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Current Treatment Options in Oncology (2009) 10:126–140

DOI 10.1007/s11864-009-0104-6
Bone Cancer

Ewing’s Sarcoma: Standard

and Experimental Treatment
Vivek Subbiah, MD
Pete Anderson, MD, PhD
Alexander J. Lazar, MD
Emily Burdett
Kevin Raymond, MD
Joseph A. Ludwig, MD*
*Department of Sarcoma Medical Oncology, Division of Cancer Medicine,
Laboratory of Sarcoma Molecular Therapeutics, M.D. Anderson Cancer
Center, Houston, TX, USA.

Springer Science+Business Media, LLC 2009

Opinion statement
Ewing sarcoma family tumors (EWS), which include classic Ewing’s sarcoma in
addition to primitive neuroectodermal tumor and Askin tumor, are the second most
common variety of primary bone cancer to afflict adolescents and young adults.
Multi-disciplinary care incorporating advances in diagnosis, surgery, chemotherapy,
and radiation has substantially improved the survival rate of patients with localized
Ewing sarcoma to nearly 70%. Unfortunately, those advances have not significantly
changed the long-term outcome for those with metastatic or recurrent disease;
5-year survival remains less than 25%. This apparent therapeutic plateau exists
despite extensive effort during the last four decades to optimize the efficacy of
cytotoxic chemotherapy through combination of chemotherapies of mechanistically
diverse action, dose-dense scheduling (provided as frequently as every 2 weeks),
increased adjuvant treatment duration, and higher dosage per cycle (facilitated with
parallel strides in supportive care incorporating growth factors). As has already
occurred for malignancies such as breast or colon cancer, the ‘‘-omics-based’’ revo-
lution has enhanced our understanding of the molecular changes responsible for
Ewing’s tumor formation and identified a number of potential targets (such as IGF-1R
or mTOR) amenable to biological therapy. It has also created both a challenge
and an opportunity to develop predictive biomarkers capable of selecting patients
most likely to benefit from targeted therapy. In this review, we discuss current
standard-of-care for patients with Ewing’s sarcoma and highlight the most promising
experimental therapies in early-phase clinical trials.
Ewing’s Sarcoma Subbiah et al. 127

The second most common bone cancer in adolescents therapy, definitive local control with surgery if feasible,
and young adults after osteosarcoma, Ewing sarcoma then eight additional cycles of adjuvant chemotherapy
family tumors (EWS) affect between 300 and 560 for consolidation. First-line drugs of proven efficacy
people in the United States each year [1]. This include vincristine, actinomycin-D, cyclophospha-
includes patients diagnosed with extraskeletal Ewing mide, doxorubicin, etoposide, and ifosfamide. Com-
sarcoma, small cell tumor of the thoracopulmonary binations of similar chemotherapies are used in those
region (Askin tumor), and soft-tissue-based primitive with metastatic disease but experimental chemothera-
neuroectodermal tumors (PNET). These Ewing’s fam- pies are considered earlier and second-line regimens
ily tumors harbor identical cytogenetic changes such as cyclophosphamide/topotecan, irinotecan/
resulting in primitive mesenchymal stem cells capable temozolomide, or high-dose ifosfamide are often used
of multilineage differentiation along an osteogenic, immediately after frontline therapy when bone marrow
adipogenic, or neurogenic spectrum [2–6]. Although reserves allow for this. Aggressive use of chemotherapy
the prognosis is markedly better for those without is often associated with complete or major partial
radiographic evidence for disseminated disease, the treatment response, which occasionally enables cura-
vast majority will develop rapid recurrence, often to tive local control that would not be otherwise possible.
the lung, unless systemic chemotherapy is provided. While the prognoses for those with metastatic or
Therefore, all patients require coordinated multimo- recurrence disease remain grim, a number of promising
dality treatment that combines systemic chemother- treatment options have transitioned from the labora-
apy (neoadjuvant and adjuvant) with local control tory to the clinical within the last year. Insulin-like
measures such as surgery and/or radiation, preferably growth factor receptor 1 (IGF-1R) targeted agents (both
at institutions with expertise caring for patients diag- monoclonal antibodies and small-molecule tyrosine
nosed with EWS. Though large tumor size (or vol- kinase inhibitors) have perhaps received the most
ume), axial/pelvic location, poor chemotherapy attention recently, given preliminary phase I clinical
response, and older age at diagnosis are known to trial results that suggest they are both well tolerated
adversely affect survival, metastatic spread portends and markedly effective in a subset of those with chemo-
the worst prognosis and serves as the major branch refractory EWS. Phase II trials, selective for sarcoma
point in guiding therapy [7]. At our institution, those subtypes including EWS, are underway to more fully
with localized disease receive six cycles of neoadjuvant asses tumor response.

