P O ediatric ncology

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Pediatric Oncology
Ewing’s Sarcoma Family of Tumors: Current Management
Mark Bernstein,a Heinrich Kovar,b Michael Paulussen,c R. Lor Randall,d
Andreas Schuck,e Lisa A. Teot,f Herbert Juergensg
Ste-Justine Hospital, University of Montreal, Montreal, Canada; bChildren’s Cancer Research Institute,
Vienna, Austria; cUniversity Children’s Hospital Basel, Basel, Switzerland; dHuntsman Cancer Institute &
Primary Children’s Medical Center, University of Utah, Salt Lake City, Utah, USA; eDepartment of
Radiotherapy, University Hospital Muenster, Münster, Germany; f Department of Pathology, University of
Pittsburgh School of Medicine and Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA;
University of Muenster, Children’s Hospital, Paediatric Haematology and Oncology, Muenster, Germany
Learning Objectives
After completing this course, the reader will be able to:
1. Describe the presentation, differential diagnosis, and prognosis for patients with Ewing’s sarcoma.
2. Explain the principles of multidisciplinary management of Ewing’s sarcoma.
3. Discuss the late effects of the therapy for Ewing’s sarcoma.
Access and take the CME test online and receive 1 AMA PRA category 1 credit at CME.TheOncologist.com
Ewing’s sarcoma is the second most frequent primary bone cancer, with approximately 225 new cases
diagnosed each year in patients less than 20 years of
age in North America. It is one of the pediatric small
round blue cell tumors, characterized by strong membrane expression of CD99 in a chain-mail pattern and
negativity for lymphoid (CD45), rhabdomyosarcoma
(myogenin, desmin, actin) and neuroblastoma (neurofilament protein) markers. Pathognomonic translocations involving the ews gene on chromosome 22
and an ets-type gene, most commonly the fli1 gene on
chromosome 11, are implicated in the great majority
of cases. Clinical presentation is usually dominated by
local bone pain and a mass. Imaging reveals a technetium pyrophosphate avid lesion that, on plain radiograph, is destructive, diaphyseal and classically causes
layered periosteal calcification. Magnetic resonance
best defines the extent of the lesion. Biopsy should be
undertaken by an experienced orthopedic oncologist.
Approximately three quarters of patients have initially
localized disease.About two thirds survive diseasefree. Management, preferably at a specialist center
with a multi-disciplinary team, includes both local control—either surgery, radiation or a combination—and
systemic chemotherapy. Chemotherapy includes cyclic
combinations, incorporating vincristine, doxorubicin,
cyclophosphamide, etoposide, ifosfamide and occasionally actinomycin D. Topotecan in combination with
cyclophosphamide has shown preliminary activity.
Patients with initially metastatic disease fare less well,
with about one quarter surviving. Studies incorporating
intensive therapy followed by stem cell infusion show no
clear benefit. New approaches include anti-angiogenic
therapy, particularly since vascular endothelial growth
factor is an apparent downstream target of the ews-fli1
oncogene. The Oncologist 2006;11:503–519
Correspondence: Mark Bernstein, M.D., F.R.C.P.(C)., Service of Hematology/Oncology, Ste-Justine Hospital, University of Montreal,
3175 Cote Ste. Catherine Road, Montreal, Quebec, H3T 1C5, Canada. Telephone: 514-345-4969; Fax: 514-345-4792; e-mail: mark.
[email protected] Received November 22, 2005; accepted for publication March 16, 2006. ©AlphaMed Press 10837159/2006/$20.00/0
The Oncologist 2006;11:503–519 www.TheOncologist.com
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Key Words. Ewing’s sarcoma • Bone cancer • Multimodal therapy • Pediatrics • Adolescents and young adults
Locoregional pain is the most common presenting symptom in patients with Ewing’s sarcoma. Pain can be intermittent and variable in intensity. Pain often does not completely disappear during the night [3]. As the majority
of Ewing’s sarcoma patients are in their second decade
of life and physically active, pain is often mistaken for
“bone growth” or injuries resulting from sport or every-
day activities. Pain may be accompanied by paresthesia in
some cases. Pain as the initial symptom may be followed
by a palpable mass. The duration of symptoms prior to
the definitive diagnosis can be weeks to months, or rarely
even years, with a median of 3–9 months [3–5]. Pain without defined trauma adequate to explain the symptoms,
lasting longer than a month, continuing at night, or with
any other unusual features should therefore prompt early
imaging studies. Slight or moderate fever and other nonspecific symptoms are more common in more advanced
and/or metastatic stages, affecting about one third of
patients [3–6].
Tumor growth eventually leads to a visible or palpable swelling of the affected site. The tumor bulk, however, may be indiscernible for a long time in patients
with pelvic, chest wall, or femoral tumors. As Ewing’s
sarcoma may arise in virtually any bone and from soft
tissue, additional symptoms, depending on the affected
site, may vary considerably. Spinal cord compression by
a tumor of a vertebral body requires emergency intervention, either laminectomy or chemotherapy or radiotherapy following biopsy. Patients with chest wall or pelvic
primaries may experience significant complaints only at
a very late stage.
On initial physical examination, tendonitis is a common
suspected diagnosis in adolescent or adult patients, while
hip inflammation and osteomyelitis are often suspected in
Figure 1. Primary tumor sites in
Ewing’s tumors. Data based on 1,426
patients from European Intergroup
Cooperative Ewing Sarcoma Studies
trials. Abbreviation: BM, bone marrow.
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Ewing’s sarcoma is the second most frequent primary
malignant bone cancer, after osteosarcoma. It is nonetheless an infrequent cancer, with approximately 225 new
cases diagnosed in patients less than 20 years of age per
year in North America. It is slightly more common in boys
(55:45 male:female ratio). The most common age of diagnosis is the second decade of life, although 20%–30% of
cases are diagnosed in the first decade. Cases continue
to be diagnosed through the third decade, at a lower frequency than in the second decade, and infrequently
beyond. In the German European Intergroup Cooperative Ewing Sarcoma Studies (EICESS) series from 1980–
1997, approximately 20% were diagnosed in patients >20
years of age. This did not represent, however, a population-based registry. Whites are much more frequently
affected than Asians and especially African-Americans,
or Africans, in whom the disease is rare [1, 2].
