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<meta name="robots" content="INDEX,FOLLOW,NOARCHIVE" /><meta name="citation_inbook_title" content="PDQ Cancer Information Summaries [Internet]" /><meta name="citation_title" content="Osteosarcoma and Undifferentiated Pleomorphic Sarcoma of Bone Treatment (PDQ®)" /><meta name="citation_publisher" content="National Cancer Institute (US)" /><meta name="citation_date" content="2022/03/03" /><meta name="citation_author" content="PDQ Pediatric Treatment Editorial Board" /><meta name="citation_pmid" content="26389179" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK65736/" /><meta name="citation_keywords" content="osteosarcoma" /><meta name="citation_keywords" content="childhood malignant fibrous histiocytoma of bone" /><meta name="citation_keywords" content="childhood malignant fibrous histiocytoma of bone" /><meta name="citation_keywords" content="osteosarcoma" /><meta name="citation_keywords" content="undifferentiated pleomorphic sarcoma of bone" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="Osteosarcoma and Undifferentiated Pleomorphic Sarcoma of Bone Treatment (PDQ®)" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="National Cancer Institute (US)" /><meta name="DC.Contributor" content="PDQ Pediatric Treatment Editorial Board" /><meta name="DC.Date" content="2022/03/03" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK65736/" /><meta name="description" content="Osteosarcoma and undifferentiated pleomorphic sarcoma (UPS) (formerly called malignant fibrous histiocytoma [MFH]) of bone treatment depends on site, extent of disease, and grade. Treatment options include surgery, chemotherapy, radiation therapy, and targeted therapy. Get detailed treatment information for osteosarcoma and UPS in this summary for clinicians." /><meta name="og:title" content="Osteosarcoma and Undifferentiated Pleomorphic Sarcoma of Bone Treatment (PDQ®)" /><meta name="og:type" content="book" /><meta name="og:description" content="Osteosarcoma and undifferentiated pleomorphic sarcoma (UPS) (formerly called malignant fibrous histiocytoma [MFH]) of bone treatment depends on site, extent of disease, and grade. Treatment options include surgery, chemotherapy, radiation therapy, and targeted therapy. Get detailed treatment information for osteosarcoma and UPS in this summary for clinicians." /><meta name="og:url" content="https://www.ncbi.nlm.nih.gov/books/NBK65736/" /><meta name="og:site_name" content="NCBI Bookshelf" /><meta name="og:image" content="https://www.ncbi.nlm.nih.gov/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-pdqcis-lrg.png" /><meta name="twitter:card" content="summary" /><meta name="twitter:site" content="@ncbibooks" /><meta name="bk-non-canon-loc" content="/books/n/pdqcis/CDR0000062698/" /><link rel="canonical" href="https://www.ncbi.nlm.nih.gov/books/NBK65736/" /><link rel="stylesheet" href="/corehtml/pmc/css/figpopup.css" type="text/css" media="screen" /><link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books.min.css" type="text/css" /><link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books_print.min.css" type="text/css" media="print" /><style type="text/css">p a.figpopup{display:inline !important} .bk_tt {font-family: monospace} .first-line-outdent .bk_ref {display: inline} .body-content h2, .body-content .h2 {border-bottom: 1px solid #97B0C8} .body-content h2.inline {border-bottom: none} a.page-toc-label , .jig-ncbismoothscroll a {text-decoration:none;border:0 !important} .temp-labeled-list .graphic {display:inline-block !important} .temp-labeled-list img{width:100%}</style><script type="text/javascript" src="/corehtml/pmc/js/jquery.hoverIntent.min.js"> </script><script type="text/javascript" src="/corehtml/pmc/js/common.min.js?_=3.18"> </script><script type="text/javascript" src="/corehtml/pmc/js/large-obj-scrollbars.min.js"> </script><script type="text/javascript">window.name="mainwindow";</script><script type="text/javascript" src="/corehtml/pmc/js/bookshelf/2.26/book-toc.min.js"> </script><script type="text/javascript" src="/corehtml/pmc/js/bookshelf/2.26/books.min.js"> </script><meta name="book-collection" content="NONE" />
