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<div class="pre-content"><div><div class="bk_prnt"><p class="small">NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.</p><p>PDQ Cancer Information Summaries [Internet]. Bethesda (MD): National Cancer Institute (US); 2002-. </p></div><div class="iconblock clearfix whole_rhythm no_top_margin bk_noprnt"><a class="img_link icnblk_img" title="Table of Contents Page" href="/books/n/pdqcis/"><img class="source-thumb" src="/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-pdqcis-lrg.png" alt="Cover of PDQ Cancer Information Summaries" height="100px" width="80px" /></a><div class="icnblk_cntnt eight_col"><h2>PDQ Cancer Information Summaries [Internet].</h2><a data-jig="ncbitoggler" href="#__NBK66045_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK66045_dtls__"><div>Bethesda (MD): <a href="http://www.cancer.gov/" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">National Cancer Institute (US)</a>; 2002-.</div></div><div class="half_rhythm"></div><div class="bk_noprnt"><form method="get" action="/books/n/pdqcis/" id="bk_srch"><div class="bk_search"><label for="bk_term" class="offscreen_noflow">Search term</label><input type="text" title="Search this book" id="bk_term" name="term" value="" data-jig="ncbiclearbutton" /> <input type="submit" class="jig-ncbibutton" value="Search this book" submit="false" style="padding: 0.1em 0.4em;" /></div></form></div></div></div></div></div>
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<div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><h1 id="_NBK66045_"><span class="title" itemprop="name">Ewing Sarcoma and Undifferentiated Small Round Cell Sarcomas of Bone and Soft Tissue Treatment (PDQ®)</span></h1><div class="subtitle whole_rhythm">Health Professional Version</div><p class="contrib-group"><span itemprop="author">PDQ Pediatric Treatment Editorial Board</span>.</p><p class="small">Published online: October 8, 2021.</p></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="_abs_rndgid_" itemprop="description"><p id="CDR0000062841__614">This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood Ewing sarcoma and undifferentiated small round cell sarcomas of bone and soft tissue. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.</p><p id="CDR0000062841__615">This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).</p></div><div id="CDR0000062841__1"><h2 id="_CDR0000062841__1_">General Information About Ewing Sarcoma and Undifferentiated Small Round Cell Sarcomas of Bone and Soft Tissue</h2><p id="CDR0000062841__88">Dramatic improvements in survival have been achieved for children and adolescents with cancer.[<a class="bk_pop" href="#CDR0000062841_rl_1_1">1</a>] Between 1975 and 2010, childhood cancer mortality decreased by more than 50%.[<a class="bk_pop" href="#CDR0000062841_rl_1_1">1</a>] For Ewing sarcoma, the 5-year survival rate has increased over the same time from 59% to 78% for children younger than 15 years and from 20% to 60% for adolescents aged 15 to 19 years.[<a class="bk_pop" href="#CDR0000062841_rl_1_1">1</a>] </p><p id="CDR0000062841__187">Studies using immunohistochemical markers,[<a class="bk_pop" href="#CDR0000062841_rl_1_2">2</a>] cytogenetics,[<a class="bk_pop" href="#CDR0000062841_rl_1_3">3</a>,<a class="bk_pop" href="#CDR0000062841_rl_1_4">4</a>] molecular genetics, and tissue culture [<a class="bk_pop" href="#CDR0000062841_rl_1_5">5</a>] indicate that Ewing sarcoma is derived from a primordial bone marrow–derived mesenchymal stem cell.[<a class="bk_pop" href="#CDR0000062841_rl_1_6">6</a>,<a class="bk_pop" href="#CDR0000062841_rl_1_7">7</a>] Older terms such as peripheral primitive neuroectodermal tumor, Askin tumor (Ewing sarcoma of chest wall), and extraosseous Ewing sarcoma (often combined in the term <i>Ewing sarcoma family of tumors</i>) refer to this same tumor.
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</p><p id="CDR0000062841__1984">The World Health Organization (WHO) classification of tumors of soft tissue and bone was modified in 2020 to introduce a new chapter on undifferentiated small round cell sarcomas of bone and soft tissue. This chapter consists of Ewing sarcoma and three main categories, including round cell sarcomas with <i>EWSR1</i>–non-ETS fusions, <i>CIC</i>-rearranged sarcoma, and sarcomas with <i>BCOR</i> genetic alterations.[<a class="bk_pop" href="#CDR0000062841_rl_1_8">8</a>]</p><p id="CDR0000062841__1985">Before the widespread availability of genomic testing, Ewing sarcoma was identified by the appearance of small round blue cells on light microscopic examination, along with positive staining for CD99 by immunohistochemistry. The identification of the recurring t(11;22) translocation in most Ewing sarcoma tumors led to the discovery that most tumors classified as Ewing sarcoma had a translocation that juxtaposed a portion of the <i>EWSR1</i> gene to a portion of an ETS gene family member, resulting in a transforming transcript. Not all undifferentiated small round cell sarcomas of bone and soft tissue have such a translocation. Further research identified additional genetic changes, including tumors with translocations of the <i>CIC</i> gene or the <i>BCOR</i> gene. These groups of tumors occur much less frequently than Ewing sarcoma, and definitive clinical outcomes for these patients are based on smaller sample sizes and less homogeneous treatment; therefore, patient outcomes are harder to quantitate with precision. Most of these tumors have been treated with regimens designed for Ewing sarcoma, and there is consensus that they were often included in clinical trials for the treatment of Ewing sarcoma, sometimes as <i>translocation-negative</i> Ewing sarcoma. There is agreement that these tumors are sufficiently different from Ewing sarcoma; they should be stratified and analyzed separately from Ewing sarcoma with the common translocation, even if they are treated with similar therapy. In this summary, they are described separately. Refer to the following sections of this summary for more information about these smaller groups of tumors:</p><ul id="CDR0000062841__2011"><li class="half_rhythm"><div>
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<a href="#CDR0000062841__1911">Undifferentiated Small Round Cell Sarcomas With <i>BCOR</i> Genetic Alterations</a>
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</div></li><li class="half_rhythm"><div>
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<a href="#CDR0000062841__1916">Undifferentiated Small Round Cell Sarcomas With <i>CIC</i> Genetic Alterations</a>
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</div></li><li class="half_rhythm"><div>
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<a href="#CDR0000062841__2001">Undifferentiated Small Round Cell Sarcomas With <i>EWSR1</i>–non-ETS Fusions</a>
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</div></li></ul><div id="CDR0000062841__153"><h3>Incidence</h3><p id="CDR0000062841__319">The incidence of Ewing sarcoma has remained unchanged for 30 years.[<a class="bk_pop" href="#CDR0000062841_rl_1_9">9</a>] The incidence for all ages is 1 case per 1 million people in the United States. In patients aged 10 to 19 years, the incidence is between 9 and 10 cases per 1 million people. The same analysis suggests that the incidence of Ewing sarcoma in the United States is nine times greater in White people than in African American people, with an intermediate incidence in Asian people.[<a class="bk_pop" href="#CDR0000062841_rl_1_10">10</a>,<a class="bk_pop" href="#CDR0000062841_rl_1_11">11</a>]</p><p id="CDR0000062841__616">The relative paucity of Ewing sarcoma in people of African or Asian descent may be explained, in part, by a specific polymorphism in the <i>EGR2</i> gene.[<a class="bk_pop" href="#CDR0000062841_rl_1_12">12</a>]</p><p id="CDR0000062841__125">The median age of patients with Ewing sarcoma is 15 years, and more than 50% of patients are adolescents. Well-characterized cases of Ewing sarcoma in neonates and infants have been described.[<a class="bk_pop" href="#CDR0000062841_rl_1_13">13</a>,<a class="bk_pop" href="#CDR0000062841_rl_1_14">14</a>] Based on data from 1,426 patients entered on European Intergroup Cooperative Ewing Sarcoma Studies, 59% of patients are male and 41% are female.[<a class="bk_pop" href="#CDR0000062841_rl_1_15">15</a>] </p></div><div id="CDR0000062841__377"><h3>Clinical Presentation</h3><p id="CDR0000062841__378">Primary sites of bone disease include the following:</p><ul id="CDR0000062841__241"><li class="half_rhythm"><div>Lower extremity (41%).</div></li><li class="half_rhythm"><div>Pelvis (26%).</div></li><li class="half_rhythm"><div>Chest wall (16%).</div></li><li class="half_rhythm"><div>Upper extremity (9%).</div></li><li class="half_rhythm"><div>Spine (6%).</div></li><li class="half_rhythm"><div>Hand and foot (3%).[<a class="bk_pop" href="#CDR0000062841_rl_1_16">16</a>]</div></li><li class="half_rhythm"><div>Skull (2%).</div></li></ul><p id="CDR0000062841__242">For extraosseous primary tumors, the most common primary sites of disease include the following:[<a class="bk_pop" href="#CDR0000062841_rl_1_17">17</a>,<a class="bk_pop" href="#CDR0000062841_rl_1_18">18</a>]</p><ul id="CDR0000062841__243"><li class="half_rhythm"><div>Trunk (32%).</div></li><li class="half_rhythm"><div>Extremity (26%).</div></li><li class="half_rhythm"><div>Head and neck (18%).</div></li><li class="half_rhythm"><div>Retroperitoneum (16%).</div></li><li class="half_rhythm"><div>Other sites (9%).</div></li></ul><p id="CDR0000062841__244">The time from first symptom to diagnosis of Ewing sarcoma is often long, with a median interval reported from 2 to 5 months. Longer times are associated with older age and pelvic primary sites. Time from first symptom to diagnosis has not been associated with metastasis, surgical outcome, or survival.[<a class="bk_pop" href="#CDR0000062841_rl_1_19">19</a>] Approximately 25% of patients with Ewing sarcoma have metastatic disease at the time of diagnosis.[<a class="bk_pop" href="#CDR0000062841_rl_1_9">9</a>] </p><p id="CDR0000062841__302">The Surveillance, Epidemiology, and End Results (SEER) Program database was used to compare patients younger than 40 years with Ewing sarcoma who presented with skeletal and extraosseous primary sites (refer to <a class="figpopup" href="/books/NBK66045.23/table/CDR0000062841__304/?report=objectonly" target="object" rid-figpopup="figCDR0000062841304" rid-ob="figobCDR0000062841304">Table 1</a>).[<a class="bk_pop" href="#CDR0000062841_rl_1_20">20</a>] Patients with extraosseous Ewing sarcoma were more likely to be older, female, of non-White race, and have axial primary sites, and were less likely to have pelvic primary sites than were patients with skeletal Ewing sarcoma.</p><div id="CDR0000062841__304" class="table"><h3><span class="title">Table 1. Characteristics of Children With Extraosseous Ewing Sarcoma and Skeletal Ewing Sarcoma</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK66045.23/table/CDR0000062841__304/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__CDR0000062841__304_lrgtbl__"><table class="no_top_margin"><thead><tr><th colspan="1" rowspan="1" style="vertical-align:top;">Characteristic</th><th colspan="1" rowspan="1" style="vertical-align:top;">Extraosseous Ewing Sarcoma</th><th colspan="1" rowspan="1" style="vertical-align:top;">Skeletal Ewing Sarcoma</th><th colspan="1" rowspan="1" style="vertical-align:top;">
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<i>P</i> Value</th></tr></thead><tbody><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Mean age (range), years</td><td colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">20 (0–39)</td><td colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">16 (0–39)</td><td colspan="1" rowspan="1" style="text-align:center;vertical-align:top;"><.001
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</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Male</td><td colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">53%</td><td colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">63%</td><td colspan="1" rowspan="1" style="text-align:center;vertical-align:top;"><.001</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">White race</td><td colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">85%</td><td colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">93%</td><td colspan="1" rowspan="1" style="text-align:center;vertical-align:top;"><.001</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Axial primary sites</td><td colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">73%</td><td colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">54%</td><td colspan="1" rowspan="1" style="text-align:center;vertical-align:top;"><.001</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Pelvic primary sites
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</td><td colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">20%</td><td colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">27%</td><td colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">.001</td></tr></tbody></table></div></div></div><div id="CDR0000062841__607"><h3>Diagnostic Evaluation</h3><p id="CDR0000062841__20">The following tests and procedures may be used to diagnose or stage Ewing sarcoma:</p><ul id="CDR0000062841__21"><li class="half_rhythm"><div>Physical examination and history.</div></li><li class="half_rhythm"><div>Magnetic resonance imaging (MRI).</div></li><li class="half_rhythm"><div>Computed tomography (CT) scan.</div></li><li class="half_rhythm"><div>Positron emission tomography (PET) scan.</div></li><li class="half_rhythm"><div>Bone scan.</div></li><li class="half_rhythm"><div>Bone marrow aspiration and biopsy.</div></li><li class="half_rhythm"><div>X-ray.</div></li><li class="half_rhythm"><div>Complete blood count.</div></li><li class="half_rhythm"><div>Blood chemistry studies, such as lactate dehydrogenase (LDH).</div></li></ul><p id="CDR0000062841__1822"> A systematic review of Ewing sarcoma studies was performed to assess the incidence of bone marrow metastasis and the role of fluorine F 18-fludeoxyglucose (18F-FDG) PET imaging to detect bone marrow metastasis.[<a class="bk_pop" href="#CDR0000062841_rl_1_21">21</a>] The review reported a pooled incidence of bone marrow metastasis of 4.8% in all patients with newly diagnosed Ewing sarcoma and 17.5% in patients with metastatic disease. Only 1.2% of patients had bone marrow metastasis as their sole metastatic site. Compared with bone marrow biopsy and aspiration, 18F-FDG PET detection of bone marrow metastasis demonstrated pooled 100% sensitivity and 96% specificity, positive predictive value of 75%, and negative predictive value of 100%. In the era of 18F-FDG PET imaging, omission of bone marrow biopsy and aspiration may be considered in patients with otherwise localized disease after initial staging studies. (Refer to the <a href="#CDR0000062841__28">Treatment Option Overview for Ewing Sarcoma</a> section of this summary for more information about diagnostic biopsy.)</p></div><div id="CDR0000062841__154"><h3>Prognostic Factors</h3><p id="CDR0000062841__155">The two major types of prognostic factors for patients with Ewing sarcoma are grouped as follows: </p><ul id="CDR0000062841__321"><li class="half_rhythm"><div><a href="#CDR0000062841__156">Pretreatment factors</a>.</div></li><li class="half_rhythm"><div><a href="#CDR0000062841__158">Response to initial therapy factors</a>.</div></li></ul><div id="CDR0000062841__156"><h4>Pretreatment factors</h4><ul id="CDR0000062841__157"><li class="half_rhythm"><div class="half_rhythm"><b>Site of tumor:</b> Patients with Ewing sarcoma in the distal extremities have the best prognosis. Patients with Ewing sarcoma in the proximal extremities have an intermediate prognosis, followed by patients with central or pelvic sites.[<a class="bk_pop" href="#CDR0000062841_rl_1_22">22</a>-<a class="bk_pop" href="#CDR0000062841_rl_1_25">25</a>] </div></li><li class="half_rhythm"><div class="half_rhythm"><b> Extraskeletal versus skeletal primary tumors:</b> The Children's Oncology Group (COG) performed a retrospective analysis from two large cooperative trials that used similar treatment regimens.[<a class="bk_pop" href="#CDR0000062841_rl_1_26">26</a>] They identified 213 patients with extraskeletal primary tumors and 826 patients with skeletal primary tumors. Patients with extraskeletal primary tumors were more likely to have an axial primary site, less likely to have large primary tumors, and had a statistically significant better prognosis than did patients with skeletal primary tumors.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Tumor size or volume:</b> Tumor size or volume has been shown to be an important prognostic factor in most studies. Cutoffs of a volume of 100 mL or 200 mL and/or single dimension greater than 8 cm are used to define larger tumors. Larger tumors tend to occur in unfavorable sites.[<a class="bk_pop" href="#CDR0000062841_rl_1_24">24</a>,<a class="bk_pop" href="#CDR0000062841_rl_1_25">25</a>,<a class="bk_pop" href="#CDR0000062841_rl_1_27">27</a>]</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Age:</b> Infants and younger patients have a better prognosis than do patients aged 15 years and older, as noted in the following studies:[<a class="bk_pop" href="#CDR0000062841_rl_1_14">14</a>,<a class="bk_pop" href="#CDR0000062841_rl_1_22">22</a>,<a class="bk_pop" href="#CDR0000062841_rl_1_23">23</a>,<a class="bk_pop" href="#CDR0000062841_rl_1_25">25</a>,<a class="bk_pop" href="#CDR0000062841_rl_1_28">28</a>-<a class="bk_pop" href="#CDR0000062841_rl_1_30">30</a>] <ul id="CDR0000062841__1820"><li class="half_rhythm"><div>In North American studies, patients younger than 10 years had a better outcome than those aged 10 to 17 years at diagnosis (relative risk [RR], 1.4). Patients older than 18 years had an inferior outcome (RR, 2.5).[<a class="bk_pop" href="#CDR0000062841_rl_1_31">31</a>-<a class="bk_pop" href="#CDR0000062841_rl_1_33">33</a>]</div></li><li class="half_rhythm"><div>A retrospective review of two consecutive German trials for Ewing sarcoma identified 47 patients older than 40 years.[<a class="bk_pop" href="#CDR0000062841_rl_1_34">34</a>] With adequate multimodal therapy, survival was comparable to the survival observed in adolescents treated on the same trials.</div></li><li class="half_rhythm"><div>Review of the SEER database from 1973 to 2011 identified 1,957 patients with Ewing sarcoma.[<a class="bk_pop" href="#CDR0000062841_rl_1_35">35</a>] Thirty-nine of these patients (2.0%) were younger than 12 months at diagnosis. Infants were less likely to receive radiation therapy and more likely to have soft tissue primary sites. Early death was more common in infants, but the overall survival (OS) did not differ significantly from that of older patients.</div></li><li class="half_rhythm"><div>A European retrospective review identified 2,635 patients with Ewing sarcoma of bone.[<a class="bk_pop" href="#CDR0000062841_rl_1_36">36</a>] Sites of primary and metastatic tumors differed according to the age groups of young children (0–9 years), early adolescence (10–14 years), late adolescence (15–19 years), young adults (20–24 years), and adults (older than 24 years). Young children had the most striking differences in site of disease, with a lower proportion of pelvic primary and axial tumors. Young children also presented less often with metastatic disease at diagnosis.</div></li></ul></div></li><li class="half_rhythm"><div class="half_rhythm"><b>Sex:</b> Girls with Ewing sarcoma have a better prognosis than do boys with Ewing sarcoma.[<a class="bk_pop" href="#CDR0000062841_rl_1_10">10</a>,<a class="bk_pop" href="#CDR0000062841_rl_1_23">23</a>,<a class="bk_pop" href="#CDR0000062841_rl_1_25">25</a>]</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Serum LDH:</b> Increased serum LDH levels before treatment are associated with inferior prognosis. Increased LDH levels are also correlated with large primary tumors and metastatic disease.[<a class="bk_pop" href="#CDR0000062841_rl_1_23">23</a>]</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Metastases:</b> The presence or absence of metastatic disease is the single most powerful predictor of outcome. Any metastatic disease defined by standard imaging techniques or bone marrow aspirate/biopsy by morphology is an adverse prognostic factor. Metastases at diagnosis are detected in about 25% of patients.[<a class="bk_pop" href="#CDR0000062841_rl_1_9">9</a>] </div><div class="half_rhythm">Patients with metastatic disease confined to the lung have a better prognosis than do patients with extrapulmonary metastatic sites.[<a class="bk_pop" href="#CDR0000062841_rl_1_22">22</a>,<a class="bk_pop" href="#CDR0000062841_rl_1_24">24</a>,<a class="bk_pop" href="#CDR0000062841_rl_1_25">25</a>,<a class="bk_pop" href="#CDR0000062841_rl_1_37">37</a>] The number of pulmonary lesions does not seem to correlate with outcome, but patients with unilateral lung involvement do better than patients with bilateral lung involvement.[<a class="bk_pop" href="#CDR0000062841_rl_1_38">38</a>]</div><div class="half_rhythm">Patients with metastasis to only bone seem to have a better outcome than do patients with metastases to both bone and lung.[<a class="bk_pop" href="#CDR0000062841_rl_1_39">39</a>,<a class="bk_pop" href="#CDR0000062841_rl_1_40">40</a>]</div><div class="half_rhythm">Based on an analysis from the SEER database, regional lymph node involvement in patients is associated with an inferior overall outcome when compared with patients without regional lymph node involvement.[<a class="bk_pop" href="#CDR0000062841_rl_1_41">41</a>]</div></li><li class="half_rhythm"><div class="half_rhythm">
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<b>Pathologic fracture:</b> A single-institution retrospective analysis of 78 patients with Ewing sarcoma suggested that pathologic fracture at initial presentation was associated with inferior event-free survival (EFS) and OS.[<a class="bk_pop" href="#CDR0000062841_rl_1_42">42</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335144/" class="def">Level of evidence: 3iiA</a>]</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Previous treatment for cancer:</b> In the SEER database, 58 patients with Ewing sarcoma who were diagnosed after treatment for a previous malignancy (2.1% of patients with Ewing sarcoma) were compared with 2,756 patients with Ewing sarcoma as a first cancer over the same period. Patients with Ewing sarcoma as a second malignant neoplasm were older (secondary Ewing sarcoma, mean age of 47.8 years; primary Ewing sarcoma, mean age of 22.5 years), more likely to have a primary tumor in an axial or extraskeletal site, and had a worse prognosis (5-year OS rates of 43.5% for patients with secondary Ewing sarcoma and 64.2% for patients with primary Ewing sarcoma).[<a class="bk_pop" href="#CDR0000062841_rl_1_43">43</a>] </div></li><li class="half_rhythm"><div class="half_rhythm"><b>Chromosomal alterations:</b>
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<ul id="CDR0000062841__1992"><li class="half_rhythm"><div>Complex karyotype (defined as the presence of five or more independent chromosome abnormalities at diagnosis) and modal chromosome numbers lower than 50 appear to have adverse prognostic significance.[<a class="bk_pop" href="#CDR0000062841_rl_1_44">44</a>]</div></li><li class="half_rhythm"><div>Gain of chromosome 1q and/or deletion of chromosome 16q has been associated with inferior prognosis for patients with Ewing sarcoma in several cohorts.[<a class="bk_pop" href="#CDR0000062841_rl_1_45">45</a>-<a class="bk_pop" href="#CDR0000062841_rl_1_47">47</a>] These two chromosomal alterations commonly occur together across a range of cancer types, including Ewing sarcoma.[<a class="bk_pop" href="#CDR0000062841_rl_1_48">48</a>] Their co-occurrence is likely a result of their derivation from an unbalanced t(1;16) translocation resulting in gain of chromosome 1q together with loss of chromosomal material from 16q.[<a class="bk_pop" href="#CDR0000062841_rl_1_49">49</a>,<a class="bk_pop" href="#CDR0000062841_rl_1_50">50</a>]</div></li></ul></div></li><li class="half_rhythm"><div class="half_rhythm"><b>Detectable circulating tumor DNA (ctDNA) in peripheral blood:</b> A next-generation sequencing hybrid capture assay and an ultra-low-pass whole-genome sequencing assay were used to detect ctDNA in banked plasma from patients with Ewing sarcoma. Among patients with newly diagnosed localized Ewing sarcoma, detectable ctDNA was associated with inferior 3-year EFS rates (48.6% vs. 82.1%; <i>P</i> = .006) and OS rates (79.8% vs. 92.6%; <i>P</i> = .01).[<a class="bk_pop" href="#CDR0000062841_rl_1_51">51</a>]</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Detectable fusion transcripts in morphologically normal marrow:</b> Reverse transcription–polymerase chain reaction (RT-PCR) can be used to detect fusion transcripts in bone marrow. In a single retrospective study utilizing patients with normal marrow morphology and no other metastatic site, fusion transcript detection in marrow or peripheral blood was associated with an increased risk of relapse.[<a class="bk_pop" href="#CDR0000062841_rl_1_52">52</a>] However, a larger cohort (n = 225) of patients with localized Ewing sarcoma did not show a difference in EFS or OS on the basis of the detection of fusion transcripts in blood or bone marrow.[<a class="bk_pop" href="#CDR0000062841_rl_1_53">53</a>]</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Gene alterations:</b> A prospective analysis of <i>TP53</i> mutations and/or <i>CDKN2A</i> deletions in patients with Ewing sarcoma enrolled on COG clinical trials found no correlation of these alterations with EFS.[<a class="bk_pop" href="#CDR0000062841_rl_1_54">54</a>]</div><div class="half_rhythm">In a study of 299 patients with Ewing sarcoma, 41 patients (14%) had <i>STAG2</i> mutations and 16 patients (5%) had <i>TP53</i> mutations.[<a class="bk_pop" href="#CDR0000062841_rl_1_47">47</a>] There was no association with OS for patients with either the <i>STAG2</i> or <i>TP53</i> mutation alone. However, the nine patients (3%) with tumors that had both <i>STAG2</i> and <i>TP53</i> mutations had a significantly decreased OS rate (<20% at 4 years).</div></li></ul><p id="CDR0000062841__246">The following are <b>not</b> considered to be adverse prognostic factors for Ewing sarcoma:</p><ul id="CDR0000062841__247"><li class="half_rhythm"><div>Histopathology: The degree of neural differentiation is not a prognostic factor in Ewing sarcoma.[<a class="bk_pop" href="#CDR0000062841_rl_1_55">55</a>,<a class="bk_pop" href="#CDR0000062841_rl_1_56">56</a>]</div></li><li class="half_rhythm"><div>Molecular pathology: The <i>EWSR1-ETS</i> translocation associated with Ewing sarcoma can occur at several potential breakpoints in each of the genes that join to form the novel segment of DNA. Once thought to be significant,[<a class="bk_pop" href="#CDR0000062841_rl_1_57">57</a>] two large series have shown that the <i>EWSR1-ETS</i> translocation breakpoint site is not an adverse prognostic factor.[<a class="bk_pop" href="#CDR0000062841_rl_1_58">58</a>,<a class="bk_pop" href="#CDR0000062841_rl_1_59">59</a>]</div></li></ul></div><div id="CDR0000062841__158"><h4>Response to initial therapy factors</h4><p id="CDR0000062841__159">Multiple studies have shown that patients with minimal or no residual viable tumor after presurgical chemotherapy have a significantly better EFS than do patients with larger amounts of viable tumor.[<a class="bk_pop" href="#CDR0000062841_rl_1_60">60</a>-<a class="bk_pop" href="#CDR0000062841_rl_1_63">63</a>] Female sex and younger age predict a good histologic response to preoperative therapy.[<a class="bk_pop" href="#CDR0000062841_rl_1_64">64</a>] For patients who receive preinduction- and postinduction-chemotherapy PET scans, decreased PET uptake after chemotherapy correlated with good histologic response and better outcome.[<a class="bk_pop" href="#CDR0000062841_rl_1_65">65</a>-<a class="bk_pop" href="#CDR0000062841_rl_1_67">67</a>]</p><p id="CDR0000062841__391">Patients with poor response to presurgical chemotherapy have an increased risk of local recurrence.[<a class="bk_pop" href="#CDR0000062841_rl_1_68">68</a>]</p><p id="CDR0000062841__1951">A retrospective analysis of risk factors for recurrence was performed in patients who received initial chemotherapy and underwent surgical resection of the primary tumor.[<a class="bk_pop" href="#CDR0000062841_rl_1_69">69</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335150/" class="def">Level of evidence: 3iiiA</a>] Among 982 patients with a median follow-up of 7.6 years, adverse risk factors for local recurrence were pelvic primary tumors (hazard ratio [HR], 2.04; 95% confidence interval [CI], 1.10–3.80) and marginal/intralesional resection (HR, 2.28; 95% CI, 1.25–4.16). The addition of radiation therapy was associated with improved outcome (HR, 0.52; 95% CI, 0.28–0.95). Adverse risk factors for pulmonary metastasis were less than 90% necrosis (HR, 2.13; 95% CI, 1.13–4.00) and previous pulmonary metastasis (HR, 4.90; 95% CI, 2.28–8.52). Adverse risk factors for death included pulmonary metastasis (HR, 8.08; 95% CI, 4.01–16.29), bone or other metastasis (HR, 10.23; 95% CI, 4.90–21.36), and less than 90% necrosis (HR, 6.35; 95% CI, 3.18–12.69). Early local recurrence (0–24 months) negatively influences survival (HR, 3.79; 95% CI, 1.34–10.76).</p></div><div id="CDR0000062841__1806"><h4>Detection of Ewing sarcoma in the peripheral blood</h4><p id="CDR0000062841__1807">Several techniques to evaluate the presence of Ewing sarcoma in the peripheral blood have been proposed. Flow cytometry for cells that express the CD99 antigen was not sufficiently sensitive to serve as a reliable biomarker.[<a class="bk_pop" href="#CDR0000062841_rl_1_52">52</a>,<a class="bk_pop" href="#CDR0000062841_rl_1_70">70</a>] RT-PCR for the <i>EWSR1-FLI1</i> translocation was also not considered a reliable biomarker.[<a class="bk_pop" href="#CDR0000062841_rl_1_71">71</a>]</p><p id="CDR0000062841__1821"> A more sensitive technique that utilized patient-specific primers designed after identification of the specific translocation breakpoint in combination with droplet digital PCR reported a sensitivity of 0.018% to 0.009%.[<a class="bk_pop" href="#CDR0000062841_rl_1_72">72</a>] Levels of circulating cell-free DNA were higher in patients with metastatic disease than in patients with localized disease. A hybrid capture sequencing assay employing the introns at which <i>EWSR1</i> and <i>FLI1</i> fusions occur has also been developed to detect evidence of the <i>EWSR1-FLI1</i> translocation in circulating cell-free DNA.[<a class="bk_pop" href="#CDR0000062841_rl_1_73">73</a>] Using this method, the translocation was detected in peripheral blood samples from 10 of 11 patients with Ewing sarcoma. Additional study is required to determine whether circulating cell-free DNA will have clinical utility as a biomarker for Ewing sarcoma to monitor disease status and response to therapy.</p></div></div><div id="CDR0000062841_rl_1"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000062841_rl_1_1">Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014. [<a href="/pmc/articles/PMC4136455/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4136455</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24853691" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24853691</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_2">Olsen SH, Thomas DG, Lucas DR: Cluster analysis of immunohistochemical profiles in synovial sarcoma, malignant peripheral nerve sheath tumor, and Ewing sarcoma. Mod Pathol 19 (5): 659-68, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16528378" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16528378</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_3">Delattre O, Zucman J, Melot T, et al.: The Ewing family of tumors--a subgroup of small-round-cell tumors defined by specific chimeric transcripts. N Engl J Med 331 (5): 294-9, 1994. [<a href="https://pubmed.ncbi.nlm.nih.gov/8022439" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8022439</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_4">Dagher R, Pham TA, Sorbara L, et al.: Molecular confirmation of Ewing sarcoma. J Pediatr Hematol Oncol 23 (4): 221-4, 2001. [<a href="https://pubmed.ncbi.nlm.nih.gov/11846300" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11846300</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_5">Llombart-Bosch A, Carda C, Peydro-Olaya A, et al.: Soft tissue Ewing's sarcoma. Characterization in established cultures and xenografts with evidence of a neuroectodermic phenotype. Cancer 66 (12): 2589-601, 1990. [<a href="https://pubmed.ncbi.nlm.nih.gov/1701108" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 1701108</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_6">Suvà ML, Riggi N, Stehle JC, et al.: Identification of cancer stem cells in Ewing's sarcoma. Cancer Res 69 (5): 1776-81, 2009. [<a href="https://pubmed.ncbi.nlm.nih.gov/19208848" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19208848</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_7">Tirode F, Laud-Duval K, Prieur A, et al.: Mesenchymal stem cell features of Ewing tumors. Cancer Cell 11 (5): 421-9, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17482132" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17482132</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_8">Choi JH, Ro JY: The 2020 WHO Classification of Tumors of Soft Tissue: Selected Changes and New Entities. Adv Anat Pathol 28 (1): 44-58, 2021. [<a href="https://pubmed.ncbi.nlm.nih.gov/32960834" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 32960834</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_9">Esiashvili N, Goodman M, Marcus RB: Changes in incidence and survival of Ewing sarcoma patients over the past 3 decades: Surveillance Epidemiology and End Results data. J Pediatr Hematol Oncol 30 (6): 425-30, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/18525458" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18525458</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_10">Jawad MU, Cheung MC, Min ES, et al.: Ewing sarcoma demonstrates racial disparities in incidence-related and sex-related differences in outcome: an analysis of 1631 cases from the SEER database, 1973-2005. Cancer 115 (15): 3526-36, 2009. [<a href="https://pubmed.ncbi.nlm.nih.gov/19548262" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19548262</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_11">Beck R, Monument MJ, Watkins WS, et al.: EWS/FLI-responsive GGAA microsatellites exhibit polymorphic differences between European and African populations. Cancer Genet 205 (6): 304-12, 2012. [<a href="/pmc/articles/PMC3389350/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3389350</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22749036" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22749036</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_12">Grünewald TG, Bernard V, Gilardi-Hebenstreit P, et al.: Chimeric EWSR1-FLI1 regulates the Ewing sarcoma susceptibility gene EGR2 via a GGAA microsatellite. Nat Genet 47 (9): 1073-8, 2015. [<a href="/pmc/articles/PMC4591073/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4591073</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26214589" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26214589</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_13">Kim SY, Tsokos M, Helman LJ: Dilemmas associated with congenital ewing sarcoma family tumors. J Pediatr Hematol Oncol 30 (1): 4-7, 2008. [<a href="/pmc/articles/PMC2668808/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2668808</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18176172" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18176172</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_14">van den Berg H, Dirksen U, Ranft A, et al.: Ewing tumors in infants. Pediatr Blood Cancer 50 (4): 761-4, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/17635001" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17635001</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_15">Paulussen M, Craft AW, Lewis I, et al.: Results of the EICESS-92 Study: two randomized trials of Ewing's sarcoma treatment--cyclophosphamide compared with ifosfamide in standard-risk patients and assessment of benefit of etoposide added to standard treatment in high-risk patients. J Clin Oncol 26 (27): 4385-93, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/18802150" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18802150</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_16">Froeb D, Ranft A, Boelling T, et al.: Ewing sarcoma of the hand or foot. Klin Padiatr 224 (6): 348-52, 2012. [<a href="https://pubmed.ncbi.nlm.nih.gov/23143762" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23143762</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_17">Raney RB, Asmar L, Newton WA, et al.: Ewing's sarcoma of soft tissues in childhood: a report from the Intergroup Rhabdomyosarcoma Study, 1972 to 1991. J Clin Oncol 15 (2): 574-82, 1997. [<a href="https://pubmed.ncbi.nlm.nih.gov/9053479" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9053479</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_18">Rowe RG, Thomas DG, Schuetze SM, et al.: Ewing sarcoma of the kidney: case series and literature review of an often overlooked entity in the diagnosis of primary renal tumors. Urology 81 (2): 347-53, 2013. [<a href="https://pubmed.ncbi.nlm.nih.gov/23374800" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23374800</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_19">Brasme JF, Chalumeau M, Oberlin O, et al.: Time to diagnosis of Ewing tumors in children and adolescents is not associated with metastasis or survival: a prospective multicenter study of 436 patients. J Clin Oncol 32 (18): 1935-40, 2014. [<a href="https://pubmed.ncbi.nlm.nih.gov/24841977" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24841977</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_20">Applebaum MA, Worch J, Matthay KK, et al.: Clinical features and outcomes in patients with extraskeletal Ewing sarcoma. Cancer 117 (13): 3027-32, 2011. [<a href="/pmc/articles/PMC3135782/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3135782</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21692057" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21692057</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_21">Campbell KM, Shulman DS, Grier HE, et al.: Role of bone marrow biopsy for staging new patients with Ewing sarcoma: A systematic review. Pediatr Blood Cancer 68 (2): e28807, 2021. [<a href="https://pubmed.ncbi.nlm.nih.gov/33219750" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 33219750</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_22">Cotterill SJ, Ahrens S, Paulussen M, et al.: Prognostic factors in Ewing's tumor of bone: analysis of 975 patients from the European Intergroup Cooperative Ewing's Sarcoma Study Group. J Clin Oncol 18 (17): 3108-14, 2000. [<a href="https://pubmed.ncbi.nlm.nih.gov/10963639" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10963639</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_23">Bacci G, Longhi A, Ferrari S, et al.: Prognostic factors in non-metastatic Ewing's sarcoma tumor of bone: an analysis of 579 patients treated at a single institution with adjuvant or neoadjuvant chemotherapy between 1972 and 1998. Acta Oncol 45 (4): 469-75, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16760184" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16760184</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_24">Rodríguez-Galindo C, Liu T, Krasin MJ, et al.: Analysis of prognostic factors in ewing sarcoma family of tumors: review of St. Jude Children's Research Hospital studies. Cancer 110 (2): 375-84, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17569105" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17569105</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_25">Karski EE, McIlvaine E, Segal MR, et al.: Identification of Discrete Prognostic Groups in Ewing Sarcoma. Pediatr Blood Cancer 63 (1): 47-53, 2016. [<a href="/pmc/articles/PMC5011751/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5011751</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26257296" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26257296</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_26">Cash