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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 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: September 24, 2015.</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. 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</h2><p id="CDR0000062841__4">Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975.[<a class="bk_pop" href="#CDR0000062841_rl_1_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__595"><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__596">(Refer to the PDQ <a href="http://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__74">Guidelines for pediatric cancer
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centers and their role in the treatment of pediatric patients with cancer have
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been outlined by the American Academy of Pediatrics.[<a class="bk_pop" href="#CDR0000062841_rl_1_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 in
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these trials is offered to most patients/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 therapy that is currently accepted as standard.
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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="http://www.cancer.gov/about-cancer/treatment/clinical-trials" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCI website</a>.
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</p><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>] Childhood and adolescent cancer survivors require close follow-up because cancer therapy side effects 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><p id="CDR0000062841__187">Studies using immunohistochemical markers,[<a class="bk_pop" href="#CDR0000062841_rl_1_3">3</a>] cytogenetics,[<a class="bk_pop" href="#CDR0000062841_rl_1_4">4</a>,<a class="bk_pop" href="#CDR0000062841_rl_1_5">5</a>] molecular genetics, and tissue culture [<a class="bk_pop" href="#CDR0000062841_rl_1_6">6</a>] indicate that Ewing sarcoma is derived from a primordial bone marrow–derived mesenchymal stem cell.[<a class="bk_pop" href="#CDR0000062841_rl_1_7">7</a>,<a class="bk_pop" href="#CDR0000062841_rl_1_8">8</a>] Older terms such as 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><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 one case per 1 million people in the United States. In patients aged 10 to 19 years, the incidence is between nine and ten cases per 1 million people. The same analysis suggests that the incidence of Ewing sarcoma in the United States is nine times greater in whites than in African Americans, with an intermediate incidence in Asians.[<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. A genome-wide association study identified a region on chromosome 10q21.3 associated with an increased risk of Ewing sarcoma.[<a class="bk_pop" href="#CDR0000062841_rl_1_12">12</a>] Deep sequencing through this region identified a polymorphism in the <i>EGR2</i> gene, which appears to cooperate with 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_1_13">13</a>] The polymorphism associated with the increased risk is found at a much higher frequency in whites than in blacks or Asians, possibly explaining the epidemiology of the relative infrequency of Ewing sarcoma in the latter populations.</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_14">14</a>,<a class="bk_pop" href="#CDR0000062841_rl_1_15">15</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_16">16</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_17">17</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_18">18</a>,<a class="bk_pop" href="#CDR0000062841_rl_1_19">19</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 median 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. This has not been associated with metastasis, surgical outcome, or survival.[<a class="bk_pop" href="#CDR0000062841_rl_1_20">20</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) 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/NBK66045.2/table/CDR0000062841__304/?report=objectonly" target="object" rid-figpopup="figCDR0000062841304" rid-ob="figobCDR0000062841304">Table 1</a>).[<a class="bk_pop" href="#CDR0000062841_rl_1_21">21</a>] Patients with extraosseous Ewing sarcoma were more likely to be older, female, nonwhite, 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/NBK66045.2/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</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 exam 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></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_24">24</a>] </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>]</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.[<a class="bk_pop" href="#CDR0000062841_rl_1_15">15</a>,<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_26">26</a>] </div><div class="half_rhythm">In North American studies, patients younger than 10 years have a better outcome than those aged 10 to 17 years at diagnosis (relative risk [RR], 1.4). Patients older than 18 years have an inferior outcome (RR, 2.5).[<a class="bk_pop" href="#CDR0000062841_rl_1_27">27</a>-<a class="bk_pop" href="#CDR0000062841_rl_1_29">29</a>] 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_30">30</a>] With adequate multimodal therapy, survival was comparable to the survival observed in adolescents treated on the same trials. Review of the SEER database from 1973 to 2011 identified 1,957 patients with Ewing sarcoma.[<a class="bk_pop" href="#CDR0000062841_rl_1_31">31</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 class="half_rhythm"><b>Gender:</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>]</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> Any metastatic disease defined by standard imaging techniques or bone marrow aspirate/biopsy by morphology is an adverse prognostic factor. The presence or absence of metastatic disease is the single most powerful predictor of outcome. 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_32">32</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_33">33</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_34">34</a>,<a class="bk_pop" href="#CDR0000062841_rl_1_35">35</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_36">36</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 for patients with secondary Ewing sarcoma, 43.5%; patients with primary Ewing sarcoma, 64.2%).[<a class="bk_pop" href="#CDR0000062841_rl_1_37">37</a>] </div></li><li class="half_rhythm"><div class="half_rhythm"><b>Standard cytogenetics:</b> 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_38">38</a>]</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Detectable fusion transcripts in morphologically normal marrow:</b> Reverse transcriptase polymerase chain reaction 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_39">39</a>]</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Other biological factors:</b> Overexpression of the p53 protein, Ki67 expression, and loss of 16q may be adverse prognostic factors.[<a class="bk_pop" href="#CDR0000062841_rl_1_40">40</a>-<a class="bk_pop" href="#CDR0000062841_rl_1_42">42</a>] High expression of microsomal glutathione S-transferase, an enzyme associated with resistance to doxorubicin, is associated with inferior outcome for Ewing sarcoma.[<a class="bk_pop" href="#CDR0000062841_rl_1_43">43</a>]</div><div class="half_rhythm">The Children's Oncology Group performed a prospective analysis of <i>TP53</i> mutations and/or <i>CDKN2A</i> deletions in patients with Ewing sarcoma; no correlation was found with event-free survival (EFS).[<a class="bk_pop" href="#CDR0000062841_rl_1_44">44</a>]</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>Pathologic fracture: Pathologic fractures do not appear to be a prognostic factor.[<a class="bk_pop" href="#CDR0000062841_rl_1_45">45</a>]</div></li><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_46">46</a>,<a class="bk_pop" href="#CDR0000062841_rl_1_47">47</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_48">48</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_49">49</a>,<a class="bk_pop" href="#CDR0000062841_rl_1_50">50</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_51">51</a>-<a class="bk_pop" href="#CDR0000062841_rl_1_54">54</a>] Female gender and younger age predict a good histologic response to preoperative therapy.[<a class="bk_pop" href="#CDR0000062841_rl_1_55">55</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_56">56</a>,<a class="bk_pop" href="#CDR0000062841_rl_1_57">57</a>]</p><p id="CDR0000062841__391">Patients with poor response to presurgical chemotherapy have an increased risk for local recurrence.[<a class="bk_pop" href="#CDR0000062841_rl_1_58">58</a>]</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">Corrigan JJ, Feig SA; American Academy of Pediatrics: Guidelines for pediatric cancer centers. Pediatrics 113 (6): 1833-5, 2004. [<a href="https://pubmed.ncbi.nlm.nih.gov/15173520" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15173520</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_1_3">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_4">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_5">Dagher R, Pham TA, Sorbara L, et al.: Molecular confirmation of Ewing sarcoma. J Pediatr Hematol Oncol 23 (4): 221-4, 2001. 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[<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_8">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_9">Esiashvili N, Goodman M, Marcus RB Jr: 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. 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[<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_55">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_56">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_57">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_58">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></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">The <i>MIC2</i>
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gene product, 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>] <i>MIC2</i> 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.