Ewing’s Sarcoma: Current Management
Bernstein, Kovar, Paulussen et al.
Figure 2. Magnetic resonance image of a pelvic Ewing’s
from the bone (Codman triangle), and spiculae of calcification in soft tissue tumor masses suggest the diagnosis
of a malignant bone tumor. Osteomyelitis may present a
pattern similar to Ewing’s sarcoma on plain radiograph.
Diaphyseal location suggests a Ewing’s sarcoma, as compared with the metaphyseal location more common in
osteosarcoma. The most precise definition of the local
extent of disease, including the intramedullary portion
and the relation of the lesion to adjacent blood vessels
and nerves, is provided by magnetic resonance imaging
(MRI) (Fig. 2) [3, 7–10].
Biopsy, Pathology, and
Molecular Pathology
As for other malignant diseases, the definitive diagnostic
test is the biopsy. Although the diagnosis can be made by
fine needle aspiration biopsy or by core needle biopsy, the
most adequate sampling is achieved by open biopsy. The
initial biopsy is usually incisional rather than excisional,
and usually from the soft tissue extension of the primary
bone mass, except in the rare case of a small lesion in an
expendable bone such as the proximal fibula. The biopsy
incision is usually longitudinal, so as to not violate tissue
flap planes and neurovascular structures. A longitudinal
incision can thus facilitate eventual complete excision and
limb salvage if surgery is to be the primary mode of local
control. The biopsy is best performed by an experienced
Figure 3. Histologic and immunohistochemical features
of Ewing’s sarcoma/pPNET. (A): Classic Ewing’s sarcoma
appears as sheets of monotonous round cells. (Hematoxylin
and eosin, original magnification 200×.) (B): The cells have
scanty cytoplasm and round nuclei with evenly distributed
finely granular chromatin and inconspicuous nucleoli. (Hematoxylin and eosin, original magnification 400×.) (C): Strong,
diffuse membrane staining is observed with the O13 monoclonal antibody to p30/32MIC2 (CD99). (Immunoperoxidase,
original magnification 400×.)
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younger children [3]. In patients with metastatic disease,
nonspecific symptoms such as malaise and fever may
resemble symptoms of septicemia. Such patients sometimes also experience loss of appetite and weight. Children
under the age of 5 years may thus present a constellation
of symptoms similar to those of disseminated neuroblastoma, although Ewing’s sarcoma is uncommon in children
<5 years of age.
No blood, serum, or urine test can specifically identify
Ewing’s sarcoma. Nonspecific signs of tumor or inflammation may be noted, such as an elevated erythrocyte sedimentation rate, moderate anemia, or leukocytosis. Elevated
levels of serum lactate dehydrogenase correlate with tumor
burden and, for this reason, with inferior outcome. In contrast to neuroblastoma, serum and urine catecholamine levels are always normal.
Most Ewing’s sarcomas occur in bones. As opposed to
osteosarcoma, flat bones of the axial skeleton are relatively
more commonly affected, and in long bones, Ewing’s sarcomas, unlike osteosarcomas, tend to arise from the diaphyseal rather than the metaphyseal portion. The most common sites of primary Ewing’s sarcoma are the pelvic bones,
the long bones of the lower extremities, and the bones of the
chest wall (Fig. 1). Primary metastases in lungs, bone, bone
marrow, or combinations thereof are detectable in about
25% of patients. Metastases to lymph nodes or other sites
like the liver or central nervous system are rare.
The initial imaging investigation when an osseous
lesion is suspected is usually a radiograph in two planes.
Tumor-related osteolysis, detachment of the periosteum
immunoreactive for myogenin, myoD1, desmin, and actin.
The distinction between poorly differentiated small cell
synovial sarcoma and poorly differentiated Ewing’s sarcoma may be difficult in some cases. Although synovial sarcoma is immunoreactive for cytokeratin and/or epithelial
membrane antigen, poorly differentiated small cell variants
may be immunoreactive for CD99 in a membrane pattern
and show only focal, weak staining for cytokeratin, thus
mimicking poorly differentiated Ewing’s sarcoma.
Molecular genetic studies, using fluorescence in situ
hybridization (FISH) and/or reverse transcription-polymerase chain reaction (RT-PCR), are valuable adjuncts for
the evaluation of undifferentiated small round-cell tumors
of childhood, particularly in cases with indeterminate
histologic and/or immunohistochemical features. Detection of characteristic translocations by these methods may
allow for definitive diagnosis of Ewing’s sarcoma, rhabdomyosarcoma, and synovial sarcoma [24, 25]. Distinction among these tumors is critical, as their treatments are
substantially different.
Ewing’s sarcoma is characterized by a relatively simple
karyotype with only a few numerical and structural aberrations. A reciprocal chromosomal translocation between
chromosomes 11 and 22, the t(11;22)(q24;q12), is present in
about 85% of these tumors [26, 27] and is therefore considered pathognomonic for the disease. In most of the remaining cases, variant translocations are observed always
involving chromosomes 22q12 and either 21q22 (10%
of Ewing’s sarcomas) or 7p22, 17q12, and 2q36 (<1% of
Ewing’s sarcomas each). These variant translocations frequently occur as either complex or interstitial chromosomal
rearrangements and are therefore difficult to diagnose by
conventional cytogenetics. Additional structural changes
affect chromosomes 1 and 16 in about 20% of tumors, most
frequently leading to a gain of 1q and a loss of 16q and the
formation of a derivative chromosome der(1;16) [28, 29].
Among numerical chromosome changes, trisomy 8 and/or
12 are observed in half and one third of cases, respectively
[29, 30]. Deletion of the chromosomal region 9p21 housing
the ink4A gene, which has been shown to be homozygously
lost in about 25% of Ewing’s sarcoma, remains cytogenetically cryptic in most patients [31, 32]. Loss of heterozygosity at 17p13 with mutation of the remaining p53 tumor
suppressor allele is rare (<10% of cases) but, together with
homozygous deletions of the ink4A gene, constitutes an
unfavorable prognostic factor in this disease [33].