T, McIlvaine E, Krailo MD, et al.: Comparison of clinical features and outcomes in patients with extraskeletal versus skeletal localized Ewing sarcoma: A report from the Children's Oncology Group. Pediatr Blood Cancer 63 (10): 1771-9, 2016. [<a href="/pmc/articles/PMC4995129/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4995129</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/27297500" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27297500</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_27">Ahrens S, Hoffmann C, Jabar S, et al.: Evaluation of prognostic factors in a tumor volume-adapted treatment strategy for localized Ewing sarcoma of bone: the CESS 86 experience. Cooperative Ewing Sarcoma Study. Med Pediatr Oncol 32 (3): 186-95, 1999. [<a href="https://pubmed.ncbi.nlm.nih.gov/10064186" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10064186</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_28">De Ioris MA, Prete A, Cozza R, et al.: Ewing sarcoma of the bone in children under 6 years of age. PLoS One 8 (1): e53223, 2013. [<a href="/pmc/articles/PMC3561359/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3561359</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23382839" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23382839</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_29">Huh WW, Daw NC, Herzog CE, et al.: Ewing sarcoma family of tumors in children younger than 10 years of age. Pediatr Blood Cancer 64 (4): , 2017. [<a href="https://pubmed.ncbi.nlm.nih.gov/27696711" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27696711</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_30">Ahmed SK, Randall RL, DuBois SG, et al.: Identification of Patients With Localized Ewing Sarcoma at Higher Risk for Local Failure: A Report From the Children's Oncology Group. Int J Radiat Oncol Biol Phys 99 (5): 1286-1294, 2017. [<a href="/pmc/articles/PMC5699950/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5699950</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/28964585" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28964585</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_31">Grier HE, Krailo MD, Tarbell NJ, et al.: Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med 348 (8): 694-701, 2003. [<a href="https://pubmed.ncbi.nlm.nih.gov/12594313" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12594313</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_32">Granowetter L, Womer R, Devidas M, et al.: Dose-intensified compared with standard chemotherapy for nonmetastatic Ewing sarcoma family of tumors: a Children's Oncology Group Study. J Clin Oncol 27 (15): 2536-41, 2009. [<a href="/pmc/articles/PMC2684856/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2684856</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19349548" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19349548</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_33">Womer RB, West DC, Krailo MD, et al.: Randomized controlled trial of interval-compressed chemotherapy for the treatment of localized Ewing sarcoma: a report from the Children's Oncology Group. J Clin Oncol 30 (33): 4148-54, 2012. [<a href="/pmc/articles/PMC3494838/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3494838</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23091096" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23091096</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_34">Pieper S, Ranft A, Braun-Munzinger G, et al.: Ewing's tumors over the age of 40: a retrospective analysis of 47 patients treated according to the International Clinical Trials EICESS 92 and EURO-E.W.I.N.G. 99. Onkologie 31 (12): 657-63, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/19060503" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19060503</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_35">Wong T, Goldsby RE, Wustrack R, et al.: Clinical features and outcomes of infants with Ewing sarcoma under 12 months of age. Pediatr Blood Cancer 62 (11): 1947-51, 2015. [<a href="https://pubmed.ncbi.nlm.nih.gov/26173989" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26173989</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_36">Worch J, Ranft A, DuBois SG, et al.: Age dependency of primary tumor sites and metastases in patients with Ewing sarcoma. Pediatr Blood Cancer 65 (9): e27251, 2018. [<a href="https://pubmed.ncbi.nlm.nih.gov/29856530" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 29856530</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_37">Miser JS, Krailo MD, Tarbell NJ, et al.: Treatment of metastatic Ewing's sarcoma or primitive neuroectodermal tumor of bone: evaluation of combination ifosfamide and etoposide--a Children's Cancer Group and Pediatric Oncology Group study. J Clin Oncol 22 (14): 2873-6, 2004. [<a href="https://pubmed.ncbi.nlm.nih.gov/15254055" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15254055</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_38">Paulussen M, Ahrens S, Craft AW, et al.: Ewing's tumors with primary lung metastases: survival analysis of 114 (European Intergroup) Cooperative Ewing's Sarcoma Studies patients. J Clin Oncol 16 (9): 3044-52, 1998. [<a href="https://pubmed.ncbi.nlm.nih.gov/9738574" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9738574</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_39">Paulussen M, Ahrens S, Burdach S, et al.: Primary metastatic (stage IV) Ewing tumor: survival analysis of 171 patients from the EICESS studies. European Intergroup Cooperative Ewing Sarcoma Studies. Ann Oncol 9 (3): 275-81, 1998. [<a href="https://pubmed.ncbi.nlm.nih.gov/9602261" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9602261</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_40">Ladenstein R, Pötschger U, Le Deley MC, et al.: Primary disseminated multifocal Ewing sarcoma: results of the Euro-EWING 99 trial. J Clin Oncol 28 (20): 3284-91, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/20547982" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20547982</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_41">Applebaum MA, Goldsby R, Neuhaus J, et al.: Clinical features and outcomes in patients with Ewing sarcoma and regional lymph node involvement. Pediatr Blood Cancer 59 (4): 617-20, 2012. [<a href="/pmc/articles/PMC3310932/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3310932</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22184129" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22184129</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_42">Schlegel M, Zeumer M, Prodinger PM, et al.: Impact of Pathological Fractures on the Prognosis of Primary Malignant Bone Sarcoma in Children and Adults: A Single-Center Retrospective Study of 205 Patients. Oncology 94 (6): 354-362, 2018. [<a href="https://pubmed.ncbi.nlm.nih.gov/29656296" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 29656296</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_43">Applebaum MA, Goldsby R, Neuhaus J, et al.: Clinical features and outcomes in patients with secondary Ewing sarcoma. Pediatr Blood Cancer 60 (4): 611-5, 2013. [<a href="/pmc/articles/PMC3488141/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3488141</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22847990" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22847990</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_44">Roberts P, Burchill SA, Brownhill S, et al.: Ploidy and karyotype complexity are powerful prognostic indicators in the Ewing's sarcoma family of tumors: a study by the United Kingdom Cancer Cytogenetics and the Children's Cancer and Leukaemia Group. Genes Chromosomes Cancer 47 (3): 207-20, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/18064647" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18064647</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_45">Hattinger CM, Pötschger U, Tarkkanen M, et al.: Prognostic impact of chromosomal aberrations in Ewing tumours. Br J Cancer 86 (11): 1763-9, 2002. [<a href="/pmc/articles/PMC2375399/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2375399</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/12087464" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12087464</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_46">Mackintosh C, Ordóñez JL, García-Domínguez DJ, et al.: 1q gain and CDT2 overexpression underlie an aggressive and highly proliferative form of Ewing sarcoma. Oncogene 31 (10): 1287-98, 2012. [<a href="https://pubmed.ncbi.nlm.nih.gov/21822310" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21822310</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_47">Tirode F, Surdez D, Ma X, et al.: Genomic landscape of Ewing sarcoma defines an aggressive subtype with co-association of STAG2 and TP53 mutations. Cancer Discov 4 (11): 1342-53, 2014. [<a href="/pmc/articles/PMC4264969/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4264969</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25223734" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25223734</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_48">Mrózek K, Bloomfield CD: Der(16)t(1;16) is a secondary chromosome aberration in at least eighteen different types of human cancer. Genes Chromosomes Cancer 23 (1): 78-80, 1998. [<a href="https://pubmed.ncbi.nlm.nih.gov/9714002" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9714002</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_49">Mugneret F, Lizard S, Aurias A, et al.: Chromosomes in Ewing's sarcoma. II. Nonrandom additional changes, trisomy 8 and der(16)t(1;16). Cancer Genet Cytogenet 32 (2): 239-45, 1988. [<a href="https://pubmed.ncbi.nlm.nih.gov/3163262" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 3163262</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_50">Hattinger CM, Rumpler S, Ambros IM, et al.: Demonstration of the translocation der(16)t(1;16)(q12;q11.2) in interphase nuclei of Ewing tumors. Genes Chromosomes Cancer 17 (3): 141-50, 1996. [<a href="https://pubmed.ncbi.nlm.nih.gov/8946192" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8946192</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_51">Shulman DS, Klega K, Imamovic-Tuco A, et al.: Detection of circulating tumour DNA is associated with inferior outcomes in Ewing sarcoma and osteosarcoma: a report from the Children's Oncology Group. Br J Cancer 119 (5): 615-621, 2018. [<a href="/pmc/articles/PMC6162271/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6162271</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/30131550" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30131550</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_52">Schleiermacher G, Peter M, Oberlin O, et al.: Increased risk of systemic relapses associated with bone marrow micrometastasis and circulating tumor cells in localized ewing tumor. J Clin Oncol 21 (1): 85-91, 2003. [<a href="https://pubmed.ncbi.nlm.nih.gov/12506175" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12506175</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_53">Vo KT, Edwards JV, Epling CL, et al.: Impact of Two Measures of Micrometastatic Disease on Clinical Outcomes in Patients with Newly Diagnosed Ewing Sarcoma: A Report from the Children's Oncology Group. Clin Cancer Res 22 (14): 3643-50, 2016. [<a href="/pmc/articles/PMC4947459/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4947459</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26861456" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26861456</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_54">Lerman DM, Monument MJ, McIlvaine E, et al.: Tumoral TP53 and/or CDKN2A alterations are not reliable prognostic biomarkers in patients with localized Ewing sarcoma: a report from the Children's Oncology Group. Pediatr Blood Cancer 62 (5): 759-65, 2015. [<a href="/pmc/articles/PMC4376595/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4376595</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25464386" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25464386</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_55">Parham DM, Hijazi Y, Steinberg SM, et al.: Neuroectodermal differentiation in Ewing's sarcoma family of tumors does not predict tumor behavior. Hum Pathol 30 (8): 911-8, 1999. [<a href="https://pubmed.ncbi.nlm.nih.gov/10452503" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10452503</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_56">Luksch R, Sampietro G, Collini P, et al.: Prognostic value of clinicopathologic characteristics including neuroectodermal differentiation in osseous Ewing's sarcoma family of tumors in children. Tumori 85 (2): 101-7, 1999 Mar-Apr. [<a href="https://pubmed.ncbi.nlm.nih.gov/10363075" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10363075</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_57">de Alava E, Kawai A, Healey JH, et al.: EWS-FLI1 fusion transcript structure is an independent determinant of prognosis in Ewing's sarcoma. J Clin Oncol 16 (4): 1248-55, 1998. [<a href="https://pubmed.ncbi.nlm.nih.gov/9552022" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9552022</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_58">van Doorninck JA, Ji L, Schaub B, et al.: Current treatment protocols have eliminated the prognostic advantage of type 1 fusions in Ewing sarcoma: a report from the Children's Oncology Group. J Clin Oncol 28 (12): 1989-94, 2010. [<a href="/pmc/articles/PMC2860404/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2860404</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20308669" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20308669</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_59">Le Deley MC, Delattre O, Schaefer KL, et al.: Impact of EWS-ETS fusion type on disease progression in Ewing's sarcoma/peripheral primitive neuroectodermal tumor: prospective results from the cooperative Euro-E.W.I.N.G. 99 trial. J Clin Oncol 28 (12): 1982-8, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/20308673" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20308673</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_60">Paulussen M, Ahrens S, Dunst J, et al.: Localized Ewing tumor of bone: final results of the cooperative Ewing's Sarcoma Study CESS 86. J Clin Oncol 19 (6): 1818-29, 2001. [<a href="https://pubmed.ncbi.nlm.nih.gov/11251014" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11251014</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_61">Rosito P, Mancini AF, Rondelli R, et al.: Italian Cooperative Study for the treatment of children and young adults with localized Ewing sarcoma of bone: a preliminary report of 6 years of experience. Cancer 86 (3): 421-8, 1999. [<a href="https://pubmed.ncbi.nlm.nih.gov/10430250" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10430250</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_62">Wunder JS, Paulian G, Huvos AG, et al.: The histological response to chemotherapy as a predictor of the oncological outcome of operative treatment of Ewing sarcoma. J Bone Joint Surg Am 80 (7): 1020-33, 1998. [<a href="https://pubmed.ncbi.nlm.nih.gov/9698007" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9698007</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_63">Oberlin O, Deley MC, Bui BN, et al.: Prognostic factors in localized Ewing's tumours and peripheral neuroectodermal tumours: the third study of the French Society of Paediatric Oncology (EW88 study). Br J Cancer 85 (11): 1646-54, 2001. [<a href="/pmc/articles/PMC2363978/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2363978</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/11742482" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11742482</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_64">Ferrari S, Bertoni F, Palmerini E, et al.: Predictive factors of histologic response to primary chemotherapy in patients with Ewing sarcoma. J Pediatr Hematol Oncol 29 (6): 364-8, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17551396" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17551396</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_65">Hawkins DS, Schuetze SM, Butrynski JE, et al.: [18F]Fluorodeoxyglucose positron emission tomography predicts outcome for Ewing sarcoma family of tumors. J Clin Oncol 23 (34): 8828-34, 2005. [<a href="https://pubmed.ncbi.nlm.nih.gov/16314643" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16314643</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_66">Denecke T, Hundsdörfer P, Misch D, et al.: Assessment of histological response of paediatric bone sarcomas using FDG PET in comparison to morphological volume measurement and standardized MRI parameters. Eur J Nucl Med Mol Imaging 37 (10): 1842-53, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/20505933" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20505933</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_67">Palmerini E, Colangeli M, Nanni C, et al.: The role of FDG PET/CT in patients treated with neoadjuvant chemotherapy for localized bone sarcomas. Eur J Nucl Med Mol Imaging 44 (2): 215-223, 2017. [<a href="/pmc/articles/PMC5215266/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5215266</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/27645694" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27645694</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_68">Lin PP, Jaffe N, Herzog CE, et al.: Chemotherapy response is an important predictor of local recurrence in Ewing sarcoma. Cancer 109 (3): 603-11, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17177205" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17177205</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_69">Bosma SE, Rueten-Budde AJ, Lancia C, et al.: Individual risk evaluation for local recurrence and distant metastasis in Ewing sarcoma: A multistate model: A multistate model for Ewing sarcoma. Pediatr Blood Cancer 66 (11): e27943, 2019. [<a href="https://pubmed.ncbi.nlm.nih.gov/31389188" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 31389188</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_70">Dubois SG, Epling CL, Teague J, et al.: Flow cytometric detection of Ewing sarcoma cells in peripheral blood and bone marrow. Pediatr Blood Cancer 54 (1): 13-8, 2010. [<a href="/pmc/articles/PMC2846759/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2846759</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19711435" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19711435</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_71">Zoubek A, Ladenstein R, Windhager R, et al.: Predictive potential of testing for bone marrow involvement in Ewing tumor patients by RT-PCR: a preliminary evaluation. Int J Cancer 79 (1): 56-60, 1998. [<a href="https://pubmed.ncbi.nlm.nih.gov/9495359" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9495359</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_72">Shukla NN, Patel JA, Magnan H, et al.: Plasma DNA-based molecular diagnosis, prognostication, and monitoring of patients with EWSR1 fusion-positive sarcomas. JCO Precis Oncol 2017: , 2017. [<a href="/pmc/articles/PMC5881916/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5881916</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/29629425" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 29629425</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_73">Klega K, Imamovic-Tuco A, Ha G, et al.: Detection of Somatic Structural Variants Enables Quantification and Characterization of Circulating Tumor DNA in Children With Solid Tumors. JCO Precis Oncol 2018: , 2018. [<a href="/pmc/articles/PMC6049092/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6049092</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/30027144" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30027144</span></a>]</div></li></ol></div></div><div id="CDR0000062841__15"><h2 id="_CDR0000062841__15_">Cellular Classification of Ewing Sarcoma</h2><p id="CDR0000062841__16"> Ewing sarcoma belongs to the group of neoplasms
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commonly referred to as small round blue cell tumors of childhood. The individual cells of Ewing sarcoma contain round-to-oval nuclei, with fine dispersed chromatin without nucleoli. Occasionally, cells with smaller, more hyperchromatic, and probably degenerative nuclei are present, giving a light cell/dark cell pattern. The cytoplasm varies in amount, but in the classic case, it is clear and contains glycogen, which can be highlighted with a periodic acid-Schiff stain. The tumor cells are tightly packed and grow in a diffuse pattern without evidence of structural organization. Tumors with the requisite translocation that show neuronal differentiation are not considered a separate entity, but rather, part of a continuum of differentiation.</p><p id="CDR0000062841__323">CD99 is a surface membrane protein that is expressed in most
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cases of Ewing sarcoma and is useful in diagnosing these tumors when the results are interpreted in the context of clinical and
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pathologic parameters.[<a class="bk_pop" href="#CDR0000062841_rl_15_1">1</a>] CD99 positivity is not unique to Ewing sarcoma, and
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positivity by immunochemistry is found in several other tumors, including
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synovial sarcoma, non-Hodgkin lymphoma, and gastrointestinal stromal tumors.</p><p id="CDR0000062841__2009">(Refer to the <a href="#CDR0000062841__1910">Undifferentiated Small Round Cell [Ewing-like] Sarcomas</a> section of this summary for more information about the cellular classification of other undifferentiated small round cell sarcomas.)</p><div id="CDR0000062841_rl_15"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000062841_rl_15_1">Parham DM, Hijazi Y, Steinberg SM, et al.: Neuroectodermal differentiation in Ewing's sarcoma family of tumors does not predict tumor behavior. Hum Pathol 30 (8): 911-8, 1999. [<a href="https://pubmed.ncbi.nlm.nih.gov/10452503" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10452503</span></a>]</div></li></ol></div></div><div id="CDR0000062841__624"><h2 id="_CDR0000062841__624_">Genomics of Ewing Sarcoma</h2><div id="CDR0000062841__sm_CDR0000777838_13"><h3>Molecular Features of Ewing Sarcoma</h3><p id="CDR0000062841__sm_CDR0000777838_15">The detection of a translocation involving the <i>EWSR1</i> gene on chromosome 22 band q12 and any one of a number of partner chromosomes is the key feature in the diagnosis of Ewing sarcoma (refer to Table 2).[<a class="bk_pop" href="#CDR0000062841_rl_624_1">1</a>] The <i>EWSR1</i> gene is a member of the TET family [TLS/EWS/TAF15] of RNA-binding proteins.[<a class="bk_pop" href="#CDR0000062841_rl_624_2">2</a>] The <i>FLI1</i> gene is a member of the ETS family of DNA-binding genes. Characteristically, the amino terminus of the <i>EWSR1</i>
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gene is juxtaposed with the carboxy terminus of the ETS family genes. In most cases (90%), the carboxy terminus is provided by <i>FLI1</i>, a member of
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the family of transcription factor genes located on chromosome 11 band q24.
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Other family members that may combine with the <i>EWSR1</i> gene are <i>ERG</i>, <i>ETV1</i>, <i>ETV4</i>, and <i>FEV</i>.[<a class="bk_pop" href="#CDR0000062841_rl_624_3">3</a>] Rarely, <i>FUS</i>, another TET family member, can substitute for <i>EWSR1</i>.[<a class="bk_pop" href="#CDR0000062841_rl_624_4">4</a>] Finally, there are a few rare cases in which <i>EWSR1</i> has translocated with partners that are not members of the ETS family of oncogenes. The significance of these alternate partners is not known.</p><p id="CDR0000062841__sm_CDR0000777838_387">Besides these
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consistent aberrations involving the <i>EWSR1</i> gene at 22q12, additional numerical
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and structural aberrations have been observed in Ewing sarcoma, including gains of
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chromosomes 2, 5, 8, 9, 12, and 15; the nonreciprocal translocation
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t(1;16)(q12;q11.2); and deletions on the short arm of chromosome 6. Trisomy 20 may be associated with a more aggressive subset of Ewing sarcoma.[<a class="bk_pop" href="#CDR0000062841_rl_624_5">5</a>]</p><p id="CDR0000062841__sm_CDR0000777838_388">Three papers have described the genomic landscape of Ewing sarcoma and all show that these tumors have a relatively silent genome, with a paucity of mutations in pathways that might be amenable to treatment with novel targeted therapies.[<a class="bk_pop" href="#CDR0000062841_rl_624_6">6</a>-<a class="bk_pop" href="#CDR0000062841_rl_624_8">8</a>] These papers identified recurring genomic alterations in several genes:</p><ul id="CDR0000062841__sm_CDR0000777838_1894"><li class="half_rhythm"><div><b><i>STAG2</i> mutations.</b> Mutations in <i>STAG2</i>, a member of the cohesin complex, occur in about 15% to 20% of the cases, and the presence of these mutations was associated with advanced-stage disease. </div></li><li class="half_rhythm"><div><b><i>CDKN2A</i> deletions.</b>
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<i>CDKN2A</i> deletions were noted in 12% to 22% of cases. </div></li><li class="half_rhythm"><div><b><i>TP53</i> mutations.</b>
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<i>TP53</i> mutations were identified in about 6% to 7% of cases and the coexistence of <i>STAG2</i> and <i>TP53</i> mutations was associated with a poor clinical outcome.</div></li><li class="half_rhythm"><div><b>Gain of whole chromosome 8 (trisomy 8).</b> The most frequent chromosomal alteration in Ewing sarcoma is gain of whole chromosome 8 (trisomy 8), occurring in close to 50% of tumors.[<a class="bk_pop" href="#CDR0000062841_rl_624_6">6</a>,<a class="bk_pop" href="#CDR0000062841_rl_624_7">7</a>]</div></li><li class="half_rhythm"><div><b>Gain of chromosome 1q and loss of chromosome 16q.</b> Gain of chromosome 1q and loss of chromosome 16q occur in approximately 20% of patients and often occur together. Chromosome 1q gain and chromosome 16q loss were each associated with inferior prognosis, when analyzed as single factors and when co-occurring.[<a class="bk_pop" href="#CDR0000062841_rl_624_6">6</a>] These two chromosomal alterations commonly occur together across a range of cancer types, including Ewing sarcoma.[<a class="bk_pop" href="#CDR0000062841_rl_624_9">9</a>] Their co-occurrence is likely a result of their derivation from an unbalanced t(1;16) translocation resulting in gain of chromosome 1q together with loss of chromosomal material from 16q.[<a class="bk_pop" href="#CDR0000062841_rl_624_10">10</a>,<a class="bk_pop" href="#CDR0000062841_rl_624_11">11</a>]</div></li></ul><p id="CDR0000062841__sm_CDR0000777838_389">Figure 1 below from a discovery cohort (n = 99) highlights the frequency of chromosome 8 gain, the co-occurrence of chromosome 1q gain and chromosome 16q loss, the mutual exclusivity of <i>CDKN2A</i> deletion and <i>STAG2</i> mutation, and the relative paucity of recurrent single nucleotide variants for Ewing sarcoma.[<a class="bk_pop" href="#CDR0000062841_rl_624_6">6</a>]</p><a id="CDR0000062841__sm_CDR0000777838_393"></a>
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<div id="CDR0000062841__sm_CDR0000777838_394" class="figure bk_fig"><div class="graphic"><img src="/books/NBK66045.23/bin/CDR0000777901.jpg" alt="Chart showing a comprehensive profile of the genetic abnormalities in Ewing sarcoma and associated clinical information." /></div><div class="caption"><p>Figure 1. A comprehensive profile of the genetic abnormalities in Ewing sarcoma and associated clinical information. Key clinical characteristics are indicated, including primary site, type of tissue, and metastatic status at diagnosis, follow-up, and last news. Below is the consistency of detection of gene fusions by RT-PCR and whole-genome sequencing (WGS). The numbers of structural variants (SV) and single-nucleotide variants (SNV) as well as indels are reported in grayscale. The presence of the main copy-number changes, chr 1q gain, chr 16 loss, chr 8 gain, chr 12 gain, and interstitial <i>CDKN2A</i> deletion is indicated. Listed last are the most significant mutations and their types. For gene mutations, “others” refers to: duplication of exon 22 leading to frameshift (<i>STAG2</i>), deletion of exon 2 to 11 (<i>BCOR</i>), and deletion of exons 1 to 6 (<i>ZMYM3</i>). Reprinted from Cancer Discovery, Copyright 2014, 4 (11), 1342–53, Tirode F, Surdez D, Ma X, et al., Genomic Landscape of Ewing Sarcoma Defines an Aggressive Subtype with Co-Association of <i>STAG2</i> and <i>TP53</i> mutations, with permission from AACR.</p></div></div>
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<p id="CDR0000062841__sm_CDR0000777838_390">Ewing sarcoma translocations can all be found with standard cytogenetic analysis. A more rapid analysis looking for a break apart of the <i>EWSR1</i> gene is now frequently done to confirm the diagnosis of Ewing sarcoma molecularly.[<a class="bk_pop" href="#CDR0000062841_rl_624_12">12</a>] This test result must be considered with caution, however. Ewing sarcomas that utilize <i>FUS</i> translocations will have negative tests because the <i>EWSR1</i> gene is not translocated in those cases. In addition, other small round tumors also contain translocations of different ETS family members with <i>EWSR1</i>, such as desmoplastic small round cell tumor, clear cell sarcoma, extraskeletal myxoid chondrosarcoma, and myxoid liposarcoma, all of which may be positive with a <i>EWSR1</i> fluorescence <i>in situ</i> hybridization (FISH) break-apart probe. A detailed analysis of 85 patients with small round blue cell tumors that were negative for <i>EWSR1</i> rearrangement by FISH with an <i>EWSR1</i> break-apart probe identified eight patients with <i>FUS</i> rearrangements.[<a class="bk_pop" href="#CDR0000062841_rl_624_13">13</a>] Four patients who had <i>EWSR1-ERG</i> fusions were not detected by FISH with an <i>EWSR1</i> break-apart probe. The authors do not recommend relying solely on <i>EWSR1</i> break-apart probes for analyzing small round blue cell tumors with strong immunohistochemical positivity for CD99.</p><p id="CDR0000062841__sm_CDR0000777838_1889">Undifferentiated small blue round cell sarcomas with the <i>EWSR1-NFATC2</i> fusion have been studied with DNA methylation profiling; this revealed a homogeneous methylation cluster for these sarcomas with <i>EWSR1-NFATC2</i> fusions, which clearly segregated them from the more common form of Ewing sarcoma with <i>EWS-ETS</i> translocations.[<a class="bk_pop" href="#CDR0000062841_rl_624_14">14</a>]</p><p id="CDR0000062841__sm_CDR0000777838_391">Small round blue cell tumors of bone and soft tissue that are histologically similar to Ewing sarcoma but do not have rearrangements of the <i>EWSR1</i> gene have been analyzed and translocations have been identified. These include <i>BCOR-CCNB3</i>, <i>CIC-DUX4</i>, and <i>CIC-FOX4</i>.[<a class="bk_pop" href="#CDR0000062841_rl_624_15">15</a>-<a class="bk_pop" href="#CDR0000062841_rl_624_18">18</a>] The molecular profile of these tumors is different from the profile of Ewing sarcoma with the <i>EWS-FLI1</i> translocation, and limited evidence suggests that they have a different clinical behavior. In almost all cases, the patients were treated with therapy designed for Ewing sarcoma on the basis of the histologic and immunohistologic similarity to Ewing sarcoma (refer to the <a href="#CDR0000062841__1911">Undifferentiated Small Round Cell Sarcomas With <i>BCOR</i> Genetic Alterations</a> and <a href="#CDR0000062841__1916">Undifferentiated Small Round Cell Sarcomas With <i>CIC</i> Genetic Alterations</a> sections of this summary for more information). There are too few cases associated with each translocation to determine whether the prognosis for patients with these small round blue cell tumors is distinct from the prognosis of patients with Ewing sarcoma of similar stage and site.[<a class="bk_pop" href="#CDR0000062841_rl_624_15">15</a>-<a class="bk_pop" href="#CDR0000062841_rl_624_18">18</a>]</p><p id="CDR0000062841__sm_CDR0000777838_1887">Some undifferentiated round cell sarcomas are characterized by paracentric inversion of chromosome X and a <i>BCOR-CCNB3</i> rearrangement; alternative <i>BCOR</i> partners, including <i>MAML3</i> and <i>ZC3H7B</i>, have also been reported.[<a class="bk_pop" href="#CDR0000062841_rl_624_19">19</a>] Despite clinical pathologic similarities to Ewing sarcoma, these tumors are biologically different by expression profiling and single-nucleotide polymorphism array analysis. (Refer to the <a href="#CDR0000062841__1911">Undifferentiated Small Round Cell Sarcomas With <i>BCOR</i> Genetic Alterations</a> section of this summary for more information about the treatment of this disease.)</p><p id="CDR0000062841__sm_CDR0000777838_1888">Other undifferentiated round cell sarcomas are characterized by a <i>CIC-DUX4</i> fusion resulting from a recurrent t(4;19) or t(10;19). They are the most common <i>EWSR1</i> fusion–negative and <i>FUS</i> fusion–negative undifferentiated round cell sarcomas.[<a class="bk_pop" href="#CDR0000062841_rl_624_20">20</a>] (Refer to the <a href="#CDR0000062841__1916">Undifferentiated Small Round Cell Sarcomas With <i>CIC</i> Genetic Alterations</a> section of this summary for more information about the treatment of this disease.)</p><p id="CDR0000062841__sm_CDR0000777838_392">Genome-wide association studies have identified susceptibility loci for Ewing sarcoma at 1p36.22, 10q21, and 15q15.[<a class="bk_pop" href="#CDR0000062841_rl_624_21">21</a>-<a class="bk_pop" href="#CDR0000062841_rl_624_23">23</a>] Deep sequencing through the 10q21.3 region identified a polymorphism in the <i>EGR2</i> gene, which appears to cooperate with and magnify the enhanced activity of the gene product of the <i>EWSR1-FLI1</i> fusion that is seen in most patients with Ewing sarcoma.[<a class="bk_pop" href="#CDR0000062841_rl_624_22">22</a>] The polymorphism associated with the increased risk is found at a much higher frequency in White people than in Black or Asian people, possibly contributing to the epidemiology of the relative infrequency of Ewing sarcoma in the latter populations. Three new susceptibility loci have been identified at 6p25.1, 20p11.22, and 20p11.23.[<a class="bk_pop" href="#CDR0000062841_rl_624_23">23</a>]</p><div id="CDR0000062841__sm_CDR0000777838_386" class="table"><h3><span class="title">Table 2. <i>EWSR1</i> and <i>FUS</i> Fusions and Translocations in Ewing Sarcoma</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK66045.23/table/CDR0000062841__sm_CDR0000777838_386/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__CDR0000062841__sm_CDR0000777838_386_lrgtbl__"><table class="no_margin"><thead><tr><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">TET Family Partner </th><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">Fusion With ETS-like Oncogene Partner </th><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">Translocation</th><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">Comment</th></tr></thead><tbody><tr><td colspan="1" rowspan="10" style="vertical-align:top;">
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<i>EWSR1</i>
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">
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<i>EWSR1-FLI1</i>
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">t(11;22)(q24;q12)</td><td colspan="1" rowspan="1" style="vertical-align:top;">Most common; ~85% to 90% of cases</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">
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<i>EWSR1-ERG</i>
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">t(21;22)(q22;q12)</td><td colspan="1" rowspan="1" style="vertical-align:top;">Second most common; ~10% of cases</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">
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<i>EWSR1-ETV1</i>
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">t(7;22)(p22;q12)</td><td colspan="1" rowspan="1" style="vertical-align:top;">Rare</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">
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<i>EWSR1-ETV4</i>
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">t(17;22)(q12;q12)</td><td colspan="1" rowspan="1" style="vertical-align:top;">Rare</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">
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<i>EWSR1-FEV</i>
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">t(2;22)(q35;q12)</td><td colspan="1" rowspan="1" style="vertical-align:top;">Rare</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">
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<i>EWSR1-NFATC2<sup>a</sup></i>
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">t(20;22)(q13;q12)</td><td colspan="1" rowspan="1" style="vertical-align:top;">Rare</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">
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<i>EWSR1-POU5F1<sup>a</sup></i>
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">t(6;22)(p21;q12)</td><td colspan="1" rowspan="1" style="vertical-align:top;"></td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">
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<i>EWSR1-SMARCA5<sup>a</sup></i>
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">t(4;22)(q31;q12)</td><td colspan="1" rowspan="1" style="vertical-align:top;">Rare</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">
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<i>EWSR1-PATZ1<sup>a</sup></i>
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">t(6;22)(p21;q12)</td><td colspan="1" rowspan="1" style="vertical-align:top;"></td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">
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<i>EWSR1-SP3<sup>a</sup></i>
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">t(2;22)(q31;q12)</td><td colspan="1" rowspan="1" style="vertical-align:top;">Rare</td></tr><tr><td colspan="1" rowspan="2" style="vertical-align:top;">
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<i>FUS</i>
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">
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<i>FUS-ERG</i>
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">t(16;21)(p11;q22)</td><td colspan="1" rowspan="1" style="vertical-align:top;">Rare</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">
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<i>FUS-FEV</i>