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</p><div id="CDR0000062841__104"><h3>Cytogenetic and Molecular Changes in Ewing Sarcoma</h3><p id="CDR0000062841__105">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 <a class="figpopup" href="/books/NBK66045.2/table/CDR0000062841__386/?report=objectonly" target="object" rid-figpopup="figCDR0000062841386" rid-ob="figobCDR0000062841386">Table 2</a>).[<a class="bk_pop" href="#CDR0000062841_rl_15_2">2</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_15_3">3</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 <i>STS</i> family gene. 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> (also termed <i>E1AF</i>), and <i>FEV</i>.[<a class="bk_pop" href="#CDR0000062841_rl_15_4">4</a>] Rarely, <i>TLS</i>, another TET family member, can substitute for <i>EWSR1</i>.[<a class="bk_pop" href="#CDR0000062841_rl_15_5">5</a>] Finally, there are a few rare cases in which <i>EWSR1</i> has translocated with partners that are not members of the <i>ETS</i> family of oncogenes. The significance of these alternate partners is not known. </p><p id="CDR0000062841__379">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_15_6">6</a>]</p><p id="CDR0000062841__376">Three publications 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. In addition, these publications identified mutations in <i>STAG2</i>, a member of the cohesin complex, in about 15% to 20% of the cases, and the presence of these mutations was associated with advanced-stage disease. Finally, <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 is associated with a poor clinical outcome.[<a class="bk_pop" href="#CDR0000062841_rl_15_7">7</a>-<a class="bk_pop" href="#CDR0000062841_rl_15_9">9</a>]</p><p id="CDR0000062841__374">These translocations can all be found with standard cytogenetic analysis. A more rapid analysis looking for a break apart of the <i>EWS</i> gene is now frequently done to confirm the diagnosis of Ewing sarcoma molecularly.[<a class="bk_pop" href="#CDR0000062841_rl_15_10">10</a>] This test result must be considered with caution, however. Ewing sarcomas that utilize the <i>TLS</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 <i>ETS</i> family members with <i>EWSR1</i>, such as desmoplastic small round tumor, clear cell sarcoma, extraskeletal myxoid chondrosarcoma, and myxoid liposarcoma, all of which may be positive with a <i>EWS</i> fluorescence <i>in situ</i> hybridization split apart probe. </p><p id="CDR0000062841__456">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>. The molecular profile of these tumors is different from the profile of <i>EWS-FLI1</i> translocated Ewing sarcoma, 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. There are too few cases associated with each translocation to determine whether the prognosis for these small round blue cell tumors is distinct from the prognosis of Ewing sarcoma of similar stage and site.[<a class="bk_pop" href="#CDR0000062841_rl_15_11">11</a>-<a class="bk_pop" href="#CDR0000062841_rl_15_14">14</a>]</p><div id="CDR0000062841__386" class="table"><h3><span class="title">Table 2. <i>EWS</i> and <i>TLS</i> Fusions and Translocations in Ewing Sarcoma</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK66045.2/table/CDR0000062841__386/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__CDR0000062841__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;"><i>EWS</i></td><td colspan="1" rowspan="1" style="vertical-align:top;"><i>EWSR1-FLI1</i></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;"><i>EWSR1-ERG</i></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;"><i>EWSR1-ETV1</i></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;"><i>EWSR1-ETV4</i></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;"><i>EWSR1-FEV</i></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;"><i>EWSR1-NFATc2<sup>a</sup></i></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;"><i>EWSR1-POU5F1<sup>a</sup></i></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;"><i>EWSR1-SMARCA5<sup>a</sup></i></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;"><i>EWSR1-ZSG<sup>a</sup></i></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;"><i>EWSR1-SP3<sup>a</sup></i></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;"><i>TLS</i> (also called <i>FUS</i>)</td><td colspan="1" rowspan="1" style="vertical-align:top;"><i>TLS-ERG</i></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;"><i>TLS-FEV</i></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 <i>ETS</i> family of oncogenes.</p></div></dd></dl></div></div></div></div><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><li><div class="bk_ref" id="CDR0000062841_rl_15_2">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_15_3">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_15_4">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_15_5">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_15_6">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_15_7">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_15_8">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_15_9">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_15_10">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_15_11">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_15_12">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_15_13">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_15_14">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></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 fluorodeoxyglucose (FDG-PET) or 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 FDG-PET or 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, 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>] FDG-PET/CT is more accurate than 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 total) 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>] 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></ol></div></div><div id="CDR0000062841__28"><h2 id="_CDR0000062841__28_">Treatment Option Overview for Ewing Sarcoma</h2><p id="CDR0000062841__29"> 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. 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 be totally excised
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or if a limb salvage procedure may be attempted. 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>] 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_2">2</a>]</p><p id="CDR0000062841__608">Table 3 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/NBK66045.2/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="4" style="vertical-align:top;">Localized Ewing sarcoma</td><td colspan="2" rowspan="1" style="vertical-align:top;"><a href="#CDR0000062841__410">Chemotherapy</a></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;"><a href="#CDR0000062841__415">Surgery</a></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></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;"><a href="#CDR0000062841__430">Chemotherapy</a></td></tr><tr><td colspan="2" rowspan="1" style="vertical-align:top;"><a href="#CDR0000062841__433">Surgery</a></td></tr><tr><td colspan="2" rowspan="1" style="vertical-align:top;"><a href="#CDR0000062841__433">Radiation therapy</a></td></tr><tr><td colspan="1" rowspan="3" 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__451">Radiation therapy</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_3">3</a>-<a class="bk_pop" href="#CDR0000062841_rl_28_9">9</a>] in conjunction with surgery and/or radiation therapy for local tumor control.[<a class="bk_pop" href="#CDR0000062841_rl_28_10">10</a>-<a class="bk_pop" href="#CDR0000062841_rl_28_14">14</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_15">15</a>-<a class="bk_pop" href="#CDR0000062841_rl_28_19">19</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_20">20</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="http://cancer.gov/clinicaltrials/search/view?version=healthprofessional&cdrid=78196" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">GER-GPOH-EICESS-92</a>).[<a class="bk_pop" href="#CDR0000062841_rl_28_21">21</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 with courses of ifosfamide/etoposide,[<a class="bk_pop" href="#CDR0000062841_rl_28_7">7</a>] while European protocols generally combine vincristine, doxorubicin, and an alkylating agent with or without etoposide in a single treatment cycle.