Diagnosis and staging
• Since a number of pediatric malignancies (such as neuroblastoma,
rhabdomyosarcoma, lymphoblastic lymphoma, desmoplastic small
round cell tumor (DSRCT), and poorly differentiated synovial sar-
coma) are included in the differential diagnosis of small round cell
tumors, immunohistochemistry and molecular studies such as
RT-PCR and fluorescent in situ hybridization (FISH) play a critical role in
confirming the appropriate diagnosis. Although the EWS-FLI1 trans-
location is prototypical, rarer pairings of the TET family of
RNA-binding protein (TLS/FUS, EWS, TAFII68) with an ETS family
transcription factors (such as FLI1 or ERG) will not be detected using
break-apart EWS FISH. Thus, translocation-negative EWS have been
reported and should be treated as such, given an appropriate clinical
scenario [8]. Attempted molecular characterization of all Ewing family
tumors is the evolving standard of clinical care in this disease, but
must be interpreted in the complete context of pathologic and disease
setting [9–11]. A role for sequential RT-PCR monitoring of peripheral
blood and/or bone marrow after therapy has been suggested to both
confirm ‘‘complete’’ therapeutic response and to allow early detection
of minimal residual disease that is predictive of clinically detectable
128 Bone Cancer

recurrence, but prospective trials of such approaches are needed [12].

• Preliminary reports suggest the type 1 EWS-FLI1 translocation confers
a better prognosis than those with type II or other types of variants.
However, until rigorously evaluated by a large clinical trial, such as
EURO-EWING99, it is not presently used to stratify high- from
low-risk patients in clinical trials [13–15]. In addition, the suggested
differences in outcome would be unlikely to modify the initial ther-
apeutic approach since even type I disease is high risk.
• At this time, there is no well-accepted staging criterion for EWS. Pre-
treatment planning should include plain X-rays of the involved bone,
MRI of the spine (or bone marrow biopsy), chest CT, LDH, and either
whole-body bone scan or PET. Despite the fact that patients with
marrow-positive disease have been reported to be an adverse prog-
nostic marker of survival, we do not routinely perform bone iliac
crest marrow biopsies to detect subclinical micrometastatic disease
since both marrow-positive and -negative patients alike are treated
with extensive systemic chemotherapy. FDG-PET/CT scans have often
been especially helpful for determining early clinical response to
therapy and for planning radiotherapy for surgically unresectable
locations. As described previously, the presence or absence of meta-
static disease at diagnosis is the single most important criterion
guiding initial treatment.

Localized disease
• Conceptually, treatment for those with localized disease includes
three distinct phases: cytoreduction (to eradicate micrometastatic
disease and facilitate effective local control measures with wide neg-
ative margins); definitive local control to eradicate all known disease
(surgery when possible); and adjuvant chemotherapy to minimize
tumor recurrence [16]. Chemotherapy response is monitored radio-
graphically to evaluate clinical response and, in the setting of pro-
gressive disease, patients receive either alternative chemotherapy or
preoperative radiation.
• Before the modern chemotherapy era 40 years ago, less than 10% of
the EWS patients survived [17]. Local control relied extensively upon
radiation therapy, rather than surgery, and most died soon after
diagnosis with pulmonary metastases. In 1962, cyclophosphamide
was the first drug shown to improve local control of Ewing’s [18, 19].
A decade later, other chemotherapies including vincristine, actino-
mycin-D, daunomycin, and doxorubicin were also shown to be
effective in combination with radiotherapy [20–23]. In 1974, Rosen
et al. [24] at Memorial Sloan-Kettering Cancer Center combined these
chemotherapies (vincristine, actinomycin-D, cyclophosphamide, and
doxorubicin (VAcCD)), signaling the advent of multimodality therapy
using chemotherapies that remain the backbone of contemporary
EWS treatment. At least eight multi-institutional collaborative trials
conducted through the mid-‘80s, both within (IESS I and II, ES-79,
and POG 8346) and outside the United States (Germany’s CESS 81,
UK’s ET-1, Italy’s REA-2, and French SFOP EW84), have confirmed the
clinical benefit of a VAcCD-based regimens [25–27] (Fig. 1).
• Regimens that incorporate ifosfamide and/or etoposide with three or
more of the previous VAcCD-based chemotherapies have further
improved event-free survival for patients with localized, but not
metastatic, disease and therefore represent the current standard of care
for frontline therapy [28, 29]. Strategies designed to optimize their
Ewing’s Sarcoma Subbiah et al. 129