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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="#__NBK65736_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK65736_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="_NBK65736_"><span class="title" itemprop="name">Osteosarcoma and Undifferentiated Pleomorphic Sarcoma of Bone 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: March 3, 2022.</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="CDR0000062698__491">This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of osteosarcoma and malignant fibrous histiocytoma of bone. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.</p><p id="CDR0000062698__492">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="CDR0000062698__1"><h2 id="_CDR0000062698__1_">General Information About Osteosarcoma and Undifferentiated Pleomorphic Sarcoma (UPS) (Formerly Called Malignant Fibrous Histiocytoma [MFH]) of Bone</h2><div id="CDR0000062698__1802"><h3>Disease Overview</h3><p id="CDR0000062698__4">Osteosarcoma occurs predominantly in adolescents and young
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adults. Review of data from the National Cancer Institute's Surveillance, Epidemiology, and End Results Program resulted in an estimated osteosarcoma incidence rate of 4.4 cases per 1 million each year in people aged 0 to 24 years.[<a class="bk_pop" href="#CDR0000062698_rl_1_1">1</a>] The U.S. Census Bureau estimated that there were 110 million people in this age range in the year 2010, resulting in an incidence of roughly 450 cases per year in children and young adults younger than 25 years. </p><p id="CDR0000062698__1803">Osteosarcoma accounts for approximately 5% of childhood tumors. In
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children and adolescents, more than 50% of these tumors arise from the long bones around the
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knee. Osteosarcoma is rarely observed in soft tissue or visceral organs. There appears to be no difference in presenting symptoms, tumor location, and outcome for younger patients (<12 years) compared with adolescents.[<a class="bk_pop" href="#CDR0000062698_rl_1_2">2</a>,<a class="bk_pop" href="#CDR0000062698_rl_1_3">3</a>] </p><p id="CDR0000062698__1804">Two trials conducted in the 1980s were designed to determine whether chemotherapy altered the natural history of osteosarcoma after surgical removal of the primary tumor. The outcome of these patients recapitulated the historical
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experience before 1970; more than one-half of these patients developed metastases
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within 6 months of diagnosis, and overall, approximately 90% developed recurrent
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disease within 2 years of diagnosis.[<a class="bk_pop" href="#CDR0000062698_rl_1_4">4</a>] Overall survival (OS) for patients
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treated with surgery alone was statistically inferior.[<a class="bk_pop" href="#CDR0000062698_rl_1_5">5</a>] The natural history
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of osteosarcoma has not changed over time, and fewer than 20% of patients with
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localized, resectable primary tumors treated with surgery alone can be expected
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to survive free of relapse.[<a class="bk_pop" href="#CDR0000062698_rl_1_4">4</a>,<a class="bk_pop" href="#CDR0000062698_rl_1_6">6</a>]; [<a class="bk_pop" href="#CDR0000062698_rl_1_7">7</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335125/" class="def">Level of evidence: 1iiA</a>]</p><p id="CDR0000062698__1926">In 2013, the World Health Organization (WHO) published an update to the Classification of Tumors of Soft Tissue and Bone.