[<a class="bk_pop" href="#CDR0000062841_rl_28_9">9</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="http://cancer.gov/clinicaltrials/search/view?version=healthprofessional&cdrid=68608" 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_22">22</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>Three-year EFS 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>A randomized clinical trial (<a href="http://cancer.gov/clinicaltrials/search/view?version=healthprofessional&cdrid=68323" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">COG-AEWS0031 [NCT00006734]</a>) from the Children’s Oncology Group showed that for patients presenting without metastases, the administration of cycles of cyclophosphamide, doxorubicin, and vincristine alternating with cycles of ifosfamide and etoposide at 2-week intervals achieved superior EFS (5-year EFS, 73%) than did alternating cycles at 3-week intervals (5-year EFS, 65%).[<a class="bk_pop" href="#CDR0000062841_rl_28_23">23</a>]</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. They found significantly increased toxicity without an improvement in outcome with the addition of carboplatin.[<a class="bk_pop" href="#CDR0000062841_rl_28_24">24</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335136/" class="def">Level of evidence: 2Dii</a>]</div></li></ol></div><div id="CDR0000062841__136"><h3>Local Control for Ewing Sarcoma</h3><p id="CDR0000062841__326">Treatment approaches for Ewing sarcoma titrate therapeutic aggressiveness with the goal of maximizing local control while 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_25">25</a>] Radiation therapy is an effective alternative modality for local control in cases where the functional 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__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 after propensity adjustment.[<a class="bk_pop" href="#CDR0000062841_rl_28_25">25</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 radiation plus surgery.[<a class="bk_pop" href="#CDR0000062841_rl_28_26">26</a>]</p><p id="CDR0000062841__172">For patients who undergo gross-total resection with microscopic residual disease, the value of adjuvant radiation therapy is controversial. Investigations addressing this issue are retrospective and nonrandomized, limiting their value. </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_13">13</a>] <ul id="CDR0000062841__401"><li class="half_rhythm"><div>Local failure for patients with positive margins was 17% and OS was 71%. Local failure for patients with negative margins was 5% and OS was 94%. </div></li></ul></div></li><li class="half_rhythm"><div>However, 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.[<a class="bk_pop" href="#CDR0000062841_rl_28_14">14</a>] It is not known whether higher doses of radiation therapy could improve outcome. These investigators concluded that patients who are anticipated to have suboptimal surgery should be considered for definitive radiation therapy.
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</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 compromise by definitive surgery. The possibility of impaired function needs to be measured against the possibility of second tumors in the radiation field (<a href="#CDR0000062841__141">see below</a>). Adjuvant radiation therapy may be considered for patients with residual microscopic disease, inadequate margins, or who have viable tumor in the resected specimen and close margins.
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</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_27">27</a>]</p></div><div id="CDR0000062841__138"><h3>High-Dose Therapy With Stem Cell Rescue 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_28">28</a>-<a class="bk_pop" href="#CDR0000062841_rl_28_40">40</a>]</p><p id="CDR0000062841__402">Evidence (high-dose therapy with stem cell rescue):</p><ol id="CDR0000062841__403"><li class="half_rhythm"><div> 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_33">33</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>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 SCT for patients with Ewing sarcoma at high risk for relapse.[<a class="bk_pop" href="#CDR0000062841_rl_28_41">41</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>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></ol><p id="CDR0000062841__406">The role of high-dose therapy followed by stem cell rescue is being investigated in the prospective, randomized Euro-Ewing trial (<a href="http://cancer.gov/clinicaltrials/search/view?version=healthprofessional&cdrid=68608" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EURO-EWING-INTERGROUP-EE99</a>) for patients who present with metastases and patients with localized tumors with poor response to initial chemotherapy.</p></div><div id="CDR0000062841__144"><h3>Ewing Sarcoma/Specific Sites</h3><p id="CDR0000062841__145">Multiple analyses have evaluated diagnostic findings, treatment, and outcome of patients with bone lesions at the following anatomic primary sites: </p><ul id="CDR0000062841__269"><li class="half_rhythm"><div>Pelvis.[<a class="bk_pop" href="#CDR0000062841_rl_28_42">42</a>-<a class="bk_pop" href="#CDR0000062841_rl_28_44">44</a>] </div></li><li class="half_rhythm"><div>Femur.[<a class="bk_pop" href="#CDR0000062841_rl_28_45">45</a>,<a class="bk_pop" href="#CDR0000062841_rl_28_46">46</a>] </div></li><li class="half_rhythm"><div>Humerus.[<a class="bk_pop" href="#CDR0000062841_rl_28_47">47</a>,<a class="bk_pop" href="#CDR0000062841_rl_28_48">48</a>]</div></li><li class="half_rhythm"><div>Hand and foot.[<a class="bk_pop" href="#CDR0000062841_rl_28_49">49</a>,<a class="bk_pop" href="#CDR0000062841_rl_28_50">50</a>] </div></li><li class="half_rhythm"><div>Chest wall/rib.[<a class="bk_pop" href="#CDR0000062841_rl_28_51">51</a>-<a class="bk_pop" href="#CDR0000062841_rl_28_54">54</a>] </div></li><li class="half_rhythm"><div>Head and neck.[<a class="bk_pop" href="#CDR0000062841_rl_28_55">55</a>] </div></li><li class="half_rhythm"><div>Spine/sacrum.[<a class="bk_pop" href="#CDR0000062841_rl_28_56">56</a>-<a class="bk_pop" href="#CDR0000062841_rl_28_59">59</a>]</div></li></ul></div><div id="CDR0000062841__148"><h3>Extraosseous Ewing Sarcoma</h3><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__151">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_60">60</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. The 5-year EFS was 59% and OS was 69%. 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. </p><p id="CDR0000062841__152">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_61">61</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 236 patients had metastases at diagnosis. Chemotherapy consisted of vincristine, doxorubicin, cyclophosphamide, and actinomycin (VACA); CEVAIE; or VIDE. The 5-year EFS was 49% and OS was 60%. Five-year survival was 70% for patients with localized disease and 33% for patients with metastasis at diagnosis. OS in patients with localized disease did not seem related to tumor site or size. 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). Patients who received the anthracycline-containing regimen had a significantly better EFS and OS than did patients who did not receive anthracyclines.[<a class="bk_pop" href="#CDR0000062841_rl_28_62">62</a>,<a class="bk_pop" href="#CDR0000062841_rl_28_63">63</a>] Two North American Ewing sarcoma trials have included patients with extraosseous Ewing sarcoma.[<a class="bk_pop" href="#CDR0000062841_rl_28_23">23</a>,<a class="bk_pop" href="#CDR0000062841_rl_28_64">64</a>] The outcome of patients with extraosseous Ewing sarcoma is no different than the outcome for patients with bone Ewing sarcoma.</p><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. In a review of 78 reported cases, some lacking molecular confirmation, the OS 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_65">65</a>,<a class="bk_pop" href="#CDR0000062841_rl_28_66">66</a>] 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 upfront unplanned resection.[<a class="bk_pop" href="#CDR0000062841_rl_28_67">67</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000716085/" class="def">Level of evidence: 3iiD</a>]</p></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">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_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. 