Among recur rent cytogenetic aber rations, the
molecular equivalent has been best characterized for the
t(11;22)(q24;q12) [34, 35] . The rearrangement results in
the translocation of the 3ʹ portion of the friend leukemia
virus integration site 1 ( fli1) gene from chromosome 11 to
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orthopedic oncologist, especially by one working as part of
a multidisciplinary oncology team [11]. Frozen section to
confirm the adequacy of the tissue sample should be organized beforehand, and the tissue should be rapidly sent in a
fresh state to the pathology department. Assessment of viability is accomplished by visual inspection, complemented
by touch preparations for rapid microscopic evaluation as
deemed necessary.
Ewing’s sarcoma encompasses tumors with a spectrum
of histologic appearances and ultrastructural and immunohistochemical features. Classic Ewing’s sarcoma, as
first described by James Ewing in 1921 [12], is composed
of a monotonous population of small round cells with high
nuclear to cytoplasmic ratios arrayed in sheets (Fig. 3A).
The cells have scant, faintly eosinophilic to amphophilic
cytoplasm, indistinct cytoplasmic borders, and round
nuclei with evenly distributed, finely granular chromatin
and inconspicuous nucleoli (Fig. 3B) [13–15]. Mitotic activity is usually low. Cytoplasmic glycogen, which appears as
periodic acid-Schiff-positive diastase-digestible granules,
is usually present.
Strong expression of the cell-surface glycoprotein
p30/32MIC2 (CD99) is characteristic of Ewing’s sarcoma and
strong, diffuse membrane staining in a “chain-mail pattern”
is present in 95%–100% of Ewing’s sarcoma with one or
more of the monoclonal antibodies to this antigen, including O13, 12E7, and HBA71 (Fig. 3C) [16–18]. In addition,
Ewing’s sarcoma is immunoreactive for vimentin [19–21].
More differentiated Ewing’s sarcomas (peripheral primitive
neuroectodermal tumors [pPNETs]) may also show immunohistochemical evidence of neural differentiation, staining
for neuron-specific enolase (NSE), S-100 protein, Leu-7,
and/or PgP 9.5 [22]. Ewing’s sarcoma is immunoreactive for
cytokeratins in up to 20% of cases, with diffuse immunoreactivity for cytokeratins noted in up to 10% of cases [23].
Because the histologic and immunophenotypic features
of Ewing’s sarcoma overlap to varying degrees with the other
small round-cell tumors of childhood, an expanded panel of
immunohistochemical studies may be necessary to exclude
other entities. Like Ewing’s sarcoma, neuroblastoma is
immunoreactive for NSE, S-100, and Leu-7, but in contrast
to the pPNET variant of Ewing’s sarcoma, it is negative for
vimentin and immunoreactive for neurofilament protein.
Like Ewing’s sarcoma, lymphoblastic lymphoma is strongly
immunoreactive for CD99 in a membrane pattern, but
unlike the former, lymphoblastic lymphoma is also immunoreactive for leukocyte common antigen (CD45) and/or
TdT and other lymphoid markers. Rhabdomyosarcoma may
also be immunoreactive with antibodies to CD99; however,
staining is usually focal, weak, and cytoplasmic, and in contradistinction to Ewing’s sarcoma, rhabdomyosarcoma is
Ewing’s Sarcoma: Current Management
Bernstein, Kovar, Paulussen et al.
the 5ʹ portion of the Ewing’s sarcoma gene ews on chromosome 22 (Fig. 4). In the rare variant translocations, ews is
fused to genes closely related to fli1, either erg, e1af/etv4/
pea3, etv1/er81, or fev. As a result of the most common,
t(11;22)(q24;q12), a chimeric EWS-FLI1 RNA is expressed
from the promoter of the rearranged ews gene encoding for
a novel fusion protein. The reciprocal translocation product fli1-ews is not expressed and is occasionally lost from
Ewing’s sarcoma cells. Using molecular detection methods
to monitor the ews-fli1 gene rearrangement, RT-PCR and
FISH, the presence of t(11;22)(q24;q12) in 85% of Ewing’s
sarcoma has been confirmed and found to correlate with
high expression of the cell surface sialoglycoprotein
CD99MIC2 [36, 37].
About 15% of histopathologically defined CD99MIC2positive Ewing’s sarcomas lack the classical Ewing’s sarcoma-specific translocation. However, in the majority of
these cases, evidence for ews gene rearrangements can
be obtained using probes flanking the Ewing’s sarcoma
breakpoint region on chromosome 22 in FISH analyses [38]. Altogether, rearrangements of ews with fli1 or
an fli1-related gene characterize 98% of all Ewing’s sarcomas. The few remaining cases of CD99MIC2 -positive
Ewing’s sarcomas lacking evidence for chromosome
22 aberrations may be associated with an alternative
but equally structured gene fusion between erg and the
close ews relative tls/fus [39]. Thus, on the genetic level,
Ewing’s sarcomas are defined by the presence of ewsets (and presumably in very rare cases tls-ets) gene rearrangements and, as a surrogate marker, by high CD99MIC2
expression levels. Individual members of this tumor family are defined along a gradient of limited neuroglial differentiation, with the poorly differentiated Ewing’s sarcoma at one end and the more mature pPNETs at the other.
With the availability of molecular tools to unambiguously
confirm the presence of ews-ets gene rearrangements,
the spectrum of Ewing’s sarcoma-related neoplasms has
recently been expanded to include rare CD99MIC2-positive
extraskeletal tumors in various anatomic sites including
the kidney [40–44], breast [41], gastrointestinal tract [45–
48], prostate [49], endometrium [50], lung [44], adrenal
gland [51], and meninges [52]. Although Ewing’s family of tumors typically arise during adolescence, there is
also an increasing number of adults being diagnosed with
a CD99MIC2 and ews-ets-positive small round-cell tumor.
The oldest patient reported to date was 77 years old [53].
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Figure 4. The reciprocal translocation between chromosomes 11 and 22 results in the formation of an ews-fli1 fusion gene on the
abnormal chromosome 22 that codes for a chimeric transcription factor with the N-terminal transcriptional regulatory domain
deriving from ews and the ets-specific DNA-binding domain derived from fli1.
Ewing’s Sarcoma: Current Management
Table 1. Staging investigations at diagnosis
Primary tumor site Staging for metastases
Radiograph in two planes: whole bone with adjacent joints
At suspicious sites
MRI and/or CT: affected bone(s) and adjacent joints
At suspicious sites
Biopsy: material for histology and molecular biology
At suspicious sites
Thoracic CT (lung window)
Bone marrow biopsy and aspirates: microscopy (molecular biology still
Whole body 99m-technetium bone scan
Abbreviations: CT, computed tomography; FDG-PET, fluorine-18 fluorodeoxyglucose positron emission tomography; MRI,
magnetic resonance imaging; +, mandatory; +2, indicated, if available.