[<a class="bk_pop" href="#CDR0000062698_rl_1_8">8</a>] They removed the term <i>malignant fibrous histiocytoma (MFH)</i> and replaced it with <i>undifferentiated pleomorphic sarcoma (UPS)</i>. This type of sarcoma is much more common in soft tissues; however, it does arise in bone. In bone, it has features that are histologically similar to osteosarcoma, but it does not produce osteoid. Most of the literature describing the clinical behavior and response to therapy for this histology in bone was published before the 2013 WHO update, and a search for <i>UPS of bone</i> will not retrieve these articles. The citations in this summary appear with their titles as published; therefore, many references will describe <i>MFH of bone</i>, a condition now called <i>UPS of bone</i>.</p></div><div id="CDR0000062698__1822"><h3>Diagnostic Evaluation</h3><p id="CDR0000062698__247">Osteosarcoma can be diagnosed by core needle biopsy or open surgical biopsy. It is preferable that the biopsy be performed by a surgeon skilled in the techniques of limb sparing (removal of the malignant bone tumor without amputation and replacement of bones or joints with allografts or prosthetic devices). In these cases, the original biopsy incision placement is crucial. Inappropriate alignment of the biopsy or inadvertent contamination of soft tissues can render subsequent limb-preserving reconstructive surgery impossible.</p></div><div id="CDR0000062698__363"><h3>Prognostic Factors</h3><p id="CDR0000062698__87">Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2010, childhood cancer mortality decreased by more than 50%.[<a class="bk_pop" href="#CDR0000062698_rl_1_9">9</a>] For osteosarcoma, the 5-year survival rate increased over the same time from 40% to 76% in children younger than 15 years and from 56% to approximately 66% in adolescents aged 15 to 19 years. However, there has been no substantial improvement since the 1980s.[<a class="bk_pop" href="#CDR0000062698_rl_1_10">10</a>]</p><p id="CDR0000062698__448">In general, prognostic factors for osteosarcoma have not been helpful in identifying patients who might benefit from treatment intensification or who might require less therapy while maintaining an excellent outcome.</p><p id="CDR0000062698__364">Factors that may influence outcome include the following:[<a class="bk_pop" href="#CDR0000062698_rl_1_11">11</a>] </p><ul id="CDR0000062698__445"><li class="half_rhythm"><div><a href="#CDR0000062698__365">Primary tumor site</a>.</div></li><li class="half_rhythm"><div><a href="#CDR0000062698__368">Size of the primary tumor</a>.</div></li><li class="half_rhythm"><div><a href="#CDR0000062698__370">Presence of clinically detectable metastatic disease</a>. </div></li><li class="half_rhythm"><div><a href="#CDR0000062698__372">Surgical resectability of primary tumor</a>.</div></li><li class="half_rhythm"><div><a href="#CDR0000062698__374">Degree of tumor necrosis after administration of neoadjuvant chemotherapy</a>. </div></li><li class="half_rhythm"><div><a href="#CDR0000062698__1975">Age and sex</a>.</div></li><li class="half_rhythm"><div><a href="#CDR0000062698__376">Other possible prognostic factors</a>.</div></li></ul><div id="CDR0000062698__365"><h4>Primary tumor site</h4><p id="CDR0000062698__344">The site of the primary tumor is a significant prognostic factor for patients with localized disease. Among extremity tumors, distal sites have a more favorable prognosis than do proximal sites. Axial skeleton primary tumors are associated with the greatest risk of progression and death, primarily related to the inability to achieve a complete surgical resection.</p><p id="CDR0000062698__1805">Prognostic considerations for the axial skeleton and extraskeletal sites are as follows:</p><ul id="CDR0000062698__345"><li class="half_rhythm"><div class="half_rhythm"><b>Pelvis:</b> Pelvic osteosarcomas make up 7% to 9% of all osteosarcomas; survival rates for patients with pelvic primary tumors are 20% to 47%.[<a class="bk_pop" href="#CDR0000062698_rl_1_12">12</a>-<a class="bk_pop" href="#CDR0000062698_rl_1_14">14</a>] Complete surgical resection is associated with a positive outcome for osteosarcoma of the pelvis in some cohorts of patients.[<a class="bk_pop" href="#CDR0000062698_rl_1_12">12</a>,<a class="bk_pop" href="#CDR0000062698_rl_1_15">15</a>]</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Craniofacial/head and neck:</b> In patients with craniofacial osteosarcoma, those with primary sites in the mandible and maxilla have a better prognosis than do patients with other primary sites in the head and neck.