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[<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_49">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_50">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_51">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_52">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_53">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_54">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_55">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_56">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_57">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_58">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_59">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_60">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_61">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_62">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_63">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_64">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_65">Collier AB 3rd, 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_66">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_67">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__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></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>] Current regimens for the treatment of localized Ewing sarcoma achieve event-free survival (EFS) and overall survival (OS) 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_2">2</a>,<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 the Euro-Ewing studies.</div></li><li class="half_rhythm"><div>Increased dose intensity of doxorubicin during the initial months of therapy was associated with an improved outcome in a meta-analysis performed before the standard use of IE.[<a class="bk_pop" href="#CDR0000062841_rl_34_12">12</a>]
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</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 an 82% 4-year EFS.[<a class="bk_pop" href="#CDR0000062841_rl_34_13">13</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_14">14</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_13">13</a>]</div></li></ol><p id="CDR0000062841__217">In a Children's Oncology Group (COG) trial (<a href="http://cancer.gov/clinicaltrials/search/view?version=healthprofessional&cdrid=68323" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">COG-AEWS0031</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 (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. </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 treated at St. Jude Children's Research Hospital who received both surgery and radiation, 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>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), EFS for patients with less than 5%
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viable tumor was 75%, EFS for patients with 5% to 30% viable tumor was 48%, and EFS for patients with more than 30% viable tumor was
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20%.[<a class="bk_pop" href="#CDR0000062841_rl_34_17">17</a>] </div></li></ul><p id="CDR0000062841__320">European investigators are
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studying whether treatment intensification (i.e., high-dose chemotherapy with
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stem cell rescue) will improve outcome for patients with a poor
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histologic response.</p><p id="CDR0000062841__419">Radiation therapy is usually employed in the following cases:</p><ul id="CDR0000062841__420"><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__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_19">19</a>]</p></div><div id="CDR0000062841__422"><h5>Radiation therapy</h5><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_20">20</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. Radiation therapy is generally administered in fractionated doses totaling approximately 55.8 Gy to the
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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__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_21">21</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 more than 8 cm in length.[<a class="bk_pop" href="#CDR0000062841_rl_34_22">22</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_23">23</a>]</p><p id="CDR0000062841__39">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_14">14</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%. Those 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_24">24</a>] (Refer to the <a href="#CDR0000062841__141">Late Effects of Treatment for Ewing Sarcoma</a> section of this summary for more information.)</p></div></div></div><div id="CDR0000062841__283"><h3>Treatment Options Under Clinical Evaluation for Localized Ewing Sarcoma</h3><p id="CDR0000062841__284">The following is an example of an international clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the <a href="http://www.cancer.gov/about-cancer/treatment/clinical-trials" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCI website</a>.</p><p id="CDR0000062841__597">Treatment options under clinical evaluation for localized Ewing sarcoma include the following:</p><ul id="CDR0000062841__285"><li class="half_rhythm"><div><b><a href="http://cancer.gov/clinicaltrials/search/view?version=healthprofessional&cdrid=687639" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">COG-AEWS1031; RTOG 1127 (NCT01231906)</a></b> (Combination Chemotherapy in Treating Patients With Nonmetastatic Extracranial Ewing Sarcoma)<b>:</b> This study is randomly assigning patients with newly diagnosed nonmetastatic Ewing sarcoma to either standard interval-compressed VDC/IE or the experimental arm consisting of interval-compressed therapy with the addition of vincristine, cyclophosphamide, and topotecan (VTC [VTC/VDC/IE]). The primary objective is to evaluate the effect of a new treatment regimen on EFS and OS. Patients younger than 50 years are eligible. This study is available in North America through the COG and in the United States for medical and radiation oncologists through the Radiation Therapy Oncology Group or the Cancer Trials Support Unit.</div></li></ul><div id="CDR0000062841__TrialSearch_283_sid_5"><h4>Current Clinical Trials</h4><p id="CDR0000062841__TrialSearch_283_20">Check the list of NCI-supported cancer clinical trials that are now accepting patients with
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<a href="http://www.cancer.gov/search/ClinicalTrialsLink.aspx?Diagnosis=43411&tt=1&format=2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">localized Ewing sarcoma/peripheral primitive neuroectodermal tumor</a>. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.</p><p id="CDR0000062841__TrialSearch_283_21">General information about clinical trials is also available from the <a href="http://www.cancer.gov/about-cancer/treatment/clinical-trials" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCI website</a>.</p></div></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">Smith MA, Ungerleider RS, Horowitz ME, et al.: Influence of doxorubicin dose intensity on response and outcome for patients with osteogenic sarcoma and Ewing's sarcoma. J Natl Cancer Inst 83 (20): 1460-70, 1991. [<a href="https://pubmed.ncbi.nlm.nih.gov/1833556" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 1833556</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_34_13">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_14">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_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">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_20">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_21">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_22">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_23">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_24">Kuttesch JF Jr, 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></ol></div></div><div id="CDR0000062841__43"><h2 id="_CDR0000062841__43_">Treatment of Metastatic Ewing Sarcoma</h2><p id="CDR0000062841__44">Metastases at diagnosis are detected in approximately 25% of patients.[<a class="bk_pop" href="#CDR0000062841_rl_43_1">1</a>] The prognosis of patients with metastatic disease is poor.