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">t(2;16)(q35;p11)</td><td colspan="1" rowspan="1" style="vertical-align:top;">Rare</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin"><sup>a</sup>These partners are not members of the ETS family of oncogenes.</p></div></dd></dl></div></div></div></div><div id="CDR0000062841_rl_624"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000062841_rl_624_1">Delattre O, Zucman J, Melot T, et al.: The Ewing family of tumors--a subgroup of small-round-cell tumors defined by specific chimeric transcripts. N Engl J Med 331 (5): 294-9, 1994. [<a href="https://pubmed.ncbi.nlm.nih.gov/8022439" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8022439</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_624_2">Urano F, Umezawa A, Yabe H, et al.: Molecular analysis of Ewing's sarcoma: another fusion gene, EWS-E1AF, available for diagnosis. Jpn J Cancer Res 89 (7): 703-11, 1998. [<a href="/pmc/articles/PMC5921883/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5921883</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/9738976" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9738976</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_624_3">Hattinger CM, Rumpler S, Strehl S, et al.: Prognostic impact of deletions at 1p36 and numerical aberrations in Ewing tumors. Genes Chromosomes Cancer 24 (3): 243-54, 1999. [<a href="https://pubmed.ncbi.nlm.nih.gov/10451705" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10451705</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_624_4">Sankar S, Lessnick SL: Promiscuous partnerships in Ewing's sarcoma. Cancer Genet 204 (7): 351-65, 2011. [<a href="/pmc/articles/PMC3164520/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3164520</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21872822" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21872822</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_624_5">Roberts P, Burchill SA, Brownhill S, et al.: Ploidy and karyotype complexity are powerful prognostic indicators in the Ewing's sarcoma family of tumors: a study by the United Kingdom Cancer Cytogenetics and the Children's Cancer and Leukaemia Group. Genes Chromosomes Cancer 47 (3): 207-20, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/18064647" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18064647</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_624_6">Tirode F, Surdez D, Ma X, et al.: Genomic landscape of Ewing sarcoma defines an aggressive subtype with co-association of STAG2 and TP53 mutations. Cancer Discov 4 (11): 1342-53, 2014. [<a href="/pmc/articles/PMC4264969/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4264969</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25223734" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25223734</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_624_7">Crompton BD, Stewart C, Taylor-Weiner A, et al.: The genomic landscape of pediatric Ewing sarcoma. Cancer Discov 4 (11): 1326-41, 2014. [<a href="https://pubmed.ncbi.nlm.nih.gov/25186949" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25186949</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_624_8">Brohl AS, Solomon DA, Chang W, et al.: The genomic landscape of the Ewing Sarcoma family of tumors reveals recurrent STAG2 mutation. PLoS Genet 10 (7): e1004475, 2014. [<a href="/pmc/articles/PMC4091782/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4091782</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25010205" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25010205</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_624_9">Mrózek K, Bloomfield CD: Der(16)t(1;16) is a secondary chromosome aberration in at least eighteen different types of human cancer. Genes Chromosomes Cancer 23 (1): 78-80, 1998. [<a href="https://pubmed.ncbi.nlm.nih.gov/9714002" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9714002</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_624_10">Mugneret F, Lizard S, Aurias A, et al.: Chromosomes in Ewing's sarcoma. II. Nonrandom additional changes, trisomy 8 and der(16)t(1;16). Cancer Genet Cytogenet 32 (2): 239-45, 1988. [<a href="https://pubmed.ncbi.nlm.nih.gov/3163262" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 3163262</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_624_11">Hattinger CM, Rumpler S, Ambros IM, et al.: Demonstration of the translocation der(16)t(1;16)(q12;q11.2) in interphase nuclei of Ewing tumors. Genes Chromosomes Cancer 17 (3): 141-50, 1996. [<a href="https://pubmed.ncbi.nlm.nih.gov/8946192" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8946192</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_624_12">Monforte-Muñoz H, Lopez-Terrada D, Affendie H, et al.: Documentation of EWS gene rearrangements by fluorescence in-situ hybridization (FISH) in frozen sections of Ewing's sarcoma-peripheral primitive neuroectodermal tumor. Am J Surg Pathol 23 (3): 309-15, 1999. [<a href="https://pubmed.ncbi.nlm.nih.gov/10078922" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10078922</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_624_13">Chen S, Deniz K, Sung YS, et al.: Ewing sarcoma with ERG gene rearrangements: A molecular study focusing on the prevalence of FUS-ERG and common pitfalls in detecting EWSR1-ERG fusions by FISH. Genes Chromosomes Cancer 55 (4): 340-9, 2016. [<a href="/pmc/articles/PMC5006947/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5006947</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26690869" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26690869</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_624_14">Koelsche C, Kriegsmann M, Kommoss FKF, et al.: DNA methylation profiling distinguishes Ewing-like sarcoma with EWSR1-NFATc2 fusion from Ewing sarcoma. J Cancer Res Clin Oncol 145 (5): 1273-1281, 2019. [<a href="/pmc/articles/PMC7607515/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7607515</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/30895378" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30895378</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_624_15">Pierron G, Tirode F, Lucchesi C, et al.: A new subtype of bone sarcoma defined by BCOR-CCNB3 gene fusion. Nat Genet 44 (4): 461-6, 2012. [<a href="https://pubmed.ncbi.nlm.nih.gov/22387997" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22387997</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_624_16">Specht K, Sung YS, Zhang L, et al.: Distinct transcriptional signature and immunoprofile of CIC-DUX4 fusion-positive round cell tumors compared to EWSR1-rearranged Ewing sarcomas: further evidence toward distinct pathologic entities. Genes Chromosomes Cancer 53 (7): 622-33, 2014. [<a href="/pmc/articles/PMC4108073/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4108073</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24723486" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24723486</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_624_17">Sugita S, Arai Y, Tonooka A, et al.: A novel CIC-FOXO4 gene fusion in undifferentiated small round cell sarcoma: a genetically distinct variant of Ewing-like sarcoma. Am J Surg Pathol 38 (11): 1571-6, 2014. [<a href="https://pubmed.ncbi.nlm.nih.gov/25007147" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25007147</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_624_18">Cohen-Gogo S, Cellier C, Coindre JM, et al.: Ewing-like sarcomas with BCOR-CCNB3 fusion transcript: a clinical, radiological and pathological retrospective study from the Société Française des Cancers de L'Enfant. Pediatr Blood Cancer 61 (12): 2191-8, 2014. [<a href="https://pubmed.ncbi.nlm.nih.gov/25176412" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25176412</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_624_19">Schaefer IM, Fletcher CDM: Recent advances in the diagnosis of soft tissue tumours. Pathology 50 (1): 37-48, 2018. [<a href="https://pubmed.ncbi.nlm.nih.gov/28950990" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28950990</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_624_20">Antonescu CR, Owosho AA, Zhang L, et al.: Sarcomas With CIC-rearrangements Are a Distinct Pathologic Entity With Aggressive Outcome: A Clinicopathologic and Molecular Study of 115 Cases. Am J Surg Pathol 41 (7): 941-949, 2017. [<a href="/pmc/articles/PMC5468475/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5468475</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/28346326" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28346326</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_624_21">Postel-Vinay S, Véron AS, Tirode F, et al.: Common variants near TARDBP and EGR2 are associated with susceptibility to Ewing sarcoma. Nat Genet 44 (3): 323-7, 2012. [<a href="https://pubmed.ncbi.nlm.nih.gov/22327514" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22327514</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_624_22">Grünewald TG, Bernard V, Gilardi-Hebenstreit P, et al.: Chimeric EWSR1-FLI1 regulates the Ewing sarcoma susceptibility gene EGR2 via a GGAA microsatellite. Nat Genet 47 (9): 1073-8, 2015. [<a href="/pmc/articles/PMC4591073/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4591073</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26214589" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26214589</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_624_23">Machiela MJ, Grünewald TGP, Surdez D, et al.: Genome-wide association study identifies multiple new loci associated with Ewing sarcoma susceptibility. Nat Commun 9 (1): 3184, 2018. [<a href="/pmc/articles/PMC6085378/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6085378</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/30093639" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30093639</span></a>]</div></li></ol></div></div><div id="CDR0000062841__22"><h2 id="_CDR0000062841__22_">Stage Information for Ewing Sarcoma</h2><p id="CDR0000062841__392">Pretreatment staging studies for Ewing sarcoma may include the following:</p><ul id="CDR0000062841__393"><li class="half_rhythm"><div>Magnetic resonance imaging (MRI).</div></li><li class="half_rhythm"><div>Computed tomography (CT) scan of the primary site and chest.</div></li><li class="half_rhythm"><div>Positron emission tomography using fluorine F 18-fludeoxyglucose (18F-FDG PET) or 18F-FDG PET-CT.</div></li><li class="half_rhythm"><div>Bone scan.</div></li><li class="half_rhythm"><div>Bone marrow aspiration and biopsy.</div></li></ul><p id="CDR0000062841__131">For patients with confirmed Ewing sarcoma, pretreatment staging studies include MRI and/or CT scan, depending on the primary site. Despite the fact that CT and MRI are both equivalent in terms of staging, use of both imaging modalities may help radiation therapy planning.[<a class="bk_pop" href="#CDR0000062841_rl_22_1">1</a>] Whole-body MRI may provide additional information that could potentially alter therapy planning.[<a class="bk_pop" href="#CDR0000062841_rl_22_2">2</a>] Additional pretreatment staging studies include bone scan and CT scan of the chest. In certain studies, determination of pretreatment tumor volume is an important variable.</p><p id="CDR0000062841__308">Although 18F-FDG PET or 18F-FDG PET-CT are optional staging modalities, they have demonstrated high sensitivity and specificity in Ewing sarcoma and may provide additional information that alters therapy planning. In one institutional study, 18F-FDG PET had a very high correlation with bone scan; the investigators suggested that it could replace bone scan for the initial extent of disease evaluation.[<a class="bk_pop" href="#CDR0000062841_rl_22_3">3</a>] This finding was confirmed in a single-institution retrospective review.[<a class="bk_pop" href="#CDR0000062841_rl_22_4">4</a>] 18F-FDG PET-CT is more accurate than 18F-FDG PET alone in Ewing sarcoma.[<a class="bk_pop" href="#CDR0000062841_rl_22_5">5</a>-<a class="bk_pop" href="#CDR0000062841_rl_22_7">7</a>]</p><p id="CDR0000062841__381">Bone marrow aspiration and biopsy have been considered the standard of care for Ewing sarcoma. However, two retrospective studies showed that for patients (N = 141) who were evaluated by bone scan and/or PET scan and lung CT without evidence of metastases, bone marrow aspirates and biopsies were negative in every case.[<a class="bk_pop" href="#CDR0000062841_rl_22_3">3</a>,<a class="bk_pop" href="#CDR0000062841_rl_22_8">8</a>] A single-institution retrospective review of 504 patients with Ewing sarcoma identified 12 patients with bone marrow metastasis.[<a class="bk_pop" href="#CDR0000062841_rl_22_9">9</a>] Only one patient was found to have bone marrow involvement without any other sites of metastatic disease, for an incidence of 1 per 367 (0.3%) in patients with clinically localized disease. The need for routine use of bone marrow aspirates and biopsies in patients without bone metastases is now in question.</p><p id="CDR0000062841__132">For Ewing sarcoma, the tumor is defined as localized when, by clinical and imaging techniques, there is no spread beyond the primary site or regional lymph node involvement. Continuous extension into adjacent soft tissue may occur. If there is a question of regional lymph node involvement, pathologic confirmation is indicated.</p><div id="CDR0000062841_rl_22"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000062841_rl_22_1">Meyer JS, Nadel HR, Marina N, et al.: Imaging guidelines for children with Ewing sarcoma and osteosarcoma: a report from the Children's Oncology Group Bone Tumor Committee. Pediatr Blood Cancer 51 (2): 163-70, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/18454470" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18454470</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_22_2">Mentzel HJ, Kentouche K, Sauner D, et al.: Comparison of whole-body STIR-MRI and 99mTc-methylene-diphosphonate scintigraphy in children with suspected multifocal bone lesions. Eur Radiol 14 (12): 2297-302, 2004. [<a href="https://pubmed.ncbi.nlm.nih.gov/15243716" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15243716</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_22_3">Newman EN, Jones RL, Hawkins DS: An evaluation of [F-18]-fluorodeoxy-D-glucose positron emission tomography, bone scan, and bone marrow aspiration/biopsy as staging investigations in Ewing sarcoma. Pediatr Blood Cancer 60 (7): 1113-7, 2013. [<a href="https://pubmed.ncbi.nlm.nih.gov/23192939" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23192939</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_22_4">Ulaner GA, Magnan H, Healey JH, et al.: Is methylene diphosphonate bone scan necessary for initial staging of Ewing sarcoma if 18F-FDG PET/CT is performed? AJR Am J Roentgenol 202 (4): 859-67, 2014. [<a href="https://pubmed.ncbi.nlm.nih.gov/24660717" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24660717</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_22_5">Völker T, Denecke T, Steffen I, et al.: Positron emission tomography for staging of pediatric sarcoma patients: results of a prospective multicenter trial. J Clin Oncol 25 (34): 5435-41, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/18048826" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18048826</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_22_6">Gerth HU, Juergens KU, Dirksen U, et al.: Significant benefit of multimodal imaging: PET/CT compared with PET alone in staging and follow-up of patients with Ewing tumors. J Nucl Med 48 (12): 1932-9, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/18006618" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18006618</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_22_7">Treglia G, Salsano M, Stefanelli A, et al.: Diagnostic accuracy of ¹⁸F-FDG-PET and PET/CT in patients with Ewing sarcoma family tumours: a systematic review and a meta-analysis. Skeletal Radiol 41 (3): 249-56, 2012. [<a href="https://pubmed.ncbi.nlm.nih.gov/22072239" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22072239</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_22_8">Kopp LM, Hu C, Rozo B, et al.: Utility of bone marrow aspiration and biopsy in initial staging of Ewing sarcoma. Pediatr Blood Cancer 62 (1): 12-5, 2015. [<a href="https://pubmed.ncbi.nlm.nih.gov/25174337" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25174337</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_22_9">Cesari M, Righi A, Colangeli M, et al.: Bone marrow biopsy in the initial staging of Ewing sarcoma: Experience from a single institution. Pediatr Blood Cancer 66 (6): e27653, 2019. [<a href="https://pubmed.ncbi.nlm.nih.gov/30724024" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30724024</span></a>]</div></li></ol></div></div><div id="CDR0000062841__28"><h2 id="_CDR0000062841__28_">Treatment Option Overview for Ewing Sarcoma</h2><p id="CDR0000062841__1823"> It is important that patients be evaluated by specialists from the appropriate disciplines (e.g.,
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radiologists, chemotherapists, pathologists, surgical or orthopedic oncologists, and
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radiation oncologists) as early as possible.</p><p id="CDR0000062841__29">Appropriate imaging studies of the site are obtained before biopsy. To ensure that the incision is placed in an acceptable location, the surgical or orthopedic
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oncologist who will perform the definitive surgery is involved in the decision regarding biopsy-incision placement. This
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is especially important if it is thought that the lesion can subsequently be totally excised after initial systemic therapy
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or if a limb salvage procedure may be attempted. It is almost never appropriate to attempt a primary resection of Ewing sarcoma. With rare exceptions, Ewing sarcoma is sensitive to chemotherapy and will respond to initial systemic therapy, which makes ultimate surgery easier and safer. Primary surgery incurs the risk of tumor spread to surrounding tissues, which is reduced by the use of initial systemic therapy. Biopsy should be from soft tissue as often as possible to avoid increasing the risk of fracture.[<a class="bk_pop" href="#CDR0000062841_rl_28_1">1</a>] If the initial biopsy sample is obtained from bone, the pathologist must be notified to reserve some tissue without decalcification because decalcification denatures DNA and makes genomic profiling of tumor tissue impossible.[<a class="bk_pop" href="#CDR0000062841_rl_28_2">2</a>] The pathologist is consulted before biopsy/surgery to ensure
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that the incision will not compromise the radiation port and that multiple
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types of adequate tissue samples are obtained. It is important to obtain fresh tissue, whenever possible, for cytogenetics and molecular pathology. A second option is to perform a needle biopsy, as long as adequate tissue is obtained for molecular biology and cytogenetics.[<a class="bk_pop" href="#CDR0000062841_rl_28_3">3</a>]</p><p id="CDR0000062841__608"><a class="figpopup" href="/books/NBK66045.23/table/CDR0000062841__604/?report=objectonly" target="object" rid-figpopup="figCDR0000062841604" rid-ob="figobCDR0000062841604">Table 3</a> describes the treatment options for localized, metastatic, and recurrent Ewing sarcoma.</p><div id="CDR0000062841__604" class="table"><h3><span class="title">Table 3. Standard Treatment Options for Ewing Sarcoma</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK66045.23/table/CDR0000062841__604/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__CDR0000062841__604_lrgtbl__"><table class="no_top_margin"><thead><tr><th colspan="1" rowspan="1" style="vertical-align:top;">Treatment Group</th><th colspan="2" rowspan="1" style="vertical-align:top;">Standard Treatment Options</th></tr></thead><tbody><tr><td colspan="1" rowspan="5" style="vertical-align:top;">Localized Ewing sarcoma</td><td colspan="2" rowspan="1" style="vertical-align:top;">
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<a href="#CDR0000062841__410">Chemotherapy</a>
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</td></tr><tr><td colspan="2" rowspan="1" style="vertical-align:top;"><a href="#CDR0000062841__413">Local-control measures</a>:</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;">
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<a href="#CDR0000062841__415">Surgery</a>
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</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;"><a href="#CDR0000062841__422">Radiation therapy</a>
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</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;">
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<a href="#CDR0000062841__1811">High-dose chemotherapy and autologous stem cell rescue</a>
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</td></tr><tr><td colspan="1" rowspan="3" style="vertical-align:top;">Metastatic Ewing sarcoma</td><td colspan="2" rowspan="1" style="vertical-align:top;">
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<a href="#CDR0000062841__430">Chemotherapy</a>
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</td></tr><tr><td colspan="2" rowspan="1" style="vertical-align:top;">
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<a href="#CDR0000062841__433">Surgery</a>
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</td></tr><tr><td colspan="2" rowspan="1" style="vertical-align:top;">
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<a href="#CDR0000062841__433">Radiation therapy</a>
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</td></tr><tr><td colspan="1" rowspan="5" style="vertical-align:top;">Recurrent Ewing sarcoma</td><td colspan="2" rowspan="1" style="vertical-align:top;"><a href="#CDR0000062841__447">Chemotherapy</a> (not considered standard treatment)</td></tr><tr><td colspan="2" rowspan="1" style="vertical-align:top;"><a href="#CDR0000062841__1987">Surgery</a> (not considered standard treatment)</td></tr><tr><td colspan="2" rowspan="1" style="vertical-align:top;"><a href="#CDR0000062841__451">Radiation therapy</a> (not considered standard treatment)</td></tr><tr><td colspan="2" rowspan="1" style="vertical-align:top;"><a href="#CDR0000062841__1854">High-dose chemotherapy with stem cell support</a> (not considered standard treatment)</td></tr><tr><td colspan="2" rowspan="1" style="vertical-align:top;"><a href="#CDR0000062841__452">Other therapies</a> (not considered standard treatment)</td></tr></tbody></table></div></div><p id="CDR0000062841__133">The successful treatment of patients with Ewing sarcoma requires systemic chemotherapy [<a class="bk_pop" href="#CDR0000062841_rl_28_4">4</a>-<a class="bk_pop" href="#CDR0000062841_rl_28_10">10</a>] in conjunction with surgery and/or radiation therapy for local tumor control.[<a class="bk_pop" href="#CDR0000062841_rl_28_11">11</a>-<a class="bk_pop" href="#CDR0000062841_rl_28_15">15</a>] In general, patients receive chemotherapy before instituting local-control measures. In patients who undergo surgery, surgical margins and histologic response are considered in planning postoperative therapy. Patients with metastatic disease often have a good initial response to preoperative chemotherapy, but in most cases, the disease is only partially controlled or recurs.[<a class="bk_pop" href="#CDR0000062841_rl_28_16">16</a>-<a class="bk_pop" href="#CDR0000062841_rl_28_21">21</a>] Patients with lung as the only metastatic site have a better prognosis than do patients with metastases to bone and/or bone marrow. Adequate local control for metastatic sites, particularly bone metastases, may be an important issue.[<a class="bk_pop" href="#CDR0000062841_rl_28_22">22</a>]</p><div id="CDR0000062841__134"><h3>Chemotherapy for Ewing Sarcoma</h3><p id="CDR0000062841__135">Multidrug chemotherapy for Ewing sarcoma always includes vincristine, doxorubicin, ifosfamide, and etoposide. Most protocols also use cyclophosphamide and some incorporate dactinomycin. The mode of administration and dose intensity of cyclophosphamide within courses differs markedly between protocols. A European Intergroup Cooperative Ewing Sarcoma Study (EICESS) trial suggested that 1.2 g of cyclophosphamide produced a similar event-free survival (EFS) compared with 6 g of ifosfamide in patients with lower-risk disease, and identified a trend toward better EFS for patients with localized Ewing sarcoma and higher-risk disease when treatment included etoposide (<a href="https://www.cancer.gov/clinicaltrials/NCT00002516" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">GER-GPOH-EICESS-92 [NCT00002516]</a>).[<a class="bk_pop" href="#CDR0000062841_rl_28_23">23</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335125/" class="def">Level of evidence: 1iiA</a>] </p><p id="CDR0000062841__394">Protocols in the United States generally alternate courses of vincristine, cyclophosphamide, and doxorubicin (VDC) with courses of ifosfamide and etoposide (IE),[<a class="bk_pop" href="#CDR0000062841_rl_28_8">8</a>] while, for many years, European protocols generally combined vincristine, doxorubicin, and an alkylating agent with or without etoposide in a single treatment cycle.[<a class="bk_pop" href="#CDR0000062841_rl_28_10">10</a>] After the completion of a randomized trial, European investigators shifted to therapy with cycles of VDC alternating with cycles of IE.[<a class="bk_pop" href="#CDR0000062841_rl_28_24">24</a>] The duration of primary chemotherapy ranges from 6 months to approximately 1 year. </p><p id="CDR0000062841__395">Evidence (chemotherapy):</p><ol id="CDR0000062841__396"><li class="half_rhythm"><div>An international consortium of European countries conducted the <a href="https://www.cancer.gov/clinicaltrials/NCT00020566" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EURO-EWING-INTERGROUP-EE99 (NCT00020566)</a> trial from 2000 to 2010.[<a class="bk_pop" href="#CDR0000062841_rl_28_25">25</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335125/" class="def">Level of evidence: 1iiA</a>] All patients received induction therapy with six cycles of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE), followed by local control, and then one cycle of vincristine, dactinomycin, and ifosfamide (VAI). Patients were classified as standard risk if they had localized disease and good histologic response to therapy or if they had localized tumors less than 200 mL in volume at presentation; they were treated with radiation therapy alone as local treatment. Standard-risk patients (n = 856) were randomly assigned to receive either maintenance therapy with seven cycles of vincristine, dactinomycin, and cyclophosphamide (VAC) or VAI. <ul id="CDR0000062841__397"><li class="half_rhythm"><div>There was no significant difference in EFS or overall survival (OS) between the VAC arm and the VAI arm.</div></li><li class="half_rhythm"><div>The 3-year EFS rate for this low-risk population was 77%.</div></li><li class="half_rhythm"><div>Acute renal toxicity was lower in the VAC arm than in the VAI arm, but long-term renal function outcome and fertility analyses are still pending.</div></li><li class="half_rhythm"><div>It is difficult to compare this outcome with that of other large series because the study population excluded patients with poor response to initial therapy or patients with tumors more than 200 mL in volume who received local-control therapy with radiation alone. All other published series report results for all patients who present without clinically detectable metastasis; thus, these other series included patients with poor response and patients with larger primary tumors treated with radiation alone, all of whom were excluded from the EURO-EWING-INTERGROUP-EE99 study.</div></li></ul></div></li><li class="half_rhythm"><div>In a Children's Oncology Group (COG) study (<a href="https://www.cancer.gov/clinicaltrials/NCT00006734" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">COG-AEWS0031 [NCT00006734]</a>), patients presenting without metastases were randomly assigned to receive cycles of VDC alternating with cycles of IE at either 2-week or 3-week intervals.[<a class="bk_pop" href="#CDR0000062841_rl_28_26">26</a>]<ul id="CDR0000062841__1824"><li class="half_rhythm"><div>The administration of cycles of VDC/IE at 2-week intervals achieved superior EFS (5-year EFS rate, 73%) than did alternating cycles at 3-week intervals (5-year EFS rate, 65%).</div></li></ul></div></li><li class="half_rhythm"><div>The EURO EWING 2012 trial was an international multicenter phase III study that included two randomized treatments, the European VIDE/VAI/VAC regimen and the North American standard VDC/IE regimen. The study was open to patients with both localized and metastatic Ewing sarcoma.[<a class="bk_pop" href="#CDR0000062841_rl_28_24">24</a>]<ul id="CDR0000062841__1981"><li class="half_rhythm"><div>The hazard ratios (HRs) for EFS (0.7) and OS (0.64) favored VDC/IE over VIDE/VAI/VAC, with posterior probabilities of 98% for both EFS and OS that showed VDC/IE was superior.</div></li><li class="half_rhythm"><div>There were no major differences in acute toxicities between the two regimens.</div></li><li class="half_rhythm"><div>Heterogeneity tests did not show that the benefit of VDC/IE differed by baseline clinical features, including patient age, sex, stage, tumor volume, or country of residence.</div></li></ul></div></li><li class="half_rhythm"><div>The Brazilian Cooperative Study Group performed a multi-institutional trial that incorporated carboplatin into a risk-adapted intensive regimen in 175 children with localized or metastatic Ewing sarcoma.[<a class="bk_pop" href="#CDR0000062841_rl_28_27">27</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335136/" class="def">Level of evidence: 2Dii</a>]<ul id="CDR0000062841__1825"><li class="half_rhythm"><div> The investigators found significantly increased toxicity without an improvement in outcome with the addition of carboplatin.</div></li></ul></div></li></ol></div><div id="CDR0000062841__136"><h3>Local Control (Surgery and Radiation Therapy) for Ewing Sarcoma</h3><p id="CDR0000062841__326">Treatment approaches for Ewing sarcoma and therapeutic aggressiveness must be adjusted in order to maximize local control while also minimizing morbidity. </p><p id="CDR0000062841__457">Surgery is the most commonly used form of local control.[<a class="bk_pop" href="#CDR0000062841_rl_28_28">28</a>] Radiation therapy is an effective alternative modality for local control in cases where the functional or cosmetic morbidity of surgery is deemed too high by experienced surgical oncologists. However, in the immature skeleton, radiation therapy can cause subsequent deformities that may be more morbid than deformities from surgery. When complete surgical resection with pathologically negative margins cannot be obtained, postoperative radiation therapy is indicated. A multidisciplinary discussion between the experienced radiation oncologist and the surgeon is necessary to determine the best treatment options for local control for a given case. For some marginally resectable lesions, a combined approach of preoperative radiation therapy followed by resection can be used.</p><p id="CDR0000062841__1954">Timing of local control may impact outcome. A retrospective review from the National Cancer Database identified 1,318 patients with Ewing sarcoma.[<a class="bk_pop" href="#CDR0000062841_rl_28_29">29</a>] Patients who initiated local therapy at 6 to 15 weeks had a 5-year OS rate of 78.7% and a 10-year OS rate of 70.3%, and patients who initiated local therapy after 16 weeks had a 5-year OS rate of 70.4% and a 10-year OS rate of 57.1% (<i>P</i> < .001). The difference in OS according to time to local therapy was more important in patients who received radiation therapy alone.</p><p id="CDR0000062841__1908">For patients with metastatic Ewing sarcoma, any benefit of combined surgery and radiation therapy compared with either therapy alone for local control is relatively less substantial because the overall prognosis of these patients is much worse than the prognosis of patients who have localized disease.</p><p id="CDR0000062841__398">Randomized trials that directly compare surgery and radiation therapy do not exist, and their relative roles remain controversial. Although retrospective institutional series suggest superior local control and survival with surgery than with radiation therapy, most of these studies are compromised by selection bias. An analysis using propensity scoring to adjust for clinical features that may influence the preference for surgery only, radiation only, or combined surgery and radiation demonstrated that similar EFS is achieved with each mode of local therapy.[<a class="bk_pop" href="#CDR0000062841_rl_28_28">28</a>] Data for patients with pelvic primary Ewing sarcoma from a North American intergroup trial showed no difference in local control or survival on the basis of local-control modality—surgery alone, radiation therapy alone, or surgery plus radiation therapy.[<a class="bk_pop" href="#CDR0000062841_rl_28_30">30</a>]</p><p id="CDR0000062841__1953">The <a href="https://www.cancer.gov/clinicaltrials/NCT00020566" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EURO-EWING-INTERGROUP-EE99 (NCT00020566)</a> trial prospectively treated 180 patients with pelvic primary tumors without clinically detectable metastatic disease.[<a class="bk_pop" href="#CDR0000062841_rl_28_31">31</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335132/" class="def">Level of evidence: 2A</a>] A retrospective analysis of outcomes for these patients showed improved survival for patients whose tumors were treated with combined radiation therapy and surgery. The study did not prospectively define criteria for the selection of local-control modalities, and the investigators did not have access to information that would allow them to clarify why decisions for local-control modalities were made. In nonsacral tumors, combined local treatment was associated with a lower local recurrence probability (14% [95% confidence interval (CI), 5%–23%] vs. 33% [95% CI, 19%–47%] at 5 years; <i>P</i> = .015) and a higher OS probability (72% [95% CI, 61%–83%] vs. 47% [95% CI, 33%–62%] at 5 years; <i>P</i> = .024) compared with surgery alone. Even in a subgroup of patients with wide surgical margins and a good histologic response to induction treatment, the combined local treatment was associated with a higher OS probability (87% [95% CI, 74%–100%] vs. 51% [95% CI, 33%–69%] at 5 years; <i>P</i> = .009) compared with surgery alone. In patients with bone tumors who underwent surgical treatment— after controlling for tumor site in the pelvis, tumor volume, and surgical margin status—patients who did not undergo complete removal of the affected bone (HR, 5.04; 95% CI, 2.07–12.24; <i>P</i> < .001), patients with a poor histologic response to induction chemotherapy (HR, 3.72; 95% CI, 1.51–9.21; <i>P</i> = .004), and patients who did not receive additional radiation therapy (HR, 4.34; 95% CI, 1.71–11.05; <i>P</i> = .002) had a higher risk of death.</p><p id="CDR0000062841__172">For patients who undergo gross-total resection with microscopic residual disease, a radiation therapy dose of 50.4 Gy is indicated; for patients treated with primary radiation therapy, the radiation dose is 55.8 Gy (45 Gy to the initial tumor volume and an additional 10.8 Gy to the postchemotherapy volume).[<a class="bk_pop" href="#CDR0000062841_rl_28_14">14</a>,<a class="bk_pop" href="#CDR0000062841_rl_28_32">32</a>]</p><p id="CDR0000062841__399">Evidence (postoperative radiation therapy):</p><ol id="CDR0000062841__400"><li class="half_rhythm"><div>Investigators from St. Jude Children’s Research Hospital reported 39 patients with localized Ewing sarcoma who received both surgery and radiation.[<a class="bk_pop" href="#CDR0000062841_rl_28_14">14</a>]<ul id="CDR0000062841__401"><li class="half_rhythm"><div>The local failure rate for patients with positive margins was 17%, and the OS rate was 71%. The local failure rate for patients with negative margins was 5%, and the OS rate was 94%.</div></li></ul></div></li><li class="half_rhythm"><div>In a large retrospective Italian study, 45 Gy of adjuvant radiation therapy for patients with inadequate margins did not appear to improve either local control or disease-free survival (DFS).[<a class="bk_pop" href="#CDR0000062841_rl_28_15">15</a>] These investigators concluded that patients who are anticipated to have suboptimal surgery should be considered for definitive radiation therapy.</div></li><li class="half_rhythm"><div>The <a href="https://www.cancer.gov/clinicaltrials/NCT00020566" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EURO-EWING-INTERGROUP-EE99 (NCT00020566)</a> study reported the outcomes of 599 patients who presented with localized disease and had surgical resection after initial chemotherapy with at least 90% necrosis of the primary tumor.[<a class="bk_pop" href="#CDR0000062841_rl_28_32">32</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335147/" class="def">Level of evidence: 3iiDi</a>] The protocol recommended postoperative radiation therapy for patients with inadequate surgical margins, vertebral primary tumors, or thoracic tumors with pleural effusion, but the decision to use postoperative radiation therapy was left to the institutional investigator.<ul id="CDR0000062841__648"><li class="half_rhythm"><div>Patients who received postoperative radiation therapy (n = 142) had a lower risk of failure than did patients who did not receive postoperative radiation therapy, even after controlling for known prognostic factors, including age, sex, tumor site, clinical response, quality of resection, and histologic necrosis. Most of the improvement was seen in a decreased risk of local recurrence. The improvement was greater in patients who had large tumors (>200 mL) and were assessed to have 100% necrosis than in patients who were assessed to have 90% to 100% necrosis.</div></li><li class="half_rhythm"><div>There is a clear interaction between systemic therapy and local-control modalities for both local control and DFS. The induction regimen used in the EURO-EWING-INTERGROUP-EE99 study is less intense than the induction regimen used in contemporaneous protocols in the COG, and it is not appropriate to extrapolate the results from the EURO-EWING-INTERGROUP-EE99 study to different systemic chemotherapy regimens.</div></li></ul></div></li></ol><div id="CDR0000062841__1922"><h4>Thoracic primary tumors</h4><p id="CDR0000062841__1923">Evidence (surgery):</p><ol id="CDR0000062841__1924"><li class="half_rhythm"><div>The treatment and outcomes for 62 patients with thoracic Ewing sarcoma were reported from the Cooperative Weichteilsarkom Studiengruppe CWS-81, -86, -91, -96, and -2002P trials.[<a class="bk_pop" href="#CDR0000062841_rl_28_33">33</a>]<ul id="CDR0000062841__1909"><li class="half_rhythm"><div>The 5-year OS rate was 58.7% (95% CI, 52.7%–64.7%), and the EFS rate was 52.8% (95% CI, 46.8%–58.8%).</div></li><li class="half_rhythm"><div>Patients with intrathoracic tumor localization (n = 24) had a worse outcome (EFS rate, 37.5% [95% CI, 27.5%–37.5%]) than did patients with chest wall tumors (n = 38; EFS rate, 62.3% [95% CI, 54.3%–70.3%]; <i>P</i> = .008).</div></li><li class="half_rhythm"><div>Patients aged 10 years and younger (n = 38) had a better survival (EFS rate, 65.7% [95% CI, 57.7%–73.7%]) than did patients older than 10 years (EFS rate, 31.3% [95% CI, 21.3%–41.3%]; <i>P</i> = .01).</div></li><li class="half_rhythm"><div>Tumor size of less than or equal to 5 cm (n = 15) was associated with significantly better survival (EFS rate, 93.3% [95% CI, 87.3%–99.3%]) compared with a tumor size greater than 5 cm (n = 47; EFS rate, 40% [95% CI, 33%–47%]; <i>P</i> = .002).</div></li><li class="half_rhythm"><div>Primary resections were carried out in 36 patients, 75% of which were incomplete, resulting in inferior EFS (<i>P</i> = .006).</div></li><li class="half_rhythm"><div>Complete secondary resections were performed in 22 of 40 patients.</div></li></ul></div></li><li class="half_rhythm"><div>The COG reviewed its results for 98 patients with chest wall tumors who were treated on the INT-0091 and INT-0154 trials from 1988 to 1998 and found the following:[<a class="bk_pop" href="#CDR0000062841_rl_28_34">34</a>]<ul id="CDR0000062841__1952"><li class="half_rhythm"><div>The 5-year EFS rate was 56%.</div></li><li class="half_rhythm"><div>Negative margins were more common in patients who received initial chemotherapy and then underwent resections (41 of 53 patients, 77%) than in patients who had up-front surgery (10 of 20 patients, 50%). </div></li><li class="half_rhythm"><div>More patients who underwent up-front surgery received radiation therapy (71%) than did patients who started with chemotherapy (48%).</div></li></ul></div></li></ol><p id="CDR0000062841__173">In summary, surgery is chosen as definitive local therapy for suitable patients, but radiation therapy is appropriate for patients with unresectable disease or those who would experience functional or cosmetic compromise by definitive surgery. The possibility of impaired function or cosmesis needs to be measured against the possibility of second tumors in the radiation field. Adjuvant radiation therapy should be considered for patients with residual microscopic disease or inadequate margins.</p><p id="CDR0000062841__268">When preoperative assessment has suggested a high probability that surgical margins will be close or positive, preoperative radiation therapy has achieved tumor shrinkage and allowed surgical resection with clear margins.[<a class="bk_pop" href="#CDR0000062841_rl_28_35">35</a>]</p></div></div><div id="CDR0000062841__138"><h3>High-Dose Chemotherapy With Stem Cell Support for Ewing Sarcoma </h3><p id="CDR0000062841__139">For patients with a high risk of relapse with conventional treatments, certain investigators have utilized high-dose chemotherapy with hematopoietic stem cell transplant (HSCT) as consolidation treatment, in an effort to improve outcome.