[<a class="bk_pop" href="#CDR0000062698_rl_1_16">16</a>-<a class="bk_pop" href="#CDR0000062698_rl_1_18">18</a>] For patients with osteosarcoma of craniofacial bones, complete resection of the primary tumor with negative margins is essential for cure.[<a class="bk_pop" href="#CDR0000062698_rl_1_19">19</a>-<a class="bk_pop" href="#CDR0000062698_rl_1_21">21</a>] When treated with surgery alone, patients who have osteosarcoma of the head and neck have a better prognosis than those who have appendicular lesions. </div><div class="half_rhythm">Despite a relatively high rate of inferior necrosis after neoadjuvant chemotherapy, fewer patients with craniofacial primaries develop systemic metastases than do patients with osteosarcoma originating in the extremities.[<a class="bk_pop" href="#CDR0000062698_rl_1_22">22</a>-<a class="bk_pop" href="#CDR0000062698_rl_1_24">24</a>] </div><div class="half_rhythm">A meta-analysis concluded that systemic adjuvant chemotherapy improves the prognosis for patients with osteosarcoma of the head and neck, while small series have not shown such a benefit.[<a class="bk_pop" href="#CDR0000062698_rl_1_22">22</a>-<a class="bk_pop" href="#CDR0000062698_rl_1_24">24</a>] Another large meta-analysis detected no benefit of chemotherapy for patients with osteosarcoma of the head and neck, but suggested that incorporating chemotherapy into the treatment plan for patients with high-grade tumors may improve survival.[<a class="bk_pop" href="#CDR0000062698_rl_1_21">21</a>] A retrospective analysis identified a trend toward better survival in patients with high-grade osteosarcoma of the mandible and maxilla who received adjuvant chemotherapy.[<a class="bk_pop" href="#CDR0000062698_rl_1_21">21</a>,<a class="bk_pop" href="#CDR0000062698_rl_1_25">25</a>] </div><div class="half_rhythm">Radiation therapy was found to improve local control, disease-specific survival, and OS in a retrospective study of patients with osteosarcoma of the craniofacial bones who had positive or uncertain margins after surgical resection.[<a class="bk_pop" href="#CDR0000062698_rl_1_26">26</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335144/" class="def">Level of evidence: 3iiA</a>] Radiation-associated craniofacial osteosarcomas are generally high-grade lesions, usually fibroblastic, and tend to recur locally with a high rate of metastasis.[<a class="bk_pop" href="#CDR0000062698_rl_1_27">27</a>]</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Extraskeletal:</b> Osteosarcoma in extraskeletal sites is rare in children and young adults. With current combined-modality therapy, the outcome of patients with extraskeletal osteosarcoma appears to be similar to that of patients with primary tumors of bone.[<a class="bk_pop" href="#CDR0000062698_rl_1_28">28</a>]</div></li></ul></div><div id="CDR0000062698__368"><h4>Size of the primary tumor</h4><p id="CDR0000062698__369">In some series, patients with larger tumors appeared to have a worse prognosis than patients with smaller tumors.[<a class="bk_pop" href="#CDR0000062698_rl_1_11">11</a>,<a class="bk_pop" href="#CDR0000062698_rl_1_29">29</a>,<a class="bk_pop" href="#CDR0000062698_rl_1_30">30</a>] Tumor size has been assessed by longest single dimension, cross-sectional area, or estimate of tumor volume; all assessments have correlated with outcome.</p><p id="CDR0000062698__1806">Serum lactate dehydrogenase (LDH), which also correlates with outcome, is a likely surrogate for tumor volume.[<a class="bk_pop" href="#CDR0000062698_rl_1_13">13</a>]</p></div><div id="CDR0000062698__370"><h4>Presence of clinically detectable metastatic disease</h4><p id="CDR0000062698__350">Patients with localized disease have a much better prognosis than patients with overt metastatic disease. As many as 20% of patients have radiographically detectable metastases at diagnosis, with the lung being the most common site.[<a class="bk_pop" href="#CDR0000062698_rl_1_31">31</a>] The prognosis for patients with metastatic disease appears to be determined largely by site(s) of metastases, number of metastases, and surgical resectability of the metastatic disease.