EURO-EWING-99 SSG-Scandinavia
Europe –(99-Current) SSG IX(90-99)
IESS-2 INT-0091
(78-82) (88-92)
(95-98) MSKCC
St.Judes P6-90-95,P6-91-01
ROI Bologona/Italy
REN-3(91-97) Europe

Figure 1. Large multi-institutional collaborative trials in USA and Europe—past and current. USA: IESS,
Intergroup Ewing’s Sarcoma Study; POG-CCG, Pediatric Oncology Group Children’s Cancer Group; INT009; COG,
Children’s Oncology Group; MSKCC, Memorial Sloan Kettering Cancer Center, New York; St. Judes, St. Judes
Research Hopital, Tennessee, Memphis. Europe: Germany: CESS, Cooperative Ewing Sarcoma Study. UK: ET Ewing’s
tumor; UK + Germany: EI–CESS, European Intergroup Cooperative Ewing’s Sarcoma Study; Scandinavia: SSG,
Scandinavian Sarcoma Group; EURO-E.W.I.N.G.99, EUROpean Ewing tumor Working Initiative of National Groups
Ewing Tumor Studies 1999; France + Austria + Switzerland + members of the European Organization for Research
and Treatment of Cancer Soft Tissue and Bone Sarcoma Group + UK + Germany

combined clinical effect have attempted to maximize the chemo-

therapy dose per cycle, increase the total number of cycles provided, or
decrease the interval between cycles. The Children’s Oncology
Group’s (COG) AEWS-0031 trial, which compared alternating courses
of VDC (vincristine, doxorubicin, and cyclophosphamide) and IE
(ifosfamide and etoposide) provided either in a ‘dose-dense’ fashion
every 2 weeks or every 3 weeks, is an example of this approach. Pre-
liminary results (ASCO 2008) suggest that dose-dense therapy sig-
nificantly improves survival in patients younger than 18 years old
[30]. Why this benefit in dose-dense apparently failed to improve the
outcome of older patients is unknown. Since this study enrolled only
a limited number of adult EWS patients and was insufficiently pow-
ered to detect a small clinical benefit (if it exists), further clinical trial
investigation is warranted before a dose-dense strategy is applied to
the adult EWS population.
• At MD Anderson Cancer Center, treatment of localized EWS varies
slightly depending upon patient age. Adults with EWS are treated with
the neoadjuvant combination of vincristine, doxorubicin, and ifosfa-
mide (with mesna) provided every 3 weeks for six cycles whereas
children typically receive alternating VDC and ifosfamide/etoposide
(IE) as described above. Preoperative restaging is obtained and
130 Bone Cancer

