of the
trunk, were cured.25 Because of ES’s
responsiveness to radiation, the Na-
tional Cancer Institute began a series
of three protocols in 1981, continu-
ing until 1986, to determine whether
total body irradiation (TBI) with an
autologous bone marrow transplant
(ABMT) would improve systemic
and local disease control. Results
were dismal, revealing that consoli-
dation therapy (TBI plus ABMT) in
patients with metastatic or high-risk
localized pediatric sarcomas failed to
improve event-free survival rates.
In the mid-1990s, a group of
investigators at the Royal Marsden
1601
 clinical review  Ewing’s sarcoma

Table 1.
Trials of Chemotherapy for Ewing’s Sarcomaa

Trialb n Regimen % Survivalc

IESS-I15 342 Vincristine, dactinomycin, cyclophosphamide 24
Vincristine, dactinomycin, cyclophosphamide, whole-lung irradiation 44
Vincristine, dactinomycin, cyclophosphamide, doxorubicin 60
IESS-II16 214 Vincristine, dactinomycin, cyclophosphamide, high-dose doxorubicin 63
Vincristine, dactinomycin, cyclophosphamide, moderate-dose 35
doxorubicin
CESS-8117 93 Vincristine, dactinomycin, cyclophosphamide, doxorubicin 80 if tumor vol <100 mL
54 if tumor vol ≥100 mL
CESS-8618 301 Vincristine, dactinomycin, cyclophosphamide, doxorubicin (for tumor vol 52d
<100 mL)
Vincristine, dactinomycin, ifosfamide, doxorubicin (for tumor vol ≥100 mL 51d
or central tumors)
INT-009119,20 398 Vincristine, dactinomycin, cyclophosphamide, doxorubicin 54
Vincristine, dactinomycin, cyclophosphamide, doxorubicin, ifosfamide, 69
etoposide
HIRISA123 11 Vincristine, doxorubicin, cyclophosphamide, ifosfamide, etoposidee Study not completed
HIRISA223 13 Vincristine, doxorubicin, cyclophosphamide, ifosfamide, etoposidef 45g
AEWS 003124 587 Vincristine, doxorubicin, cyclophosphamide alternating with ifosfamide,
etoposide
  Alternating every 2 wk 91h
  Alternating every 3 wk 85h
a
Adapted in part from reference 6.
b
IESS = Intergroup Ewing’s Sarcoma Study, CESS = Cooperative Ewing’s Sarcoma Study, HIRISA = high-risk sarcoma.
c
5-year disease-free survival unless otherwise indicated.
d
10-year event-free survival.
e
Local control (radiotherapy, surgery, or both) commenced during week 9 of chemotherapy.
f
Local control (radiotherapy, surgery, or both) commenced during week 16 of chemotherapy.
g
Estimate.
h
4-year overall survival.

NHS Trust in London attempted to
capitalize on the sensitivity of ES
to alkylating agents and treated 18
patients using a protocol for high-
dose busulfan and melphalan with
autologous stem cell rescue.26 With
a median follow-up of only two
years, the authors concluded that
the treatment was well tolerated and
should be evaluated for efficacy in a
larger clinical trial. Other investiga-
tors have postulated that tumor cell
contamination of stem cell products
is a potential risk factor for relapse
and that better CD34+ cell selection
techniques or improved methods of
detecting residual disease to avoid tu-
mor cell contamination of autologous
cells at the time of reinfusion might
improve survival.27 To date, random-
ized clinical trials have not been con-
ducted to test this hypothesis.
In February 1996, protocol CCG-
7951 opened for accrual to determine
whether consolidation therapy with
high-dose melphalan, etoposide,
and TBI with autologous stem cell
transplant (ASCT) would improve
the prognosis for patients with newly
diagnosed, metastatic ES.28 Of the 32
patients eligible for this protocol, 23
proceeded to high-dose therapy con-
solidation. These patients had a two-
year event-free survival rate of only
24%, and the investigators concluded
that this regimen failed to improve
the probability of event-free survival
in these patients. Results from sev-
eral other trials published in 2005 and
2006 demonstrated five-year overall
survival rates of 23–63% and justified
the continued investigation of ASCT
as a consolidation therapy in patients
with metastatic or relapsed ES.29-31
Ninety-seven newly diagnosed
patients with metastatic ES were
enrolled in a prospective study
that used etoposide and ifosfamide
during induction, followed by con-
solidation therapy with busulfan
and melphalan, and the five-year
event-free survival rate was 37%.31
Patients in this trial who had meta-
static disease to the lungs only had
a five-year event-free survival rate
of 52%, suggesting that this subset
of patients may benefit from my-
eloablative chemotherapy followed
by ASCT.