[<a class="bk_pop" href="#CDR0000062698_rl_1_32">32</a>,<a class="bk_pop" href="#CDR0000062698_rl_1_33">33</a>]</p><ul id="CDR0000062698__351"><li class="half_rhythm"><div><b>Site of metastases:</b> Prognosis appears more favorable for patients with fewer pulmonary nodules and for those with unilateral rather than bilateral pulmonary metastases.[<a class="bk_pop" href="#CDR0000062698_rl_1_32">32</a>] Not all patients with suspected pulmonary metastases at diagnosis have osteosarcoma confirmed at the time of lung resection. In one large series, approximately 25% of patients had exclusively benign lesions removed at the time of surgery.[<a class="bk_pop" href="#CDR0000062698_rl_1_33">33</a>] </div></li><li class="half_rhythm"><div><b>Number of metastases:</b> Patients with <i>skip</i> metastases (at least two discontinuous lesions in the same bone) have been reported to have inferior prognoses.[<a class="bk_pop" href="#CDR0000062698_rl_1_34">34</a>] However, an analysis of the German Cooperative Osteosarcoma Study suggests that skip lesions in the same bone do not confer an inferior prognosis if they are included in planned surgical resection. Skip metastasis in a bone other than the primary bone should be considered systemic metastasis.[<a class="bk_pop" href="#CDR0000062698_rl_1_35">35</a>] </div><div>Historically, metastasis across a joint was referred to as a skip lesion. Skip lesions across a joint might be considered hematogenous spread and have a worse prognosis.[<a class="bk_pop" href="#CDR0000062698_rl_1_35">35</a>]</div><div>Patients with multifocal osteosarcoma (defined as multiple bone lesions without a clear primary tumor) have an extremely poor prognosis.[<a class="bk_pop" href="#CDR0000062698_rl_1_36">36</a>,<a class="bk_pop" href="#CDR0000062698_rl_1_37">37</a>]</div></li><li class="half_rhythm"><div><b>Surgical resectability of metastases:</b> Patients who have complete surgical ablation of the primary and metastatic tumor (when confined to the lung) after chemotherapy may attain long-term survival, although overall event-free survival (EFS) rates remain about 20% to 30% for patients with metastatic disease at diagnosis.[<a class="bk_pop" href="#CDR0000062698_rl_1_32">32</a>,<a class="bk_pop" href="#CDR0000062698_rl_1_33">33</a>,<a class="bk_pop" href="#CDR0000062698_rl_1_38">38</a>,<a class="bk_pop" href="#CDR0000062698_rl_1_39">39</a>] </div></li></ul></div><div id="CDR0000062698__372"><h4>Surgical resectability of the primary tumor</h4><p id="CDR0000062698__373">Resectability of the tumor is a critical prognostic feature because osteosarcoma is relatively resistant to radiation therapy. Complete resection of the primary tumor and any skip lesions with adequate margins is generally considered essential for cure. A retrospective review of patients with craniofacial osteosarcoma performed by the cooperative German-Austrian-Swiss osteosarcoma study group reported that incomplete surgical resection was associated with inferior survival probability.[<a class="bk_pop" href="#CDR0000062698_rl_1_16">16</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335145/" class="def">Level of evidence: 3iiB</a>] In a European cooperative study, the size of the margin was not significant. However, prognosis was better when both the biopsy and resection were performed at a center with orthopedic oncology experience.[<a class="bk_pop" href="#CDR0000062698_rl_1_13">13</a>]</p><p id="CDR0000062698__449">For patients with axial skeletal primaries who either do not undergo surgery for their primary tumor or who undergo surgery that results in positive margins, radiation therapy may improve survival.[<a class="bk_pop" href="#CDR0000062698_rl_1_15">15</a>,<a class="bk_pop" href="#CDR0000062698_rl_1_40">40</a>]</p></div><div id="CDR0000062698__374"><h4>Degree of tumor necrosis after neoadjuvant chemotherapy</h4><p id="CDR0000062698__375">Most treatment protocols for osteosarcoma use an initial period of systemic chemotherapy before definitive resection of the primary tumor (or resection of sites of metastases). The pathologist assesses necrosis in the resected tumor. Patients with at least 90% necrosis in the primary tumor after induction chemotherapy have a better prognosis than do patients with less necrosis.