followed by surgery of the primary tumor unless negative margins or

substantial morbidity would be predicted; definitive radiation is
provided otherwise. While patients convalesce from surgery over a
3- to 4-week period before starting adjuvant therapy, our pathologists
assess the extent to which neoadjuvant therapy induced tumor
necrosis (reported in percentage). Though all patients are universally
treated with eight or more additional cycles of chemotherapy (for a
total of 14), the type of chemotherapy chosen is personalized to
account for each individual’s response to neoadjuvant treatment.
Those with either no reduction in tumor size or suboptimal
tumor necrosis within their surgical specimen (less than 98% based
on institutional experience) are treated with second-line regimens
typically reserved for those with metastatic spread (high dose ifosfa-
mide, topoisomerase I inhibitor/alkylating agent combinations, etc.)
[31]. This approach is similar to that taken in the ongoing EURO-
EWING99 trial, which randomizes poor-chemotherapy-responders to
receive either seven additional cycles of VAcI or high-dose Melphalan-
based chemotherapy with autologous stem cell rescue.
• Known to be radiation sensitive since the earliest clinical reports,
localized EWS tumors had been treated throughout most of the 20th
century primarily with radiation [32–34]. Today, both improvements
in surgical technique (that avoid amputation, preserve function, and
achieve high local control) and a greater appreciation of the risks
associated with radiation (such as leg-length disparity and rare sec-
ondary malignancies) have reduced the reliance upon radiation.
Though there are no randomized controlled studies that directly
compared surgery to radiation for definitive local control, most large
clinical trials report local failure rates nearly three-fold higher in
patients treated with radiation alone (30% failure) compared to
surgery alone (10% or less) [35–38]. Selection bias for those with
larger, unresectable tumors may partially explain this difference, but
our institutional practice echoes that of most other centers, favoring
surgery unless margin-negative resection is unachievable or morbid. If
radiation is necessary, results from St. Jude Children’s Research
Hospital indicate that more than 40 Gy is associated with improved
local control. COG protocols currently use 55.8 Gy dose [39]. Tumor
debulking prior to radiation has failed to improve local control
compared to radiation alone and should be avoided. Though infre-
quently used, proton therapy may allow for improved delivery of
radiation to the tumor in certain sites while limiting the exposure
of adjacent normal tissues to scatter-related effects of conventional
radiation. Proton radiation has greatest advantage in axial locations
such as skull base and sacrum.
• Older age (>14 years) has consistently been associated with a poor
survival outcome from EWS [28, 40–44]. The explanation for this
remains unclear, as recent studies suggest no difference in metastasis
at diagnosis (28%), tumor location, or histological response to neo-
adjuvant therapy [45–47]. Two differences reported by Pieper et al.
[48] were an increase in tumor size and a higher proportion of
extraskeletal origin among patients >40 years enrolled in either
EICESS 92 or EURO-EWING 99. As those treated at referral
centers with significant experience in EWS management appear to
have better outcomes, improved survival among children compared to
Ewing’s Sarcoma Subbiah et al. 131

adults could also be related to an increased familiarity of pediatric-

oncologists treating this disease as has been suggested by Paulussen
et al. [49]. Most recently, the AEWS-0031 trial, alternating vincristine,
doxorubicin, and cyclophosphamide with ifosfamide/etoposide every
2 instead of every 3 weeks, suggests that older patients (>18) failed to
benefit. Until a clear biological explanation for this is reconciled, the
optimal regimen used to treat adult EWS patients with localized dis-
ease remains to be determined in future clinical trials.
• Pathologic assessment of response to therapy involves evaluation of
treated tumor for degree of necrosis similar to what is done for oste-
osarcoma. Although there is general agreement that a complete
response (inability to detect viable tumor cells with extensive sam-
pling) is associated with better outcome than residual gross disease in
the resection specimen, more work is needed to establish uniform
cutoffs linking degree of necrosis to disease-specific survival [44].
Radiographic correlates of tumor necrosis may also provide important
information regarding treatment efficacy [50].

Recurrent or metastatic disease

• Whereas chemotherapy often enables patients with localized disease
to be cured, in those with metastatic spread its benefit is more often
limited to extending progression-free survival [51, 52]. Durable
responses remain elusive. Overall survival of patients with metastatic
disease at the time of diagnosis remains around 25% and those with
solitary pulmonary metastases fare only slightly better than those
with either isolated osseous metastases or spread to bone and lung
(5-year event-free survival of 29, 19, and 8%, respectively) [40].
Patients with recurrent disease within the first two years fare even
worse with 5-year survival around 7% (compared to 30% for
recurrent disease ‡2 years) [53]. This suggests that treatment of
metastatic disease requires a fresh approach distinct from that for
local control. Described below are treatment options available to
patients both on- and off-study.

Options using commercially available agents

• Cyclophosphamide is of course well studied in EWS with proven
efficacy [18, 19, 54]. Its combination with topotecan, a derivative of
camptothecin that inhibits topoisomerase I, has proved to be syner-
gistic, with proven efficacy first in pediatric solid malignancies col-
lectively [55] and later for EWS [56]. Our experience using the
cyclophosphamide/topotecan regimen for second-line therapy dem-
onstrates both effectiveness, as the majority derive clinical benefit
define by CR or PR, and safety [57]. As part of a clinical trial, topo-
tecan is currently being included in the COG study and is being
contemplated for inclusion in upcoming EURO-EWING trials
(Table 1). Similarly, the combination of temozolomide and irino-
tecan has also proved to be effective for EWS [58, 59]. These results
have been confirmed internationally and, at present, either of the two
combinations should be considered for use as second-line or salvage
therapy [57]. In our hands, this regimen can be delivered outpatient
with limited cytopenias and has gained a warm reception among
young adults since alopecia is avoided [60]. Of significance, neither
topoisomerase I inhibitor appears to be effective when used alone.
132 Bone Cancer