A retrospective review published
in 2007 examined children with
high-risk ES who were treated with
ASCT at The Hospital for Sick Chil-
dren in Toronto from 1990 to 2005
and concluded that randomized tri-
als continue to be warranted.32

1602 Am J Health-Syst Pharm—Vol 67 Oct 1, 2010


In Japan, a clinical study to in-
vestigate the effects of high-dose
chemotherapy followed by an au-
tologous peripheral blood stem cell
transplant in adults and adolescents
with the ESFT and rhabdomyosar-
coma was undertaken.33 Overall, sur-
vival was 46% and failure-free sur-
vival was 33% at three years. Patients
with the ESFT did better than those
with rhabdomyosarcoma, suggesting
prolonged survival benefits from this
therapy. To date, the role of high-dose
chemotherapy supported by stem
cell rescue as a consolidation therapy
for high-risk ES tumors has yet to be
conclusively determined.34
While ASCT remains controver-
sial in treating the ESFT, two conclu-
sions can be drawn with the infor-
mation currently available.34 First, a
prospective, randomized study with
adequate follow-up to determine
both progression-free survival and
overall survival must be conducted to
settle the question of survival benefit
for ASCT versus standard chemo-
therapy in the ESFT. Second, it is
clear that ASCT will not substantially
change the fact that most patients
diagnosed with metastatic ESFT will
die of their disease.34 New approaches
that rely on strategies other than
radiation and dose intensification
of conventional chemotherapeutic
agents must be considered.
Chemotherapy for recurrent ES
Hunold et al.35 conducted a ret-
rospective analysis of 54 patients
with refractory or relapsed Ewing’s
tumors treated with topotecan and
cyclophosphamide. Of these patients,
32% had a partial response, 26% had
stable disease, and 29% had disease
progression. Of the remaining pa-
tients, response was not documented
in 4 patients, and 5 patients were
excluded from the response analysis.
The regimen was administered on
an outpatient basis, making it an ap-
propriate choice for chemotherapy in
relapsed ES when quality of life is the
defining issue.35
clinical review  Ewing’s sarcoma
Most recently, a chemotherapy
regimen consisting of temozolomide
and irinotecan has shown activity in
recurrent ES. Wagner et al.36 reported
that 7 of 11 patients with advanced
ES achieved complete response, par-
tial response, or a minor response
with the regimen. In addition to the
clinical benefit of temozolomide
and irinotecan in this population,
the combination therapy is very well
tolerated, can be given as an outpa-
tient regimen, and is associated with
limited cytopenias, no alopecia, and a
high rate of patient acceptance.37
Angiogensis inhibitors
Angiogensis, or the development
of a vascular bed, is necessary for
the development of highly vascular-
ized bone tumors such as ES.37 In
addition to allowing for growth of
the primary tumor, neovasculariza-
tion develops a pathway by which
migrating tumor cells gain access to
the systemic circulation and establish
distant metastasis.37,38 Bevacizumab
is an angiogensis inhibitor that binds
to vascular endothelial growth factor
(VEGF), inhibiting the proliferation
of endothelial cells and the forma-
tion of new blood vessels.39 Angio-
genesis inhibitors reduce interstitial
pressure in tumors, aiding in the
effective delivery of chemotherapy
and improving the oxygenation of
tumors, leading to better radiation
effectiveness.37 Several inhibitors of
VEGF have been evaluated in ES
and have been shown to be potent
inhibitors of tumor growth in mouse
models.38 In February 2010, the Chil-
dren’s Oncology Group completed
a clinical trial (COG-AEWS0521) of
vincristine, cyclophosphamide, and
topotecan with or without bevaci-
zumab in patients with their first
episode of recurrent ES.39 No study
resulted have been posted to date.