[<a class="bk_pop" href="#CDR0000062698_rl_1_29">29</a>] Patients with less necrosis (<90%) in the primary tumor after initial chemotherapy have a higher rate of recurrence within the first 2 years than do patients with a more favorable amount of necrosis (≥90%).[<a class="bk_pop" href="#CDR0000062698_rl_1_41">41</a>]</p><p id="CDR0000062698__1808">Less necrosis should not be interpreted to mean that chemotherapy has been ineffective; cure rates for patients with little or no necrosis after induction chemotherapy are much higher than cure rates for patients who receive no chemotherapy. The EFS rate for patients who receive no adjuvant chemotherapy is approximately 11%.[<a class="bk_pop" href="#CDR0000062698_rl_1_42">42</a>] Many large published series of patients treated with chemotherapy have reported EFS rates of 40% to 50% for patients with little or no necrosis in the primary tumor after initial systemic chemotherapy.[<a class="bk_pop" href="#CDR0000062698_rl_1_43">43</a>-<a class="bk_pop" href="#CDR0000062698_rl_1_45">45</a>] A review of two consecutive prospective trials performed by the Children’s Oncology Group showed that histologic necrosis in the primary tumor after initial chemotherapy was affected by the duration and intensity of the initial period of chemotherapy. More necrosis was associated with better outcome in both trials, but the magnitude of the difference between patients with more and less necrosis was diminished with a longer and more intensive period of initial chemotherapy.[<a class="bk_pop" href="#CDR0000062698_rl_1_46">46</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000632558/" class="def">Level of evidence: 1iiD</a>]</p></div><div id="CDR0000062698__1975"><h4>Age and sex</h4><p id="CDR0000062698__1925">Patients in the older adolescent and young adult age group, typically defined as age 18 to 40 years, tend to have a worse prognosis. In addition, male sex has been associated with a worse prognosis.[<a class="bk_pop" href="#CDR0000062698_rl_1_30">30</a>,<a class="bk_pop" href="#CDR0000062698_rl_1_47">47</a>,<a class="bk_pop" href="#CDR0000062698_rl_1_48">48</a>] Compared with the other prognostic factors listed, both age and sex have a relatively minor impact on outcome.</p></div><div id="CDR0000062698__376"><h4>Other possible prognostic factors</h4><p id="CDR0000062698__450">Other factors that may be prognostic but with either limited or conflicting data include the following:</p><ul id="CDR0000062698__451"><li class="half_rhythm"><div class="half_rhythm"><b>Subsequent neoplasms.</b> Patients with osteosarcoma as a subsequent neoplasm, including tumors arising in a radiation field, share the same prognosis as patients with de novo osteosarcoma if they are treated aggressively with complete surgical resection and multiagent chemotherapy.[<a class="bk_pop" href="#CDR0000062698_rl_1_49">49</a>-<a class="bk_pop" href="#CDR0000062698_rl_1_52">52</a>]</div><div class="half_rhythm"> In a German series, approximately 25% of patients with craniofacial osteosarcoma had osteosarcoma as a second tumor, and in 8 of these 13 patients, osteosarcoma arose after treatment for retinoblastoma. In this series, there was no difference in outcome for primary or secondary craniofacial osteosarcoma.[<a class="bk_pop" href="#CDR0000062698_rl_1_16">16</a>]</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Laboratory abnormalities.</b> Possible prognostic factors identified for patients with conventional localized high-grade osteosarcoma include LDH level, alkaline phosphatase level, and histologic subtype.[<a class="bk_pop" href="#CDR0000062698_rl_1_29">29</a>,<a class="bk_pop" href="#CDR0000062698_rl_1_44">44</a>,<a class="bk_pop" href="#CDR0000062698_rl_1_47">47</a>,<a class="bk_pop" href="#CDR0000062698_rl_1_53">53</a>-<a class="bk_pop" href="#CDR0000062698_rl_1_56">56</a>]</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Body mass index. </b>Higher body mass index at initial presentation is associated with worse OS.[<a class="bk_pop" href="#CDR0000062698_rl_1_57">57</a>]</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Pathological fracture. </b>Some studies have suggested that a pathological fracture at diagnosis or during preoperative chemotherapy does not have adverse prognostic significance.