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Current therapies for patients who present with metastatic disease achieve 6-year event-free survival (EFS) of approximately 28% and overall survival (OS) 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, 6-year EFS 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 of approximately 28% and patients with combined lung and bone/bone
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marrow metastases have a 4-year EFS 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">Standard treatment for patients with metastatic Ewing sarcoma utilizing alternating 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 not 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>In a retrospective data analysis of 120 patients with multifocal metastatic Ewing sarcoma, patients receiving local treatment of both primary tumor and metastases had a better outcome than patients receiving local treatment of primary tumor only or with no local treatment (3-year EFS, 39% vs. 17% and 14%, <i>P</i> < .001).[<a class="bk_pop" href="#CDR0000062841_rl_43_9">9</a>]</div></li><li class="half_rhythm"><div>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>] 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 based on 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="http://cancer.gov/clinicaltrials/search/view?version=healthprofessional&cdrid=68608" 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 sem cell transplant and demonstrated a 3-year EFS of 27% and OS 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 impact of high-dose chemotherapy with
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peripheral blood stem cell support for patients with isolated lung metastases is
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unknown and is being studied in the <a href="http://cancer.gov/clinicaltrials/search/view?version=healthprofessional&cdrid=68608" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EURO-EWING-INTERGROUP-EE99</a> trial, for which results are pending.[<a class="bk_pop" href="#CDR0000062841_rl_43_16">16</a>] </div></li><li class="half_rhythm"><div><b>Melphalan. </b>Melphalan, at nonmyeloablative doses, proved to be an active agent in an upfront window study for patients with metastatic disease at diagnosis; however, the cure rate remained extremely low.[<a class="bk_pop" href="#CDR0000062841_rl_43_20">20</a>]</div></li><li class="half_rhythm"><div><b>Irinotecan. </b>Irinotecan was administered as a single agent in an upfront window for newly diagnosed metastatic Ewing sarcoma patients and showed modest activity (partial response in 5 of 24 patients).[<a class="bk_pop" href="#CDR0000062841_rl_43_21">21</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__60"><h3>Treatment Options Under Clinical Evaluation for Metastatic Ewing Sarcoma</h3><p id="CDR0000062841__108">The following is an example of an international clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the <a href="http://www.cancer.gov/about-cancer/treatment/clinical-trials" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCI website</a>.</p><p id="CDR0000062841__599">Treatment options under clinical evaluation for metastatic Ewing sarcoma include the following:</p><ul id="CDR0000062841__65"><li class="half_rhythm"><div><b><a href="http://cancer.gov/clinicaltrials/search/view?version=healthprofessional&cdrid=767063" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">AEWS1221; NCI-2014-02380 (NCT02306161)</a></b> (Combination Chemotherapy With or Without Ganitumab in Treating Patients With Newly Diagnosed Metastatic Ewing Sarcoma)<b>:</b> This phase II study is randomly assigning newly diagnosed patients with metastatic Ewing sarcoma to multiagent chemotherapy (vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide) with or without the addition of ganitumab (AMG 479). Stereotactic body radiation therapy is being evaluated to sites of bone metastases at a dose of 40 Gy in five fractions. This is a shorter course of therapy than is the standard treatment.</div></li></ul><div id="CDR0000062841__TrialSearch_60_sid_8"><h4>Current Clinical Trials</h4><p id="CDR0000062841__TrialSearch_60_20">Check the list of NCI-supported cancer clinical trials that are now accepting patients with
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<a href="http://www.cancer.gov/search/ClinicalTrialsLink.aspx?Diagnosis=43412&tt=1&format=2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">metastatic Ewing sarcoma/peripheral primitive neuroectodermal tumor</a>. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.</p><p id="CDR0000062841__TrialSearch_60_21">General information about clinical trials is also available from the <a href="http://www.cancer.gov/about-cancer/treatment/clinical-trials" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCI website</a>.</p></div></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 Jr: 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">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_21">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>] </p><p id="CDR0000062841__440">The overall prognosis for patients with recurrent Ewing sarcoma is poor; 5-year survival 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_4">4</a>,<a class="bk_pop" href="#CDR0000062841_rl_51_5">5</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 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 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_6">6</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 relapsed or refractory Ewing sarcoma.</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__451">Radiation therapy</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_7">7</a>-<a class="bk_pop" href="#CDR0000062841_rl_51_12">12</a>]</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_7">7</a>,<a class="bk_pop" href="#CDR0000062841_rl_51_9">9</a>]</div></li><li class="half_rhythm"><div>In one retrospective series, 20 patients received temozolomide and irinotecan after recurrence. Five patients achieved a complete response and seven patients achieved a partial response.[<a class="bk_pop" href="#CDR0000062841_rl_51_11">11</a>]</div></li><li class="half_rhythm"><div>The combination of docetaxel either with gemcitabine or irinotecan has achieved objective responses in relapsed Ewing sarcoma.[<a class="bk_pop" href="#CDR0000062841_rl_51_13">13</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_14">14</a>,<a class="bk_pop" href="#CDR0000062841_rl_51_15">15</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_16">16</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__451"><h4>Radiation therapy</h4><p id="CDR0000062841__287">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.[<a class="bk_pop" href="#CDR0000062841_rl_51_17">17</a>] Residual disease in the lung may be surgically
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removed.