[<a class="bk_pop" href="#CDR0000062841_rl_28_19">19</a>,<a class="bk_pop" href="#CDR0000062841_rl_28_36">36</a>-<a class="bk_pop" href="#CDR0000062841_rl_28_48">48</a>]</p><p id="CDR0000062841__402">Evidence (high-dose therapy with stem cell support):</p><ol id="CDR0000062841__403"><li class="half_rhythm"><div class="half_rhythm"> In a prospective study, patients with bone and/or bone marrow metastases at diagnosis were treated with aggressive chemotherapy, surgery, and/or radiation and HSCT if a good initial response was achieved.[<a class="bk_pop" href="#CDR0000062841_rl_28_41">41</a>] <ul id="CDR0000062841__404"><li class="half_rhythm"><div>The study showed no benefit for HSCT compared with historical controls. </div></li></ul></div></li><li class="half_rhythm"><div class="half_rhythm">A retrospective review using international bone marrow transplant registries compared the outcomes after treatment with either reduced-intensity conditioning or high-intensity conditioning followed by allogeneic HSCT for patients with Ewing sarcoma at high risk of relapse.[<a class="bk_pop" href="#CDR0000062841_rl_28_49">49</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335150/" class="def">Level of evidence: 3iiiA</a>] <ul id="CDR0000062841__405"><li class="half_rhythm"><div>There was no difference in outcome, and the authors concluded that this suggested the absence of a clinically relevant graft-versus-tumor effect against Ewing sarcoma tumor cells with current approaches. </div></li></ul></div></li><li class="half_rhythm"><div class="half_rhythm">Multiple small studies that report benefit for HSCT have been published but are difficult to interpret because only patients who have a good initial response to standard chemotherapy are considered for HSCT. </div></li><li class="half_rhythm"><div class="half_rhythm">The role of high-dose therapy with busulfan-melphalan (BuMel) followed by stem cell rescue was investigated in the prospective, randomized <a href="https://www.cancer.gov/clinicaltrials/NCT00020566" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EURO-EWING-INTERGROUP-EE99 (NCT00020566)</a> trial for two distinct groups:[<a class="bk_pop" href="#CDR0000062841_rl_28_50">50</a>]<ol id="CDR0000062841__1876" class="lower-alpha"><li class="half_rhythm"><div class="half_rhythm">Patients who presented with isolated pulmonary metastases (R2pulm).</div></li><li class="half_rhythm"><div class="half_rhythm">Patients with localized tumors with poor response to initial chemotherapy (<90% necrosis) or with large tumors (>200 mL) (R2loc).</div><div class="half_rhythm"> Both study arms were compromised by the potential for selection bias for patients who were eligible for and accepted randomization, which may limit the generalizability of the results. Only 40% of eligible patients were randomized.<ul id="CDR0000062841__1808"><li class="half_rhythm"><div>For R2pulm patients, there was no statistically significant difference in EFS or OS between the treatment groups.[<a class="bk_pop" href="#CDR0000062841_rl_28_51">51</a>]<dl id="CDR0000062841__1970" class="temp-labeled-list"><dt>-</dt><dd><p class="no_top_margin">The EFS rates at 3 years were 50.6% for patients who received VAI plus whole-lung irradiation versus 56.6% for patients who received BuMel; the EFS rates at 8 years were 43.1% for patients who received VAI plus whole-lung irradiation versus 52.9% for patients who received BuMel.</p></dd><dt>-</dt><dd><p class="no_top_margin">The OS rates at 3 years were 68.0% for patients who received VAI plus whole-lung irradiation versus 68.2% for patients who received BuMel; the OS rates at 8 years were 54.2% for patients who received VAI plus whole-lung irradiation versus 55.3% for patients who received BuMel.</p></dd></dl></div></li><li class="half_rhythm"><div>Among R2loc patients, 3-year EFS rate was superior with BuMel compared with continued chemotherapy (66.9% vs. 53.1%; <i>P</i> = .019). The 3-year OS rate was 78.0% with BuMel and 72.2% with continued chemotherapy (<i>P</i> = .028).[<a class="bk_pop" href="#CDR0000062841_rl_28_50">50</a>]</div></li></ul></div></li></ol></div><div class="half_rhythm">The induction regimen employed in the EURO-EWING-INTERGROUP-EE99 trial was VIDE. This regimen is less dose intensive than the regimen employed in COG studies. This can be inferred from the intended dose intensity of the agents employed for the 21-week period that preceded randomization in the EURO-EWING-INTERGROUP-EE99 study (refer to <a class="figpopup" href="/books/NBK66045.23/table/CDR0000062841__1816/?report=objectonly" target="object" rid-figpopup="figCDR00000628411816" rid-ob="figobCDR00000628411816">Table 4</a>). The lower dose intensity can also be inferred from the outcome of the EURO-EWING-INTERGROUP-EE99 study for patients in the localized disease stratum. Results from this study include the following:<ul id="CDR0000062841__1884"><li class="half_rhythm"><div>Patients assigned to the most favorable risk stratum, R1, were patients with small primary tumors, less than 200 mL in volume. In addition, patients who had poor response to the initial six cycles of therapy with VIDE, as assessed by pathology or radiology, were removed from the R1 stratum and assigned to the R2 stratum. As a result, the R1 stratum includes only patients with small primary tumors and favorable response to initial therapy. The probability for EFS at 3 years for this favorable group was 76%, and the OS rate at 3 years was 85%.[<a class="bk_pop" href="#CDR0000062841_rl_28_25">25</a>] </div></li><li class="half_rhythm"><div>For all patients with localized Ewing sarcoma, including patients with large primary tumors and patients with poor response to initial therapy treated on the <a href="https://www.cancer.gov/clinicaltrials/NCT01231906" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">COG-AEWS1031 (NCT01231906)</a> trial, the 5-year probability for EFS was 73%, and the 5-year OS rate was 88%.[<a class="bk_pop" href="#CDR0000062841_rl_28_26">26</a>]</div></li></ul></div><div class="half_rhythm"> The observation that high-dose therapy with autologous stem cell rescue improved outcomes for patients with a poor response to initial therapy in the EURO-EWING-INTERGROUP-EE99 study must be interpreted in this context. The advantage of high-dose therapy as consolidation for patients with a poor response to initial treatment with a less intensive regimen cannot be extrapolated to a population of patients who received a more intensive treatment regimen as initial therapy.<div id="CDR0000062841__1816" class="table"><h3><span class="title">Table 4. Comparison of the Dose Intensity of the EURO-EWING-INTERGROUP-EE99 Trial Versus COG Interval Dose Compression</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK66045.23/table/CDR0000062841__1816/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__CDR0000062841__1816_lrgtbl__"><table class="no_margin"><thead><tr><th colspan="1" rowspan="1" style="vertical-align:top;">Chemotherapy Agent</th><th colspan="2" rowspan="1" style="vertical-align:top;">Prescribed Dose Intensity (mg/week)</th></tr><tr><th colspan="1" rowspan="1" style="vertical-align:top;"></th><th colspan="1" rowspan="1" style="vertical-align:top;"> EURO-EWING-INTERGROUP-EE99 Trial </th><th colspan="1" rowspan="1" style="vertical-align:top;">COG Interval Dose Compression</th></tr></thead><tbody><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Vincristine </td><td colspan="1" rowspan="1" style="vertical-align:top;">0.5 mg/m<sup>2</sup>
|
|
</td><td colspan="1" rowspan="1" style="vertical-align:top;">0.43 mg/m<sup>2</sup></td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Doxorubicin </td><td colspan="1" rowspan="1" style="vertical-align:top;">17.1 mg/m<sup>2</sup>
|
|
</td><td colspan="1" rowspan="1" style="vertical-align:top;">21.4 mg/m<sup>2</sup></td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Ifosfamide </td><td colspan="1" rowspan="1" style="vertical-align:top;">3,000 mg/m<sup>2</sup>
|
|
</td><td colspan="1" rowspan="1" style="vertical-align:top;">2,150 mg/m<sup>2</sup></td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Cyclophosphamide</td><td colspan="1" rowspan="1" style="vertical-align:top;"> 0 </td><td colspan="1" rowspan="1" style="vertical-align:top;">343 mg/m<sup>2</sup></td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Cyclophosphamide equivalent dose (= cyclophosphamide dose + ifosfamide dose × 0.244)</td><td colspan="1" rowspan="1" style="vertical-align:top;">732 mg/m<sup>2</sup></td><td colspan="1" rowspan="1" style="vertical-align:top;">868 mg/m<sup>2</sup></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">COG = Children's Oncology Group.</p></div></dd></dl></div></div></div></div></li></ol></div><div id="CDR0000062841__148"><h3>Extraosseous Ewing Sarcoma</h3><p id="CDR0000062841__1826">Multiple analyses have evaluated diagnostic findings, treatment, and outcome of patients with bone lesions at the following anatomic primary sites: </p><ul id="CDR0000062841__1827"><li class="half_rhythm"><div>Pelvis.[<a class="bk_pop" href="#CDR0000062841_rl_28_52">52</a>-<a class="bk_pop" href="#CDR0000062841_rl_28_54">54</a>] </div></li><li class="half_rhythm"><div>Femur.[<a class="bk_pop" href="#CDR0000062841_rl_28_55">55</a>,<a class="bk_pop" href="#CDR0000062841_rl_28_56">56</a>] </div></li><li class="half_rhythm"><div>Humerus.[<a class="bk_pop" href="#CDR0000062841_rl_28_57">57</a>,<a class="bk_pop" href="#CDR0000062841_rl_28_58">58</a>]</div></li><li class="half_rhythm"><div>Hand and foot.[<a class="bk_pop" href="#CDR0000062841_rl_28_59">59</a>,<a class="bk_pop" href="#CDR0000062841_rl_28_60">60</a>] </div></li><li class="half_rhythm"><div>Chest wall/rib.[<a class="bk_pop" href="#CDR0000062841_rl_28_34">34</a>,<a class="bk_pop" href="#CDR0000062841_rl_28_61">61</a>-<a class="bk_pop" href="#CDR0000062841_rl_28_63">63</a>] </div></li><li class="half_rhythm"><div>Head and neck.[<a class="bk_pop" href="#CDR0000062841_rl_28_64">64</a>] </div></li><li class="half_rhythm"><div>Spine/sacrum.[<a class="bk_pop" href="#CDR0000062841_rl_28_65">65</a>-<a class="bk_pop" href="#CDR0000062841_rl_28_68">68</a>]</div></li></ul><p id="CDR0000062841__149">Extraosseous Ewing sarcoma is biologically similar to Ewing sarcoma arising in bone. Historically, most children and young adults with extraosseous Ewing sarcoma were treated on protocols designed for the treatment of rhabdomyosarcoma. This is important because many of the treatment regimens for rhabdomyosarcoma do not include an anthracycline, which is a critical component of current treatment regimens for Ewing sarcoma. Currently, patients with extraosseous Ewing sarcoma are eligible for studies that include Ewing sarcoma of bone.</p><p id="CDR0000062841__1828">Evidence (treatment of extraosseous Ewing sarcoma):</p><ol id="CDR0000062841__1829"><li class="half_rhythm"><div>From 1987 to 2004, 111 patients with nonmetastatic extraosseous Ewing sarcoma were enrolled on the RMS-88 and RMS-96 protocols.[<a class="bk_pop" href="#CDR0000062841_rl_28_69">69</a>] Patients with initial complete tumor resection received ifosfamide, vincristine, and actinomycin (IVA) while patients with residual tumor received IVA plus doxorubicin (VAIA) or IVA plus carboplatin, epirubicin, and etoposide (CEVAIE). Seventy-six percent of patients received radiation.<ul id="CDR0000062841__1830"><li class="half_rhythm"><div>The 5-year EFS rate was 59%, and the OS rate was 69%.</div></li><li class="half_rhythm"><div>In a multivariate analysis, independent adverse prognostic factors included axial primary, tumor size greater than 10 cm, Intergroup Rhabdomyosarcoma Studies Group III, and lack of radiation therapy.</div></li></ul></div></li><li class="half_rhythm"><div>Two hundred thirty-six patients with extraosseous Ewing sarcoma were entered on studies of the German Pediatric Oncology Group.[<a class="bk_pop" href="#CDR0000062841_rl_28_70">70</a>] The median age at diagnosis was 15 years and 133 patients were male. Primary tumor site was either extremity (n = 62) or central site (n = 174). Sixty of the 236 patients had metastases at diagnosis. Chemotherapy consisted of vincristine, doxorubicin, cyclophosphamide, and actinomycin (VACA), CEVAIE, or VIDE. <ul id="CDR0000062841__1831"><li class="half_rhythm"><div>The 5-year EFS rate was 49%, and the OS rate was 60%.</div></li><li class="half_rhythm"><div>The 5-year survival rate was 70% for patients with localized disease and 33% for patients with metastasis at diagnosis.</div></li><li class="half_rhythm"><div>OS in patients with localized disease did not seem related to tumor site or size.</div></li></ul></div></li><li class="half_rhythm"><div>In a retrospective French study, patients with extraosseous Ewing sarcoma were treated using a rhabdomyosarcoma regimen (no anthracyclines) or a Ewing sarcoma regimen (includes anthracyclines).[<a class="bk_pop" href="#CDR0000062841_rl_28_71">71</a>,<a class="bk_pop" href="#CDR0000062841_rl_28_72">72</a>]<ul id="CDR0000062841__1832"><li class="half_rhythm"><div>Patients who received the anthracycline-containing regimen had a significantly better EFS and OS than did patients who did not receive anthracyclines.</div></li></ul></div></li><li class="half_rhythm"><div>Two North American Ewing sarcoma trials have included patients with extraosseous Ewing sarcoma.[<a class="bk_pop" href="#CDR0000062841_rl_28_26">26</a>,<a class="bk_pop" href="#CDR0000062841_rl_28_73">73</a>] In a review of data from the POG-9354 (INT-0154) and <a href="https://www.cancer.gov/clinicaltrials/NCT00006734" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EWS0031 (NCT00006734)</a> studies, 213 patients with extraosseous Ewing sarcoma and 826 patients with Ewing sarcoma of bone were identified.[<a class="bk_pop" href="#CDR0000062841_rl_28_74">74</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335147/" class="def">Level of evidence: 3iiDi</a>]<ul id="CDR0000062841__1833"><li class="half_rhythm"><div> The HR of extraosseous Ewing sarcoma was superior (0.62), and extraosseous Ewing sarcoma was a favorable risk factor, independent of age, race, and primary site.</div></li></ul></div></li></ol><p id="CDR0000062841__310">Cutaneous Ewing sarcoma is a soft tissue tumor in the skin or subcutaneous tissue that seems to behave as a less-aggressive tumor than primary bone or soft tissue Ewing sarcoma. Tumors can form throughout the body, although the extremity is the most common site, and they are almost always localized. </p><p id="CDR0000062841__1834">Evidence (treatment of cutaneous Ewing sarcoma):</p><ol id="CDR0000062841__1835"><li class="half_rhythm"><div>In a review of 78 reported cases, some lacking molecular confirmation, the OS rate was 91%. Adequate local control, defined as a complete resection with negative margins, radiation therapy, or a combination, significantly reduced the incidence of relapse. Standard chemotherapy for Ewing sarcoma is often used for these patients because there are no data to suggest which patients could be treated less aggressively.[<a class="bk_pop" href="#CDR0000062841_rl_28_75">75</a>,<a class="bk_pop" href="#CDR0000062841_rl_28_76">76</a>]</div></li><li class="half_rhythm"><div>A series of 56 patients with cutaneous or subcutaneous Ewing sarcoma confirmed the excellent outcome with the use of standard systemic therapy and local control. Attempted primary definitive surgery often resulted in the need for either radiation therapy or more function-compromising surgery, supporting the recommendation of biopsy only as initial surgery, rather than up-front unplanned resection.[<a class="bk_pop" href="#CDR0000062841_rl_28_77">77</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000716085/" class="def">Level of evidence: 3iiD</a>]</div></li></ol></div><div id="CDR0000062841_rl_28"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000062841_rl_28_1">Fuchs B, Valenzuela RG, Sim FH: Pathologic fracture as a complication in the treatment of Ewing's sarcoma. Clin Orthop (415): 25-30, 2003. [<a href="https://pubmed.ncbi.nlm.nih.gov/14612626" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14612626</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_2">Singh VM, Salunga RC, Huang VJ, et al.: Analysis of the effect of various decalcification agents on the quantity and quality of nucleic acid (DNA and RNA) recovered from bone biopsies. Ann Diagn Pathol 17 (4): 322-6, 2013. [<a href="https://pubmed.ncbi.nlm.nih.gov/23660273" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23660273</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_3">Hoffer FA, Gianturco LE, Fletcher JA, et al.: Percutaneous biopsy of peripheral primitive neuroectodermal tumors and Ewing's sarcomas for cytogenetic analysis. AJR Am J Roentgenol 162 (5): 1141-2, 1994. [<a href="https://pubmed.ncbi.nlm.nih.gov/8165999" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8165999</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_4">Craft A, Cotterill S, Malcolm A, et al.: Ifosfamide-containing chemotherapy in Ewing's sarcoma: The Second United Kingdom Children's Cancer Study Group and the Medical Research Council Ewing's Tumor Study. J Clin Oncol 16 (11): 3628-33, 1998. [<a href="https://pubmed.ncbi.nlm.nih.gov/9817284" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9817284</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_5">Shankar AG, Pinkerton CR, Atra A, et al.: Local therapy and other factors influencing site of relapse in patients with localised Ewing's sarcoma. United Kingdom Children's Cancer Study Group (UKCCSG). Eur J Cancer 35 (12): 1698-704, 1999. [<a href="https://pubmed.ncbi.nlm.nih.gov/10674016" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10674016</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_6">Nilbert M, Saeter G, Elomaa I, et al.: Ewing's sarcoma treatment in Scandinavia 1984-1990--ten-year results of the Scandinavian Sarcoma Group Protocol SSGIV. Acta Oncol 37 (4): 375-8, 1998. [<a href="https://pubmed.ncbi.nlm.nih.gov/9743460" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9743460</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_7">Ferrari S, Mercuri M, Rosito P, et al.: Ifosfamide and actinomycin-D, added in the induction phase to vincristine, cyclophosphamide and doxorubicin, improve histologic response and prognosis in patients with non metastatic Ewing's sarcoma of the extremity. J Chemother 10 (6): 484-91, 1998. [<a href="https://pubmed.ncbi.nlm.nih.gov/9876058" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9876058</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_8">Grier HE, Krailo MD, Tarbell NJ, et al.: Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med 348 (8): 694-701, 2003. [<a href="https://pubmed.ncbi.nlm.nih.gov/12594313" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12594313</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_9">Thacker MM, Temple HT, Scully SP: Current treatment for Ewing's sarcoma. Expert Rev Anticancer Ther 5 (2): 319-31, 2005. [<a href="https://pubmed.ncbi.nlm.nih.gov/15877528" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15877528</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_10">Juergens C, Weston C, Lewis I, et al.: Safety assessment of intensive induction with vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) in the treatment of Ewing tumors in the EURO-E.W.I.N.G. 99 clinical trial. Pediatr Blood Cancer 47 (1): 22-9, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16572419" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16572419</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_11">Dunst J, Schuck A: Role of radiotherapy in Ewing tumors. Pediatr Blood Cancer 42 (5): 465-70, 2004. [<a href="https://pubmed.ncbi.nlm.nih.gov/15049022" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15049022</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_12">Donaldson SS: Ewing sarcoma: radiation dose and target volume. Pediatr Blood Cancer 42 (5): 471-6, 2004. [<a href="https://pubmed.ncbi.nlm.nih.gov/15049023" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15049023</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_13">Bacci G, Ferrari S, Longhi A, et al.: Role of surgery in local treatment of Ewing's sarcoma of the extremities in patients undergoing adjuvant and neoadjuvant chemotherapy. Oncol Rep 11 (1): 111-20, 2004. [<a href="https://pubmed.ncbi.nlm.nih.gov/14654912" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14654912</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_14">Krasin MJ, Rodriguez-Galindo C, Davidoff AM, et al.: Efficacy of combined surgery and irradiation for localized Ewings sarcoma family of tumors. Pediatr Blood Cancer 43 (3): 229-36, 2004. [<a href="https://pubmed.ncbi.nlm.nih.gov/15266406" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15266406</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_15">Bacci G, Longhi A, Briccoli A, et al.: The role of surgical margins in treatment of Ewing's sarcoma family tumors: experience of a single institution with 512 patients treated with adjuvant and neoadjuvant chemotherapy. Int J Radiat Oncol Biol Phys 65 (3): 766-72, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16626886" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16626886</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_16">Paulussen M, Ahrens S, Burdach S, et al.: Primary metastatic (stage IV) Ewing tumor: survival analysis of 171 patients from the EICESS studies. European Intergroup Cooperative Ewing Sarcoma Studies. Ann Oncol 9 (3): 275-81, 1998. [<a href="https://pubmed.ncbi.nlm.nih.gov/9602261" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9602261</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_17">Pinkerton CR, Bataillard A, Guillo S, et al.: Treatment strategies for metastatic Ewing's sarcoma. Eur J Cancer 37 (11): 1338-44, 2001. [<a href="https://pubmed.ncbi.nlm.nih.gov/11435062" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11435062</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_18">Bernstein ML, Devidas M, Lafreniere D, et al.: Intensive therapy with growth factor support for patients with Ewing tumor metastatic at diagnosis: Pediatric Oncology Group/Children's Cancer Group Phase II Study 9457--a report from the Children's Oncology Group. J Clin Oncol 24 (1): 152-9, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16382125" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16382125</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_19">Ladenstein R, Pötschger U, Le Deley MC, et al.: Primary disseminated multifocal Ewing sarcoma: results of the Euro-EWING 99 trial. J Clin Oncol 28 (20): 3284-91, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/20547982" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20547982</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_20">Miser JS, Krailo MD, Tarbell NJ, et al.: Treatment of metastatic Ewing's sarcoma or primitive neuroectodermal tumor of bone: evaluation of combination ifosfamide and etoposide--a Children's Cancer Group and Pediatric Oncology Group study. J Clin Oncol 22 (14): 2873-6, 2004. [<a href="https://pubmed.ncbi.nlm.nih.gov/15254055" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15254055</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_21">Miser JS, Goldsby RE, Chen Z, et al.: Treatment of metastatic Ewing sarcoma/primitive neuroectodermal tumor of bone: evaluation of increasing the dose intensity of chemotherapy--a report from the Children's Oncology Group. Pediatr Blood Cancer 49 (7): 894-900, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17584910" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17584910</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_22">Haeusler J, Ranft A, Boelling T, et al.: The value of local treatment in patients with primary, disseminated, multifocal Ewing sarcoma (PDMES). Cancer 116 (2): 443-50, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/19924786" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19924786</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_23">Paulussen M, Craft AW, Lewis I, et al.: Results of the EICESS-92 Study: two randomized trials of Ewing's sarcoma treatment--cyclophosphamide compared with ifosfamide in standard-risk patients and assessment of benefit of etoposide added to standard treatment in high-risk patients. J Clin Oncol 26 (27): 4385-93, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/18802150" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18802150</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_24">Brennan B, Kirton L, Marec-Berard P, et al.: Comparison of two chemotherapy regimens in Ewing sarcoma (ES): Overall and subgroup results of the Euro Ewing 2012 randomized trial (EE2012). [Abstract] J Clin Oncol 38 (Suppl 15): A-11500, 2020. <a href="https://ascopubs.org/doi/abs/10.1200/JCO.2020.38.15_suppl.11500" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">Also available online</a>. Last accessed June 29, 2021.</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_25">Le Deley MC, Paulussen M, Lewis I, et al.: Cyclophosphamide compared with ifosfamide in consolidation treatment of standard-risk Ewing sarcoma: results of the randomized noninferiority Euro-EWING99-R1 trial. J Clin Oncol 32 (23): 2440-8, 2014. [<a href="https://pubmed.ncbi.nlm.nih.gov/24982464" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24982464</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_26">Womer RB, West DC, Krailo MD, et al.: Randomized controlled trial of interval-compressed chemotherapy for the treatment of localized Ewing sarcoma: a report from the Children's Oncology Group. J Clin Oncol 30 (33): 4148-54, 2012. [<a href="/pmc/articles/PMC3494838/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3494838</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23091096" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23091096</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_27">Brunetto AL, Castillo LA, Petrilli AS, et al.: Carboplatin in the treatment of Ewing sarcoma: Results of the first Brazilian collaborative study group for Ewing sarcoma family tumors-EWING1. Pediatr Blood Cancer 62 (10): 1747-53, 2015. [<a href="https://pubmed.ncbi.nlm.nih.gov/25917418" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25917418</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_28">DuBois SG, Krailo MD, Gebhardt MC, et al.: Comparative evaluation of local control strategies in localized Ewing sarcoma of bone: a report from the Children's Oncology Group. Cancer 121 (3): 467-75, 2015. [<a href="/pmc/articles/PMC4305012/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4305012</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25251206" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25251206</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_29">Lin TA, Ludmir EB, Liao KP, et al.: Timing of Local Therapy Affects Survival in Ewing Sarcoma. Int J Radiat Oncol Biol Phys 104 (1): 127-136, 2019. [<a href="https://pubmed.ncbi.nlm.nih.gov/30593906" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30593906</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_30">Yock TI, Krailo M, Fryer CJ, et al.: Local control in pelvic Ewing sarcoma: analysis from INT-0091--a report from the Children's Oncology Group. J Clin Oncol 24 (24): 3838-43, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16921035" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16921035</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_31">Andreou D, Ranft A, Gosheger G, et al.: Which Factors Are Associated with Local Control and Survival of Patients with Localized Pelvic Ewing's Sarcoma? A Retrospective Analysis of Data from the Euro-EWING99 Trial. Clin Orthop Relat Res 478 (2): 290-302, 2020. [<a href="/pmc/articles/PMC7438129/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7438129</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/31580267" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 31580267</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_32">Foulon S, Brennan B, Gaspar N, et al.: Can postoperative radiotherapy be omitted in localised standard-risk Ewing sarcoma? An observational study of the Euro-E.W.I.N.G group. Eur J Cancer 61: 128-36, 2016. [<a href="https://pubmed.ncbi.nlm.nih.gov/27176931" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27176931</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_33">Seitz G, Urla C, Sparber-Sauer M, et al.: Treatment and outcome of patients with thoracic tumors of the Ewing sarcoma family: A report from the Cooperative Weichteilsarkom Studiengruppe CWS-81, -86, -91, -96, and -2002P trials. Pediatr Blood Cancer 66 (3): e27537, 2019. [<a href="https://pubmed.ncbi.nlm.nih.gov/30421578" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30421578</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_34">Shamberger RC, LaQuaglia MP, Gebhardt MC, et al.: Ewing sarcoma/primitive neuroectodermal tumor of the chest wall: impact of initial versus delayed resection on tumor margins, survival, and use of radiation therapy. Ann Surg 238 (4): 563-7; discussion 567-8, 2003. [<a href="/pmc/articles/PMC1360114/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1360114</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/14530727" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14530727</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_35">Wagner TD, Kobayashi W, Dean S, et al.: Combination short-course preoperative irradiation, surgical resection, and reduced-field high-dose postoperative irradiation in the treatment of tumors involving the bone. Int J Radiat Oncol Biol Phys 73 (1): 259-66, 2009. [<a href="https://pubmed.ncbi.nlm.nih.gov/19100921" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19100921</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_36">Kushner BH, Meyers PA: How effective is dose-intensive/myeloablative therapy against Ewing's sarcoma/primitive neuroectodermal tumor metastatic to bone or bone marrow? The Memorial Sloan-Kettering experience and a literature review. J Clin Oncol 19 (3): 870-80, 2001. [<a href="https://pubmed.ncbi.nlm.nih.gov/11157041" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11157041</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_37">Marina N, Meyers PA: High-dose therapy and stem-cell rescue for Ewing's family of tumors in second remission. J Clin Oncol 23 (19): 4262-4, 2005. [<a href="https://pubmed.ncbi.nlm.nih.gov/15781877" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15781877</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_38">Burdach S: Treatment of advanced Ewing tumors by combined radiochemotherapy and engineered cellular transplants. Pediatr Transplant 8 (Suppl 5): 67-82, 2004. [<a href="https://pubmed.ncbi.nlm.nih.gov/15125708" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15125708</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_39">McTiernan A, Driver D, Michelagnoli MP, et al.: High dose chemotherapy with bone marrow or peripheral stem cell rescue is an effective treatment option for patients with relapsed or progressive Ewing's sarcoma family of tumours. Ann Oncol 17 (8): 1301-5, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16782749" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16782749</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_40">Burdach S, Meyer-Bahlburg A, Laws HJ, et al.: High-dose therapy for patients with primary multifocal and early relapsed Ewing's tumors: results of two consecutive regimens assessing the role of total-body irradiation. J Clin Oncol 21 (16): 3072-8, 2003. [<a href="https://pubmed.ncbi.nlm.nih.gov/12915596" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12915596</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_41">Meyers PA, Krailo MD, Ladanyi M, et al.: High-dose melphalan, etoposide, total-body irradiation, and autologous stem-cell reconstitution as consolidation therapy for high-risk Ewing's sarcoma does not improve prognosis. J Clin Oncol 19 (11): 2812-20, 2001. [<a href="https://pubmed.ncbi.nlm.nih.gov/11387352" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11387352</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_42">Oberlin O, Rey A, Desfachelles AS, et al.: Impact of high-dose busulfan plus melphalan as consolidation in metastatic Ewing tumors: a study by the Société Française des Cancers de l'Enfant. J Clin Oncol 24 (24): 3997-4002, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16921053" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16921053</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_43">Hawkins D, Barnett T, Bensinger W, et al.: Busulfan, melphalan, and thiotepa with or without total marrow irradiation with hematopoietic stem cell rescue for poor-risk Ewing-Sarcoma-Family tumors. Med Pediatr Oncol 34 (5): 328-37, 2000. [<a href="https://pubmed.ncbi.nlm.nih.gov/10797354" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10797354</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_44">Rosenthal J, Bolotin E, Shakhnovits M, et al.: High-dose therapy with hematopoietic stem cell rescue in patients with poor prognosis Ewing family tumors. Bone Marrow Transplant 42 (5): 311-8, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/18587438" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18587438</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_45">Burdach S, Thiel U, Schöniger M, et al.: Total body MRI-governed involved compartment irradiation combined with high-dose chemotherapy and stem cell rescue improves long-term survival in Ewing tumor patients with multiple primary bone metastases. Bone Marrow Transplant 45 (3): 483-9, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/19684633" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19684633</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_46">Gaspar N, Rey A, Bérard PM, et al.: Risk adapted chemotherapy for localised Ewing's sarcoma of bone: the French EW93 study. Eur J Cancer 48 (9): 1376-85, 2012. [<a href="https://pubmed.ncbi.nlm.nih.gov/22516209" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22516209</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_47">Drabko K, Raciborska A, Bilska K, et al.: Consolidation of first-line therapy with busulphan and melphalan, and autologous stem cell rescue in children with Ewing's sarcoma. Bone Marrow Transplant 47 (12): 1530-4, 2012. [<a href="https://pubmed.ncbi.nlm.nih.gov/22609883" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22609883</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_48">Loschi S, Dufour C, Oberlin O, et al.: Tandem high-dose chemotherapy strategy as first-line treatment of primary disseminated multifocal Ewing sarcomas in children, adolescents and young adults. Bone Marrow Transplant 50 (8): 1083-8, 2015. [<a href="https://pubmed.ncbi.nlm.nih.gov/26030048" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26030048</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_49">Thiel U, Wawer A, Wolf P, et al.: No improvement of survival with reduced- versus high-intensity conditioning for allogeneic stem cell transplants in Ewing tumor patients. Ann Oncol 22 (7): 1614-21, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/21245159" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21245159</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_50">Whelan J, Le Deley MC, Dirksen U, et al.: High-Dose Chemotherapy and Blood Autologous Stem-Cell Rescue Compared With Standard Chemotherapy in Localized High-Risk Ewing Sarcoma: Results of Euro-E.W.I.N.G.99 and Ewing-2008. J Clin Oncol : JCO2018782516, 2018. [<a href="/pmc/articles/PMC6209090/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6209090</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/30188789" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30188789</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_51">Dirksen U, Brennan B, Le Deley MC, et al.: High-Dose Chemotherapy Compared With Standard Chemotherapy and Lung Radiation in Ewing Sarcoma With Pulmonary Metastases: Results of the European Ewing Tumour Working Initiative of National Groups, 99 Trial and EWING 2008. J Clin Oncol 37 (34): 3192-3202, 2019. [<a href="/pmc/articles/PMC6881099/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6881099</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/31553693" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 31553693</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_52">Hoffmann C, Ahrens S, Dunst J, et al.: Pelvic Ewing sarcoma: a retrospective analysis of 241 cases. Cancer 85 (4): 869-77, 1999. [<a href="https://pubmed.ncbi.nlm.nih.gov/10091764" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10091764</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_53">Sucato DJ, Rougraff B, McGrath BE, et al.: Ewing's sarcoma of the pelvis. Long-term survival and functional outcome. Clin Orthop (373): 193-201, 2000. [<a href="https://pubmed.ncbi.nlm.nih.gov/10810477" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10810477</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_54">Bacci G, Ferrari S, Mercuri M, et al.: Multimodal therapy for the treatment of nonmetastatic Ewing sarcoma of pelvis. J Pediatr Hematol Oncol 25 (2): 118-24, 2003. [<a href="https://pubmed.ncbi.nlm.nih.gov/12571462" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12571462</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_55">Bacci G, Ferrari S, Longhi A, et al.: Local and systemic control in Ewing's sarcoma of the femur treated with chemotherapy, and locally by radiotherapy and/or surgery. J Bone Joint Surg Br 85 (1): 107-14, 2003. [<a href="https://pubmed.ncbi.nlm.nih.gov/12585587" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12585587</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_56">Ozaki T, Hillmann A, Hoffmann C, et al.: Ewing's sarcoma of the femur. Prognosis in 69 patients treated by the CESS group. Acta Orthop Scand 68 (1): 20-4, 1997. [<a href="https://pubmed.ncbi.nlm.nih.gov/9057563" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9057563</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_57">Ayoub KS, Fiorenza F, Grimer RJ, et al.: Extensible endoprostheses of the humerus after resection of bone tumours. J Bone Joint Surg Br 81 (3): 495-500, 1999. [<a href="https://pubmed.ncbi.nlm.nih.gov/10872374" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10872374</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_58">Bacci G, Palmerini E, Staals EL, et al.: Ewing's sarcoma family tumors of the humerus: outcome of patients treated with radiotherapy, surgery or surgery and adjuvant radiotherapy. Radiother Oncol 93 (2): 383-7, 2009. [<a href="https://pubmed.ncbi.nlm.nih.gov/19576648" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19576648</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_59">Casadei R, Magnani M, Biagini R, et al.: Prognostic factors in Ewing's sarcoma of the foot. Clin Orthop (420): 230-8, 2004. [<a href="https://pubmed.ncbi.nlm.nih.gov/15057103" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15057103</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_60">Anakwenze OA, Parker WL, Wold LE, et al.: Ewing's sarcoma of the hand. J Hand Surg Eur Vol 34 (1): 35-9, 2009. [<a href="https://pubmed.ncbi.nlm.nih.gov/19091738" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19091738</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_61">Shamberger RC, Laquaglia MP, Krailo MD, et al.: Ewing sarcoma of the rib: results of an intergroup study with analysis of outcome by timing of resection. J Thorac Cardiovasc Surg 119 (6): 1154-61, 2000. [<a href="https://pubmed.ncbi.nlm.nih.gov/10838532" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10838532</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_62">Sirvent N, Kanold J, Levy C, et al.: Non-metastatic Ewing's sarcoma of the ribs: the French Society of Pediatric Oncology Experience. Eur J Cancer 38 (4): 561-7, 2002. [<a href="https://pubmed.ncbi.nlm.nih.gov/11872350" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11872350</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_63">Schuck A, Ahrens S, Konarzewska A, et al.: Hemithorax irradiation for Ewing tumors of the chest wall. Int J Radiat Oncol Biol Phys 54 (3): 830-8, 2002. [<a href="https://pubmed.ncbi.nlm.nih.gov/12377336" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12377336</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_64">Windfuhr JP: Primitive neuroectodermal tumor of the head and neck: incidence, diagnosis, and management. Ann Otol Rhinol Laryngol 113 (7): 533-43, 2004. [<a href="https://pubmed.ncbi.nlm.nih.gov/15274413" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15274413</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_65">Venkateswaran L, Rodriguez-Galindo C, Merchant TE, et al.: Primary Ewing tumor of the vertebrae: clinical characteristics, prognostic factors, and outcome. Med Pediatr Oncol 37 (1): 30-5, 2001. [<a href="https://pubmed.ncbi.nlm.nih.gov/11466720" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11466720</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_66">Marco RA, Gentry JB, Rhines LD, et al.: Ewing's sarcoma of the mobile spine. Spine 30 (7): 769-73, 2005. [<a href="https://pubmed.ncbi.nlm.nih.gov/15803079" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15803079</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_67">Schuck A, Ahrens S, von Schorlemer I, et al.: Radiotherapy in Ewing tumors of the vertebrae: treatment results and local relapse analysis of the CESS 81/86 and EICESS 92 trials. Int J Radiat Oncol Biol Phys 63 (5): 1562-7, 2005. [<a href="https://pubmed.ncbi.nlm.nih.gov/16137838" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16137838</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_68">Bacci G, Boriani S, Balladelli A, et al.: Treatment of nonmetastatic Ewing's sarcoma family tumors of the spine and sacrum: the experience from a single institution. Eur Spine J 18 (8): 1091-5, 2009. [<a href="/pmc/articles/PMC2899506/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2899506</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19277725" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19277725</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_69">Spiller M, Bisogno G, Ferrari A, et al.: Prognostic factors in localized extraosseus Ewing family tumors. [Abstract] Pediatr Blood Cancer 46 (10) : A-PD.024, 434, 2006.</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_70">Ladenstein R, Pötschger U, Jürgens H, et al.: Comparison of treatment concepts for extraosseus Ewing tumors (EET) within consecutive trials of two GPOH Cooperative Study Groups. [Abstract] Pediatr Blood Cancer 45 (10) : A-P.C.004, 450, 2005.</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_71">Castex MP, Rubie H, Stevens MC, et al.: Extraosseous localized ewing tumors: improved outcome with anthracyclines--the French society of pediatric oncology and international society of pediatric oncology. J Clin Oncol 25 (10): 1176-82, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17401006" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17401006</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_72">Dantonello TM, Int-Veen C, Harms D, et al.: Cooperative trial CWS-91 for localized soft tissue sarcoma in children, adolescents, and young adults. J Clin Oncol 27 (9): 1446-55, 2009. [<a href="https://pubmed.ncbi.nlm.nih.gov/19224858" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19224858</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_73">Granowetter L, Womer R, Devidas M, et al.: Dose-intensified compared with standard chemotherapy for nonmetastatic Ewing sarcoma family of tumors: a Children's Oncology Group Study. J Clin Oncol 27 (15): 2536-41, 2009. [<a href="/pmc/articles/PMC2684856/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2684856</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19349548" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19349548</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_74">Cash T, McIlvaine E, Krailo MD, et al.: Comparison of clinical features and outcomes in patients with extraskeletal versus skeletal localized Ewing sarcoma: A report from the Children's Oncology Group. Pediatr Blood Cancer 63 (10): 1771-9, 2016. [<a href="/pmc/articles/PMC4995129/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4995129</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/27297500" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27297500</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_75">Collier AB, Simpson L, Monteleone P: Cutaneous Ewing sarcoma: report of 2 cases and literature review of presentation, treatment, and outcome of 76 other reported cases. J Pediatr Hematol Oncol 33 (8): 631-4, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/22042282" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22042282</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_76">Terrier-Lacombe MJ, Guillou L, Chibon F, et al.: Superficial primitive Ewing's sarcoma: a clinicopathologic and molecular cytogenetic analysis of 14 cases. Mod Pathol 22 (1): 87-94, 2009. [<a href="https://pubmed.ncbi.nlm.nih.gov/18820660" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18820660</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_28_77">Di Giannatale A, Frezza AM, Le Deley MC, et al.: Primary cutaneous and subcutaneous Ewing sarcoma. Pediatr Blood Cancer 62 (9): 1555-61, 2015. [<a href="https://pubmed.ncbi.nlm.nih.gov/25894676" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25894676</span></a>]</div></li></ol></div></div><div id="CDR0000062841__642"><h2 id="_CDR0000062841__642_">Special Considerations for the Treatment of Children With Cancer</h2><p id="CDR0000062841__643">Cancer in children and adolescents is rare, although the overall incidence has been slowly increasing since 1975.[<a class="bk_pop" href="#CDR0000062841_rl_642_1">1</a>] Children and adolescents with