Diagnostic staging at presentation must include appropriate search and staging for metastases, which are detected
in about 25% of patients (Table 1). The most common metastatic sites are the lungs and the pleural space, the skeletal system, and the bone marrow, or combinations thereof.
Locoregional lymph node involvement is rare. Imaging
studies should include computed tomography (CT) scan of
the chest to document or exclude intrathoracic metastases
and 99m-technetium whole-body radionuclide bone scans
to search for skeletal metastases. Fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET)
has recently been proven to be a highly sensitive screening
method for the detection of bone metastases in Ewing’s
sarcoma, although its exact role in the management of
Ewing’s sarcoma remains to be defined. In detecting
bone metastases, FDG-PET may be even more sensitive
than whole-body MRI scans [54]. Moreover, the initial
response to therapy as shown by change in the standard
uptake value (SUV), and, perhaps more importantly, the
measured SUV after induction chemotherapy, may predict outcome [55].
Microscopically detectable bone marrow metastases
occur in <10% of patients and are associated with a poor
prognosis [56]. As tumor cells may be focally distributed
in bone marrow, bone marrow samples should be harvested from multiple sites, conventionally both posterior
iliac crests. Aspirates or trephine biopsies are analyzed by
light microscopy. If the tumor is of pelvic origin, an aspirate or trephine may contain tumor from the primary site
and not reflect metastatic disease. The prognostic relevance of detection of micrometastatic disease by RT-PCR
in the absence of overt bone marrow metastases is under
current evaluation in prospective studies. Because of the
sensitivity of RT-PCR, ipsilateral iliac samples to a pelvic
primary site may demonstrate tumor that is of a primary
site rather than of metastatic origin. Preliminary results
from retrospective analyses seem to indicate that RT-PCR
detection of Ewing’s sarcoma-specific RNA in the bone
marrow at diagnosis [57, 58], and persistence of such findings despite adequate chemotherapy [59], may be related
to an inferior outcome.
Current Treatment
Before the era of chemotherapy, fewer than 10% of
patients with Ewing’s sarcoma survived despite the wellknown radiosensitivity of this tumor [60, 61]. Patients
commonly died of metastases within 2 years, indicating the need for systemic treatment [60]. With the use
of modern multimodal therapeutic regimens including
combination chemotherapy, surgery, and radiotherapy,
cure rates of 50% and more can be achieved [62–76]. The
treatment of Ewing’s sarcoma patients worldwide is organized in cooperative trials, aiming to further improve
treatment outcome.
Prognostic Features
As discussed in the section on staging, the presence of metastatic disease is the most unfavorable prognostic feature.
Those with isolated pulmonary metastases have a slightly
better outcome (approximately 30% survive) than those
with bone or bone marrow metastases at initial diagnosis
(20% or less) [70, 75, 77]. Persistence of Ewing’s sarcomaspecific RNA in bone marrow after treatment may be unfavorable [58, 59]. Children <10 years of age do somewhat
better than older patients [75] Size and location of disease
are often interrelated, with many larger (>200 ml) lesions
located in the pelvis. Patients with such lesions have a lesser
chance of survival [73, 75]. The exact translocation type
may be of prognostic importance, and the presence of additional cytogenetic changes (see above) may carry unfavorable prognostic weight. The response to initial therapy may
also predict outcome [73].
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Bernstein, Kovar, Paulussen et al.
Table 2. Enneking classification of surgical intervention
Intralesional resection
Marginal resection
Wide resection
Radical resection
Tumor opened during surgery, or surgical field contaminated, or microscopic or macroscopic
residual disease.
Tumor removed en bloc; however, resection through the pseudocapsule of the tumor; microscopic
residual disease likely.
Tumor and its pseudocapsule removed en bloc, surrounded by healthy tissue, within the tumorbearing compartment.
The whole tumor-bearing compartment removed en bloc (e..g., above-the-knee amputation for a
lower-leg tumor).
From Enneking WF, Spanier SS, Goodman MA, A system for the surgical staging of musculoskeletal sarcoma. Clin Orthop
Relat Res 1980;153:106–120.
Local Therapy
Surgical Treatment of Ewing’s Sarcoma
In general, patients with an isolated, resectable tumor after
induction chemotherapy should have their tumors treated
with surgery alone. Preoperative radiotherapy may be necessary to avoid an intralesional resection (Table 2). When
a negative surgical margin is obtained following preoperative irradiation, local failure rates that are comparable with
those achieved with negative margin surgery for more amenable lesions are observed. In Children’s Oncology Group
protocols, negative margins are defined as bony margins
of at least 1 cm, with a 2- to 5-cm margin recommended. In
soft tissue, at least 5 mm in fat or muscle is required, with 2
mm through fascial planes, with the margin being through
noninflammatory tissue.
When surgery is planned, limb salvage is almost always
attempted, although there remain a small number of lesions
for which either limb salvage surgery or irradiation would
lead to an unsatisfactory orthopedic result, and in whom
amputation is warranted.
Types of Reconstruction
The main reconstructive options include autogenous bone
grafts, structural bone allografts (intercalary or osteoarticular), and metallic endoprosthetics. Allografts and
endoprosthetics may also be used as part of a composite
reconstruction. Autogenous bone grafts may be vascularized (e.g., fibula). The technique employed is a function of
the location of the tumor, age of the patient, and types of
adjuvant therapies that will be employed (i.e., chemotherapy and/or radiation). Infection, nonunion, and fracture
may complicate the surgery, especially since patients will
be receiving continuing chemotherapy and possibly radiotherapy. [83–85].
Generally, after induction (neoadjuvant) chemotherapy,
a preoperative follow-up assessment of the tumor must be
performed. The response to chemotherapy can be assessed
by dynamic MRI. PET and thallium may also provide useful information [55, 86–90]. In certain cases, an individual
who was a questionable candidate for limb salvage may be
eligible after induction chemotherapy. Patients who remain
borderline candidates following induction chemotherapy
may be considered for preoperative radiotherapy. If the
margins are certain to be inadequate at the preoperative
staging evaluation, then amputation is the only available
surgical option.