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</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 class="half_rhythm"><b>High-dose chemotherapy with stem cell support. </b>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_18">18</a>,<a class="bk_pop" href="#CDR0000062841_rl_51_19">19</a>]; [<a class="bk_pop" href="#CDR0000062841_rl_51_20">20</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_21">21</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335158/" class="def">Level of evidence: 3iiiDiii</a>] </div><div class="half_rhythm">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. Surveys of patients undergoing allogeneic stem cell transplantation (SCT) for recurrent Ewing sarcoma did not show improved event-free survival when compared with autologous SCT and was
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associated with a higher complication rate.[<a class="bk_pop" href="#CDR0000062841_rl_51_18">18</a> ,<a class="bk_pop" href="#CDR0000062841_rl_51_22">22</a>,<a class="bk_pop" href="#CDR0000062841_rl_51_23">23</a>]</div></li><li class="half_rhythm"><div class="half_rhythm"><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_24">24</a>-<a class="bk_pop" href="#CDR0000062841_rl_51_27">27</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 Ewing sarcoma patients.[<a class="bk_pop" href="#CDR0000062841_rl_51_28">28</a>,<a class="bk_pop" href="#CDR0000062841_rl_51_29">29</a>] Further studies are needed to identify patients who are likely to benefit from IGF1R therapy.</div></li><li class="half_rhythm"><div class="half_rhythm"><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_30">30</a>] GD2,[<a class="bk_pop" href="#CDR0000062841_rl_51_31">31</a>] CD99 (MIC2 antigens),[<a class="bk_pop" href="#CDR0000062841_rl_51_32">32</a>] and STEAP1 (six-transmembrane epithelial antigens of the prostate).[<a class="bk_pop" href="#CDR0000062841_rl_51_33">33</a>] Some are in early-phase testing in sarcoma patients.[<a class="bk_pop" href="#CDR0000062841_rl_51_30">30</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">The following are examples of international clinical trials that are currently being conducted. Information about ongoing clinical trials is available from the <a href="http://www.cancer.gov/about-cancer/treatment/clinical-trials" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCI website</a>.</p><p id="CDR0000062841__601">Treatment options under clinical evaluation for recurrent Ewing sarcoma include the following:</p><ul id="CDR0000062841__385"><li class="half_rhythm"><div>
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<b><a href="http://cancer.gov/clinicaltrials/search/view?version=healthprofessional&cdrid=766927" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">SARC028; NCI-2015-00320 (NCT02301039)</a></b> (A Phase II Study of the Anti-PD1 Antibody Pembrolizumab [MK-3475] in Patients With Advanced Sarcomas): The objective response rate to the anti-PD1 inhibitor pembrolizumab will be assessed in patients with refractory, recurrent, and/or metastatic high-grade soft tissue sarcomas and bone sarcomas. Patients aged 18 years and older with soft tissue sarcomas and patients aged 12 years and older with bone sarcomas are eligible.
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</div></li><li class="half_rhythm"><div><b><a href="http://cancer.gov/clinicaltrials/search/view?version=healthprofessional&cdrid=762562" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCT02173093</a></b> (Activated T cells armed with GD2 Bispecific Antibody in Children and Young Adults with Neuroblastoma and Osteosarcoma)<b>:</b> Patients with GD2-positive tumors are also eligible.</div></li><li class="half_rhythm"><div><b><a href="http://cancer.gov/clinicaltrials/search/view?version=healthprofessional&cdrid=767035" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ADVL1412 (NCT02304458)</a></b> (Nivolumab With or Without Ipilimumab in Treating Younger Patients With Recurrent or Refractory Solid Tumors or Sarcomas)<b>:</b> Nivolumab is an anti-PD1 inhibitor that is being studied alone and in combination with ipilimumab in relapsed sarcoma patients, including patients with Ewing sarcoma.</div></li><li class="half_rhythm"><div><b><a href="http://cancer.gov/clinicaltrials/search/view?version=healthprofessional&cdrid=760110" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ADVL1411 (NCT02116777)</a></b> (BMN-673 and Temozolomide in Treating Younger Patients With Refractory or Recurrent Malignancies)<b>:</b> In this study, the PARP inhibitor BMN-673 is combined with low-dose short duration temozolomide. This is based on the <i>in vitro</i> and mouse human tumor xenograft models, which showed impressive activity in a broad range of pediatric cancers, including Ewing sarcoma.[<a class="bk_pop" href="#CDR0000062841_rl_51_34">34</a>]</div></li></ul><div id="CDR0000062841__TrialSearch_383_sid_9"><h4>Current Clinical Trials</h4><p id="CDR0000062841__TrialSearch_383_20">Check the list of NCI-supported cancer clinical trials that are now accepting patients with
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<a href="http://www.cancer.gov/search/ClinicalTrialsLink.aspx?Diagnosis=43413&tt=1&format=2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">recurrent Ewing sarcoma/peripheral primitive neuroectodermal tumor</a>. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.</p><p id="CDR0000062841__TrialSearch_383_21">General information about clinical trials is also available from the <a href="http://www.cancer.gov/about-cancer/treatment/clinical-trials" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCI website</a>.</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">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_5">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_6">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_7">Saylors RL 3rd, 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_8">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_9">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_10">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_11">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_12">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_13">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_14">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_15">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_16">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_17">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_18">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_19">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_20">Rasper M, Jabar S, Ranft A, et al.: The value of high-dose chemotherapy in patients with first relapsed Ewing sarcoma. Pediatr Blood Cancer 61 (8): 1382-6, 2014. [<a href="https://pubmed.ncbi.nlm.nih.gov/24729428" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24729428</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_51_21">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_22">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_23">Eapen M: Response to Dr Gilman. Bone Marrow Transplant 42 (11): 763, 2008.