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cancer should be referred to medical centers that have a multidisciplinary team
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of cancer specialists with experience treating the cancers that occur during
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childhood and adolescence. This multidisciplinary team approach incorporates the skills of the following health care professionals and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life:</p><ul id="CDR0000062841__644"><li class="half_rhythm"><div>Primary care physicians.</div></li><li class="half_rhythm"><div>Pediatric surgeons.</div></li><li class="half_rhythm"><div>Radiation oncologists. </div></li><li class="half_rhythm"><div>Pediatric oncologists/hematologists.</div></li><li class="half_rhythm"><div>Rehabilitation specialists.</div></li><li class="half_rhythm"><div>Pediatric nurse specialists.</div></li><li class="half_rhythm"><div>Social workers.</div></li><li class="half_rhythm"><div>Child-life professionals.</div></li><li class="half_rhythm"><div>Psychologists.</div></li></ul><p id="CDR0000062841__645">(Refer to the PDQ <a href="https://www.cancer.gov/publications/pdq/information-summaries/supportive-care" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Supportive and Palliative Care</a> summaries for specific information about supportive care for children and adolescents with cancer.)</p><p id="CDR0000062841__646">The American Academy of Pediatrics has outlined guidelines for pediatric cancer
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centers and their role in the treatment of pediatric patients with cancer.[<a class="bk_pop" href="#CDR0000062841_rl_642_2">2</a>] At these pediatric
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cancer centers, clinical trials are available for most types of cancer
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that occur in children and adolescents, and the opportunity to participate is offered to most patients and their families. Clinical trials for
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children and adolescents with cancer are generally designed to compare
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potentially better therapy with current standard therapy.
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Most of the progress made in identifying curative therapies for
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childhood cancers has been achieved through clinical trials. Information about
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ongoing clinical trials is available from the <a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCI website</a>.</p><p id="CDR0000062841__1800">Childhood and adolescent cancer survivors require close monitoring because side effects of cancer therapy may persist or develop months or years after treatment. (Refer to the PDQ summary on <a href="/books/n/pdqcis/CDR0000343584/">Late Effects of Treatment for Childhood Cancer</a> for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)</p><div id="CDR0000062841_rl_642"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000062841_rl_642_1">Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014. [<a href="/pmc/articles/PMC4136455/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4136455</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24853691" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24853691</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_642_2">American Academy of Pediatrics: Standards for pediatric cancer centers. Pediatrics 134 (2): 410-4, 2014. <a href="https://pediatrics.aappublications.org/content/134/2/410" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">Also available online</a>. Last accessed August 18, 2021.</div></li></ol></div></div><div id="CDR0000062841__34"><h2 id="_CDR0000062841__34_">Treatment of Localized Ewing Sarcoma</h2><div id="CDR0000062841__63"><h3>Standard Treatment Options for Localized Ewing Sarcoma</h3><p id="CDR0000062841__407">Standard treatment options for localized Ewing sarcoma include the following:</p><ol id="CDR0000062841__408"><li class="half_rhythm"><div><a href="#CDR0000062841__410">Chemotherapy</a>.</div></li><li class="half_rhythm"><div><a href="#CDR0000062841__413">Local-control measures</a>:<ul id="CDR0000062841__409"><li class="half_rhythm"><div><a href="#CDR0000062841__415">Surgery</a>.</div></li><li class="half_rhythm"><div><a href="#CDR0000062841__422">Radiation therapy</a>.</div></li><li class="half_rhythm"><div><a href="#CDR0000062841__1811">High-dose chemotherapy and autologous stem cell rescue</a>.</div></li></ul></div></li></ol><p id="CDR0000062841__35">Because most patients with apparently localized disease at diagnosis have
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occult metastatic disease, multidrug chemotherapy and local disease
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control with surgery and/or radiation therapy is indicated in the treatment of all
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patients.[<a class="bk_pop" href="#CDR0000062841_rl_34_1">1</a>-<a class="bk_pop" href="#CDR0000062841_rl_34_8">8</a>] Patients with localized Ewing sarcoma who receive current treatment regimens achieve event-free survival (EFS) and overall survival (OS) rates of approximately 70% at 5 years after diagnosis.[<a class="bk_pop" href="#CDR0000062841_rl_34_9">9</a>] </p><div id="CDR0000062841__410"><h4>Chemotherapy</h4><p id="CDR0000062841__36">Current standard chemotherapy in the United States includes vincristine,
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doxorubicin, and cyclophosphamide (VDC), alternating with ifosfamide and
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etoposide (IE) or VDC/IE.[<a class="bk_pop" href="#CDR0000062841_rl_34_9">9</a>]; [<a class="bk_pop" href="#CDR0000062841_rl_34_10">10</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335125/" class="def">Level of evidence: 1iiA</a>] </p><p id="CDR0000062841__411">Evidence (chemotherapy):</p><ol id="CDR0000062841__412"><li class="half_rhythm"><div>IE has shown activity in Ewing sarcoma, and a large randomized clinical trial and a nonrandomized trial demonstrated that outcome was improved when IE was alternated with VDC.[<a class="bk_pop" href="#CDR0000062841_rl_34_9">9</a>,<a class="bk_pop" href="#CDR0000062841_rl_34_11">11</a>]</div></li><li class="half_rhythm"><div>Dactinomycin is no longer used for Ewing sarcoma in the United States but continues to be used in Euro-Ewing Consortium studies.</div></li><li class="half_rhythm"><div>The use of
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high-dose VDC has shown promising results in small numbers of patients. A single-institution study of 44 patients treated with high-dose VDC and IE showed a 4-year EFS rate of 82%.[<a class="bk_pop" href="#CDR0000062841_rl_34_12">12</a>]</div></li><li class="half_rhythm"><div>However, in an intergroup trial of the Pediatric Oncology Group and the Children's Cancer Group, which compared an alkylator dose-intensified VDC/IE regimen with standard alkylator doses of the same VDC/IE regimen, no differences in outcome were observed.[<a class="bk_pop" href="#CDR0000062841_rl_34_13">13</a>] Unlike the single-institution trial, this trial did not maintain the dose intensity of cyclophosphamide for the duration of treatment.[<a class="bk_pop" href="#CDR0000062841_rl_34_12">12</a>]</div></li></ol><p id="CDR0000062841__217">In a Children's Oncology Group (COG) trial (<a href="https://www.cancer.gov/clinicaltrials/NCT00006734" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">COG-AEWS0031 [NCT00006734]</a>), 568 patients with newly diagnosed localized extradural Ewing sarcoma were randomly assigned to receive chemotherapy (VDC/IE) given either every 2 weeks (interval compression) or every 3 weeks (standard).
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Patients randomly assigned to the every 2-week interval of treatment had an improved 5-year EFS rate (73% vs. 65%, <i>P</i> = .048). There was no increase in toxicity observed with the every 2-week schedule.[<a class="bk_pop" href="#CDR0000062841_rl_34_10">10</a>] </p></div><div id="CDR0000062841__413"><h4>Local-control measures</h4><p id="CDR0000062841__414">Local control can be achieved by surgery and/or radiation therapy. Decisions regarding the optimal modality for local control for an individual patient involve consideration of the following:</p><ul id="CDR0000062841__1809"><li class="half_rhythm"><div>The possibility of complete resection with adequate margins after an initial period of systemic therapy.</div></li><li class="half_rhythm"><div>The predicted functional impact of a surgical procedure.</div></li><li class="half_rhythm"><div>The predicted morbidity after radiation therapy.</div></li><li class="half_rhythm"><div>The possibility of increased risk of second malignant neoplasms after radiation therapy.</div></li></ul><p id="CDR0000062841__1810">An analysis using propensity scoring (a method that adjusts for the inherent selection bias of the location and size of the tumor) to adjust for clinical features that may influence the preference for surgery only, radiation only, or combined surgery and radiation demonstrated that similar EFS rates are achieved with each mode of local therapy after propensity adjustment.[<a class="bk_pop" href="#CDR0000062841_rl_34_14">14</a>]</p><div id="CDR0000062841__415"><h5>Surgery</h5><p id="CDR0000062841__37">Surgery is
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generally the preferred approach if the lesion is resectable.[<a class="bk_pop" href="#CDR0000062841_rl_34_15">15</a>,<a class="bk_pop" href="#CDR0000062841_rl_34_16">16</a>] The
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superiority of resection for local control has never been tested in a
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prospective randomized trial. The apparent superiority may represent selection
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bias. </p><ol id="CDR0000062841__416"><li class="half_rhythm"><div>In past studies, smaller, more peripheral tumors were more likely to be
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treated with surgery, and larger, more central tumors were more likely to be
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treated with radiation therapy.[<a class="bk_pop" href="#CDR0000062841_rl_34_17">17</a>]</div></li><li class="half_rhythm"><div>An Italian retrospective study showed that surgery improved outcome only in extremity tumors, although the number of patients with central axis Ewing sarcoma who achieved adequate margins was small.[<a class="bk_pop" href="#CDR0000062841_rl_34_8">8</a>]</div></li><li class="half_rhythm"><div>In a series of 39 patients who received both surgery and radiation therapy at St. Jude Children's Research Hospital, the 8-year local failure rate was 5% for patients with negative surgical margins and 17% for those with positive margins.[<a class="bk_pop" href="#CDR0000062841_rl_34_5">5</a>]</div></li><li class="half_rhythm"><div>Data for patients with pelvic primary Ewing sarcoma from a North American intergroup trial showed no difference in local control or survival based on local-control modality—surgery alone, radiation therapy alone, or radiation plus surgery.[<a class="bk_pop" href="#CDR0000062841_rl_34_18">18</a>]</div></li></ol><p id="CDR0000062841__417">Potential benefits of surgery include the following:</p><ul id="CDR0000062841__418"><li class="half_rhythm"><div>If a very young child has Ewing sarcoma, surgery
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may be a less-morbid therapy than radiation therapy because of the retardation
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of bone growth caused by radiation.</div></li><li class="half_rhythm"><div>Treatment with surgery may allow for the omission of radiation therapy, which might be associated with an increased risk of subsequent neoplasms.</div></li><li class="half_rhythm"><div>Another potential benefit for surgical
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resection of the primary tumor is related to the amount of necrosis
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in the resected tumor. Patients with residual viable tumor in the resected
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specimen have a worse outcome than those with complete necrosis. In a
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French Ewing study (EW88), the EFS rates were 75% for patients with less than 5%
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viable tumor, 48% for patients with 5% to 30% viable tumor, and 20% for patients with more than 30% viable tumor.[<a class="bk_pop" href="#CDR0000062841_rl_34_17">17</a>] </div></li></ul><p id="CDR0000062841__320">One arm of the prospective, randomized <a href="https://www.cancer.gov/clinicaltrials/NCT00020566" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EURO-EWING-INTERGROUP-EE99 (NCT00020566</a>) trial demonstrated a benefit of high-dose therapy with busulfan-melphalan followed by stem cell rescue compared with continued chemotherapy for patients with localized tumor and poor response to initial chemotherapy.[<a class="bk_pop" href="#CDR0000062841_rl_34_19">19</a>]</p><p id="CDR0000062841__421">
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Pathologic fracture at the time of diagnosis does not preclude surgical resection and is not associated with adverse outcome.[<a class="bk_pop" href="#CDR0000062841_rl_34_20">20</a>]</p></div><div id="CDR0000062841__422"><h5>Radiation therapy</h5><p id="CDR0000062841__1836">Radiation therapy is usually employed in the following cases:</p><ul id="CDR0000062841__1837"><li class="half_rhythm"><div>Patients who do
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not have a surgical option that preserves function.</div></li><li class="half_rhythm"><div>Patients whose tumors have been excised but with inadequate margins.</div></li></ul><p id="CDR0000062841__38">Radiation therapy is delivered in a setting in which stringent planning
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techniques are applied by those experienced in the treatment of Ewing sarcoma. Such an approach will result in local control of the tumor with
|
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acceptable morbidity in most patients.[<a class="bk_pop" href="#CDR0000062841_rl_34_1">1</a>,<a class="bk_pop" href="#CDR0000062841_rl_34_2">2</a>,<a class="bk_pop" href="#CDR0000062841_rl_34_21">21</a>]</p><p id="CDR0000062841__424">The radiation dose may
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be adjusted depending on the extent of residual disease after the initial surgical
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procedure. When no surgical resection is performed, radiation therapy is generally administered in fractionated doses totaling approximately 55.8 Gy to the prechemotherapy tumor volume. A randomized study of 40 patients with Ewing sarcoma using
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55.8 Gy to the prechemotherapy tumor extent with a 2-cm margin compared with the
|
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same total-tumor dose after 39.6 Gy to the entire bone showed no
|
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difference in local control or EFS.[<a class="bk_pop" href="#CDR0000062841_rl_34_3">3</a>] Hyperfractionated
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radiation therapy has not been associated with improved local control or decreased morbidity.[<a class="bk_pop" href="#CDR0000062841_rl_34_1">1</a>]</p><p id="CDR0000062841__1838">For patients with residual disease after an attempt at surgical resection, the Intergroup Ewing Sarcoma Study (INT-0091) recommended 45 Gy to the original disease site plus a 10.8 Gy boost for patients with gross residual disease and 45 Gy plus a 5.4 Gy
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boost for patients with microscopic residual disease. No radiation therapy was recommended for those who have no evidence of
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microscopic residual disease after surgical resection.[<a class="bk_pop" href="#CDR0000062841_rl_34_13">13</a>]</p><p id="CDR0000062841__318">Comparison of proton-beam radiation therapy and intensity-modulated radiation therapy (IMRT) treatment plans has shown that proton-beam radiation therapy can spare more normal tissue adjacent to Ewing sarcoma primary tumors than IMRT.[<a class="bk_pop" href="#CDR0000062841_rl_34_22">22</a>] Follow-up remains relatively short, and there are no data available to determine whether the reduction in dose to adjacent tissue will result in improved functional outcome or reduce the risk of secondary malignancy. Because patient numbers are small and follow-up is relatively short, it is not possible to determine whether the risk of local recurrence might be increased by reducing radiation dose in tissue adjacent to the primary tumor.</p><p id="CDR0000062841__75"> Higher rates of local failure are seen in patients older than 14 years who have tumors larger than 8 cm in length.[<a class="bk_pop" href="#CDR0000062841_rl_34_23">23</a>] A retrospective analysis of patients with Ewing sarcoma of the chest wall compared patients who received hemithorax radiation therapy with those who received radiation therapy to the chest wall only. Patients with pleural invasion, pleural effusion, or intraoperative contamination were assigned to hemithorax radiation therapy. EFS was longer for patients who received hemithorax radiation, but the difference was not statistically significant. In addition, most patients with primary vertebral tumors did not receive hemithorax radiation and had a lower probability for EFS.[<a class="bk_pop" href="#CDR0000062841_rl_34_24">24</a>]</p><p id="CDR0000062841__69">Radiation therapy is associated with the development of subsequent neoplasms. A retrospective
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study noted that patients who received 60 Gy or more had an incidence
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of second malignancy of 20%. Patients who received 48 Gy to 60 Gy had an
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incidence of 5%, and those who received less than 48 Gy did not develop a
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second malignancy.[<a class="bk_pop" href="#CDR0000062841_rl_34_25">25</a>]</p></div><div id="CDR0000062841__1811"><h5>High-dose chemotherapy and autologous stem cell rescue</h5><p id="CDR0000062841__1812">Evidence (high-dose chemotherapy and autologous stem cell rescue):</p><ol id="CDR0000062841__1818"><li class="half_rhythm"><div class="half_rhythm">The role of high-dose therapy with busulfan-melphalan (BuMel) followed by stem cell rescue was investigated in the prospective, randomized <a href="https://www.cancer.gov/clinicaltrials/NCT00020566" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EURO-EWING-INTERGROUP-EE99 (NCT00020566)</a> trial for two distinct groups:[<a class="bk_pop" href="#CDR0000062841_rl_34_19">19</a>]<ol id="CDR0000062841__1890" class="lower-alpha"><li class="half_rhythm"><div class="half_rhythm">Patients who presented with isolated pulmonary metastases (R2pulm).</div></li><li class="half_rhythm"><div class="half_rhythm">Patients with localized tumors with poor response to initial chemotherapy (<90% necrosis) or with large tumors (>200 mL) (R2loc).</div><div class="half_rhythm"> Both study arms were compromised by the potential for selection bias for patients who were eligible for and accepted randomization, which may limit the generalizability of the results. Only 40% of eligible patients were randomized. <ul id="CDR0000062841__1892"><li class="half_rhythm"><div>For R2pulm patients, there was no statistically significant difference in EFS or OS between the treatment groups.[<a class="bk_pop" href="#CDR0000062841_rl_34_26">26</a>]<dl id="CDR0000062841__1971" class="temp-labeled-list"><dt>-</dt><dd><p class="no_top_margin">The EFS rates at 3 years were 50.6% for patients who received VAI plus whole-lung irradiation versus 56.6% for patients who received BuMel; the EFS rates at 8 years were 43.1% for patients who received VAI plus whole-lung irradiation versus 52.9% for patients who received BuMel.</p></dd><dt>-</dt><dd><p class="no_top_margin">The OS rates at 3 years were 68.0% for patients who received VAI plus whole-lung irradiation versus 68.2% for patients who received BuMel; the OS rates at 8 years were 54.2% for patients who received VAI plus whole-lung irradiation versus 55.3% for patients who received BuMel.</p></dd></dl></div></li><li class="half_rhythm"><div>Among R2loc patients, the 3-year EFS rate was superior with BuMel compared with continued chemotherapy (66.9% vs. 53.1%; <i>P</i> = .019). The 3-year OS rate was 78.0% with BuMel and 72.2% with continued chemotherapy (<i>P</i> = .028).</div></li></ul></div></li></ol></div><div class="half_rhythm">The induction regimen employed in the EURO-EWING-INTERGROUP-EE99 trial included vincristine, ifosfamide, doxorubicin, and etoposide (VIDE). This regimen is less dose intensive than the regimen employed in COG studies. This can be inferred from the intended dose intensity of the agents employed for the 21-week period that preceded randomization in the EURO-EWING-INTERGROUP-EE99 study (refer to <a class="figpopup" href="/books/NBK66045.23/table/CDR0000062841__1816/?report=objectonly" target="object" rid-figpopup="figCDR00000628411816" rid-ob="figobCDR00000628411816">Table 4</a>). The lower dose intensity can also be inferred from the outcome of the EURO-EWING-INTERGROUP-EE99 study for patients in the localized disease stratum. Results from this study include the following:<ul id="CDR0000062841__1894"><li class="half_rhythm"><div>Patients assigned to the most favorable risk stratum, R1, were patients with small primary tumors, less than 200 mL in volume. In addition, patients who had poor response to the initial six cycles of therapy with VIDE, as assessed by pathology or radiology, were removed from the R1 stratum and assigned to the R2 stratum. As a result, the R1 stratum includes only patients with small primary tumors and favorable response to initial therapy. The probability for EFS at 3 years for this favorable group was 76%, and the OS rate at 3 years was 85%.[<a class="bk_pop" href="#CDR0000062841_rl_34_27">27</a>] </div></li><li class="half_rhythm"><div>For all patients with localized Ewing sarcoma, including patients with large primary tumors and patients with poor response to initial therapy treated on the <a href="https://www.cancer.gov/clinicaltrials/NCT01231906" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">COG-AEWS1031 (NCT01231906)</a> trial, the 5-year probability for EFS was 73%, and the 5-year OS rate was 88%.[<a class="bk_pop" href="#CDR0000062841_rl_34_10">10</a>]</div></li></ul></div><div class="half_rhythm"> The observation that high-dose therapy with autologous stem cell rescue improved outcomes for patients with a poor response to initial therapy in the EURO-EWING-INTERGROUP-EE99 study must be interpreted in this context. The advantage of high-dose therapy as consolidation for patients with a poor response to initial treatment with a less intensive regimen cannot be extrapolated to a population of patients who received a more intensive treatment regimen as initial therapy.</div></li></ol></div></div></div><div id="CDR0000062841__TrialSearch_34_sid_7"><h3>Current Clinical Trials</h3><p id="CDR0000062841__TrialSearch_34_22">Use our <a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials/advanced-search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">advanced clinical trial search</a> to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. <a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">General information</a> about clinical trials is also available.</p></div><div id="CDR0000062841_rl_34"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000062841_rl_34_1">Dunst J, Jürgens H, Sauer R, et al.: Radiation therapy in Ewing's sarcoma: an update of the CESS 86 trial. Int J Radiat Oncol Biol Phys 32 (4): 919-30, 1995. [<a href="https://pubmed.ncbi.nlm.nih.gov/7607966" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7607966</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_34_2">Donaldson SS, Torrey M, Link MP, et al.: A multidisciplinary study investigating radiotherapy in Ewing's sarcoma: end results of POG #8346. Pediatric Oncology Group. Int J Radiat Oncol Biol Phys 42 (1): 125-35, 1998. [<a href="https://pubmed.ncbi.nlm.nih.gov/9747829" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9747829</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_34_3">Craft A, Cotterill S, Malcolm A, et al.: Ifosfamide-containing chemotherapy in Ewing's sarcoma: The Second United Kingdom Children's Cancer Study Group and the Medical Research Council Ewing's Tumor Study. J Clin Oncol 16 (11): 3628-33, 1998. [<a href="https://pubmed.ncbi.nlm.nih.gov/9817284" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9817284</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_34_4">Nilbert M, Saeter G, Elomaa I, et al.: Ewing's sarcoma treatment in Scandinavia 1984-1990--ten-year results of the Scandinavian Sarcoma Group Protocol SSGIV. Acta Oncol 37 (4): 375-8, 1998. [<a href="https://pubmed.ncbi.nlm.nih.gov/9743460" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9743460</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_34_5">Krasin MJ, Davidoff AM, Rodriguez-Galindo C, et al.: Definitive surgery and multiagent systemic therapy for patients with localized Ewing sarcoma family of tumors: local outcome and prognostic factors. Cancer 104 (2): 367-73, 2005. [<a href="https://pubmed.ncbi.nlm.nih.gov/15948159" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15948159</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_34_6">Bacci G, Forni C, Longhi A, et al.: Long-term outcome for patients with non-metastatic Ewing's sarcoma treated with adjuvant and neoadjuvant chemotherapies. 402 patients treated at Rizzoli between 1972 and 1992. Eur J Cancer 40 (1): 73-83, 2004. [<a href="https://pubmed.ncbi.nlm.nih.gov/14687792" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14687792</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_34_7">Rosito P, Mancini AF, Rondelli R, et al.: Italian Cooperative Study for the treatment of children and young adults with localized Ewing sarcoma of bone: a preliminary report of 6 years of experience. Cancer 86 (3): 421-8, 1999. [<a href="https://pubmed.ncbi.nlm.nih.gov/10430250" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10430250</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_34_8">Bacci G, Longhi A, Briccoli A, et al.: The role of surgical margins in treatment of Ewing's sarcoma family tumors: experience of a single institution with 512 patients treated with adjuvant and neoadjuvant chemotherapy. Int J Radiat Oncol Biol Phys 65 (3): 766-72, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16626886" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16626886</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_34_9">Grier HE, Krailo MD, Tarbell NJ, et al.: Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med 348 (8): 694-701, 2003. [<a href="https://pubmed.ncbi.nlm.nih.gov/12594313" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12594313</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_34_10">Womer RB, West DC, Krailo MD, et al.: Randomized controlled trial of interval-compressed chemotherapy for the treatment of localized Ewing sarcoma: a report from the Children's Oncology Group. J Clin Oncol 30 (33): 4148-54, 2012. [<a href="/pmc/articles/PMC3494838/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3494838</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23091096" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23091096</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_34_11">Ferrari S, Mercuri M, Rosito P, et al.: Ifosfamide and actinomycin-D, added in the induction phase to vincristine, cyclophosphamide and doxorubicin, improve histologic response and prognosis in patients with non metastatic Ewing's sarcoma of the extremity. J Chemother 10 (6): 484-91, 1998. [<a href="https://pubmed.ncbi.nlm.nih.gov/9876058" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9876058</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_34_12">Kolb EA, Kushner BH, Gorlick R, et al.: Long-term event-free survival after intensive chemotherapy for Ewing's family of tumors in children and young adults. J Clin Oncol 21 (18): 3423-30, 2003. [<a href="https://pubmed.ncbi.nlm.nih.gov/12972518" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12972518</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_34_13">Granowetter L, Womer R, Devidas M, et al.: Dose-intensified compared with standard chemotherapy for nonmetastatic Ewing sarcoma family of tumors: a Children's Oncology Group Study. J Clin Oncol 27 (15): 2536-41, 2009. [<a href="/pmc/articles/PMC2684856/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2684856</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19349548" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19349548</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_34_14">DuBois SG, Krailo MD, Gebhardt MC, et al.: Comparative evaluation of local control strategies in localized Ewing sarcoma of bone: a report from the Children's Oncology Group. Cancer 121 (3): 467-75, 2015. [<a href="/pmc/articles/PMC4305012/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4305012</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25251206" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25251206</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_34_15">Hoffmann C, Ahrens S, Dunst J, et al.: Pelvic Ewing sarcoma: a retrospective analysis of 241 cases. Cancer 85 (4): 869-77, 1999. [<a href="https://pubmed.ncbi.nlm.nih.gov/10091764" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10091764</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_34_16">Shamberger RC, Laquaglia MP, Krailo MD, et al.: Ewing sarcoma of the rib: results of an intergroup study with analysis of outcome by timing of resection. J Thorac Cardiovasc Surg 119 (6): 1154-61, 2000. [<a href="https://pubmed.ncbi.nlm.nih.gov/10838532" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10838532</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_34_17">Oberlin O, Deley MC, Bui BN, et al.: Prognostic factors in localized Ewing's tumours and peripheral neuroectodermal tumours: the third study of the French Society of Paediatric Oncology (EW88 study). Br J Cancer 85 (11): 1646-54, 2001. [<a href="/pmc/articles/PMC2363978/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2363978</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/11742482" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11742482</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_34_18">Yock TI, Krailo M, Fryer CJ, et al.: Local control in pelvic Ewing sarcoma: analysis from INT-0091--a report from the Children's Oncology Group. J Clin Oncol 24 (24): 3838-43, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16921035" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16921035</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_34_19">Whelan J, Le Deley MC, Dirksen U, et al.: High-Dose Chemotherapy and Blood Autologous Stem-Cell Rescue Compared With Standard Chemotherapy in Localized High-Risk Ewing Sarcoma: Results of Euro-E.W.I.N.G.99 and Ewing-2008. J Clin Oncol : JCO2018782516, 2018. [<a href="/pmc/articles/PMC6209090/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6209090</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/30188789" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30188789</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_34_20">Bramer JA, Abudu AA, Grimer RJ, et al.: Do pathological fractures influence survival and local recurrence rate in bony sarcomas? Eur J Cancer 43 (13): 1944-51, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17698347" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17698347</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_34_21">Krasin MJ, Rodriguez-Galindo C, Billups CA, et al.: Definitive irradiation in multidisciplinary management of localized Ewing sarcoma family of tumors in pediatric patients: outcome and prognostic factors. Int J Radiat Oncol Biol Phys 60 (3): 830-8, 2004. [<a href="https://pubmed.ncbi.nlm.nih.gov/15465200" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15465200</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_34_22">Rombi B, DeLaney TF, MacDonald SM, et al.: Proton radiotherapy for pediatric Ewing's sarcoma: initial clinical outcomes. Int J Radiat Oncol Biol Phys 82 (3): 1142-8, 2012. [<a href="https://pubmed.ncbi.nlm.nih.gov/21856094" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21856094</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_34_23">Fuchs B, Valenzuela RG, Sim FH: Pathologic fracture as a complication in the treatment of Ewing's sarcoma. Clin Orthop (415): 25-30, 2003. [<a href="https://pubmed.ncbi.nlm.nih.gov/14612626" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14612626</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_34_24">Schuck A, Ahrens S, Konarzewska A, et al.: Hemithorax irradiation for Ewing tumors of the chest wall. Int J Radiat Oncol Biol Phys 54 (3): 830-8, 2002. [<a href="https://pubmed.ncbi.nlm.nih.gov/12377336" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12377336</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_34_25">Kuttesch JF, Wexler LH, Marcus RB, et al.: Second malignancies after Ewing's sarcoma: radiation dose-dependency of secondary sarcomas. J Clin Oncol 14 (10): 2818-25, 1996. [<a href="https://pubmed.ncbi.nlm.nih.gov/8874344" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8874344</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_34_26">Dirksen U, Brennan B, Le Deley MC, et al.: High-Dose Chemotherapy Compared With Standard Chemotherapy and Lung Radiation in Ewing Sarcoma With Pulmonary Metastases: Results of the European Ewing Tumour Working Initiative of National Groups, 99 Trial and EWING 2008. J Clin Oncol 37 (34): 3192-3202, 2019. [<a href="/pmc/articles/PMC6881099/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6881099</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/31553693" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 31553693</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_34_27">Le Deley MC, Paulussen M, Lewis I, et al.: Cyclophosphamide compared with ifosfamide in consolidation treatment of standard-risk Ewing sarcoma: results of the randomized noninferiority Euro-EWING99-R1 trial. J Clin Oncol 32 (23): 2440-8, 2014. [<a href="https://pubmed.ncbi.nlm.nih.gov/24982464" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24982464</span></a>]</div></li></ol></div></div><div id="CDR0000062841__43"><h2 id="_CDR0000062841__43_">Treatment of Metastatic Ewing Sarcoma</h2><p id="CDR0000062841__44">Approximately 25% of patients with Ewing sarcoma have metastases at diagnosis.[<a class="bk_pop" href="#CDR0000062841_rl_43_1">1</a>] The prognosis of patients with metastatic disease is poor.