Because Ewing’s sarcomas are radiosensitive, radiation
may be used instead of or in addition to surgery.
Indications for Radiotherapy
To date, there has been no randomized trial comparing local
therapy modalities. Therefore, the question as to which
modality, radiotherapy or surgery, is preferred for local
therapy in Ewing’s sarcoma has been a matter of debate for
some time. From retrospective analyses of several groups,
the impression has been that local control is better when
surgery is possible [81, 91, 92]. These data are usually confounded by the fact that there is a selection bias favoring
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Cure from Ewing’s sarcoma can only be achieved with
both chemotherapy and local control. Current treatment
schedules favor primary induction chemotherapy, followed
by local therapy and adjuvant chemotherapy. For several
decades, radiotherapy was regarded as the standard local
treatment modality; contemporary orthopedic surgery,
however, is aimed at preserving function and improving
limb salvage rates without compromising survival rates
[78–81]. In planning the optimal local therapy, an interdisciplinary approach involving experts experienced in
this field is essential. The efficacy of this approach was
shown in two consecutive European trials by the reduction
in local recurrences following the institution of centralized counseling regarding local therapy, including radiation therapy [82]. Local treatment should be individually
adapted depending upon the site and size of the tumor, the
anatomical structures near the tumor, the patient’s age, and
individual preference.
Ewing’s Sarcoma: Current Management
patients in whom surgery is possible. Several European and
North American collaborative trials have been performed.
Overall, local control rates are in the range of 53%–93%
with the poorer results usually reported in the earlier series
[68, 69, 71, 93, 94].
Radiation Dose and Fractionation
In order to control Ewing’s sarcomas, a radiation dose above
40 Gy is necessary. In the St. Jude’s Children’s Research
Hospital experience with the use of lower radiation doses,
a high rate of local recurrence was observed [93]. A clear
dose-response correlation at doses above 40 Gy has not
yet been established. For definitive radiotherapy, doses
between 55 Gy and 60 Gy, most frequently not exceeding
55.8 Gy, are usually given. When surgery precedes or follows radiotherapy, the doses range between 45 Gy and 55
Gy depending on the individual risk factors (i.e., resection
margins and response). It is uncertain whether irradiation
of the site of completely resected lesions that demonstrate
a poor histologic response is of benefit. European investigators recommend such irradiation, whereas it is not incorporated into North American protocols. There has been no
controlled trial addressing this issue.
Target Volume Definition and Treatment Planning
In a randomized trial, the treatment of the whole tumor-bearing compartment showed no better results than radiation to
the tumor and an additional safety margin [94]. Therefore,
the planning target volume is defined as the initial tumor
extent on MRI with an additional longitudinal margin of at
least 2–3 cm and lateral margins of 2 cm in long bones. If
doses of more than 45 Gy are used, a shrinking field technique is applied. In patients with an axial tumor site, a minimum of a 2-cm safety margin around the initial tumor extent
must be employed. In tumors protruding into preformed
cavities (i.e., thorax, pelvis) without infiltration, the residual intracavitary tumor volume following chemotherapy is
used for treatment planning. Surgically contaminated areas,
scars, and drainage sites must be included in the radiation
fields. Circumferential irradiation of extremities should be
avoided in order to reduce the risk of lymphedema. In growing children, growth plates must be considered. They should
either be fully included in the radiation field or they should
not be included at all. A dose gradient through the epiphysis results in asymmetric growth and may lead to functional
deficits. Similarly, vertebral bodies should either be fully
included or spared from the radiation field.
Three-dimensional conformal radiotherapy should be
given in patients with Ewing’s sarcoma. In selected cases,
that is, in vertebral tumors, intensity-modulated radiotherapy or proton therapy may be beneficial.
The first reports of drug treatment of Ewing’s sarcoma stem
from the 1960s. In 1962, Sutow and Sullivan [96] and Pinkel
[97] independently published reports on the use of cyclophosphamide for Ewing’s sarcoma. With Hustu et al.’s publication on the combination of cyclophosphamide, vincristine, and radiotherapy that resulted in sustained responses
in five patients, the era of modern multimodality treatment
of Ewing’s sarcoma began [63]. Results of selected phase III
studies in Ewing’s sarcoma are listed in Table 3 [5, 67–69,
In brief, in 1974, Rosen et al. [65] from the Memorial
Sloan-Kettering Cancer Center published the first results
of a trial of radiotherapy given with a four-drug regimen
consisting of vincristine, actinomycin D, cyclophos-
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Definitive Radiotherapy
Patients who receive radiotherapy as the only local therapy modality usually represent an unfavorably selected
group of patients. They frequently present with large
tumors or tumors in unfavorable locations (e.g., vertebral
tumors) or both, making radiotherapy difficult but surgery impossible. In a recent analysis of 1,058 patients with
localized Ewing’s sarcoma treated in the EICESS trials,
266 patients had radiotherapy alone. Local or combined
local and systemic failures in this subgroup occurred in
26% of patients [81, 91], which was worse than the recurrence rate following surgery with or without radiotherapy
(4% –10%). It was not possible to define a subgroup of
patients in whom the use of radiotherapy alone achieved
the same local control rate as surgery. Even for the favorable subgroup of patients with small extremity tumors,
local control was better with surgery than with definitive
radiotherapy. Therefore, when marginal or wide resection
is possible, surgery should be performed.
Definitive radiotherapy is indicated when only an intralesional resection is possible. Debulking procedures do not
improve local control and are associated with additional
unnecessary morbidity. In the experience of the European
Cooperative Ewing Sarcoma Studies (CESS) and EICESS
trials, patients who had an intralesional resection followed
by radiotherapy had the same local control rate as patients
who had radiotherapy alone [81, 91].
Usually conventional fractionation with daily fractions
of 1.8–2 Gy is given. In the CESS 86 and EICESS 92 trials,
hyperfractionated radiotherapy with twice daily 1.6 Gy was
also applied; after 22.4 Gy, a 10-day break was scheduled to
permit the administration of chemotherapy. There has been
no detectable difference in local control between the two
different fractionation groups [95].
Bernstein, Kovar, Paulussen et al.