</div></li><li><div class="bk_ref" id="CDR0000062841_rl_51_24">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_25">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_26">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_27">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_28">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_29">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_30">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_31">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_32">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_33">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_34">Smith MA, Reynolds CP, Kang MH, et al.: Synergistic activity of PARP inhibition by talazoparib (BMN 673) with temozolomide in pediatric cancer models in the pediatric preclinical testing program. Clin Cancer Res 21 (4): 819-32, 2015. [<a href="/pmc/articles/PMC4587665/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4587665</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25500058" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25500058</span></a>]</div></li></ol></div></div><div id="CDR0000062841__141"><h2 id="_CDR0000062841__141_">Late Effects of Treatment for Ewing Sarcoma</h2><p id="CDR0000062841__327">Patients treated for Ewing sarcoma have a significantly higher risk of developing subsequent neoplasms than do patients in the general population. </p><p id="CDR0000062841__142">Treatment-related acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) have generally been reported to occur in 1% to 2% of survivors of Ewing sarcoma,[<a class="bk_pop" href="#CDR0000062841_rl_141_1">1</a>]; [<a class="bk_pop" href="#CDR0000062841_rl_141_2">2</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335153/" class="def">Level of evidence: 3iiiDi</a>] although some dose-intensive regimens appear to be associated with a higher risk of hematological malignancy.[<a class="bk_pop" href="#CDR0000062841_rl_141_3">3</a>,<a class="bk_pop" href="#CDR0000062841_rl_141_4">4</a>]; [<a class="bk_pop" href="#CDR0000062841_rl_141_5">5</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000641572/" class="def">Level of evidence: 3ii</a>] Treatment-related AML and MDS arise most commonly at 2 to 5 years after diagnosis. </p><p id="CDR0000062841__328">Survivors of Ewing sarcoma remain at increased risk of developing a subsequent solid tumor throughout their lifetime. Sarcomas usually occur within the previous radiation field.[<a class="bk_pop" href="#CDR0000062841_rl_141_6">6</a>,<a class="bk_pop" href="#CDR0000062841_rl_141_7">7</a>] The risk of developing a sarcoma after radiation therapy is dose-dependent, with higher doses associated with an increased risk of sarcoma development.[<a class="bk_pop" href="#CDR0000062841_rl_141_1">1</a>]; [<a class="bk_pop" href="#CDR0000062841_rl_141_2">2</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335153/" class="def">Level of evidence: 3iiiDi</a>] The cumulative incidence of subsequent neoplasms in children treated for Ewing sarcoma between 1970 and 1986 at 25 years after diagnosis was 9.0% (confidence interval, 5.8–12.2). Most of these patients received radiation therapy; comparable long-term data do not yet exist for significant numbers of patients who did not receive radiation therapy.[<a class="bk_pop" href="#CDR0000062841_rl_141_8">8</a>]</p><p id="CDR0000062841__329">(Refer to the PDQ summary on <a href="/books/n/pdqcis/CDR0000343584/">Late Effects of Treatment for Childhood Cancer</a> for a full discussion of the late effects of cancer treatment in children and adolescents.) </p><div id="CDR0000062841_rl_141"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000062841_rl_141_1">Fuchs B, Valenzuela RG, Petersen IA, et al.: Ewing's sarcoma and the development of secondary malignancies. Clin Orthop (415): 82-9, 2003. 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[<a href="/pmc/articles/PMC2765980/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2765980</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18823030" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18823030</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_141_3">Bhatia S, Krailo MD, Chen Z, et al.: Therapy-related myelodysplasia and acute myeloid leukemia after Ewing sarcoma and primitive neuroectodermal tumor of bone: A report from the Children's Oncology Group. Blood 109 (1): 46-51, 2007. [<a href="/pmc/articles/PMC1785079/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1785079</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/16985182" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16985182</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_141_4">Kushner BH, Heller G, Cheung NK, et al.: High risk of leukemia after short-term dose-intensive chemotherapy in young patients with solid tumors. J Clin Oncol 16 (9): 3016-20, 1998. [<a href="https://pubmed.ncbi.nlm.nih.gov/9738570" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9738570</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_141_5">Navid F, Billups C, Liu T, et al.: Second cancers in patients with the Ewing sarcoma family of tumours. Eur J Cancer 44 (7): 983-91, 2008. [<a href="/pmc/articles/PMC2423466/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2423466</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18353632" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18353632</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_141_6">Kuttesch JF Jr, 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_141_7">Hawkins MM, Wilson LM, Burton HS, et al.: Radiotherapy, alkylating agents, and risk of bone cancer after childhood cancer. J Natl Cancer Inst 88 (5): 270-8, 1996. [<a href="https://pubmed.ncbi.nlm.nih.gov/8614005" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8614005</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062841_rl_141_8">Ginsberg JP, Goodman P, Leisenring W, et al.: Long-term survivors of childhood Ewing sarcoma: report from the childhood cancer survivor study. J Natl Cancer Inst 102 (16): 1272-83, 2010. [<a href="/pmc/articles/PMC2948841/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2948841</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20656964" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20656964</span></a>]</div></li></ol></div></div><div id="CDR0000062841__70"><h2 id="_CDR0000062841__70_">Changes to This Summary (09/24/2015)</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__617"><b><a href="#CDR0000062841__1">General Information About Ewing Sarcoma</a></b></p><p id="CDR0000062841__618">Added <a href="#CDR0000062841__616">text</a> about a genome-wide association study that found a specific polymorphism that may explain the higher frequency of Ewing sarcoma in whites and the lower frequency in blacks and Asians (cited Postel-Vinay et al. and Grünewald et al. as references 12 and 13, respectively).</p><p id="CDR0000062841__619">Added <a href="#CDR0000062841__387">text</a> to state that review of the Surveillance, Epidemiology, and End Results database from 1973 to 2011 identified 1,957 patients with Ewing sarcoma; 39 of these patients 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 did not differ significantly from that of older patients (cited Wong et al. as reference 31).</p><p id="CDR0000062841__disclaimerHP_3">This summary is written and maintained by the <a href="http://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="http://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. 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></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="http://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 Treatment are:</p><ul><li class="half_rhythm"><div>Holcombe Edwin Grier, MD (Dana-Farber Cancer Institute/Boston Children's Hospital)</div></li><li class="half_rhythm"><div>Karen J. Marcus, MD (Dana-Farber Cancer Institute/Boston Children's Hospital)</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 Center and Blood Disorders Service 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="http://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">National Cancer Institute: PDQ® Ewing Sarcoma Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: <a href="http://www.cancer.gov/types/bone/hp/ewing-treatment-pdq" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">http://www.cancer.gov/types/bone/hp/ewing-treatment-pdq</a>. Accessed <MM/DD/YYYY>.</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="http://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="http://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="http://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="http://www.cancer.gov/contact/email-us" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Email Us</a>.</p></div></div><div id="CDR0000062841__GetMore_3"><h2 id="_CDR0000062841__GetMore_3_">Get More Information From NCI</h2><p id="CDR0000062841__GetMore_15"><i><b>Call 1-800-4-CANCER</b></i></p><p id="CDR0000062841__GetMore_16">For more information, U.S. residents may call the National Cancer Institute's (NCI's) Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237) Monday through Friday from 8:00 a.m. to 8:00 p.m., Eastern Time. A trained Cancer Information Specialist is available to answer your questions.</p><p id="CDR0000062841__GetMore_25"><i><b>Chat online