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With current therapies, patients who present with metastatic disease have a 6-year event-free survival (EFS) rate of approximately 28% and an overall survival (OS) rate of approximately 30%.[<a class="bk_pop" href="#CDR0000062841_rl_43_2">2</a>,<a class="bk_pop" href="#CDR0000062841_rl_43_3">3</a>] For patients
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with lung/pleural metastases only, the 6-year EFS rate is approximately 40% when utilizing bilateral lung irradiation.[<a class="bk_pop" href="#CDR0000062841_rl_43_2">2</a>,<a class="bk_pop" href="#CDR0000062841_rl_43_4">4</a>] In contrast, patients with bone/bone marrow metastases have a 4-year EFS rate of approximately 28%, and patients with combined lung and bone/bone
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marrow metastases have a 4-year EFS rate of approximately 14%.[<a class="bk_pop" href="#CDR0000062841_rl_43_4">4</a>,<a class="bk_pop" href="#CDR0000062841_rl_43_5">5</a>]
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</p><p id="CDR0000062841__425">The following factors independently predict a poor outcome in patients presenting with metastatic disease:[<a class="bk_pop" href="#CDR0000062841_rl_43_3">3</a>]</p><ul id="CDR0000062841__426"><li class="half_rhythm"><div>Age older than 14 years.</div></li><li class="half_rhythm"><div>Primary tumor volume of more than 200 mL.</div></li><li class="half_rhythm"><div>More than one bone metastatic site.</div></li><li class="half_rhythm"><div>Bone marrow metastases.</div></li><li class="half_rhythm"><div>Additional lung metastases.</div></li></ul><div id="CDR0000062841__59"><h3>Standard Treatment Options for Metastatic Ewing Sarcoma</h3><p id="CDR0000062841__427">Standard treatment options for metastatic Ewing sarcoma include the following:</p><ol id="CDR0000062841__428"><li class="half_rhythm"><div><a href="#CDR0000062841__430">Chemotherapy</a>.</div></li><li class="half_rhythm"><div><a href="#CDR0000062841__433">Surgery</a>.</div></li><li class="half_rhythm"><div><a href="#CDR0000062841__433">Radiation therapy</a>.</div></li></ol><div id="CDR0000062841__430"><h4>Chemotherapy</h4><p id="CDR0000062841__46">For patients with metastatic Ewing sarcoma, standard treatment that uses alternating cycles of vincristine/doxorubicin/cyclophosphamide
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and ifosfamide/etoposide combined with adequate local-control measures applied to both primary and metastatic sites often results in complete or
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partial responses; however, the overall cure rate is 20%.[<a class="bk_pop" href="#CDR0000062841_rl_43_5">5</a>-<a class="bk_pop" href="#CDR0000062841_rl_43_7">7</a>] </p><p id="CDR0000062841__431">The following chemotherapy regimens have <b>not</b> shown benefit:</p><ul id="CDR0000062841__432"><li class="half_rhythm"><div>In the Intergroup Ewing Sarcoma Study, patients with metastatic disease showed no benefit from the addition of ifosfamide and etoposide to a standard regimen of vincristine, doxorubicin, cyclophosphamide, and dactinomycin.[<a class="bk_pop" href="#CDR0000062841_rl_43_7">7</a>]</div></li><li class="half_rhythm"><div>In another Intergroup study, increasing dose intensity of cyclophosphamide, ifosfamide, and doxorubicin did not improve outcome compared with regimens utilizing standard-dose intensity. This regimen increased toxicity and risk of second malignancy without improving EFS or OS.[<a class="bk_pop" href="#CDR0000062841_rl_43_2">2</a>]</div></li><li class="half_rhythm"><div>Intensification of ifosfamide to 2.8 g/m<sup>2</sup> per day for 5 days did not improve outcome when administered with standard chemotherapy in patients with newly diagnosed metastatic Ewing sarcoma.[<a class="bk_pop" href="#CDR0000062841_rl_43_8">8</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335153/" class="def">Level of evidence: 3iiiDi</a>]</div></li></ul></div><div id="CDR0000062841__433"><h4>Surgery and radiation therapy</h4><p id="CDR0000062841__47">Systematic use of surgery and radiation therapy for metastatic sites may improve overall outcome in patients with extrapulmonary metastases. </p><p id="CDR0000062841__434">Evidence (surgery and radiation therapy):</p><ol id="CDR0000062841__435"><li class="half_rhythm"><div class="half_rhythm">In a retrospective data analysis of 120 patients with multifocal metastatic Ewing sarcoma, patients who received local treatment to both the primary tumor and metastases had a better outcome than did patients who received local treatment to the primary tumor only or with no local treatment (3-year EFS rate, 39% vs. 17% and 14%, respectively; <i>P</i> < .001).[<a class="bk_pop" href="#CDR0000062841_rl_43_9">9</a>]</div></li><li class="half_rhythm"><div class="half_rhythm">A similar trend for better outcome with irradiation of all sites of metastatic disease was seen in three retrospective analyses of smaller groups of patients receiving radiation therapy to all tumor sites.[<a class="bk_pop" href="#CDR0000062841_rl_43_10">10</a>-<a class="bk_pop" href="#CDR0000062841_rl_43_12">12</a>]</div><div class="half_rhythm"> These results must be interpreted with caution. The patients who received local-control therapy to all known sites of metastatic disease were selected by the treating investigator, not randomly assigned. Patients with so many metastases that radiation to all sites would result in bone marrow failure were not selected to receive radiation to all sites of metastatic disease. Patients who did not achieve control of the primary tumor did not go on to have local control of all sites of metastatic disease. There was a selection bias such that while all patients in these reports had multiple sites of metastatic disease, the patients who had surgery and/or radiation therapy to all sites of clinically detectable metastatic disease had better responses to systemic therapy and fewer sites of metastasis than did patients who did not undergo similar therapy of metastatic sites. </div></li></ol><p id="CDR0000062841__330">Radiation therapy, delivered in a setting in which stringent planning techniques are applied by those experienced in the treatment of Ewing sarcoma, should be considered. Such an approach will result in local control of tumor with acceptable morbidity in most patients.[<a class="bk_pop" href="#CDR0000062841_rl_43_13">13</a>] </p><p id="CDR0000062841__436">The radiation dose depends on the metastatic site of disease:</p><ul id="CDR0000062841__437"><li class="half_rhythm"><div><b>Bone and soft tissue. </b> Stereotactic body radiation therapy has been used to treat metastatic sites in bone and soft tissue. The median total curative/definitive stereotactic body radiation therapy dose delivered was 40 Gy in five fractions (range, 30–60 Gy in 3–10 fractions). The median total palliative stereotactic body radiation therapy dose delivered was 40 Gy in five fractions (range, 16–50 Gy in 1–10 fractions). These short-course regimens with large-dose fractions are biologically equivalent to higher doses delivered with smaller-dose fractions given over longer treatment courses.[<a class="bk_pop" href="#CDR0000062841_rl_43_14">14</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335152/" class="def">Level of evidence: 3iiiC</a>]</div></li><li class="half_rhythm"><div><b>Pulmonary. </b>For all
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patients with pulmonary metastases, whole-lung irradiation should be considered, even if
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complete resolution of overt pulmonary metastatic disease has been achieved with
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chemotherapy.[<a class="bk_pop" href="#CDR0000062841_rl_43_4">4</a>,<a class="bk_pop" href="#CDR0000062841_rl_43_5">5</a>,<a class="bk_pop" href="#CDR0000062841_rl_43_15">15</a>] Radiation doses are modulated on the basis of the amount of
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lung to be irradiated and on pulmonary function. Doses between 12 Gy and 15 Gy are generally used if whole
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lungs are treated.</div></li></ul></div><div id="CDR0000062841__438"><h4>Other therapies</h4><p id="CDR0000062841__48">More intensive therapies, many of which incorporate high-dose chemotherapy with
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or without total-body irradiation in conjunction with stem cell support, have
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not shown improvement in EFS rates for patients with bone
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and/or bone marrow metastases.[<a class="bk_pop" href="#CDR0000062841_rl_43_2">2</a>,<a class="bk_pop" href="#CDR0000062841_rl_43_3">3</a>,<a class="bk_pop" href="#CDR0000062841_rl_43_10">10</a>,<a class="bk_pop" href="#CDR0000062841_rl_43_16">16</a>-<a class="bk_pop" href="#CDR0000062841_rl_43_18">18</a>]; [<a class="bk_pop" href="#CDR0000062841_rl_43_19">19</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335153/" class="def">Level of evidence: 3iiiDi</a>] (Refer to the <a href="#CDR0000062841__138">High-Dose Therapy With Stem Cell Rescue for Ewing Sarcoma</a> section of this summary for more information.)</p><ul id="CDR0000062841__439"><li class="half_rhythm"><div><b>High-dose chemotherapy with stem cell support. </b>One of the largest studies was the <a href="https://www.cancer.gov/clinicaltrials/NCT00020566" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EURO-EWING-INTERGROUP-EE99</a> R3 trial that enrolled 281 patients with primary disseminated metastatic Ewing sarcoma. Patients were treated with six cycles of vincristine, ifosfamide, doxorubicin, and etoposide followed by high-dose therapy and autologous stem cell transplant and demonstrated a 3-year EFS rate of 27% and an OS rate of 34%. Factors such as the presence and number of bone lesions, primary tumor volume greater than 200 mL, age older than 14 years, additional pulmonary metastases, and bone marrow involvement were identified as independent prognostic factors.[<a class="bk_pop" href="#CDR0000062841_rl_43_3">3</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335147/" class="def">Level of evidence: 3iiDi</a>] The role of high-dose therapy with busulfan-melphalan (BuMel) followed by stem cell rescue was investigated in the prospective, randomized <a href="https://www.cancer.gov/clinicaltrials/NCT00020566" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EURO-EWING-INTERGROUP-EE99 (NCT00020566)</a> trial. Among patients with isolated pulmonary metastases, there was no difference in 3-year EFS rates (55.7% with BuMel vs. 50.3% with continued chemotherapy and whole-lung radiation therapy; <i>P</i> = .21).[<a class="bk_pop" href="#CDR0000062841_rl_43_20">20</a>]</div></li><li class="half_rhythm"><div><b>Melphalan. </b>Melphalan, at nonmyeloablative doses, proved to be an active agent in an up-front window study for patients with metastatic disease at diagnosis; however, the cure rate remained extremely low.[<a class="bk_pop" href="#CDR0000062841_rl_43_21">21</a>]</div></li><li class="half_rhythm"><div><b>Irinotecan. </b>Irinotecan was administered as a single agent in an up-front window for patients with newly diagnosed metastatic Ewing sarcoma and showed modest activity (partial response in 5 of 24 patients).[<a class="bk_pop" href="#CDR0000062841_rl_43_22">22</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000587991/" class="def">Level of evidence: 3iiiDiv</a>] Further investigation is needed to determine irinotecan dosing and combinations with other agents for patients with Ewing sarcoma.</div></li></ul></div></div><div id="CDR0000062841__TrialSearch_43_sid_8"><h3>Current Clinical Trials</h3><p id="CDR0000062841__TrialSearch_43_22">Use our <a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials/advanced-search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">advanced clinical trial search</a> to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. <a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">General information</a> about clinical trials is also available.</p></div><div id="CDR0000062841_rl_43"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000062841_rl_43_1">Esiashvili N, Goodman M, Marcus RB: Changes in incidence and survival of Ewing sarcoma patients over the past 3 decades: Surveillance Epidemiology and End Results data. J Pediatr Hematol Oncol 30 (6): 425-30, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/18525458" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18525458</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_43_2">Miser JS, Goldsby RE, Chen Z, et al.: Treatment of metastatic Ewing sarcoma/primitive neuroectodermal tumor of bone: evaluation of increasing the dose intensity of chemotherapy--a report from the Children's Oncology Group. Pediatr Blood Cancer 49 (7): 894-900, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17584910" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17584910</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_43_3">Ladenstein R, Pötschger U, Le Deley MC, et al.: Primary disseminated multifocal Ewing sarcoma: results of the Euro-EWING 99 trial. J Clin Oncol 28 (20): 3284-91, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/20547982" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20547982</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_43_4">Paulussen M, Ahrens S, Craft AW, et al.: Ewing's tumors with primary lung metastases: survival analysis of 114 (European Intergroup) Cooperative Ewing's Sarcoma Studies patients. J Clin Oncol 16 (9): 3044-52, 1998. [<a href="https://pubmed.ncbi.nlm.nih.gov/9738574" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9738574</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_43_5">Paulussen M, Ahrens S, Burdach S, et al.: Primary metastatic (stage IV) Ewing tumor: survival analysis of 171 patients from the EICESS studies. European Intergroup Cooperative Ewing Sarcoma Studies. Ann Oncol 9 (3): 275-81, 1998. [<a href="https://pubmed.ncbi.nlm.nih.gov/9602261" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9602261</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_43_6">Pinkerton CR, Bataillard A, Guillo S, et al.: Treatment strategies for metastatic Ewing's sarcoma. Eur J Cancer 37 (11): 1338-44, 2001. [<a href="https://pubmed.ncbi.nlm.nih.gov/11435062" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11435062</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_43_7">Miser JS, Krailo MD, Tarbell NJ, et al.: Treatment of metastatic Ewing's sarcoma or primitive neuroectodermal tumor of bone: evaluation of combination ifosfamide and etoposide--a Children's Cancer Group and Pediatric Oncology Group study. J Clin Oncol 22 (14): 2873-6, 2004. [<a href="https://pubmed.ncbi.nlm.nih.gov/15254055" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15254055</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_43_8">Magnan H, Goodbody CM, Riedel E, et al.: Ifosfamide dose-intensification for patients with metastatic Ewing sarcoma. Pediatr Blood Cancer 62 (4): 594-7, 2015. [<a href="/pmc/articles/PMC4474186/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4474186</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25630954" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25630954</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_43_9">Haeusler J, Ranft A, Boelling T, et al.: The value of local treatment in patients with primary, disseminated, multifocal Ewing sarcoma (PDMES). Cancer 116 (2): 443-50, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/19924786" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19924786</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_43_10">Burdach S, Thiel U, Schöniger M, et al.: Total body MRI-governed involved compartment irradiation combined with high-dose chemotherapy and stem cell rescue improves long-term survival in Ewing tumor patients with multiple primary bone metastases. Bone Marrow Transplant 45 (3): 483-9, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/19684633" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19684633</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_43_11">Paulino AC, Mai WY, Teh BS: Radiotherapy in metastatic ewing sarcoma. Am J Clin Oncol 36 (3): 283-6, 2013. [<a href="https://pubmed.ncbi.nlm.nih.gov/22547005" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22547005</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_43_12">Casey DL, Wexler LH, Meyers PA, et al.: Radiation for bone metastases in Ewing sarcoma and rhabdomyosarcoma. Pediatr Blood Cancer 62 (3): 445-9, 2015. [<a href="/pmc/articles/PMC5045248/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5045248</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25346208" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25346208</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_43_13">Donaldson SS, Torrey M, Link MP, et al.: A multidisciplinary study investigating radiotherapy in Ewing's sarcoma: end results of POG #8346. Pediatric Oncology Group. Int J Radiat Oncol Biol Phys 42 (1): 125-35, 1998. [<a href="https://pubmed.ncbi.nlm.nih.gov/9747829" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9747829</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_43_14">Brown LC, Lester RA, Grams MP, et al.: Stereotactic body radiotherapy for metastatic and recurrent ewing sarcoma and osteosarcoma. Sarcoma 2014: 418270, 2014. [<a href="/pmc/articles/PMC4274855/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4274855</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25548538" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25548538</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_43_15">Spunt SL, McCarville MB, Kun LE, et al.: Selective use of whole-lung irradiation for patients with Ewing sarcoma family tumors and pulmonary metastases at the time of diagnosis. J Pediatr Hematol Oncol 23 (2): 93-8, 2001. [<a href="https://pubmed.ncbi.nlm.nih.gov/11216713" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11216713</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_43_16">Meyers PA, Krailo MD, Ladanyi M, et al.: High-dose melphalan, etoposide, total-body irradiation, and autologous stem-cell reconstitution as consolidation therapy for high-risk Ewing's sarcoma does not improve prognosis. J Clin Oncol 19 (11): 2812-20, 2001. [<a href="https://pubmed.ncbi.nlm.nih.gov/11387352" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11387352</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_43_17">Burdach S, Meyer-Bahlburg A, Laws HJ, et al.: High-dose therapy for patients with primary multifocal and early relapsed Ewing's tumors: results of two consecutive regimens assessing the role of total-body irradiation. J Clin Oncol 21 (16): 3072-8, 2003. [<a href="https://pubmed.ncbi.nlm.nih.gov/12915596" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12915596</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_43_18">Thiel U, Wawer A, Wolf P, et al.: No improvement of survival with reduced- versus high-intensity conditioning for allogeneic stem cell transplants in Ewing tumor patients. Ann Oncol 22 (7): 1614-21, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/21245159" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21245159</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_43_19">Loschi S, Dufour C, Oberlin O, et al.: Tandem high-dose chemotherapy strategy as first-line treatment of primary disseminated multifocal Ewing sarcomas in children, adolescents and young adults. Bone Marrow Transplant 50 (8): 1083-8, 2015. [<a href="https://pubmed.ncbi.nlm.nih.gov/26030048" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26030048</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_43_20">Whelan J, Le Deley MC, Dirksen U, et al.: High-Dose Chemotherapy and Blood Autologous Stem-Cell Rescue Compared With Standard Chemotherapy in Localized High-Risk Ewing Sarcoma: Results of Euro-E.W.I.N.G.99 and Ewing-2008. J Clin Oncol : JCO2018782516, 2018. [<a href="/pmc/articles/PMC6209090/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6209090</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/30188789" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30188789</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_43_21">Luksch R, Grignani G, Fagioli F, et al.: Response to melphalan in up-front investigational window therapy for patients with metastatic Ewing's family tumours. Eur J Cancer 43 (5): 885-90, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17254770" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17254770</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_43_22">Morland B, Platt K, Whelan JS: A phase II window study of irinotecan (CPT-11) in high risk Ewing sarcoma: a Euro-E.W.I.N.G. study. Pediatr Blood Cancer 61 (3): 442-5, 2014. [<a href="https://pubmed.ncbi.nlm.nih.gov/24019263" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24019263</span></a>]</div></li></ol></div></div><div id="CDR0000062841__51"><h2 id="_CDR0000062841__51_">Treatment of Recurrent Ewing Sarcoma</h2><p id="CDR0000062841__340"> Recurrence of Ewing sarcoma is most common within 2 years of initial diagnosis (approximately 80%).[<a class="bk_pop" href="#CDR0000062841_rl_51_1">1</a>,<a class="bk_pop" href="#CDR0000062841_rl_51_2">2</a>] However, late relapses occurring more than 5 years from initial diagnosis are more common in Ewing sarcoma (13%; 95% confidence interval, 9.4%–16.5%) than in other pediatric solid tumors.[<a class="bk_pop" href="#CDR0000062841_rl_51_3">3</a>] An analysis of the Surveillance, Epidemiology, and End Results (SEER) Program database identified 1,351 patients who survived more than 60 months from diagnosis.[<a class="bk_pop" href="#CDR0000062841_rl_51_4">4</a>] Of these patients, 209 died; 144 of the deaths (69%) were attributed to recurrent, progressive Ewing sarcoma. Black race, male sex, older age at initial diagnosis, and primary tumors of the pelvis and axial skeleton were associated with a higher risk of late death. This analysis covered the period from 1973 to 2013, and the 1,351 patients represented only 38% of the patients in the original sample, which reflects the inferior treatment outcomes from the earlier era. It is possible that patients who reach the 5-year point after more contemporary treatment may not recapitulate this experience.</p><p id="CDR0000062841__440">The overall prognosis for patients with recurrent Ewing sarcoma is poor; the 5-year survival rate after recurrence is approximately 10% to 15%.[<a class="bk_pop" href="#CDR0000062841_rl_51_2">2</a>,<a class="bk_pop" href="#CDR0000062841_rl_51_5">5</a>,<a class="bk_pop" href="#CDR0000062841_rl_51_6">6</a>]; [<a class="bk_pop" href="#CDR0000062841_rl_51_1">1</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335144/" class="def">Level of evidence: 3iiA</a>] </p><p id="CDR0000062841__441">Prognostic factors include the following:</p><ul id="CDR0000062841__442"><li class="half_rhythm"><div><b>Time to recurrence. </b>Time to recurrence is the most important prognostic factor. Patients whose Ewing sarcoma recurred more than 2 years from initial diagnosis had a 5-year survival rate of 30%, versus 7% for patients whose Ewing sarcoma recurred within 2 years.[<a class="bk_pop" href="#CDR0000062841_rl_51_1">1</a>,<a class="bk_pop" href="#CDR0000062841_rl_51_2">2</a>]</div></li><li class="half_rhythm"><div><b>Local and distant recurrence. </b>Patients with both local recurrence and distant metastases have a worse outcome than do patients with either isolated local recurrence or metastatic recurrence alone.[<a class="bk_pop" href="#CDR0000062841_rl_51_1">1</a>,<a class="bk_pop" href="#CDR0000062841_rl_51_2">2</a>]</div></li><li class="half_rhythm"><div><b>Isolated pulmonary recurrence. </b>Isolated pulmonary recurrence was not an important prognostic factor in a North American series.[<a class="bk_pop" href="#CDR0000062841_rl_51_1">1</a>] In the Italian/Scandinavian experience, younger age, longer disease-free interval, and lung-only recurrence were associated with longer progression-free survival (PFS) after recurrence. In this experience, patients with Ewing sarcoma that recurred after initial therapy, which included high-dose therapy with autologous stem cell rescue, were less likely to achieve a second complete remission.[<a class="bk_pop" href="#CDR0000062841_rl_51_7">7</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335149/" class="def">Level of evidence: 3iiDiii</a>]</div></li></ul><div id="CDR0000062841__66"><h3>Treatment Options for Recurrent Ewing Sarcoma</h3><p id="CDR0000062841__225">The selection of treatment for patients with recurrent disease depends on many
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factors, including the following:</p><ul id="CDR0000062841__443"><li class="half_rhythm"><div> Site of recurrence.</div></li><li class="half_rhythm"><div>Previous treatment.</div></li><li class="half_rhythm"><div>Individual patient considerations. </div></li></ul><p id="CDR0000062841__444">There is no standardized second-line treatment for patients with relapsed or refractory Ewing sarcoma. Most patients in first relapse are treated with conventional systemic chemotherapy. Patients who demonstrate a response to therapy may undergo local control to sites of recurrence.</p><p id="CDR0000062841__445">Treatment options for recurrent Ewing sarcoma include the following:</p><ol id="CDR0000062841__446"><li class="half_rhythm"><div><a href="#CDR0000062841__447">Chemotherapy</a>.</div></li><li class="half_rhythm"><div><a href="#CDR0000062841__1987">Surgery</a>.</div></li><li class="half_rhythm"><div><a href="#CDR0000062841__451">Radiation therapy</a>.</div></li><li class="half_rhythm"><div><a href="#CDR0000062841__1854">High-dose chemotherapy with stem cell support</a>.</div></li><li class="half_rhythm"><div><a href="#CDR0000062841__452">Other therapies</a>.</div></li></ol><div id="CDR0000062841__447"><h4>Chemotherapy</h4><p id="CDR0000062841__448">Combinations of chemotherapy, such as cyclophosphamide and topotecan or irinotecan and temozolomide with or without vincristine, are active in recurrent Ewing sarcoma and can be considered for these patients.[<a class="bk_pop" href="#CDR0000062841_rl_51_8">8</a>-<a class="bk_pop" href="#CDR0000062841_rl_51_13">13</a>]</p><div id="CDR0000062841__1874" class="table"><h3><span class="title">Table 5. Results from Studies that Used Cyclophosphamide and Topotecan Regimens to Treat Patients With Relapsed and/or Refractory Ewing Sarcoma</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK66045.23/table/CDR0000062841__1874/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__CDR0000062841__1874_lrgtbl__"><table class="no_margin"><thead><tr><th colspan="1" rowspan="1" style="vertical-align:top;">Study Reference </th><th colspan="1" rowspan="1" style="vertical-align:top;">Trial Phase (Total No. of Patients)</th><th colspan="1" rowspan="1" style="vertical-align:top;">Median
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Age (Range) (y) </th><th colspan="1" rowspan="1" style="vertical-align:top;">CR/PR</th><th colspan="1" rowspan="1" style="vertical-align:top;">RR</th><th colspan="1" rowspan="1" style="vertical-align:top;">Cyclophosphamide
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(mg/m<sup>2</sup>)/Topotecan
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(mg/m<sup>2</sup>) × d</th><th colspan="1" rowspan="1" style="vertical-align:top;">Other
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Agents
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</th></tr></thead><tbody><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Saylors et al.[<a class="bk_pop" href="#CDR0000062841_rl_51_8">8</a>]
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">II (17)</td><td colspan="1" rowspan="1" style="vertical-align:top;">13.8 (1–21)
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">1/3
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">29%
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">250 × 5/0.75 × 5
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">None</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Hunold et al.[<a class="bk_pop" href="#CDR0000062841_rl_51_10">10</a>]</td><td colspan="1" rowspan="1" style="vertical-align:top;">
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R (54)
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">17.4 (3–49)
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">0/16
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">30%
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">250 × 5/0.75 × 5
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">
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None
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</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Farhat et al.[<a class="bk_pop" href="#CDR0000062841_rl_51_14">14</a>]</td><td colspan="1" rowspan="1" style="vertical-align:top;">R (14)
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">11 (2–19)
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">0/3
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">21%
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">250 × 5/0.75 × 5
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">None
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</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Kebudi et al.[<a class="bk_pop" href="#CDR0000062841_rl_51_15">15</a>]</td><td colspan="1" rowspan="1" style="vertical-align:top;">R (14)
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">13 (3–16)
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">2/5
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">50%
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">250 × 5/0.75 × 5</td><td colspan="1" rowspan="1" style="vertical-align:top;">VCR
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</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">II = phase II trial; CR = complete response; PR = partial response; R = retrospective; RR = objective response rate; VCR = vincristine. </p></div></dd></dl></div></div></div><p id="CDR0000062841__1872">These studies were retrospective, not prospective; prospective trials with clearly defined eligibility cohorts and intent-to-treat analyses are lacking. When combined, these studies accrued 99 patients and observed 3 complete remissions and 27 partial remissions. The objective response rate was 30%.</p><div id="CDR0000062841__1875" class="table"><h3><span class="title">Table 6. Results from Studies that Used Temozolomide and Irinotecan Regimens to Treat Patients With Relapsed and/or Refractory Ewing Sarcoma</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK66045.23/table/CDR0000062841__1875/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__CDR0000062841__1875_lrgtbl__"><table class="no_margin"><thead><tr><th colspan="1" rowspan="1" style="vertical-align:top;">Study Reference </th><th colspan="1" rowspan="1" style="vertical-align:top;">Trial Phase (Total No. of Patients)</th><th colspan="1" rowspan="1" style="vertical-align:top;">Median
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Age (Range) (y) </th><th colspan="1" rowspan="1" style="vertical-align:top;">CR/PR</th><th colspan="1" rowspan="1" style="vertical-align:top;">RR</th><th colspan="1" rowspan="1" style="vertical-align:top;">Temozolomide
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(mg/m<sup>2</sup>)/Irinotecan
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(mg/m<sup>2</sup>) × d × wk</th><th colspan="1" rowspan="1" style="vertical-align:top;">Other
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Agents
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</th></tr></thead><tbody><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Wagner et al.[<a class="bk_pop" href="#CDR0000062841_rl_51_11">11</a>]