Tyrosine kinase inhibitors
Tyrosine kinase (TK) inhibitors
are a new generation of anticancer
drugs that are effective alone and
Am J Health-Syst Pharm—Vol 67 Oct 1, 2010
in combination with conventional
chemotherapeutic agents in treat-
ing a variety of different cancers.38,40
TKs play a critical role in modulat-
ing growth factor signaling, and,
when activated, these enzymes cause
increases in tumor cell growth by
inducing cellular proliferation. Acti-
vated TK inhibitors are also involved
in apoptosis and angiogenesis and
promote migration and metastasis
by setting into motion a cascade of
protein interactions, releasing signals
of positive and negative regulators
and resulting in a variety of cellular
processes, including adhesion, mi-
gration, invasion, transcription, and
survival.
Under normal conditions, this
process is tightly regulated, but in the
oncogenic state, signaling becomes
activated by a myriad of cellular
mechanisms, including mutation
and overexpression of the TK re-
ceptors or receptor ligands.38 It is
hypothesized that malignant cells are
much more reliant on TK signaling
than are normal cells. Mutations in
the platelet-derived growth factor
receptor (PDGFR), c-kit (a cytokine
receptor expressed on the surface
of hematopoietic stem cells), VEGF
receptor, and insulinlike growth
factor (IGF)-1 receptor signaling
pathways make up the majority of
the defective signaling pathways in
sarcomas. Imatinib, a TK inhibitor
of the BCR-ABL fusion protein, also
inhibits the c-kit and PDGFR TKs
that play a role in gastrointestinal
stromal tumor formation.40 However,
preclinical data suggest that c-kit and
PDGFR are not critical targets for ES
survival, as no real difference in clini-
cal outcome has been demonstrated
with the maximum dosage tolerated
of imatanib.38 The results of a Phase
II clinical trial of imatinib at a dose of
440 mg/m2/day demonstrated little
or no activity in relapsed or refrac-
tory ES.41 Phase I clinical trials have
determined that the maximum toler-
ated dosage of imatinib is 1000 mg
daily.42 This results in a physiological
1603
 clinical review  Ewing’s sarcoma
concentration that is below what is
required to inhibit the proliferation
and induce apoptosis of ES cell lines
in vitro.
Dasatinib, a multitargeted TK
inhibitor, is another promising thera-
peutic agent with oral bioavailability
that works by inhibiting src kinase
activity. This is accompanied by
blockade of cell migration and in-
vasion, actions that might provide
therapeutic benefit by preventing
growth and metastasis of sarcomas.
Dasatinib has been found to induce
apoptosis at nanomolar concentra-
tions in ES cell lines.43 A Phase II
trial of dasatinib (Dasatinib in Ad-
vanced Sarcomas) manufactured by
the Sarcoma Alliance for Research
through Collaboration and the drug
manufacturer is currently recruiting
participants.44
One TK receptor that is a promis-
ing therapeutic target is IGF-1 recep-
tor, a cell membrane receptor that is
activated by IGF-1 and IGF-2. IGF-1
plays an important role in cancer
cells by contributing to inhibition
of apoptosis and transformation,
metastasis, and induction of angio-
genesis through VEGF.38 Ahlen et al.45
examined IGF-1 receptor expression
in 101 patients with soft tissue sar-
comas and found that patients with
a high expression of IGF-1 receptor
had a more favorable outcome than
did those with lower expression.
NVP-AEW541, an IGF-1 receptor
inhibitor, was evaluated in a panel
of 10 ES cell lines and induced cell
cycle arrest and apoptosis in a dose-
dependent manner in all of the cell
lines tested.46 Trials are ongoing to
further elucidate the therapeutic po-
tential of IGF-1 receptor in soft tissue
sarcomas.47,48
Bisphosphonates
Bisphosphonates have many ac-
tions, including increasing bone
density and inhibiting osteoclastic
activity, resulting in reduced skel-
etal morbidity and improved sur-
vival and quality of life in cancer
1604 Am J Health-Syst Pharm—Vol 67 Oct 1, 2010
patients with neoplasms involving
the bones.49 Bisphosphonates may
be helpful as an adjunct to bone
healing after treatment for ES.37,49
Experimental evidence suggests that
bisphosphonates act on the tumor
cells themselves, either by inhibiting
mechanisms involved in the develop-
ment of bone metastasis or by induc-
ing apoptosis.37,49,50
Further investigation of the anti-
tumor effects of bisphosphonates in
clinical trials may be warranted.