Table 1. Currently available Large Group Collaborative trials

Cooperative Country Eligible patient criteria Comments

or group/phase
COG-AEWS0331* USA Isolated pulmonary or pleural metastases VDC + IE with/without topotecan
at the initial diagnosis of Ewing’s sarcoma
SARC 003/Phase II USA Recurrent ESFT Gemcitabine + docetaxel
EURO-EWINGS 99/ Europe 1. Newly diagnosed-nonmetastatic 1. VAI vs VAC; VAI vs. HDT
Phase III 2. ESFT with lung mets 2. VAI + pulmonary radiotherapy vs HDT
SARC-011/Phase II USA Recurrent or refractory Ewing’s sarcoma R1507, a recombinant human monoclonal
antibody to the IGF1-R
*R2 Randomization of EURO-EWINGS 99.

• Gemcitabine and docetaxel have proven benefit for the treatment of

soft tissue sarcomas [61]. The Sarcoma Alliance for Research through
Collaboration (SARC) is currently accruing pediatric and adult
patients for a Phase II study of gemcitabine and docetaxel in relapsed
ESFT. EWS patients have been reported to respond to this regimen;
however, it appears to be a small minority.

Whole lung irradiation (WLI)

• Although metastatic sites should not routinely be resected, the
exception is for isolated pulmonary metastasis, where surgery may be
curative in patients whose primary tumor was well controlled. Fol-
lowing resection of limited lung-only metastases, irradiation may be
considered. Since the CESS-I trial results were reported, there has been
controversy regarding the potential benefit of WLI. In that trial, the
rate of pulmonary relapse following pneumonectomy significantly
decreased from 34% (VAcC alone) to 20% with the inclusion of WLI.
However, because the addition of doxorubicin to VAcC chemotherapy
reduced pulmonary relapse to 10%, without WLI, one could not be
certain that WLI improved survival in those who receive a ‘modern’
chemotherapy regimen that includes doxorubicin [27]. More recently,
retrospective analysis of the EICESS-92 trial suggests a nonsignificant
trend toward improved survival (P = 0.363). Among the pediatric
population treated at our institution, most will receive low-dose WLI
in the appropriate clinical setting whereas this is generally avoided in
our adult population. The impact WLI has on patients that receive
today’s combination of effective chemotherapies will hopefully be
determined in a randomized, prospective fashion in the EURO-EW-
ING 99 trial.

Experimental therapies (generally available only as part of a clinical trial)

• As the number of prognostic biomarkers of potential importance
grows, so has the interest in using them as potential therapeutic targets
[62, 63] (Fig. 2). Described below are several drugs, techniques, and/
or biological targets in evaluation by large collaborative groups
experienced in EWS management.
Ewing’s Sarcoma Subbiah et al. 133

Figure 2. Targets for Ewing’s current options and possible future therapies. Abbreviations: IGF1R, insulin-like
growth factor; GRB2, growth receptor binding protein 2; SOS, exchange factor Son of sevenless; MAPK/ERK ½,
mitogen-activated serine/threonine protein kinase (MAPK) or extracellular signal-regulated kinase (Erk); P1P2,
phosphatidyl inositol 4-5 bisphosphate; P1P3, phosphatidyl inositol 3 kinase; PTEN, phosphatase and tensin
homolog; mTOR, mammalian target of rapamycin; S6K, protein S6 kinase; 4EB1, eukaryotic initiation factor 4E
binding protein-1; PDGFR, platelet derived growth factor receptor; EGFR, epidermal growth factor receptor; HER2/
NEU, human epidermal growth factor receptor 2; VEGFR, vascular endothelial growth factor receptor; HDAC,
histone deacetylases; TKI, tyrosine kinase Inhibitors. IGF1-R system: IGF1R, a tyrosine kinase traverses the plasma
membrane and is composed of 2 ab chains. The IGF ligands found in circulation binds with varying affinities to
the receptor. Activation of IGF-1R leads to phosphorylation of adaptor proteins of IRS or SHC family. Activation of
IRS and SHC leads to ERK1/2 of MAPK cascade via GRB2 fi SOS fi RAS fi RAF fi MAPK pathway. IRS
protein approximates to P13K leading to P1P3. This is followed by AKT activation, then PDK1. This leads to
downstream activation of mTOR (mTOR, mlST8 and raptor) activation. Activation of mTOR phosphorylates S6K1
and 4E-BP1 (top-dependant and cap-dependant translation). As indicated they all are implicated in proliferation,
migration, differentiation, and autophagy of the Tumor. EWS-FL1 fusion protein resulting from t(22:11)
translocation serving as aberrant transcription factors. Currently available cytotoxic chemotherapeutic options
(standard and commercially available). Other agents: pre-clinical or tested in other soft tissue sarcomas. TKI as a
potential treatment option. As a family they make up the maximum number of signaling pathways which include
IGF1-R (expanded in A) and others like PDGFR, c-KIT, VEGFR, HER2/neu which may have potential