Table 3. Treatment results in selected clinical studies of localized Ewing’s sarcoma
IESS studies
Patients 5-year EFS
p valuea
Nesbit et al.
VAC vs. VAC Value of D
+ WLI, .001
VAC vs.
Benefit of WLI?
VACD, .001
vs. VACD, .05
Value of aggressive cytoreduction
Value of combination IE in localized
disease, no benefit in metastatic disease
75% (3 yrs)
No benefit of dose-time compression
76% (3 yrs)
After local therapy only, cumulative dose
of D up to 600 mg/m2
Kushner et al.
Kolb et al.
+ IE
+ IE
77% (2 yrs)
C dose escalation 4.2 g/m2 per course
localized, 81%
(4 yrs); metastatic,
12% (4 yrs)
Good results in localized disease, poor
outcome in metastatic patients
St. Jude studies
Hayes et al.
82%, <8 cm
(3 yrs); 64%,
≥8 cm (3 yrs)
Tumor size as prognostic factor
Meyer et al.
Clinical responses
in 96%
Combination IE effective
78% (3 yrs)
Tumor size (< or ≥8 cm) loses prognostic
relevance with more intensive treatment
Surgery in 78% of patients
Histological response better predictor of
outcome than tumor volume
58% (metastasisfree survival)
70% overall survival after 5 years
41%: extremity,
52%; axial, 38%;
pelvic, 13%
62%: extremity,
73%; axial, 55%;
pelvic, 41%
Tumor site as the most important
prognostic factor
P6 (1991–2001)
Therapeutic 26
with IE
Marina et al. VCD-IE × 3 34
ROI, Bologna, Italy
Bacci et al. VDC + VIA 157
+ IE
SFOP, France
Oberlin et al. VD + VD/ 141
SSG, Scandinavia
Elomaa et al. VID + PID 88
UKCCSG/MRC studies
ET-1 (1978–1986) Craft et al.
ET-2 (1987–1993) Craft et al.
Importance of the administration of
high-dose alkylating agents (I)
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Burgert et al. VACD-HD 214
First POG–CCG, Grier et al.
VACD + IE 198
Second POG–
Granowetter VCD + IE 48 492
CCG (1995–1998) et al. [98]
VCD + IE 30
Memorial Sloan-Kettering Cancer Center studies
T2 (1970–1978) Rosen et al. VACD
P6 (1990–1995)
Ewing’s Sarcoma: Current Management
Table 3. (conituned)
CESS studies
Jürgens et al. VACD
p valuea
Patients 5-year EFS
Tumor volume (< or ≥100 ml) and histological response are prognostic factors
<100 ml
52% (10 yrs)
≥100 ml
SR: VAID 155
group, per- vs. VACD
sonal communication,
May 2004
HR: VAID 326
51% (10 yrs)
Intensive treatment with I for high-risk
patients. Tumor volume (< or ≥200 ml)
and histologic response as prognostic
et al. [73]
68% vs. 61%
51% vs. 61%
Stage, histologic response, type of local
therapy as prognostic factors; randomized comparisons not significant
p values are given only for trials comparing randomized treatment arms.
Abbreviations: A, actinomycin D; C, cyclophosphamide; CESS, Cooperative Ewing Sarcoma Studies; D, doxorubicin; E, etoposide; EFS, event-free survival; EICESS, European Intergroup Cooperative Ewing Sarcoma Studies; HD, high dose; HR, high
risk; I, ifosfamide; IESS, Intergroup Ewing Sarcoma Study; MD, moderate dose; MRC, Medical Research Council; NA, not
available; P, cisplatinum; POG-CCG, Pediatric Oncology Group–Children’s Cancer Group; ROI, Rizzoli Orthopaedic Institute;
SFOP, French Society of Paediatric Oncology; SSG, Scandinavian Sarcoma Group; SR, standard risk; UKCCSG, United Kingdom Children’s Cancer Study Group; V, vincristine; WLI, whole lung irradiation.
phamide, and doxorubicin used in combination rather
than sequentially (the VACD scheme), leading to longterm survival in 12 patients with Ewing’s sarcoma [65].
The VACD scheme then became a standard therapy in
numerous clinical trials. The first Intergroup Ewing Sarcoma Study, IESS-I, showed the superiority of the VACD
four-drug regimen over a three-drug VAC regimen (without doxorubicin), in terms of effectiveness of local control (96% vs. 86%) and event-free survival (EFS) (60%
vs. 24%) [68]. On the basis of excellent phase II results
achieved with the combination of ifosfamide and etoposide (IE) [106–108], in the Pediatric Oncology Group–
Children’s Cancer Group (POG-CCG) study INT-0091
patients were randomized to receive either VACD or
VACD-IE. The VACD arm achieved a 5-year EFS rate
of 54% in patients with localized disease, versus a 69%
EFS rate in the experimental arm with the addition of IE
[75]. Therefore, in North America, the five-drug alternating regimen (VDC-IE) is considered standard. There have
been parallel investigations in Europe.
The ongoing EURO-E.W.I.N.G. study includes induction vincristine-ifosfamide-doxorubicin-etoposide for all
patients with newly diagnosed Ewing’s sarcoma [109].
Current investigations include the recently completed
Children’s Oncology Group study AEWS 0031 that used
the strategy of interval compression, with therapy administered every 2 weeks in the experimental arm compared with
every 3 weeks in the standard arm. Time-dose intensity of
all drugs was thus increased, perhaps interacting in a favorable way with cell cycle kinetics of the malignant cell population. Interval compression was successfully achieved in a
preceding limited institution pilot study [110], and preliminary information from the group-wide study supports its
feasibility (unpublished data, R. Womer). Efficacy results
are not yet available, with the first analysis expected in
late 2006. The next Children’s Oncology Group study will
incorporate vincristine, topotecan, and cyclophosphamidecontaining cycles for a randomized one half of the patients,
on the basis of encouraging classic and window phase II
studies [111, 112].