Conclusion
Treatments for ES include surgery,
radiation, and cytotoxic regimens,
many of which include vincristine.
Treatment for recurrent ES has
included topotecan, cyclophospha-
mide, temozolomide, and irinotecan.
Angiogenesis inhibitors, TK inhibi-
tors, and bisphosphonates have also
been studied.
References
1. Bernstein M, Heinrich K, Paulussen M
et al. Ewing sarcoma family of tumors:
Ewing sarcoma of bone and soft tissue
and the peripheral primitive neuroecto-
dermal tumors. In: Pizzo PA, Poplack DG,
eds. Principles and practice of pediatric
oncology, 5th ed. Philadelphia: Lippin-
cott, Williams and Wilkins; 2005:1002-32.
2. Ricchetti ET, Erol B, Stern J et al. Lower
back pain and mass in a 13-year-old girl.
Clin Orthop Relat Res. 2005; 430:248-57.
3. Carvajal R, Meyers P. Ewing’s sarcoma
and primitive neuroectodermal family of
tumors. Hematol Oncol Clin North Am.
2005; 19:501-25.
4. Cotterill S. About James Ewing, 1866–
1943. www.cancerindex.org/bone/ewing.
htm (accessed 2009 Nov 6).
5. Kretschmar CS. Ewing’s sarcoma and the
“peanut” tumors. N Engl J Med. 1994;
331:325-7. Editorial.
6. Iwamoto Y. Diagnosis and treatment of
Ewing’s sarcoma. Jpn J Clin Oncol. 2007;
37:79-89.
7. Maki RG. Pediatric sarcomas occurring in
adults. J Surg Oncol. 2008; 97:360-8.
8. Cheung CC, Kandel RA, Bell RS et al.
Extraskeletal Ewing sarcoma in a 77-year-
old woman. Arch Pathol Lab Med. 2001;
125:1358-60.
9. Delaney TF, Hornicek FJ, Mankin MD et al.
Clinical presentation, staging and progno-
sis of the Ewing sarcoma family of tumors.
www.uptodate.com/patients/content/
topic.do?topicKey=~qUJJb5xA6pg6IO
(accessed 2010 Jul 12).
10. Yock TI, Krailo M, Fryer CJ et al. Local
control in pelvic Ewing sarcoma: analy-
sis from INT-0091—a report from the
Children’s Oncology Group. J Clin Oncol.
2006; 24:3838-43. [Erratum, J Clin Oncol.
2006; 24:4947.]
11. Sutow WW, Sullivan MP. Cyclophos-
phamide therapy in children with Ewing’s
sarcoma. Cancer Chemother Rep. 1962;
23:55-60.
12. Pinkel D. Cyclophosphamide in children
with cancer. Cancer. 1962; 15:42-9.
13. Hustu HO, Pinkel D, Pratt CB. Treatment
of clinically localized Ewing’s sarcoma
with radiotherapy and combination che-
motherapy. Cancer. 1972; 30:1522-7.
14. Rosen G, Wollner N, Tan C et al. Proceed-
ings: disease-free survival in children
with Ewing’s sarcoma treated with ra-
diation therapy and adjuvant four-drug
sequential chemotherapy. Cancer. 1974;
33:384-93.
15. Nesbit ME Jr, Gehan EA, Burgert EO Jr et
al. Multimodal therapy for the manage-
ment of primary, nonmetastatic Ewing’s
sarcoma of bone: a long-term follow-up
of the First Intergroup Study. J Clin On-
col. 1990; 8:1664-74.
16. Evans RG, Nesbit ME, Gehan EA et al.
Multimodal therapy for the management
of localized Ewing’s sarcoma of pelvic
and sacral bones: a report from the Sec-
ond Intergroup Study. J Clin Oncol. 1991;
9:1173-80.