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">R (16) </td><td colspan="1" rowspan="1" style="vertical-align:top;">18 (7–33) </td><td colspan="1" rowspan="1" style="vertical-align:top;">1/3 </td><td colspan="1" rowspan="1" style="vertical-align:top;">29% </td><td colspan="1" rowspan="1" style="vertical-align:top;">100 × 5/IV 10–20 × 5 × 2 </td><td colspan="1" rowspan="1" style="vertical-align:top;">None</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Casey et al.[<a class="bk_pop" href="#CDR0000062841_rl_51_12">12</a>]</td><td colspan="1" rowspan="1" style="vertical-align:top;">R (19) </td><td colspan="1" rowspan="1" style="vertical-align:top;">19.5 (2–40) </td><td colspan="1" rowspan="1" style="vertical-align:top;">5/7 </td><td colspan="1" rowspan="1" style="vertical-align:top;">63% </td><td colspan="1" rowspan="1" style="vertical-align:top;">100 × 5/IV 20 × 5 × 2 </td><td colspan="1" rowspan="1" style="vertical-align:top;">None</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Hernandez-Marques et al.[<a class="bk_pop" href="#CDR0000062841_rl_51_16">16</a>]</td><td colspan="1" rowspan="1" style="vertical-align:top;">R (8) </td><td colspan="1" rowspan="1" style="vertical-align:top;">13 (6–18) </td><td colspan="1" rowspan="1" style="vertical-align:top;">0/3 </td><td colspan="1" rowspan="1" style="vertical-align:top;">37% </td><td colspan="1" rowspan="1" style="vertical-align:top;">80–100 × 5/IV 10–20 × 5 × 2 </td><td colspan="1" rowspan="1" style="vertical-align:top;">None</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Raciborska et al.[<a class="bk_pop" href="#CDR0000062841_rl_51_13">13</a>]</td><td colspan="1" rowspan="1" style="vertical-align:top;">R (22) </td><td colspan="1" rowspan="1" style="vertical-align:top;">14.3 </td><td colspan="1" rowspan="1" style="vertical-align:top;">5/7 </td><td colspan="1" rowspan="1" style="vertical-align:top;">54% </td><td colspan="1" rowspan="1" style="vertical-align:top;">125 × 5/IV 50 × 5 </td><td colspan="1" rowspan="1" style="vertical-align:top;">VCR</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">McKnall-Knapp et al.[<a class="bk_pop" href="#CDR0000062841_rl_51_17">17</a>]</td><td colspan="1" rowspan="1" style="vertical-align:top;">I (1) </td><td colspan="1" rowspan="1" style="vertical-align:top;">N/A </td><td colspan="1" rowspan="1" style="vertical-align:top;">0/1 </td><td colspan="1" rowspan="1" style="vertical-align:top;">100% </td><td colspan="1" rowspan="1" style="vertical-align:top;">100 × 5/IV 20 × 5 × 2 </td><td colspan="1" rowspan="1" style="vertical-align:top;">VCR</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Wagner et al.[<a class="bk_pop" href="#CDR0000062841_rl_51_18">18</a>]</td><td colspan="1" rowspan="1" style="vertical-align:top;">I (5) </td><td colspan="1" rowspan="1" style="vertical-align:top;">(<21) </td><td colspan="1" rowspan="1" style="vertical-align:top;">1/1 </td><td colspan="1" rowspan="1" style="vertical-align:top;">40% </td><td colspan="1" rowspan="1" style="vertical-align:top;">100–150 × 5/PO 35–90 × 5 </td><td colspan="1" rowspan="1" style="vertical-align:top;">VCR</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Wagner et al.[<a class="bk_pop" href="#CDR0000062841_rl_51_19">19</a>]</td><td colspan="1" rowspan="1" style="vertical-align:top;">I (2) </td><td colspan="1" rowspan="1" style="vertical-align:top;">20, 22 </td><td colspan="1" rowspan="1" style="vertical-align:top;">1/1 </td><td colspan="1" rowspan="1" style="vertical-align:top;">100% </td><td colspan="1" rowspan="1" style="vertical-align:top;">150 × 5/PO 90 × 5 </td><td colspan="1" rowspan="1" style="vertical-align:top;">VCR, BEV</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Bagatell et al.[<a class="bk_pop" href="#CDR0000062841_rl_51_20">20</a>]</td><td colspan="1" rowspan="1" style="vertical-align:top;">I (7) </td><td colspan="1" rowspan="1" style="vertical-align:top;">(<21) </td><td colspan="1" rowspan="1" style="vertical-align:top;">0/1 </td><td colspan="1" rowspan="1" style="vertical-align:top;">14% </td><td colspan="1" rowspan="1" style="vertical-align:top;">100–150 × 5/PO 50–90 × 5 </td><td colspan="1" rowspan="1" style="vertical-align:top;">TMS</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Kurucu et al.[<a class="bk_pop" href="#CDR0000062841_rl_51_21">21</a>]</td><td colspan="1" rowspan="1" style="vertical-align:top;">R (20) </td><td colspan="1" rowspan="1" style="vertical-align:top;">14 (1–18) </td><td colspan="1" rowspan="1" style="vertical-align:top;">UK </td><td colspan="1" rowspan="1" style="vertical-align:top;">55% </td><td colspan="1" rowspan="1" style="vertical-align:top;">100 × 5/IV 20 × 5 × 2 </td><td colspan="1" rowspan="1" style="vertical-align:top;">None</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Anderson et al.[<a class="bk_pop" href="#CDR0000062841_rl_51_22">22</a>]</td><td colspan="1" rowspan="1" style="vertical-align:top;">R (25) </td><td colspan="1" rowspan="1" style="vertical-align:top;">15 </td><td colspan="1" rowspan="1" style="vertical-align:top;">7/9 </td><td colspan="1" rowspan="1" style="vertical-align:top;">64% </td><td colspan="1" rowspan="1" style="vertical-align:top;">100 × 5/IV 10 × 5 × 2 </td><td colspan="1" rowspan="1" style="vertical-align:top;">None</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Palmerini et al.[<a class="bk_pop" href="#CDR0000062841_rl_51_23">23</a>]</td><td colspan="1" rowspan="1" style="vertical-align:top;">R (51) </td><td colspan="1" rowspan="1" style="vertical-align:top;">21 (3–65) </td><td colspan="1" rowspan="1" style="vertical-align:top;">5/12 </td><td colspan="1" rowspan="1" style="vertical-align:top;">34% </td><td colspan="1" rowspan="1" style="vertical-align:top;">100 × 5/IV 40 × 5 </td><td colspan="1" rowspan="1" style="vertical-align:top;">None</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">I = phase I trial; BEV = bevacizumab; CR = complete response; IV = intravenous; PO = oral; PR = partial response; R = retrospective trial; RR = objective response rate; TMS = temsirolimus; UK = unknown; VCR = vincristine. </p></div></dd></dl></div></div></div><p id="CDR0000062841__1873">Most of these studies were retrospective, not prospective; there are only four prospective trials with well-defined eligibility cohorts and report by intent to treat. In addition, there is significant variability among the reports in doses and dose schedules of irinotecan and temozolomide and the use of additional agents. When combined, these studies accrued 176 patients and observed 18 complete remissions and 56 partial remissions. The objective response rate was 42%.</p><p id="CDR0000062841__449">Evidence (chemotherapy):</p><ol id="CDR0000062841__450"><li class="half_rhythm"><div>One phase II study of topotecan and cyclophosphamide showed a response in 6 of 17 patients with Ewing sarcoma; 16 of 49 patients had a clinical response in a similar trial in Germany.[<a class="bk_pop" href="#CDR0000062841_rl_51_8">8</a>,<a class="bk_pop" href="#CDR0000062841_rl_51_10">10</a>]</div></li><li class="half_rhythm"><div>Several retrospective studies have demonstrated the activity of temozolomide and irinotecan in patients with recurrent Ewing sarcoma.[<a class="bk_pop" href="#CDR0000062841_rl_51_12">12</a>,<a class="bk_pop" href="#CDR0000062841_rl_51_21">21</a>,<a class="bk_pop" href="#CDR0000062841_rl_51_23">23</a>] </div><div>In the largest retrospective multicenter study of the combination of temozolomide and irinotecan in patients with recurrent and primary refractory Ewing sarcoma, 51 patients (66% of patients were aged ≥18 years; median age, 21 years) were treated with temozolomide (100 mg/m<sup>2</sup>/day orally) and irinotecan (40 mg/m<sup>2</sup>/day intravenously), on days 1 to 5, every 21 days. Twenty-five percent of the patients were in first relapse/progression, while the remainder of the patients were in second or greater relapse/progression.[<a class="bk_pop" href="#CDR0000062841_rl_51_23">23</a>]<ul id="CDR0000062841__1853"><li class="half_rhythm"><div>Five patients (10%) achieved complete remissions, 12 patients (24%) achieved partial remissions, and 19 patients (37%) had stable disease, with a disease control rate of 71%.</div></li><li class="half_rhythm"><div>On univariate analysis, the only two factors predicting response to temozolomide and irinotecan in PFS were performance score and lactate dehydrogenase levels.</div></li><li class="half_rhythm"><div>Two patients were rechallenged with temozolomide and irinotecan after disease remission was induced. Both patients achieved partial remissions on rechallenge; one patient's remission lasted at least 15 cycles and the other remission lasted 22 cycles.[<a class="bk_pop" href="#CDR0000062841_rl_51_23">23</a>]</div></li></ul></div></li><li class="half_rhythm"><div>The combination of docetaxel either with gemcitabine or irinotecan has achieved objective responses in patients with relapsed Ewing sarcoma.[<a class="bk_pop" href="#CDR0000062841_rl_51_24">24</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335144/" class="def">Level of evidence: 3iiA</a>]; [<a class="bk_pop" href="#CDR0000062841_rl_51_25">25</a>,<a class="bk_pop" href="#CDR0000062841_rl_51_26">26</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000587991/" class="def">Level of evidence: 3iiiDiv</a>]</div></li><li class="half_rhythm"><div>High-dose ifosfamide (3 g/m<sup>2</sup> per day for 5 days = 15 g/m<sup>2</sup>) has shown activity in patients whose Ewing sarcoma recurred after therapy that included standard ifosfamide (1.8 g/m<sup>2</sup> per day for 5 days = 9 g/m<sup>2</sup>).[<a class="bk_pop" href="#CDR0000062841_rl_51_27">27</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000587991/" class="def">Level of evidence: 3iiiDiv</a>] </div></li></ol></div><div id="CDR0000062841__1986"><h4>Local therapy for relapsed disease</h4><div id="CDR0000062841__1987"><h5>Surgery</h5><p id="CDR0000062841__1988">Treatment with aggressive surgery (such as amputation or hemipelvectomy) may be considered for patients with nonmetastatic locally recurrent disease, even if the prognosis is limited.[<a class="bk_pop" href="#CDR0000062841_rl_51_28">28</a>]</p><p id="CDR0000062841__1989">The role of pulmonary metastasectomy in patients with relapsed disease and isolated lung metastases is controversial.[<a class="bk_pop" href="#CDR0000062841_rl_51_29">29</a>,<a class="bk_pop" href="#CDR0000062841_rl_51_30">30</a>]</p></div><div id="CDR0000062841__451"><h5>Radiation therapy</h5><p id="CDR0000062841__287">In the relapsed setting, radiation therapy may be used (similar to first-line strategies) for patients who relapsed after the beginning of front-line therapy and/or who present only with pulmonary metastases.[<a class="bk_pop" href="#CDR0000062841_rl_51_29">29</a>]; [<a class="bk_pop" href="#CDR0000062841_rl_51_31">31</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335150/" class="def">Level of evidence: 3iiiA</a>] Radiation therapy to bone
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lesions may provide palliation, although radical resection may improve outcome.[<a class="bk_pop" href="#CDR0000062841_rl_51_2">2</a>] Patients with pulmonary metastases who have not received radiation therapy to the lungs should be considered for whole-lung irradiation and/or treated with stereotactic body radiation therapy.[<a class="bk_pop" href="#CDR0000062841_rl_51_29">29</a>]; [<a class="bk_pop" href="#CDR0000062841_rl_51_31">31</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335150/" class="def">Level of evidence: 3iiiA</a>]; [<a class="bk_pop" href="#CDR0000062841_rl_51_32">32</a>] Residual disease in the lung may be surgically
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removed.
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</p></div></div><div id="CDR0000062841__1854"><h4>High-dose chemotherapy with stem cell support</h4><p id="CDR0000062841__1855">Aggressive
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attempts to control the disease, including myeloablative regimens, have been used, but there is no evidence at this time to conclude that myeloablative therapy is superior to standard chemotherapy.[<a class="bk_pop" href="#CDR0000062841_rl_51_33">33</a>-<a class="bk_pop" href="#CDR0000062841_rl_51_35">35</a>]; [<a class="bk_pop" href="#CDR0000062841_rl_51_36">36</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335158/" class="def">Level of evidence: 3iiiDiii</a>]</p><p id="CDR0000062841__1856">Most published reports about the use of high-dose therapy and stem cell support for patients with high-risk Ewing sarcoma have significant flaws in methodology. The most common error is the comparison of this high-risk group with an inappropriate control group. Patients with Ewing sarcoma at high risk of treatment failure who received high-dose therapy are compared with patients who did not receive high-dose therapy. Patients who undergo high-dose therapy must respond to systemic therapy, remain alive and respond to treatment long enough to reach the time at which stem cell therapy can be applied, be free of comorbid toxicity that precludes high-dose therapy, and have an adequate stem cell collection. Patients who undergo high-dose therapy and stem cell support are a highly selected group; comparing this patient group with all patients with high-risk Ewing sarcoma is inappropriate and leads to the erroneous conclusion that this strategy improves outcome.</p><p id="CDR0000062841__1857">Surveys of patients who underwent allogeneic stem cell transplantation (SCT) for recurrent Ewing sarcoma did not show improved event-free survival when compared with patients who underwent autologous SCT, and allogeneic SCT was
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associated with a higher complication rate.[<a class="bk_pop" href="#CDR0000062841_rl_51_33">33</a> ,<a class="bk_pop" href="#CDR0000062841_rl_51_37">37</a>,<a class="bk_pop" href="#CDR0000062841_rl_51_38">38</a>]</p></div><div id="CDR0000062841__452"><h4>Other therapies</h4><p id="CDR0000062841__453">Other therapies that have been studied in the treatment of recurrent Ewing sarcoma include the following:</p><ul id="CDR0000062841__454"><li class="half_rhythm"><div><b>Monoclonal antibody therapy. </b>Monoclonal antibodies against the insulin-like growth factor 1 receptor (IGF1R) are reported to produce objective responses in metastatic recurrent Ewing sarcoma in roughly 10% of cases.[<a class="bk_pop" href="#CDR0000062841_rl_51_39">39</a>-<a class="bk_pop" href="#CDR0000062841_rl_51_42">42</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000587990/" class="def">Level of evidence: 3iiDiv</a>] In these studies, it was suggested that time-to-progression was prolonged compared with historical controls. Objective responses have been reported in studies combining the mTOR inhibitor temsirolimus with an IGF1R antibody. Stratification by IGF1R expression by immunohistochemistry in one of the studies did not predict clinical outcome in patients with Ewing sarcoma.[<a class="bk_pop" href="#CDR0000062841_rl_51_43">43</a>,<a class="bk_pop" href="#CDR0000062841_rl_51_44">44</a>] Further studies are needed to identify patients who are likely to benefit from IGF1R therapy. However, the <a href="https://www.cancer.gov/clinicaltrials/NCT02306161" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">AEWS1221 (NCT02306161)</a> randomized study of ganitumab in patients with newly diagnosed metastatic Ewing sarcoma closed early because of the low likelihood of significant efficacy when ganitumab was given with interval-compressed chemotherapy.[<a class="bk_pop" href="#CDR0000062841_rl_51_45">45</a>]</div></li><li class="half_rhythm"><div><b>Immunotherapy. </b>Immunotherapy with antigen-specific T cells is being studied in patients with Ewing sarcoma because immune-mediated killing does not rely on pathways used by conventional therapies to which such tumors are often resistant. Several potential chimeric antigen receptors target antigens that have been identified for Ewing sarcomas. These include HER2 (human epidermal growth factor receptor 2),[<a class="bk_pop" href="#CDR0000062841_rl_51_46">46</a>] GD2,[<a class="bk_pop" href="#CDR0000062841_rl_51_47">47</a>] CD99 (MIC2 antigens),[<a class="bk_pop" href="#CDR0000062841_rl_51_48">48</a>] and STEAP1 (six-transmembrane epithelial antigens of the prostate).[<a class="bk_pop" href="#CDR0000062841_rl_51_49">49</a>] Some of these therapies are in early-phase testing in patients with sarcoma.[<a class="bk_pop" href="#CDR0000062841_rl_51_46">46</a>] Treatment with single-agent checkpoint inhibitors in patients with Ewing sarcoma has demonstrated limited efficacy.[<a class="bk_pop" href="#CDR0000062841_rl_51_50">50</a>-<a class="bk_pop" href="#CDR0000062841_rl_51_52">52</a>]</div></li></ul></div></div><div id="CDR0000062841__383"><h3>Treatment Options Under Clinical Evaluation for Recurrent Ewing Sarcoma</h3><p id="CDR0000062841__384">Information about National Cancer Institute (NCI)–supported clinical trials can be found on the <a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials/search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCI website</a>. For information about clinical trials sponsored by other organizations, refer to the <a href="https://clinicaltrials.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ClinicalTrials.gov website</a>.</p><p id="CDR0000062841__601">The following are examples of national and/or institutional clinical trials that are currently being conducted:</p><ul id="CDR0000062841__385"><li class="half_rhythm"><div class="half_rhythm"><b><a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials/nci-supported/pediatric-match" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">APEC1621 (NCT03155620)</a></b> (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders)<b>:</b> NCI–Children's Oncology Group Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 4,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.</div><div class="half_rhythm">Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the <a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials/nci-supported/pediatric-match" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCI website</a> and <a href="https://clinicaltrials.gov/ct2/show/NCT03155620" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ClinicalTrials.gov website</a>.
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</div></li><li class="half_rhythm"><div class="half_rhythm"><b><a href="https://www.cancer.gov/clinicaltrials/NCT02657005" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">TK216-01 (NCT02657005)</a></b> (TK216 in Patients With Relapsed or Refractory Ewing Sarcoma)<b>:</b> TK216 is a novel agent that directly targets the EWSR1-FLI1 interaction with a partner protein RNA helicase A and, in turn, downregulates transcriptional activity of the EWSR1-FLI1 fusion protein.[<a class="bk_pop" href="#CDR0000062841_rl_51_53">53</a>,<a class="bk_pop" href="#CDR0000062841_rl_51_54">54</a>] This is a first-in-human study of TK216 in patients with Ewing sarcoma. The study is designed to establish initial safety and efficacy data to assess the potential of TK216 for further development.</div></li></ul><div id="CDR0000062841__TrialSearch_383_sid_8"><h4>Current Clinical Trials</h4><p id="CDR0000062841__TrialSearch_383_22">Use our <a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials/advanced-search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">advanced clinical trial search</a> to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. <a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">General information</a> about clinical trials is also available.</p></div></div><div id="CDR0000062841_rl_51"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000062841_rl_51_1">Leavey PJ, Mascarenhas L, Marina N, et al.: Prognostic factors for patients with Ewing sarcoma (EWS) at first recurrence following multi-modality therapy: A report from the Children's Oncology Group. Pediatr Blood Cancer 51 (3): 334-8, 2008. [<a href="/pmc/articles/PMC2728357/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2728357</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18506764" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18506764</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_51_2">Stahl M, Ranft A, Paulussen M, et al.: Risk of recurrence and survival after relapse in patients with Ewing sarcoma. Pediatr Blood Cancer 57 (4): 549-53, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/21442722" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21442722</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_51_3">Wasilewski-Masker K, Liu Q, Yasui Y, et al.: Late recurrence in pediatric cancer: a report from the Childhood Cancer Survivor Study. J Natl Cancer Inst 101 (24): 1709-20, 2009. [<a href="/pmc/articles/PMC2800799/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2800799</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19966206" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19966206</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_51_4">Davenport JR, Vo KT, Goldsby R, et al.: Conditional Survival and Predictors of Late Death in Patients With Ewing Sarcoma. Pediatr Blood Cancer 63 (6): 1091-5, 2016. [<a href="https://pubmed.ncbi.nlm.nih.gov/26891183" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26891183</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_51_5">Barker LM, Pendergrass TW, Sanders JE, et al.: Survival after recurrence of Ewing's sarcoma family of tumors. J Clin Oncol 23 (19): 4354-62, 2005. [<a href="https://pubmed.ncbi.nlm.nih.gov/15781881" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15781881</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_51_6">Bacci G, Longhi A, Ferrari S, et al.: Pattern of relapse in 290 patients with nonmetastatic Ewing's sarcoma family tumors treated at a single institution with adjuvant and neoadjuvant chemotherapy between 1972 and 1999. Eur J Surg Oncol 32 (9): 974-9, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16621429" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16621429</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_51_7">Ferrari S, Luksch R, Hall KS, et al.: Post-relapse survival in patients with Ewing sarcoma. Pediatr Blood Cancer 62 (6): 994-9, 2015. [<a href="https://pubmed.ncbi.nlm.nih.gov/25585917" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25585917</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_51_8">Saylors RL, Stine KC, Sullivan J, et al.: Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: a Pediatric Oncology Group phase II study. J Clin Oncol 19 (15): 3463-9, 2001. [<a href="https://pubmed.ncbi.nlm.nih.gov/11481351" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11481351</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_51_9">McTiernan A, Driver D, Michelagnoli MP, et al.: High dose chemotherapy with bone marrow or peripheral stem cell rescue is an effective treatment option for patients with relapsed or progressive Ewing's sarcoma family of tumours. Ann Oncol 17 (8): 1301-5, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16782749" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16782749</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_51_10">Hunold A, Weddeling N, Paulussen M, et al.: Topotecan and cyclophosphamide in patients with refractory or relapsed Ewing tumors. Pediatr Blood Cancer 47 (6): 795-800, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16411206" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16411206</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_51_11">Wagner LM, McAllister N, Goldsby RE, et al.: Temozolomide and intravenous irinotecan for treatment of advanced Ewing sarcoma. Pediatr Blood Cancer 48 (2): 132-9, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/16317751" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16317751</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_51_12">Casey DA, Wexler LH, Merchant MS, et al.: Irinotecan and temozolomide for Ewing sarcoma: the Memorial Sloan-Kettering experience. Pediatr Blood Cancer 53 (6): 1029-34, 2009. [<a href="https://pubmed.ncbi.nlm.nih.gov/19637327" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19637327</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_51_13">Raciborska A, Bilska K, Drabko K, et al.: Vincristine, irinotecan, and temozolomide in patients with relapsed and refractory Ewing sarcoma. Pediatr Blood Cancer 60 (10): 1621-5, 2013. [<a href="https://pubmed.ncbi.nlm.nih.gov/23776128" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23776128</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_51_14">Farhat R, Raad R, Khoury NJ, et al.: Cyclophosphamide and topotecan as first-line salvage therapy in patients with relapsed ewing sarcoma at a single institution. J Pediatr Hematol Oncol 35 (5): 356-60, 2013. [<a href="https://pubmed.ncbi.nlm.nih.gov/23042020" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23042020</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_51_15">Kebudi R, Cakir FB, Gorgun O, et al.: A modified protocol with vincristine, topotecan, and cyclophosphamide for recurrent/progressive ewing sarcoma family tumors. Pediatr Hematol Oncol 30 (3): 170-7, 2013. [<a href="https://pubmed.ncbi.nlm.nih.gov/23484903" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23484903</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_51_16">Hernández-Marqués C, Lassaletta-Atienza A, Ruiz Hernández A, et al.: [Irinotecan plus temozolomide in refractory or relapsed pediatric solid tumors]. An Pediatr (Barc) 79 (2): 68-74, 2013. [<a href="https://pubmed.ncbi.nlm.nih.gov/23332825" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23332825</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_51_17">McNall-Knapp RY, Williams CN, Reeves EN, et al.: Extended phase I evaluation of vincristine, irinotecan, temozolomide, and antibiotic in children with refractory solid tumors. Pediatr Blood Cancer 54 (7): 909-15, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/20405511" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20405511</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_51_18">Wagner LM, Perentesis JP, Reid JM, et al.: Phase I trial of two schedules of vincristine, oral irinotecan, and temozolomide (VOIT) for children with relapsed or refractory solid tumors: a Children's Oncology Group phase I consortium study. Pediatr Blood Cancer 54 (4): 538-45, 2010. [<a href="/pmc/articles/PMC3074342/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3074342</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20049936" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20049936</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_51_19">Wagner L, Turpin B, Nagarajan R, et al.: Pilot study of vincristine, oral irinotecan, and temozolomide (VOIT regimen) combined with bevacizumab in pediatric patients with recurrent solid tumors or brain tumors. Pediatr Blood Cancer 60 (9): 1447-51, 2013. [<a href="https://pubmed.ncbi.nlm.nih.gov/23630159" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23630159</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_51_20">Bagatell R, Norris R, Ingle AM, et al.: Phase 1 trial of temsirolimus in combination with irinotecan and temozolomide in children, adolescents and young adults with relapsed or refractory solid tumors: a Children's Oncology Group Study. Pediatr Blood Cancer 61 (5): 833-9, 2014. [<a href="/pmc/articles/PMC4196713/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4196713</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24249672" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24249672</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_51_21">Kurucu N, Sari N, Ilhan IE: Irinotecan and temozolamide treatment for relapsed Ewing sarcoma: a single-center experience and review of the literature. Pediatr Hematol Oncol 32 (1): 50-9, 2015. [<a href="https://pubmed.ncbi.nlm.nih.gov/25252096" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25252096</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_51_22">Anderson P, Kopp L, Anderson N, et al.: Novel bone cancer drugs: investigational agents and control paradigms for primary bone sarcomas (Ewing's sarcoma and osteosarcoma). Expert Opin Investig Drugs 17 (11): 1703-15, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/18922107" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18922107</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_51_23">Palmerini E, Jones RL, Setola E, et al.: Irinotecan and temozolomide in recurrent Ewing sarcoma: an analysis in 51 adult and pediatric patients. Acta Oncol 57 (7): 958-964, 2018. [<a href="https://pubmed.ncbi.nlm.nih.gov/29533113" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 29533113</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_51_24">Fox E, Patel S, Wathen JK, et al.: Phase II study of sequential gemcitabine followed by docetaxel for recurrent Ewing sarcoma, osteosarcoma, or unresectable or locally recurrent chondrosarcoma: results of Sarcoma Alliance for Research Through Collaboration Study 003. Oncologist 17 (3): 321, 2012. [<a href="/pmc/articles/PMC3316916/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3316916</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22363068" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22363068</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_51_25">Mora J, Cruz CO, Parareda A, et al.: Treatment of relapsed/refractory pediatric sarcomas with gemcitabine and docetaxel. J Pediatr Hematol Oncol 31 (10): 723-9, 2009. [<a href="https://pubmed.ncbi.nlm.nih.gov/19727011" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19727011</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_51_26">Yoon JH, Kwon MM, Park HJ, et al.: A study of docetaxel and irinotecan in children and young adults with recurrent or refractory Ewing sarcoma family of tumors. BMC Cancer 14: 622, 2014. [<a href="/pmc/articles/PMC4155244/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4155244</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25164234" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25164234</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_51_27">Ferrari S, del Prever AB, Palmerini E, et al.: Response to high-dose ifosfamide in patients with advanced/recurrent Ewing sarcoma. Pediatr Blood Cancer 52 (5): 581-4, 2009. [<a href="https://pubmed.ncbi.nlm.nih.gov/19142994" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19142994</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_51_28">Gerrand C, Bate J, Seddon B, et al.: Seeking international consensus on approaches to primary tumour treatment in Ewing sarcoma. Clin Sarcoma Res 10 (1): 21, 2020. [<a href="/pmc/articles/PMC7672819/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7672819</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/33292535" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 33292535</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_51_29">Rodriguez-Galindo C, Billups CA, Kun LE, et al.: Survival after recurrence of Ewing tumors: the St Jude Children's Research Hospital experience, 1979-1999. Cancer 94 (2): 561-9, 2002. [<a href="https://pubmed.ncbi.nlm.nih.gov/11900241" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11900241</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_51_30">Briccoli A, Rocca M, Ferrari S, et al.: Surgery for lung metastases in Ewing's sarcoma of bone. Eur J Surg Oncol 30 (1): 63-7, 2004. [<a href="https://pubmed.ncbi.nlm.nih.gov/14736525" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14736525</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_51_31">Scobioala S, Ranft A, Wolters H, et al.: Impact of Whole Lung Irradiation on Survival Outcome in Patients With Lung Relapsed Ewing Sarcoma. Int J Radiat Oncol Biol Phys 102 (3): 584-592, 2018. [<a href="https://pubmed.ncbi.nlm.nih.gov/30244879" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30244879</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_51_32">Liu KX, Chen YH, Kozono D, et al.: Phase I/II Study of Stereotactic Body Radiation Therapy for Pulmonary Metastases in Pediatric Patients. Adv Radiat Oncol 5 (6): 1267-1273, 2020 Nov-Dec. [<a href="/pmc/articles/PMC7718514/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7718514</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/33305087" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 33305087</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_51_33">Burdach S, van Kaick B, Laws HJ, et al.: Allogeneic and autologous stem-cell transplantation in advanced Ewing tumors. An update after long-term follow-up from two centers of the European Intergroup study EICESS. Stem-Cell Transplant Programs at Düsseldorf University Medical Center, Germany and St. Anna Kinderspital, Vienna, Austria. Ann Oncol 11 (11): 1451-62, 2000. [<a href="https://pubmed.ncbi.nlm.nih.gov/11142486" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11142486</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_51_34">Burdach S, Meyer-Bahlburg A, Laws HJ, et al.: High-dose therapy for patients with primary multifocal and early relapsed Ewing's tumors: results of two consecutive regimens assessing the role of total-body irradiation. J Clin Oncol 21 (16): 3072-8, 2003. [<a href="https://pubmed.ncbi.nlm.nih.gov/12915596" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12915596</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_51_35">Pawlowska AB, Sun V, Calvert GT, et al.: Long-Term Follow-up of High-Dose Chemotherapy with Autologous Stem Cell Transplantation in Children and Young Adults with Metastatic or Relapsed Ewing Sarcoma: A Single-Institution Experience. Transplant Cell Ther 27 (1): 72.e1-72.e7, 2021. [<a href="https://pubmed.ncbi.nlm.nih.gov/33007495" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 33007495</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_51_36">Gardner SL, Carreras J, Boudreau C, et al.: Myeloablative therapy with autologous stem cell rescue for patients with Ewing sarcoma. Bone Marrow Transplant 41 (10): 867-72, 2008. [<a href="/pmc/articles/PMC3164955/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3164955</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18246113" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18246113</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_51_37">Gilman AL, Oesterheld J: Myeloablative chemotherapy with autologous stem cell rescue for Ewing sarcoma. Bone Marrow Transplant 42 (11): 761; author reply 763, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/18679365" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18679365</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_51_38">Eapen M: Response to Dr Gilman. Bone Marrow Transplant 42 (11): 763, 2008.</div></li><li><div class="bk_ref" id="CDR0000062841_rl_51_39">Malempati S, Weigel B, Ingle AM, et al.: Phase I/II trial and pharmacokinetic study of cixutumumab in pediatric patients with refractory solid tumors and Ewing sarcoma: a report from the Children's Oncology Group. J Clin Oncol 30 (3): 256-62, 2012. [<a href="/pmc/articles/PMC3269952/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3269952</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22184397" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22184397</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_51_40">Juergens H, Daw NC, Geoerger B, et al.: Preliminary efficacy of the anti-insulin-like growth factor type 1 receptor antibody figitumumab in patients with refractory Ewing sarcoma. J Clin Oncol 29 (34): 4534-40, 2011. [<a href="/pmc/articles/PMC3236653/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3236653</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22025154" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22025154</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_51_41">Pappo AS, Patel SR, Crowley J, et al.: R1507, a monoclonal antibody to the insulin-like growth factor 1 receptor, in patients with recurrent or refractory Ewing sarcoma family of tumors: results of a phase II Sarcoma Alliance for Research through Collaboration study. J Clin Oncol 29 (34): 4541-7, 2011. [<a href="/pmc/articles/PMC3236654/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3236654</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22025149" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22025149</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_51_42">Tap WD, Demetri G, Barnette P, et al.: Phase II study of ganitumab, a fully human anti-type-1 insulin-like growth factor receptor antibody, in patients with metastatic Ewing family tumors or desmoplastic small round cell tumors. J Clin Oncol 30 (15): 1849-56, 2012. [<a href="https://pubmed.ncbi.nlm.nih.gov/22508822" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22508822</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_51_43">Naing A, LoRusso P, Fu S, et al.: Insulin growth factor-receptor (IGF-1R) antibody cixutumumab combined with the mTOR inhibitor temsirolimus in patients with refractory Ewing's sarcoma family tumors. Clin Cancer Res 18 (9): 2625-31, 2012. [<a href="/pmc/articles/PMC3875297/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3875297</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22465830" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22465830</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_51_44">Schwartz GK, Tap WD, Qin LX, et al.: Cixutumumab and temsirolimus for patients with bone and soft-tissue sarcoma: a multicentre, open-label, phase 2 trial. Lancet Oncol 14 (4): 371-82, 2013. [<a href="/pmc/articles/PMC3766955/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3766955</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23477833" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23477833</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_51_45">Dubois S, Glade-Bender J, Buxton A, et al.: Randomized phase 3 trial of ganitumab added to interval compressed chemotherapy for patients with newly diagnosed metastatic Ewing sarcoma: a report from the Children’s Oncology Group. [Abstract] 2019 Connective Tissue Oncology Society (CTOS) Annual Meeting, November 13-16, 2019, Tokyo, Japan. A-3222400, 2019. <a href="https://www.ctos.org/Portals/0/PDF/2019%20CTOS%20Final%20Program.pdf" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">Available online</a>. Last accessed June 29, 2021.