• The vast majority of clinical evidence suggests that bone marrow (or
peripheral blood stem cell) transplants fail to improve survival when
compared to historical controls [41, 64–68]. That overall survival
134 Bone Cancer

remains unchanged despite a significant risk of death approaching

8% from treatment-related complications (treatment-related leuke-
mia and myelodysplastic syndromes (t-AML/MDS), graft-vs-host
disease, and infection) indicates that a small subset who avoid acute
toxicity achieve long-term survival [69]. Too few patients have been
treated using allogeneic stem cell transplant to ascertain its clinical
effect, however, a recent case report interestingly noted potential
graft-vs-tumor effect in one patient [70]. Pending results from the
BMT arm of EURO-EWING 99, neither autologous nor allogeneic
transplant should be offered to patients outside of a clinical trial

VEGF inhibition

• Vasculogenesis in addition to angiogenesis plays an important role in

EWS in vivo [71]. Given high levels of VEGF expression in vitro and a
murine model that suggest a role for angiogenesis in EWS tumor for-
mation, the combination of bevacizumab (Avastin) with vincristine,
cyclophosphamide and topotecan is being evaluated in the COG-
AEWS-0521 trial in patients with recurrent Ewing’s sarcoma. Other
agents like sunitinib and semaxanib may also have potential
[57, 71, 72].

Ecteinascidin 743 (ET-743; Yondelis, Trabectedin)

• Trabectedin is a murine derivative from the Ecteinascidia turbinate

(sea squirt) that, unlike other alkylating agents, binds the N2 position
of guanine in the DNA minor groove [73–75]. It has proven efficacy as
a third-line agent for subtypes of soft tissue sarcoma, but its effect
remains to be determined for EWS. This agent is approved in Europe
for sarcomas.


• In vitro downregulation of the EWS:FLI1 translocation via antisense

oligonucleotides, dominant-negative transcripts, and RNAi has been
shown to limit malignant transformation and reduce cell growth
[76–79]. Translation of these basic science findings to the clinical
setting remains challenging, limited in part by the inability for these
agents to enter the cell as required to exert their respective effects.
Another strategy is to impair the down-stream effects of EWS-FLI1
transcription. It was reported recently that EWS cells treated with
cytarabine in vitro induced a genetic signature indicative of more
quiescent EWS/FLI-‘‘off’’ state [80]. This was reinforced by xenograft
and cell line studies. The COG-AEWS-0621 study of cytarabine in
patients with EWS, unfortunately, demonstrated minimal activity and
significant hematologic toxicity [81].
Ewing’s Sarcoma Subbiah et al. 135

Insulin-like growth factor-1 receptor (IGF-1R)