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class="simple-list"><li><a href="#CDR0000062841__1" ref="log$=inpage&link_id=inpage">General Information About Ewing Sarcoma</a></li><li><a href="#CDR0000062841__15" ref="log$=inpage&link_id=inpage">Cellular Classification 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__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$=inpage&link_id=inpage">Treatment of Recurrent Ewing Sarcoma</a></li><li><a href="#CDR0000062841__141" ref="log$=inpage&link_id=inpage">Late Effects of Treatment for Ewing Sarcoma</a></li><li><a href="#CDR0000062841__70" ref="log$=inpage&link_id=inpage">Changes to This Summary (09/24/2015)</a></li><li><a href="#CDR0000062841__AboutThis_1" ref="log$=inpage&link_id=inpage">About This PDQ Summary</a></li><li><a href="#CDR0000062841__GetMore_3" ref="log$=inpage&link_id=inpage">Get More Information From NCI</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Related publications</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="document-links" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="/books/NBK65912/">Patient Version</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Related information</span></h3></div><a name="Shutter" sid="1" href="#" 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class="portlet_content"><ul><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/26389179" ref="ordinalpos=1&linkpos=1&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Osteosarcoma and Undifferentiated Pleomorphic Sarcoma of Bone Treatment (PDQ®): Health Professional Version.</a><span class="source">[PDQ Cancer Information Summari...]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Osteosarcoma and Undifferentiated Pleomorphic Sarcoma of Bone Treatment (PDQ®): Health Professional Version.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">PDQ Pediatric Treatment Editorial Board. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">PDQ Cancer Information Summaries. 2002</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/26389481" ref="ordinalpos=1&linkpos=2&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Soft Tissue Sarcoma Treatment (PDQ®): Health Professional Version.</a><span class="source">[PDQ Cancer Information Summari...]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Soft Tissue Sarcoma Treatment (PDQ®): Health Professional Version.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">PDQ Adult Treatment Editorial Board. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">PDQ Cancer Information Summaries. 2002</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/26389335" ref="ordinalpos=1&linkpos=3&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Kaposi Sarcoma Treatment (PDQ®): Health Professional Version.</a><span class="source">[PDQ Cancer Information Summari...]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Kaposi Sarcoma Treatment (PDQ®): Health Professional Version.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">PDQ Adult Treatment Editorial Board. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">PDQ Cancer Information Summaries. 2002</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/26389327" ref="ordinalpos=1&linkpos=4&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Uterine Sarcoma Treatment (PDQ®): Health Professional Version.</a><span class="source">[PDQ Cancer Information Summari...]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Uterine Sarcoma Treatment (PDQ®): Health Professional Version.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">PDQ Adult Treatment Editorial Board. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">PDQ Cancer Information Summaries. 2002</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/26389361" ref="ordinalpos=1&linkpos=5&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Childhood Soft Tissue Sarcoma Treatment (PDQ®): Health Professional Version.</a><span class="source">[PDQ Cancer Information Summari...]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Childhood Soft Tissue Sarcoma Treatment (PDQ®): Health Professional Version.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">PDQ Pediatric Treatment Editorial Board. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">PDQ Cancer Information Summaries. 2002</em></div></div></li></ul><a class="seemore" href="/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed_reviews&uid=26389480" ref="ordinalpos=1&log$=relatedreviews_seeall&logdbfrom=pubmed">See reviews...</a><a class="seemore" href="/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed&uid=26389480" ref="ordinalpos=1&log$=relatedarticles_seeall&logdbfrom=pubmed">See all...</a></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Recent Activity</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" 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<title>Youtube</title>
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<path class="st5" d="M88.4,1037.4c-10.4,0-18.7,8.3-18.7,18.7v40.1c0,10.4,8.3,18.7,18.7,18.7h72.1c10.4,0,18.7-8.3,18.7-18.7 v-40.1c0-10.4-8.3-18.7-18.7-18.7H88.4z M115.2,1058.8l29.4,17.4l-29.4,17.4V1058.8z"></path>
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<a href="https://www.google.com/maps/place/8600+Rockville+Pike,+Bethesda,+MD+20894/@38.9959508,-77.101021,17z/data=!3m1!4b1!4m5!3m4!1s0x89b7c95e25765ddb:0x19156f88b27635b8!8m2!3d38.9959508!4d-77.0988323" class="text-white" target="_blank" rel="noopener noreferrer">8600 Rockville Pike<br />
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Bethesda, MD 20894</a></p>
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<p><a href="https://www.nlm.nih.gov/web_policies.html" class="text-white">Web Policies</a><br />
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<a href="https://www.nih.gov/institutes-nih/nih-office-director/office-communications-public-liaison/freedom-information-act-office" class="text-white">FOIA</a><br />
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<a href="https://www.hhs.gov/vulnerability-disclosure-policy/index.html" class="text-white" id="vdp">HHS Vulnerability Disclosure</a></p>
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<p><a class="supportLink text-white" href="https://support.nlm.nih.gov/">Help</a><br />
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<a href="https://www.nlm.nih.gov/accessibility.html" class="text-white">Accessibility</a><br />
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<a href="https://www.nlm.nih.gov/careers/careers.html" class="text-white">Careers</a></p>
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<a class="text-white" href="https://www.nih.gov/">NIH</a>
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