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DOI 10.1007/s11864-009-0104-6
Bone Cancer
ª
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
Introduction
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.
Treatment
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
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
UK
UKCCSG/MRC
ET1(78-86)
ET2(87-93)
EI-CESS-92(92-99)-
UK+Germany
IESS-1
EURO-EWING-99 SSG-Scandinavia
(73-78)
Europe –(99-Current) SSG IX(90-99)
IESS-2 INT-0091
(78-82) (88-92)
Future?
POG-CCG
CESS(Germany)
(95-98) MSKCC
CESS-81(81-85)
T2-70-78
CESS-86(86-91)
St.Judes P6-90-95,P6-91-01
SFOP-France
ES-79-(78-86)
EW-88(88-91)
ES-87(87-91)
EW-92(92-96)
COG-AEWS-0031
ROI Bologona/Italy
(01-05)
REN-3(91-97) Europe
USA
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
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
BMT
• 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
VEGF inhibition
EWS/FL1
mTOR
Figure 3. Response of a patient to IGF-1R targeted therapy—before and after 7 weeks of treatment
136 Bone Cancer
Preclinical
• 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.
Conclusion
• 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’.
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