Another treatment intensification strategy in Ewing’s
sarcoma is high-dose chemotherapy with autologous hematopoietic stem cell rescue (HDT) [113]. Because of the considerable toxicity of this approach, most studies investigate
HDT for very high risk patients, most commonly those with
metastatic disease at diagnosis, or following recurrence
[77, 114–116]. A controlled, randomized study of HDT
in Ewing’s sarcoma has recently been undertaken in the
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<100 ml, 80%;
≥100 ml 31%
(both 3 yrs)
Viable tumor
<10%, 79%;
>10%, 31%
(both 3 yrs)
Bernstein, Kovar, Paulussen et al.
framework of the EURO-E.W.I.N.G. 99 studies for patients
with large primary tumors locally treated with both surgery
and irradiation, or small primary tumors (<200 ml) and
an unfavorable histologic or radiologic response to induction chemotherapy (arm R2loc). Accrual is ongoing [109].
Because of the intrinsic risk of using high-dose therapy,
such efforts should be strictly limited to the setting of controlled clinical trials [117, 118].
Metastatic Disease
Recurrent Disease
Superior multimodal therapeutic regimens that combine
more intensive systemic treatment with chemotherapy,
better surgical approaches, and advanced radiotherapy
planning have led to a reduced frequency of recurrent disease, in particular, of local recurrence [67, 129]. Nevertheless, 30%–40% of patients still experience recurrent
disease either locally, distantly, or combined, and have a
dismal prognosis. Patients with primary metastatic disease have a higher risk for relapse than those with localized disease [70, 129]. The likelihood of long-term survival after recurrence is less than 20%–25% [130–132].
The timing and type of recurrence are important prognostic factors [133]. Patients with early relapse, within
the first 2 years following initial diagnosis, have a poorer
prognosis, with a 4%–8.5% 5-year survival probability.
Those with later recurrence experience a 23%–35% 5-year
survival probability [133, 134]. Recurrence may be very
late, as compared with most other pediatric and adolescent
cancers. A report from the Dana-Farber Cancer Institute
described 82 patients initially diagnosed and treated with
localized (60 patients) or metastatic (22 patients) Ewing’s
sarcoma in 1971–1988. Thirty-one patients survived at
least 5 years from diagnosis, of whom five subsequently
developed recurrent disease at 5.7, 6.7, 6.9, 9.3, and 17.1
years [135]. Simultaneous local and distant recurrences
have been observed to be associated with more aggressive
disease with earlier recurrence and poorer outcome [71,
130, 132, 133, 136].
Patients with suspected recurrence should be evaluated
appropriately to assess the extent of the local recurrence
and the presence of metastatic disease and to plan treatment
strategies. The majority of patients with local treatment failure have concomitant distant gross or microscopic disease.
Detection of metastases with diagnostic imaging including
CT, total body MRI, FDG-PET, and Tc-methylene diphosphonate bone scans is recommended. However, the images
may be difficult to interpret because of prior therapy.
There is no established treatment regimen for these
patients. Salvage treatment includes multiagent chemotherapy, local control measures with radiotherapy and surgery,
or a combination of these as appropriate.
Patients with local recurrence are usually treated with
surgery and further chemotherapy [133]. Recurrent distant
disease involving the lungs or bones occurs in more than
50% of patients presenting with local recurrence and mandates further chemotherapy [56, 67, 69, 104, 123, 130, 137].
Patients with a single pulmonary nodule appear to benefit
from additional whole-lung irradiation and have better outcomes, especially if the recurrence is late, longer than 2
years following the primary diagnosis [123].
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At initial diagnosis, approximately 25% of Ewing’s sarcoma
patients present with clinically detectable metastases in the
lung and/or in bone and/or in bone marrow. The presence of
metastatic disease is the most important adverse prognostic
factor [56, 70, 75, 119]. Patients with isolated lung metastases have been shown to have a better prognosis than those
with extrapulmonary metastases; however, survival is still
disappointing [56, 120]. Bilateral pulmonary irradiation at
a dose of 14–20 Gy was reported to improve the outcome of
patients with pulmonary disease [121–124]. The Children’s
Oncology Group has recently joined the EURO-E.W.I.N.G.
randomized study comparing standard therapy including pulmonary irradiation with high-dose therapy using
busulfan and melphalan followed by stem cell reinfusion
for patients with initially isolated pulmonary metastatic
disease (R2pulm) [109].
Solitary or circumscribed bony metastases should be
irradiated to doses of 40–50 Gy, in addition to local therapy
to the primary site and Ewing’s sarcoma-directed chemotherapy. However, the survival rates of patients with multiple bony metastases are reported to be below 20% [56, 74,
119]. The discouraging results of treatment of metastatic
disease has led to more aggressive approaches, including
myeloablative high-dose therapy with stem cell rescue.
Conclusive results are pending, but preliminary data are
discouraging [77, 116].
Alternate approaches include the targeting of the
tumor vasculature. Angiogenesis, the generation of new
blood vessels, is crucial to the progression of malignant
disease [125]. These new blood vessels are sensitive to lowdose chemotherapy given over an extended period of time
(“metronomic chemotherapy”) [126, 127]. In Ewing’s
sarcoma, the ews-fli1 oncogene product may function as
a promoter for vascular endothelial growth factor. This
pathway may thus present a particularly attractive target
in Ewing’s sarcoma. The Children’s Oncology Group has
recently opened a pilot study, AEWS 02P1, examining the
tolerability of a background of low-dose vinblastine and
celecoxib [128] therapy incorporated into a standard fivedrug regimen (vincristine-doxorubicin-cyclophosphamide alternating with ifosfamide-etoposide).
Ewing’s Sarcoma: Current Management
Targeted Therapy
Since the EWS-ETS fusion protein is unique to Ewing’s
sarcoma and present in almost all cases, it or critical gene
products regulated by the fusion protein represent ideal
tumor-specific targets. Experimentally, proof of principle
has been obtained by both antisense and RNA interference
studies that demonstrated that modulation of EWS-FLI1
expression results in growth inhibition of Ewing’s sarcoma
in vitro and in vivo [142–148]. The clinical use of antisense
RNA oligonucleotides or small inhibitory RNAs is impeded
by the difficulty of efficiently delivering nucleic acids into
disseminated tumor cells. One possible method to achieve
this goal is the inclusion of oligonucleotides (stabilized as
phosphorothioates) into nanocapsules or nanospheres. This
approach has been successfully applied to stop Ewing’s sarcoma growth in xenotransplanted nude mice [144, 149].