• IGF1-R plays an important role in transformation, apoptosis protec-

tion, invasion and metastasis, and resistance. Ubiquitous in EWS, IGF-
1R is a tyrosine kinase receptor with approximately 50% homology to
the insulin receptor [82]. Preclinically, activation of this receptor has
been found to be essential for EWS-FLI-1 induced malignant trans-
formation of murine fibroblasts [83]. Influenced by EWS-FLI-1, EWS
appears to exploit an activated IGF-1R pathway as a key step in
malignant transformation. Upon binding of the EWS/FLI-1 fusion
protein to the insulin-like growth factor binding protein (IGF-BP3)
promotor, IGF-BP-3 transcriptional activity is reduced, free IGF-BP-3
decreases, and more IGF-I ligand is available for ligand-induced acti-
vation of the ubiquitous IGF1R [84, 85]. This positive feedback loop
driving neoplastic cell growth and metastasis is reinforced by down-
stream activation of the mitogen-activation protein kinase (MAPK)
and phosphatidylinositol-3-kinase (PI3-K)/Akt pathways that shift the
regulatory balance in favor of cell survival rather than apoptosis [86].
Given the weight of evidence suggesting an important role for IGF-1R
inhibition for EWS and other cancer types, clinical development has
been pursued. The Pediatric Preclinical Testing Program showed initial
activity of IGF-1R-targeted monoclonal antibodies (mAb) in a murine
xenograft model of human EWS. In a phase I trial conducted by our
institution’s Experimental Therapeutics Program, four of nine patients
appeared to derive clinical benefit from mAb-based single-agent
therapy without significant toxicity. SARC and other large collabora-
tive group have begun phase II trials limited to sarcoma patients,
including EWS, and the results are eagerly awaited (Fig. 3). Although
not yet in clinical trials, Manara et al. [87] have reported upon
NVP-AEW541, a small-molecule IGF-1R antagonist with preclinical
efficacy against Ewing’s cell xenografts in murine models.


• Given that mTOR serves as a potential bypass pathway for IGF-1R

targeting, its inhibition in combination with IGF-1R suppression may
prove synergistic. Similarly, combined inhibition of IGF-1R and

Figure 3. Response of a patient to IGF-1R targeted therapy—before and after 7 weeks of treatment
136 Bone Cancer

mTOR may avoid the counterproductive rapamycin-induced upregu-

lation of Akt that occurs within 6 h of treatment. Phase I clinical trials
are currently open to investigate this potential synergy.

• Preclinical models have demonstrated value in designing clinical
studies investigating epigenetic treatment approaches. 5-Aza-2¢-deox-
ycytidine and MS-275 may be possible candidates in patients with
advanced Ewing’s sarcoma [88].
• Tubulin binding vascular disrupting agents (VDAs) like OXi4503/
CA1P slows subcutaneous ESFT growth. In combination with con-
ventional cytotoxic agents or hypoxia-activated prodrugs, this may
provide a novel therapeutic strategy to treat ESFT [89].
• Though EWS-FLI-1, or an alternative fusion variant, appears to be
necessary for transformation and growth, it is not sufficient without a
complex interplay of activated molecules such as IGF-1R, mTOR,
MAPK, PI3K/Akt, EGFR, VEGF, and the like [90]. Highlighting this,
many of these molecules and others (or their associated pathways)
were found to be dysregulated, as assessed by gene microarray, in
patients whose tumors responded poorly to neoadjuvant therapy
provided as per the EURO-EWING99 protocol [91]. Other potential
targets include the Wnt signaling pathway [92], the Hedgehog sig-
naling pathway [93, 94], and the p53 pathway. The relationship of
those pathways with the downstream effects of the fusion protein are
topics of active research.

• Multimodality care that incorporates progress in surgical technique,
radiation, and poly-chemotherapy has dramatically improved the
survival of EWS patients that present with localized disease. This is not
true, unfortunately, for those with metastatic or recurrent disease;
5-year survival has remained fixed at 25–29%. Poor prognostic factors
(such as older patient age, high tumor volume, pelvic location, and
inadequate response to chemotherapy) remain as true today as when
they were first described. Recognizing the need for a paradigm shift
caring of poor-risk patients, most collaborative group trials now
stratify patients to promote the use of novel, investigational therapies
in high-risk subsets. Some of the most promising drugs have been
described, yet they remain rarely used. As the molecular etiologies
responsible for poor prognosis become better understood—through
greater reliance upon patient specimens and improved integration of
pharmacodynamic endpoints into clinical trials—we will increasingly
be able to circumvent those mechanisms using less toxic and more
targeted personalized biological therapies. Already, this process has
begun in earnest, with clinical trials designed to affect specific path-
ways or interfere with known mechanisms of resistance. The study of
IGF-1R inhibitors and other targeted therapies represents just the
first step in the journey to ‘make cancer history’.

Acknowledgments We thank Kim-Anh Vu for the graphic

design. Grant support: UT MD Anderson Cancer Center Intra-
mural funding (J.A.L.), UT MD Anderson Physician Scientist
program (A.J.L.) and Jeremy Rosen Memorial fund (P.A.).
Ewing’s Sarcoma Subbiah et al. 137

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