17. Jurgens H, Exner U, Gadner H et al.
Multidisciplinary treatment of primary
Ewing’s sarcoma of bone. A 6-year expe-
rience of a European Cooperative Trial.
Cancer. 1988; 61:23-32.
18. Paulussen M, Ahrens S, Dunst J et al.
Localized Ewing tumor of bone: final
results of the Cooperative Ewing’s Sar-
coma Study CESS 86. J Clin Oncol. 2001;
19:1818-29.
19. Kung FH, Pratt CB, Vega RA et al. Ifos-
famide/etoposide combination in the
treatment of recurrent malignant solid
tumors of childhood. A Pediatric Oncol-
ogy Group Phase II study. Cancer. 1993;
71:1898-903.
20. Miser JS, Kinsella TJ, Triche TJ et al.
Ifosfamide with mesna uroprotection
and etoposide: an effective regimen in
the treatment of recurrent sarcomas
and other tumors of children and young
adults. J Clin Oncol. 1987; 5:1191-8.
21. Grier HE, Krailo MD, Tarbell NJ et al.
Addition of ifosfamide and etoposide
to standard chemotherapy for Ewing’s
sarcoma and primitive neuroectodermal
tumor of bone. N Engl J Med. 2003;
348:694-701.
22. Miser JS, Krailo MD, Tarbell NJ et al.
Treatment of metastatic Ewing’s sarcoma
or primitive neuroectodermal tumor of
bone: evaluation of combination ifos-
famide and etoposide—a Children’s Can-
cer Group and Pediatric Oncology Group
study. J Clin Oncol. 2004; 22:2873-6.
23. Navid F, Santana VM, Billups CA et al.
Concomitant administration of vincris-
tine, doxorubicin, cyclophosphamide,
ifosfamide, and etoposide for high-risk
sarcomas. The St. Jude Children’s Re-

search Hospital experience. Cancer. 2006;
106:1846-56.
24. Womer RB, West DC, Krailo MD et al.
Randomized comparison of every-two-
week v. every-three-week chemotherapy
in Ewing sarcoma family tumors (ESFT).
J Clin Oncol. 2008; 26 (May 20 suppl):
10504. Abstract.
25. Horowitz ME, Kinsella TJ, Wexler LH et
al. Total-body irradiation and autologous
bone marrow transplant in the treat-
ment of high-risk Ewing’s sarcoma and
rhabdomyosarcoma. J Clin Oncol. 1993;
11:1911-8.
26. Atra A, Whelan JS, Calvagna V et al.
High-dose busulphan/melphalan with
autologous stem cell rescue in Ewing’s
sarcoma. Bone Marrow Transplant. 1997;
20:843-6.
27. Mehta P, Wingard JR. Musculoskeletal
tumors of childhood. N Engl J Med. 1999;
341:1702-3.
28. Meyers PA, Krailo MD, Ladanyi M et
al. High-dose melphalan, etoposide,
total-body irradiation, and autologous
stem-cell reconstitution as consolidation
therapy for high-risk Ewing’s sarcoma
does not improve prognosis. J Clin Oncol.
2001; 19:2812-20.
29. Barker LM, Pendergrass TW, Sanders JE
et al. Survival after recurrence of Ewing’s
sarcoma family of tumors. J Clin Oncol.
2005; 23:4354-62.
30. Fraser CJ, Weigel BJ, Perentesis JP et al.
Autologous stem cell transplantation
for high-risk Ewing’s sarcoma and other
pediatric solid tumors. Bone Marrow
Transplant. 2006; 37:175-81.
31. Oberlin O, Rey A, Desfachelles AS et
al. Impact of high-dose busulfan plus
melphalan as consolidation in metastatic
Ewing tumors: a study by the Société
Francaise des Cancers de l’Enfant. J Clin
Oncol. 2006; 24:3997-4002.
32. Al-Faris N, Al Harbi T, Goia C et al. Does
consolidation with autologous stem cell
transplantation improve the outcome
of children with metastatic or relapsed
clinical review  Ewing’s sarcoma
Ewing sarcoma? Pediatr Blood Cancer.
2007; 49:190-5.