CD99MIC2 may represent another promising candidate
for targeted therapy in Ewing’s sarcoma. Although neither a
ligand for CD99MIC2 nor the mechanisms by which this antigen is involved in Ewing’s sarcoma are known, in vitro studies on cell lines demonstrated that CD99MIC2 binding and
silencing by specific antibodies induces rapid tumor cell
death, enhanced by combination with conventional chemotherapeutic drugs. In vivo studies have been restricted to
athymic mice xenografted s.c. with a Ewing’s sarcoma cell
line and have indicated reduced Ewing’s sarcoma growth
upon anti-CD99MIC2 treatment [150]. However, there is no
direct homolog of CD99MIC2 in mice and thus toxicity of
anti-CD99MIC2 treatment cannot be assessed in this model.
Because of high-level expression of CD99MIC2 in hematopoietic stem cells and several cell types in the gonads and
the pancreas in humans, clinical trials using anti-CD99MIC2
antibodies have not yet been attempted.
Late Effects
Late effects can be grouped into two major categories: orthopedic outcome, based on the location of the primary tumor
and the surgery or radiotherapy used in its therapy, and overall outcome, based on the symptoms initially caused by the
disease as well as the entire therapeutic package. Preservation of the hand in patients with upper extremity primaries
is associated with a superior functional outcome and better self-image. Orthopedic outcome for patients with lower
extremity lesions can be quite satisfactory, even if distal
amputation is required. Limb salvage procedures using
massive internal prostheses or bone allografts can be complicated by late prosthetic failure or infection, requiring
reoperation and, sometimes, delayed amputation.
Radiation therapy can be complicated by growth disturbances of both bone and soft tissue. In addition, irradiation can induce second cancers, most frequently osteosarcoma. This is dose related, with a significantly greater
rate at administered doses above 40 Gy. On the other hand,
a higher rate of osteosarcoma has been reported after as
little as 10 Gy. Moreover, the onset may be late [151–153].
Similarly, chemotherapy has been associated with induced
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Chemotherapy options are limited and dependent on the
patient’s prior treatment and possible impaired function of
vital organs (e.g., heart and kidneys). Agents that are considered for combination therapy are chosen to potentiate each
other’s activity and circumvent the emergence of drug resistance. These have included combinations of topoisomerase I
or topoisomerase II inhibitors with alkylating agents and, in
addition, several myeloablative high-dose consolidation therapy regimens with and without total body irradiation.
Ifosfamide and etoposide have been shown to be active
agents in phase II studies [106–108], although many patients,
especially in North America, will already have received
these agents as part of their primary therapy. Topotecan in
combination with cyclophosphamide produced responses
in approximately 35% of patients with recurrent Ewing’s
sarcoma [111, 112]. The combination of gemcitabine and
docetaxel has been shown to have unexpectedly good activity in leiomyosarcoma and will be investigated in some recurrent sarcomas, including recurrent Ewing’s sarcoma. Both in
vitro and anecdotal clinical evidence support this development in the context of a controlled clinical trial. In the pilot
study, two patients with Ewing’s sarcoma were among the
35 patients treated. One patient showed a partial response
and the other had stable disease [138]. High-dose consolidation therapy with melphalan and etoposide with hyperfractionated total body irradiation with or without carboplatin,
followed by autologous stem cell reinfusion, despite initial
response, has failed to result in long-term remission in the
treatment of early relapse [77, 139, 140]. Results from a
hematopoietic stem cell transplantation regimen using combinations of active alkylating agents including busulfan and
melphalan seem more encouraging and may improve the
prognosis [113, 141]. However, the role of stem cell transplantation in the treatment of patients with recurrent disease is
under discussion. Further studies to define the best approach
for these patients are needed [77, 113, 134, 139].
Results of treatment of recurrent disease are still unsatisfactory. Whenever possible the patient should be included
in organized clinical trials. New drug combinations offering a potential therapeutic benefit are still to be established.
Molecular research and a better understanding of Ewing’s
sarcoma cell biology with its interplay regulating cell
growth, apoptosis, differentiation, genomic integrity, and
treatment resistance are needed to enrich the limited portfolio of active agents.
Bernstein, Kovar, Paulussen et al.
Gurney JG, Swensen AR, Bulterys M. Malignant bone tumors. In: Ries
LAG, Smith MA, Gurney JG et al., eds. Cancer Incidence and Survival
ing of the testes and transposition of the ovaries should be
considered when appropriate. In addition, ifosfamide can
cause a persistent renal tubular electrolyte loss and, less
commonly, a decrease in glomerular function, again in a
dose-dependent fashion.
Despite these concerns, the overall functioning of survivors of Ewing’s sarcoma is reasonably good [156]. There is
frequent need for medical services among survivors, however, so that assuring adequate follow-up and the provision
of adequate resources are necessary [157].
Summary and Conclusions
Ewing’s sarcomas are the second most frequent primary
bone cancer, affecting primarily patients in the second and
third decades of life. Patients presenting with localized
disease have an approximately two thirds chance of being
cured. Those whose disease is initially metastatic have
a much worse outcome. Those with isolated pulmonary
metastases experience an approximately 30% event-free
survival rate, whereas those with more widespread disease, usually involving bone or bone marrow, have a less
than 20% chance of cure with currently available therapy.
Patients whose disease has recurred share this grim outlook. Advances in the biology of Ewing’s sarcoma have led
to increased knowledge concerning the underlying molecular basis of the disease, which is as yet insufficient to have
led to new therapeutic approaches required to cure those
with currently refractory disease, and to cure all with fewer
short- and long-term toxicities.
Authors’ Note
This review article is abridged from chapter 33, Ewing’s
sarcoma family of tumors: Ewing’s sarcoma of bone and
soft tissue and the peripheral primitive neuroectodermal
tumors. In: Pizzo P, Poplack D, eds. Principles and Practice
of Pediatric Oncology, Fifth Edition. Philadelphia: Lippincott, Williams and Wilkins, in press, with permission.
Disclosure of Potential Conflicts
of Interest
The authors indicate no potential conflicts of interest.
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malignancy. There has been a 1%–2% rate of secondary
leukemia following a sequence of protocols for Ewing’s
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doses are therefore usually limited to less than a lifetime
total of 450 mg/m 2 . In addition, administration is often
either prolonged over a 48-hour period or, if given as a
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to the institution of chemotherapy. When the technology
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A. Teot and Herbert Juergensg
Oncologist 2006;11;503-519
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