</div></li><li><div class="bk_ref" id="CDR0000062841_rl_51_46">Ahmed N, Brawley VS, Hegde M, et al.: Human Epidermal Growth Factor Receptor 2 (HER2) -Specific Chimeric Antigen Receptor-Modified T Cells for the Immunotherapy of HER2-Positive Sarcoma. J Clin Oncol 33 (15): 1688-96, 2015. [<a href="/pmc/articles/PMC4429176/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4429176</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25800760" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25800760</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_51_47">Pule MA, Savoldo B, Myers GD, et al.: Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma. Nat Med 14 (11): 1264-70, 2008. [<a href="/pmc/articles/PMC2749734/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2749734</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18978797" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18978797</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_51_48">Scotlandi K, Baldini N, Cerisano V, et al.: CD99 engagement: an effective therapeutic strategy for Ewing tumors. Cancer Res 60 (18): 5134-42, 2000. [<a href="https://pubmed.ncbi.nlm.nih.gov/11016640" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11016640</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_51_49">Grunewald TG, Diebold I, Esposito I, et al.: STEAP1 is associated with the invasive and oxidative stress phenotype of Ewing tumors. Mol Cancer Res 10 (1): 52-65, 2012. [<a href="https://pubmed.ncbi.nlm.nih.gov/22080479" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22080479</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_51_50">D'Angelo SP, Mahoney MR, Van Tine BA, et al.: Nivolumab with or without ipilimumab treatment for metastatic sarcoma (Alliance A091401): two open-label, non-comparative, randomised, phase 2 trials. Lancet Oncol 19 (3): 416-426, 2018. [<a href="/pmc/articles/PMC6126546/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6126546</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/29370992" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 29370992</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_51_51">Tawbi HA, Burgess M, Bolejack V, et al.: Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial. Lancet Oncol 18 (11): 1493-1501, 2017. [<a href="/pmc/articles/PMC7939029/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7939029</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/28988646" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28988646</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_51_52">Davis KL, Fox E, Merchant MS, et al.: Nivolumab in children and young adults with relapsed or refractory solid tumours or lymphoma (ADVL1412): a multicentre, open-label, single-arm, phase 1-2 trial. Lancet Oncol 21 (4): 541-550, 2020. [<a href="/pmc/articles/PMC7255545/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7255545</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/32192573" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 32192573</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_51_53">Erkizan HV, Kong Y, Merchant M, et al.: A small molecule blocking oncogenic protein EWS-FLI1 interaction with RNA helicase A inhibits growth of Ewing's sarcoma. Nat Med 15 (7): 750-6, 2009. [<a href="/pmc/articles/PMC2777681/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2777681</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19584866" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19584866</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_51_54">Lamhamedi-Cherradi SE, Menegaz BA, Ramamoorthy V, et al.: An Oral Formulation of YK-4-279: Preclinical Efficacy and Acquired Resistance Patterns in Ewing Sarcoma. Mol Cancer Ther 14 (7): 1591-604, 2015. [<a href="https://pubmed.ncbi.nlm.nih.gov/25964201" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25964201</span></a>]</div></li></ol></div></div><div id="CDR0000062841__1910"><h2 id="_CDR0000062841__1910_">Undifferentiated Small Round Cell (Ewing-like) Sarcomas</h2><p id="CDR0000062841__1991">There are undifferentiated small round cell sarcomas of bone and soft tissue that do not have the <i>EWSR1</i>-ETS gene family member translocations and appear to be biologically distinctive from Ewing sarcoma with <i>EWSR1</i>-ETS gene family member translocations. This includes tumors with translocations of the <i>CIC</i> gene or the <i>BCOR</i> gene, as well as tumors with <i>EWSR1</i> translocations involving non-ETS gene family members. These groups occur much less frequently than Ewing sarcoma, and descriptions of clinical outcomes for these patients are based on smaller sample sizes and less homogeneous treatment; therefore, patient outcomes are hard to quantitate with precision. Most of these tumors have been treated with regimens designed for Ewing sarcoma, and there is consensus that they were often included in past clinical trials for the treatment of Ewing sarcoma, sometimes as <i>translocation-negative</i> Ewing sarcoma. There is agreement that these tumors are sufficiently different from Ewing sarcoma; they should be stratified and analyzed separately from Ewing sarcoma with the common translocations, even if they are treated with similar therapy. The summary of these entities are presented below and follows the categorization of the 2020 World Health Organization (WHO) Classification of Tumours: Soft Tissue and Bone Tumours (5th edition).[<a class="bk_pop" href="#CDR0000062841_rl_1910_1">1</a>]</p><div id="CDR0000062841__1911"><h3>Undifferentiated Small Round Cell Sarcomas With <i>BCOR</i> Genetic Alterations</h3><div id="CDR0000062841__1912"><h4>Clinical presentation</h4><p id="CDR0000062841__1913">Undifferentiated round cell sarcomas with <i>BCOR-CCNB3</i> rearrangements account for about 5% of all <i>EWSR1</i>-negative rearranged sarcomas and more commonly affects males. More than 70% of cases occur in patients younger than 18 years (median age at diagnosis, 13–15 years).[<a class="bk_pop" href="#CDR0000062841_rl_1910_2">2</a>,<a class="bk_pop" href="#CDR0000062841_rl_1910_3">3</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335144/" class="def">Level of evidence: 3iiA</a>] These tumors more commonly arise in the bones of the pelvis and extremities, and metastases are present in approximately 30% of cases.</p></div><div id="CDR0000062841__1994"><h4>Genomic characteristics</h4><p id="CDR0000062841__1995">The most common types of undifferentiated small round cell sarcoma with <i>BCOR</i> rearrangements are those with the <i>BCOR-CCNB3</i> rearrangement.[<a class="bk_pop" href="#CDR0000062841_rl_1910_2">2</a>,<a class="bk_pop" href="#CDR0000062841_rl_1910_4">4</a>] The <i>BCOR-MAML3</i> rearrangement is less commonly observed, but tumors with this translocation appear to have biological characteristics that are similar to tumors with the <i>BCOR-CCNB3</i> rearrangement.[<a class="bk_pop" href="#CDR0000062841_rl_1910_2">2</a>,<a class="bk_pop" href="#CDR0000062841_rl_1910_5">5</a>,<a class="bk_pop" href="#CDR0000062841_rl_1910_6">6</a>]</p><p id="CDR0000062841__1996"><i>BCOR</i> internal tandem duplications (ITD) involving exon 15 are observed in infantile undifferentiated round cell sarcomas and primitive myxoid mesenchymal tumors of infancy (PMMTI).[<a class="bk_pop" href="#CDR0000062841_rl_1910_7">7</a>-<a class="bk_pop" href="#CDR0000062841_rl_1910_9">9</a>] These two entities have significant histologic overlap as well as similar transcriptional profiles, and they are distinguished by more prominent myxoid stroma in PMMTI. <i>BCOR</i> ITD may be occasionally observed in undifferentiated round cell sarcomas arising in older children.[<a class="bk_pop" href="#CDR0000062841_rl_1910_9">9</a>]</p><p id="CDR0000062841__1997"><i>BCOR</i> ITD have been reported in 90% of cases of clear cell sarcoma of the kidney, with a smaller subset harboring <i>YWHAE-NUTM2B/E</i> or <i>BCOR-CCNB3</i> gene fusions.[<a class="bk_pop" href="#CDR0000062841_rl_1910_10">10</a>,<a class="bk_pop" href="#CDR0000062841_rl_1910_11">11</a>] (Refer to the <a href="/books/n/pdqcis/CDR0000062789/#CDR0000062789__10">Clear Cell Sarcoma of the Kidney</a> section in the PDQ summary on <a href="/books/n/pdqcis/CDR0000062789/">Wilms Tumor and Other Childhood Kidney Tumors Treatment</a> for more information).</p><p id="CDR0000062841__1998">The transcriptional profiles induced by <i>BCOR</i> gene fusions, <i>BCOR</i> ITD, and <i>YWHAE-NUTM2B/E</i> fusions appear to be similar to each other and distinctive from that of Ewing sarcoma.[<a class="bk_pop" href="#CDR0000062841_rl_1910_2">2</a>,<a class="bk_pop" href="#CDR0000062841_rl_1910_6">6</a>,<a class="bk_pop" href="#CDR0000062841_rl_1910_7">7</a>] As an example, elevated BCOR expression is observed across all of these entities, which can be useful in distinguishing these entities from other undifferentiated small round cell tumors.</p></div><div id="CDR0000062841__1914"><h4>Treatment of undifferentiated round cell sarcomas with <i>BCOR</i> genetic alterations</h4><p id="CDR0000062841__1915">When treated with Ewing sarcoma–like therapies, 75% of patients show significant treatment-associated pathologic responses. In one series of 36 cases, the 3-year and 5-year survival rates were 93% and 72%, respectively.[<a class="bk_pop" href="#CDR0000062841_rl_1910_2">2</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335144/" class="def">Level of evidence: 3iiA</a>] In another series of 26 patients, the 5-year overall survival rate was 76.5%, and survival was better for patients who received induction therapy using an Ewing sarcoma–type regimen.[<a class="bk_pop" href="#CDR0000062841_rl_1910_12">12</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335144/" class="def">Level of evidence: 3iiA</a>] Most of the tumors in these series arose in the bone.</p></div></div><div id="CDR0000062841__1916"><h3>Undifferentiated Small Round Cell Sarcomas With <i>CIC</i> Genetic Alterations</h3><div id="CDR0000062841__1917"><h4>Clinical presentation</h4><p id="CDR0000062841__1918">Undifferentiated small round cell sarcomas with <i>CIC-DUX4</i> rearrangements most commonly affect young adults, with 50% of cases occurring between the ages of 21 and 40 years. In a series of 115 cases, the median age at diagnosis was 32 years, and 22% of cases occurred in patients younger than 18 years.[<a class="bk_pop" href="#CDR0000062841_rl_1910_3">3</a>,<a class="bk_pop" href="#CDR0000062841_rl_1910_13">13</a>] This entity more commonly affects males and usually originates from the soft tissues of the trunk and extremities.</p></div><div id="CDR0000062841__1999"><h4>Genomic characteristics</h4><p id="CDR0000062841__2000"><i>CIC</i>-rearranged sarcomas most commonly have a <i>CIC</i> gene fusion with <i>DUX4</i>, resulting from either a t(4;19)(q35;q13) or a t(10;19)(q26;q13) translocation.[<a class="bk_pop" href="#CDR0000062841_rl_1910_14">14</a>,<a class="bk_pop" href="#CDR0000062841_rl_1910_15">15</a>] <i>CIC</i> is located at chromosome 19q13.1 and <i>DUX4</i> is located on either chromosome 4q35 or 10q26.3. Sarcomas with the <i>CIC-DUX4</i> rearrangement have a transcriptional profile and DNA methylation profile that differs from that of Ewing sarcoma, supporting their characterization as a distinct entity.[<a class="bk_pop" href="#CDR0000062841_rl_1910_6">6</a>,<a class="bk_pop" href="#CDR0000062841_rl_1910_16">16</a>,<a class="bk_pop" href="#CDR0000062841_rl_1910_17">17</a>] For example, the vast majority of sarcomas with <i>CIC-DUX4</i> rearrangements express WT1 and ETV4, in contrast to Ewing sarcoma and <i>BCOR</i>-rearranged tumors, making immunohistochemistry for these proteins useful in distinguishing between these diagnoses.[<a class="bk_pop" href="#CDR0000062841_rl_1910_13">13</a>,<a class="bk_pop" href="#CDR0000062841_rl_1910_16">16</a>]</p></div><div id="CDR0000062841__1919"><h4>Treatment of undifferentiated small round cell sarcomas with <i>CIC</i> genetic alterations</h4><p id="CDR0000062841__1920">In a series of 115 cases of <i>CIC</i>-rearranged small round cell sarcomas, 57 patients had adequate follow-up information.[<a class="bk_pop" href="#CDR0000062841_rl_1910_13">13</a>] Nine patients presented with metastases, and 53% of patients with localized disease experienced a recurrence commonly involving the lung. Patients treated with neoadjuvant chemotherapy had an inferior survival than did patients who were treated with up-front surgical resection; however, this difference might have been related to a larger tumor size at presentation in the former group. The 2-year and 5-year survival rates were 53% and 43%, respectively. These survival rates are significantly lower than the survival rates observed in patients with Ewing sarcoma. Further study is required to identify optimal treatments for this disease.</p></div><div id="CDR0000062841__1955"><h4>Undifferentiated small round cell sarcomas with <i>CIC-NUTM1</i> rearrangements</h4><p id="CDR0000062841__1956">Undifferentiated small round cell sarcomas with <i>CIC-NUTM1</i> rearrangements have been described and occur much less frequently than undifferentiated round cell sarcomas with <i>CIC-DUX4</i> rearrangements.[<a class="bk_pop" href="#CDR0000062841_rl_1910_18">18</a>-<a class="bk_pop" href="#CDR0000062841_rl_1910_20">20</a>] These tumors occur in younger patients, and primary tumors occur in the central nervous system and in the periphery. The histologic appearance of these tumors is similar to <i>CIC-DUX4</i>–rearranged sarcomas. The prognosis of patients with these tumors is reported to be very poor despite treatment with surgery, multiagent chemotherapy, and radiation therapy.</p></div></div><div id="CDR0000062841__2001"><h3>Undifferentiated Small Round Cell Sarcomas With <i>EWSR1</i>–non-ETS Fusions</h3><div id="CDR0000062841__2002"><h4>Sarcomas with <i>EWSR1-NFATC2</i> and <i>FUS-NFATC2</i> fusions</h4><p id="CDR0000062841__2003">Sarcomas with <i>EWSR1-NFATC2</i> and <i>FUS-NFATC2</i> fusions typically arise in long bones, show a strong male predominance, and are more common in adults than in children.[<a class="bk_pop" href="#CDR0000062841_rl_1910_21">21</a>,<a class="bk_pop" href="#CDR0000062841_rl_1910_22">22</a>] These entities have transcriptional and DNA methylation profiles that distinguish them from Ewing sarcoma and other small round cell sarcomas.[<a class="bk_pop" href="#CDR0000062841_rl_1910_6">6</a>,<a class="bk_pop" href="#CDR0000062841_rl_1910_17">17</a>] Additionally, the transcriptional profiles for <i>EWSR1-NFATC2</i> and <i>FUS-NFATC2</i> differ from each other,[<a class="bk_pop" href="#CDR0000062841_rl_1910_6">6</a>] although the significance of this observation is unclear. The two entities also differ in that amplification of the <i>EWSR1-NFATC2</i> gene fusion is commonly observed, but the <i>FUS-NFATC2</i> gene fusion is generally not amplified.[<a class="bk_pop" href="#CDR0000062841_rl_1910_17">17</a>,<a class="bk_pop" href="#CDR0000062841_rl_1910_21">21</a>,<a class="bk_pop" href="#CDR0000062841_rl_1910_23">23</a>] Sarcomas with <i>EWSR1-NFATC2</i> and <i>FUS-NFATC2</i> fusions have metastatic potential and appear to be poorly responsive to chemotherapy regimens that are commonly used to treat sarcomas.[<a class="bk_pop" href="#CDR0000062841_rl_1910_21">21</a>,<a class="bk_pop" href="#CDR0000062841_rl_1910_22">22</a>]</p><p id="CDR0000062841__2004"><i>EWSR1-NFATC2</i> and <i>FUS-NFATC2</i> rearrangements are also observed in a substantial proportion of solitary bone cysts (also known as simple bone cysts), a benign condition that typically presents in the metadiaphyses of the long bones of skeletally immature individuals.[<a class="bk_pop" href="#CDR0000062841_rl_1910_24">24</a>,<a class="bk_pop" href="#CDR0000062841_rl_1910_25">25</a>] Therefore, the presence of either <i>EWSR1-NFATC2</i> or <i>FUS-NFATC2</i> should not be taken as an indicator of malignancy, but rather needs to be interpreted in light of the clinical setting.</p></div><div id="CDR0000062841__2005"><h4>Sarcomas with <i>EWSR1-PATZ1</i> fusions</h4><p id="CDR0000062841__2006">Sarcomas with the <i>EWSR1-PATZ1</i> fusion are very uncommon. In the small number of cases described, there appears to be gender balance, a propensity for presentation at truncal primary sites (particularly the chest), and a median age of presentation of between 40 to 50 years, with cases rarely occurring in the pediatric age range.[<a class="bk_pop" href="#CDR0000062841_rl_1910_26">26</a>,<a class="bk_pop" href="#CDR0000062841_rl_1910_27">27</a>] Sarcomas with the <i>EWSR1-PATZ1</i> fusion have gene expression and DNA methylation profiles that distinguish them from other sarcomas,[<a class="bk_pop" href="#CDR0000062841_rl_1910_6">6</a>,<a class="bk_pop" href="#CDR0000062841_rl_1910_17">17</a>] and <i>CDKN2A</i> deletions appear to commonly occur as secondary genomic alterations.[<a class="bk_pop" href="#CDR0000062841_rl_1910_26">26</a>,<a class="bk_pop" href="#CDR0000062841_rl_1910_27">27</a>]</p></div></div><div id="CDR0000062841_rl_1910"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000062841_rl_1910_1">WHO Classification of Tumours Editorial Board: WHO Classification of Tumours. Volume 3: Soft Tissue and Bone Tumours. 5th ed., IARC Press, 2020.</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1910_2">Kao YC, Owosho AA, Sung YS, et al.: BCOR-CCNB3 Fusion Positive Sarcomas: A Clinicopathologic and Molecular Analysis of 36 Cases With Comparison to Morphologic Spectrum and Clinical Behavior of Other Round Cell Sarcomas. Am J Surg Pathol 42 (5): 604-615, 2018. [<a href="/pmc/articles/PMC5893395/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5893395</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/29300189" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 29300189</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1910_3">Machado I, Navarro S, Llombart-Bosch A: Ewing sarcoma and the new emerging Ewing-like sarcomas: (CIC and BCOR-rearranged-sarcomas). A systematic review. Histol Histopathol 31 (11): 1169-81, 2016. [<a href="https://pubmed.ncbi.nlm.nih.gov/27306060" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27306060</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1910_4">Pierron G, Tirode F, Lucchesi C, et al.: A new subtype of bone sarcoma defined by BCOR-CCNB3 gene fusion. Nat Genet 44 (4): 461-6, 2012. [<a href="https://pubmed.ncbi.nlm.nih.gov/22387997" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22387997</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1910_5">Specht K, Zhang L, Sung YS, et al.: Novel BCOR-MAML3 and ZC3H7B-BCOR Gene Fusions in Undifferentiated Small Blue Round Cell Sarcomas. Am J Surg Pathol 40 (4): 433-42, 2016. [<a href="/pmc/articles/PMC4792719/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4792719</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26752546" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26752546</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1910_6">Watson S, Perrin V, Guillemot D, et al.: Transcriptomic definition of molecular subgroups of small round cell sarcomas. J Pathol 245 (1): 29-40, 2018. [<a href="https://pubmed.ncbi.nlm.nih.gov/29431183" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 29431183</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1910_7">Kao YC, Sung YS, Zhang L, et al.: Recurrent BCOR Internal Tandem Duplication and YWHAE-NUTM2B Fusions in Soft Tissue Undifferentiated Round Cell Sarcoma of Infancy: Overlapping Genetic Features With Clear Cell Sarcoma of Kidney. Am J Surg Pathol 40 (8): 1009-20, 2016. [<a href="/pmc/articles/PMC4942366/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4942366</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26945340" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26945340</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1910_8">Kao YC, Sung YS, Zhang L, et al.: BCOR Overexpression Is a Highly Sensitive Marker in Round Cell Sarcomas With BCOR Genetic Abnormalities. Am J Surg Pathol 40 (12): 1670-1678, 2016. [<a href="/pmc/articles/PMC5106294/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5106294</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/27428733" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27428733</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1910_9">Antonescu CR, Kao YC, Xu B, et al.: Undifferentiated round cell sarcoma with BCOR internal tandem duplications (ITD) or YWHAE fusions: a clinicopathologic and molecular study. Mod Pathol 33 (9): 1669-1677, 2020. [<a href="/pmc/articles/PMC7483745/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7483745</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/32372022" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 32372022</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1910_10">Ueno-Yokohata H, Okita H, Nakasato K, et al.: Consistent in-frame internal tandem duplications of BCOR characterize clear cell sarcoma of the kidney. Nat Genet 47 (8): 861-3, 2015. [<a href="https://pubmed.ncbi.nlm.nih.gov/26098867" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26098867</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1910_11">Roy A, Kumar V, Zorman B, et al.: Recurrent internal tandem duplications of BCOR in clear cell sarcoma of the kidney. Nat Commun 6: 8891, 2015. [<a href="/pmc/articles/PMC4660214/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4660214</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26573325" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26573325</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1910_12">Cohen-Gogo S, Cellier C, Coindre JM, et al.: Ewing-like sarcomas with BCOR-CCNB3 fusion transcript: a clinical, radiological and pathological retrospective study from the Société Française des Cancers de L'Enfant. Pediatr Blood Cancer 61 (12): 2191-8, 2014. [<a href="https://pubmed.ncbi.nlm.nih.gov/25176412" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25176412</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1910_13">Antonescu CR, Owosho AA, Zhang L, et al.: Sarcomas With CIC-rearrangements Are a Distinct Pathologic Entity With Aggressive Outcome: A Clinicopathologic and Molecular Study of 115 Cases. Am J Surg Pathol 41 (7): 941-949, 2017. [<a href="/pmc/articles/PMC5468475/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5468475</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/28346326" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28346326</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1910_14">Kawamura-Saito M, Yamazaki Y, Kaneko K, et al.: Fusion between CIC and DUX4 up-regulates PEA3 family genes in Ewing-like sarcomas with t(4;19)(q35;q13) translocation. Hum Mol Genet 15 (13): 2125-37, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16717057" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16717057</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1910_15">Italiano A, Sung YS, Zhang L, et al.: High prevalence of CIC fusion with double-homeobox (DUX4) transcription factors in EWSR1-negative undifferentiated small blue round cell sarcomas. Genes Chromosomes Cancer 51 (3): 207-18, 2012. [<a href="/pmc/articles/PMC3404826/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3404826</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22072439" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22072439</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1910_16">Specht K, Sung YS, Zhang L, et al.: Distinct transcriptional signature and immunoprofile of CIC-DUX4 fusion-positive round cell tumors compared to EWSR1-rearranged Ewing sarcomas: further evidence toward distinct pathologic entities. Genes Chromosomes Cancer 53 (7): 622-33, 2014. [<a href="/pmc/articles/PMC4108073/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4108073</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24723486" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24723486</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1910_17">Koelsche C, Kriegsmann M, Kommoss FKF, et al.: DNA methylation profiling distinguishes Ewing-like sarcoma with EWSR1-NFATc2 fusion from Ewing sarcoma. J Cancer Res Clin Oncol 145 (5): 1273-1281, 2019. [<a href="/pmc/articles/PMC7607515/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7607515</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/30895378" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30895378</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1910_18">Le Loarer F, Pissaloux D, Watson S, et al.: Clinicopathologic Features of CIC-NUTM1 Sarcomas, a New Molecular Variant of the Family of CIC-Fused Sarcomas. Am J Surg Pathol 43 (2): 268-276, 2019. [<a href="https://pubmed.ncbi.nlm.nih.gov/30407212" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30407212</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1910_19">Mangray S, Kelly DR, LeGuellec S, et al.: Clinicopathologic Features of a Series of Primary Renal CIC-rearranged Sarcomas With Comprehensive Molecular Analysis. Am J Surg Pathol 42 (10): 1360-1369, 2018. [<a href="https://pubmed.ncbi.nlm.nih.gov/29901569" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 29901569</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1910_20">Schaefer IM, Dal Cin P, Landry LM, et al.: CIC-NUTM1 fusion: A case which expands the spectrum of NUT-rearranged epithelioid malignancies. Genes Chromosomes Cancer 57 (9): 446-451, 2018. [<a href="/pmc/articles/PMC6881821/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6881821</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/29700887" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 29700887</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1910_21">Bode-Lesniewska B, Fritz C, Exner GU, et al.: EWSR1-NFATC2 and FUS-NFATC2 Gene Fusion-Associated Mesenchymal Tumors: Clinicopathologic Correlation and Literature Review. Sarcoma 2019: 9386390, 2019. [<a href="/pmc/articles/PMC6458862/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6458862</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/31049020" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 31049020</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1910_22">Wang GY, Thomas DG, Davis JL, et al.: EWSR1-NFATC2 Translocation-associated Sarcoma Clinicopathologic Findings in a Rare Aggressive Primary Bone or Soft Tissue Tumor. Am J Surg Pathol 43 (8): 1112-1122, 2019. [<a href="https://pubmed.ncbi.nlm.nih.gov/30994538" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30994538</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1910_23">Szuhai K, Ijszenga M, de Jong D, et al.: The NFATc2 gene is involved in a novel cloned translocation in a Ewing sarcoma variant that couples its function in immunology to oncology. Clin Cancer Res 15 (7): 2259-68, 2009. [<a href="https://pubmed.ncbi.nlm.nih.gov/19318479" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19318479</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1910_24">Pižem J, Šekoranja D, Zupan A, et al.: FUS-NFATC2 or EWSR1-NFATC2 Fusions Are Present in a Large Proportion of Simple Bone Cysts. Am J Surg Pathol 44 (12): 1623-1634, 2020. [<a href="https://pubmed.ncbi.nlm.nih.gov/32991339" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 32991339</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1910_25">Hung YP, Fisch AS, Diaz-Perez JA, et al.: Identification of EWSR1-NFATC2 fusion in simple bone cysts. Histopathology 78 (6): 849-856, 2021. [<a href="https://pubmed.ncbi.nlm.nih.gov/33316098" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 33316098</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1910_26">Bridge JA, Sumegi J, Druta M, et al.: Clinical, pathological, and genomic features of EWSR1-PATZ1 fusion sarcoma. Mod Pathol 32 (11): 1593-1604, 2019. [<a href="https://pubmed.ncbi.nlm.nih.gov/31189996" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 31189996</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1910_27">Michal M, Rubin BP, Agaimy A, et al.: EWSR1-PATZ1-rearranged sarcoma: a report of nine cases of spindle and round cell neoplasms with predilection for thoracoabdominal soft tissues and frequent expression of neural and skeletal muscle markers. Mod Pathol 34 (4): 770-785, 2021. [<a href="https://pubmed.ncbi.nlm.nih.gov/33012788" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 33012788</span></a>]</div></li></ol></div></div><div id="CDR0000062841__70"><h2 id="_CDR0000062841__70_">Changes to This Summary (10/08/2021)</h2><p id="CDR0000062841__73">The PDQ cancer information summaries are reviewed regularly and updated as
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new information becomes available. This section describes the latest
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changes made to this summary as of the date above.</p><p id="CDR0000062841__2389">
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<b>
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<a href="#CDR0000062841__642">Special Considerations for the Treatment of Children With Cancer</a>
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</b>
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</p><p id="CDR0000062841__2390">Added American Academy of Pediatrics as <a href="#CDR0000062841__646">reference 2</a>.</p><p id="CDR0000062841__disclaimerHP_3">This summary is written and maintained by the <a href="https://www.cancer.gov/publications/pdq/editorial-boards/pediatric-treatment" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PDQ Pediatric Treatment Editorial Board</a>, which is
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editorially independent of NCI. The summary reflects an independent review of
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the literature and does not represent a policy statement of NCI or NIH. More
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information about summary policies and the role of the PDQ Editorial Boards in
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maintaining the PDQ summaries can be found on the <a href="#CDR0000062841__AboutThis_1">About This PDQ Summary</a> and <a href="https://www.cancer.gov/publications/pdq" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PDQ® - NCI's Comprehensive Cancer Database</a> pages.
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</p></div><div id="CDR0000062841__AboutThis_1"><h2 id="_CDR0000062841__AboutThis_1_">About This PDQ Summary</h2><div id="CDR0000062841__AboutThis_2"><h3>Purpose of This Summary</h3><p id="CDR0000062841__AboutThis_3">This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood Ewing sarcoma and undifferentiated small round cell sarcomas of bone and soft tissue. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.</p></div><div id="CDR0000062841__AboutThis_4"><h3>Reviewers and Updates</h3><p id="CDR0000062841__AboutThis_5">This summary is reviewed regularly and updated as necessary by the <a href="https://www.cancer.gov/publications/pdq/editorial-boards/pediatric-treatment" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PDQ Pediatric Treatment Editorial Board</a>, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).</p><p id="CDR0000062841__AboutThis_22"> Board members review recently published articles each month to determine whether an article should:</p><ul id="CDR0000062841__AboutThis_6"><li class="half_rhythm"><div>be discussed at a meeting,</div></li><li class="half_rhythm"><div>be cited with text, or</div></li><li class="half_rhythm"><div>replace or update an existing article that is already cited.</div></li></ul><p id="CDR0000062841__AboutThis_7">Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.</p><p>The lead reviewers for Ewing Sarcoma and Undifferentiated Small Round Cell Sarcomas of Bone and Soft Tissue Treatment are:</p><ul><li class="half_rhythm"><div>Holcombe Edwin Grier, MD</div></li><li class="half_rhythm"><div>Andrea A. Hayes-Jordan, MD, FACS, FAAP (University of North Carolina - Chapel Hill School of Medicine)</div></li><li class="half_rhythm"><div>Karen J. Marcus, MD, FACR (Dana-Farber Cancer Institute/Boston Children's Hospital)</div></li><li class="half_rhythm"><div>William H. Meyer, MD (University of Oklahoma Health Sciences Center)</div></li><li class="half_rhythm"><div>Paul A. Meyers, MD (Memorial Sloan-Kettering Cancer Center)</div></li><li class="half_rhythm"><div>Thomas A. Olson, MD (Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta - Egleston Campus)</div></li><li class="half_rhythm"><div>Nita Louise Seibel, MD (National Cancer Institute)</div></li></ul><p id="CDR0000062841__AboutThis_9">Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's <a href="https://www.cancer.gov/contact/email-us" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Email Us</a>. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.</p></div><div id="CDR0000062841__AboutThis_10"><h3>Levels of Evidence</h3><p id="CDR0000062841__AboutThis_11">Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a <a href="/books/n/pdqcis/CDR0000062796/">formal evidence ranking system</a> in developing its level-of-evidence designations.</p></div><div id="CDR0000062841__AboutThis_12"><h3>Permission to Use This Summary</h3><p id="CDR0000062841__AboutThis_13">PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”</p><p id="CDR0000062841__AboutThis_14">The preferred citation for this PDQ summary is:</p><p id="CDR0000062841__AboutThis_15">PDQ® Pediatric Treatment Editorial Board. PDQ Ewing Sarcoma and Undifferentiated Small Round Cell Sarcomas of Bone and Soft Tissue Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: <a href="https://www.cancer.gov/types/bone/hp/ewing-treatment-pdq" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">https://www.cancer.gov/types/bone/hp/ewing-treatment-pdq</a>. Accessed <MM/DD/YYYY>. [PMID: 26389480]</p><p id="CDR0000062841__AboutThis_16">Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in <a href="https://visualsonline.cancer.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Visuals Online</a>, a collection of over 2,000 scientific images.
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</p></div><div id="CDR0000062841__AboutThis_17"><h3>Disclaimer</h3><p id="CDR0000062841__AboutThis_18">Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the <a href="https://www.cancer.gov/about-cancer/managing-care" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Managing Cancer Care</a> page.</p></div><div id="CDR0000062841__AboutThis_20"><h3>Contact Us</h3><p id="CDR0000062841__AboutThis_21">More information about contacting us or receiving help with the Cancer.gov website can be found on our <a href="https://www.cancer.gov/contact" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Contact Us for Help</a> page. Questions can also be submitted to Cancer.gov through the website’s <a href="https://www.cancer.gov/contact/email-us" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Email Us</a>.</p></div></div></div></div>
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class="simple-list"><li><a href="#CDR0000062841__1" ref="log$=inpage&link_id=inpage">General Information About Ewing Sarcoma and Undifferentiated Small Round Cell Sarcomas of Bone and Soft Tissue</a></li><li><a href="#CDR0000062841__15" ref="log$=inpage&link_id=inpage">Cellular Classification of Ewing Sarcoma</a></li><li><a href="#CDR0000062841__624" ref="log$=inpage&link_id=inpage">Genomics of Ewing Sarcoma</a></li><li><a href="#CDR0000062841__22" ref="log$=inpage&link_id=inpage">Stage Information for Ewing Sarcoma</a></li><li><a href="#CDR0000062841__28" ref="log$=inpage&link_id=inpage">Treatment Option Overview for Ewing Sarcoma</a></li><li><a href="#CDR0000062841__642" ref="log$=inpage&link_id=inpage">Special Considerations for the Treatment of Children With Cancer</a></li><li><a href="#CDR0000062841__34" ref="log$=inpage&link_id=inpage">Treatment of Localized Ewing Sarcoma</a></li><li><a href="#CDR0000062841__43" ref="log$=inpage&link_id=inpage">Treatment of Metastatic Ewing Sarcoma</a></li><li><a href="#CDR0000062841__51" ref="log$=inpage&link_id=inpage">Treatment of Recurrent Ewing Sarcoma</a></li><li><a href="#CDR0000062841__1910" ref="log$=inpage&link_id=inpage">Undifferentiated Small Round Cell (Ewing-like) Sarcomas</a></li><li><a href="#CDR0000062841__70" ref="log$=inpage&link_id=inpage">Changes to This Summary (10/08/2021)</a></li><li><a href="#CDR0000062841__AboutThis_1" ref="log$=inpage&link_id=inpage">About This PDQ Summary</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Related publications</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="document-links" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="/books/NBK65912/">Patient 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