33. Yamada K, Takahaski M, Ogura M et al.
High-dose chemotherapy and autologous
peripheral blood stem cell transfusion for
adult and adolescent patients with small
round cell sarcomas. Bone Marrow Trans-
plant. 2007; 39:471-6.
34. Snyder KM, Mackall CL. Therapy for
metastatic ESFT: is it time to ask new
questions? Pediatr Blood Cancer. 2007;
49:115-6.
35. Hunold A, Weddeling N, Paulussen M et
al. Topotecan and cyclophosphamide in
patients with refractory or relapsed Ew-
ing tumors. Pediatr Blood Cancer. 2006;
47:795-800.
36. Wagner LM, McAllister N, Goldsby RE
et al. Temozolomide and intravenous
irinotecan for treatment of advanced
Ewing sarcoma. Pediatr Blood Cancer.
2007; 48:132-9.
37. Anderson P, Kopp L, Anderson N et al.
Novel bone cancer drugs: investigational
agents and control paradigms for pri-
mary bone sarcomas (Ewing’s sarcoma
and osteosarcoma). Expert Opin Investig
Drugs. 2008; 17:1703-15.
38. Shor AC, Agreata SV, D’Amato GZ et al.
Therapeutic potential of directed tyro-
sine kinase inhibitor therapy in sarcomas.
Cancer Control. 2008; 15:47-54.
39. ClinicalTrials.gov. Vincristine, topo-
tecan, and cyclophosphamide with or
without bevacizumab in treating young
patients with refractory or first recur-
rent extracranial Ewing sarcoma. http://
clinicaltrials.gov/ct/show/
NCT00516295 (accessed 2010 Aug 5).
40. Arora A, Scholar EM. Role of tyrosine
kinase inhibitors in cancer therapy. J
Pharmacol Exp Ther. 2005; 315:971-9.
41. Bond M, Bernstein M, Pappo A et al.
A phase II study of imatinib mesylate
in children with refractory or relapsed
solid tumors: a Children’s Oncology
Group study. Pediatr Blood Cancer. 2008;
50:254-8.
Am J Health-Syst Pharm—Vol 67 Oct 1, 2010
42. Champagne MA, Capdeville R, Krailo
M et al. Imatinib mesylate (STI571) for
treatment of children with Philadelphia
chromosome-positive leukemia: results
from a Children’s Oncology Group
phase 1 study. Blood. 2004; 104:2655-
2660.
43. Shor AC, Keschman EA, Lee FY et al.
Dasatinib inhibits migration and inva-
sion in diverse human sarcoma cell lines
and induces apoptosis in bone sarcoma
cells dependent or Src kinase for survival.
Cancer Res. 2007; 67:2800-8.
44. ClinicalTrials.gov. Trial of dasatinib in ad-
vanced sarcomas. http://clinicaltrials.gov/
ct2/show/NCT00464620 (accessed 2010
Jul 8).
45. Ahlen J, Wejde J, Brosjo O et al. Insulin-
like growth factor type 1 receptor ex-
pression correlates to good prognosis in
highly malignant soft tissue sarcoma. Clin
Cancer Res. 2005; 11:206-16.
46. Scotlandi K, Manara MC, Nicoletti G et
al. Antitumor activity of the insulin-like
growth factor-1 receptor kinase inhibitor
NVP-AEW541 in musculoskeletal tu-
mors. Cancer Res. 2005; 65:3868-76.
47. Mariani S. Targeting cancer cells:
IGF receptor-1 kinase inhibitors.
www.medscape.com (accessed 2009 May
12).
48. Children’s Oncology Group. Phase II
study of IMC-A12, a recombinant human
monoclonal antibody to the insulin-like
growth factor-I receptor in pediat-
ric patients with recurrent/refractory
solid tumors, ADVL0821. www.childrens
oncologygroup.org (accessed 2009 Dec
7).
49. Clezardin P, Gligorov J, Delmas P. Mecha-
nisms of action of bisphosphonates on
tumor cells and prospects for use in the
treatment of malignant osteolysis. Joint
Bone Spine. 2000; 67:22-9.
50. Ashford RU, McCloskey EV, Purohit OP
et al. Ten-year follow-up of a patient with
metastatic Ewing’s sarcoma of the pelvis.
Sarcoma. 2002; 6:131-3.
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