[<a class="bk_pop" href="#CDR0000062698_rl_1_6">6</a>]; [<a class="bk_pop" href="#CDR0000062698_rl_1_58">58</a>,<a class="bk_pop" href="#CDR0000062698_rl_1_59">59</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335150/" class="def">Level of evidence: 3iiiA</a>]; [<a class="bk_pop" href="#CDR0000062698_rl_1_60">60</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000716085/" class="def">Level of evidence: 3iiD</a>]</div><div class="half_rhythm"> However, a systematic review of nine cohort studies examined the impact of pathological fractures on outcome in patients with osteosarcoma. The review included 2,187 patients, 311 of whom had a pathological fracture. The presence of a pathological fracture correlated with decreased EFS and OS.[<a class="bk_pop" href="#CDR0000062698_rl_1_61">61</a>] In two additional series, a pathological fracture at diagnosis was associated with a worse overall outcome.[<a class="bk_pop" href="#CDR0000062698_rl_1_62">62</a>]; [<a class="bk_pop" href="#CDR0000062698_rl_1_63">63</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335144/" class="def">Level of evidence: 3iiA</a>] A retrospective analysis of 2,847 patients with osteosarcoma from the German cooperative group identified 321 patients (11.3%) with a pathological fracture before the initiation of systemic therapy.[<a class="bk_pop" href="#CDR0000062698_rl_1_64">64</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335138/" class="def">Level of evidence: 3iA</a>] In pediatric patients, OS and EFS did not differ significantly between patients with and without a pathological fracture. In adults, the 5-year OS rate in patients with a pathological fracture was 46% versus 69% for patients without a pathological fracture (<i>P</i> < .001). The 5-year EFS rate in adults was 36% for patients with a pathological fracture versus 56% for patients without a pathological fracture (<i>P</i> < .001). In a multivariable analysis, the presence of a pathological fracture was not a statistically significant factor for OS or EFS in the total cohort or in pediatric patients. In adult patients, presence of a pathological fracture remained an independent prognostic factor for OS (hazard ratio, 1.893; <i>P</i> = .013).</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Time to definitive surgery.</b> In a large series, a delay of 21 days or longer from the time of definitive surgery to the resumption of chemotherapy was an adverse prognostic factor.[<a class="bk_pop" href="#CDR0000062698_rl_1_65">65</a>] </div></li><li class="half_rhythm"><div class="half_rhythm"><b>Genetic factors.</b> (Refer to the <a href="#CDR0000062698__1974">Genomics of Osteosarcoma</a> section of this summary for more information.)<dl id="CDR0000062698__1947" class="temp-labeled-list"><dt>-</dt><dd><p class="no_top_margin"><i>ERBB2</i> expression. There are conflicting data concerning the prognostic significance of this human epidermal growth factor.[<a class="bk_pop" href="#CDR0000062698_rl_1_66">66</a>-<a class="bk_pop" href="#CDR0000062698_rl_1_68">68</a>]</p></dd><dt>-</dt><dd><p class="no_top_margin">Tumor cell ploidy.[<a class="bk_pop" href="#CDR0000062698_rl_1_69">69</a>]</p></dd><dt>-</dt><dd><p class="no_top_margin">Specific chromosomal gains or losses.[<a class="bk_pop" href="#CDR0000062698_rl_1_70">70</a>]</p></dd><dt>-</dt><dd><p class="no_top_margin">Loss of heterozygosity of the <i>RB1</i> gene.[<a class="bk_pop" href="#CDR0000062698_rl_1_71">71</a>
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,<a class="bk_pop" href="#CDR0000062698_rl_1_72">72</a>]</p></dd><dt>-</dt><dd><p class="no_top_margin">Loss of heterozygosity of the <i>p53</i> locus.[<a class="bk_pop" href="#CDR0000062698_rl_1_73">73</a>]</p></dd><dt>-</dt><dd><p class="no_top_margin">Increased expression of p-glycoprotein.[<a class="bk_pop" href="#CDR0000062698_rl_1_74">74</a>,<a class="bk_pop" href="#CDR0000062698_rl_1_75">75</a>] A prospective analysis of p-glycoprotein expression determined by immunohistochemistry failed to identify prognostic significance for patients with newly diagnosed osteosarcoma, although earlier studies suggested that overexpression of p-glycoprotein predicted poor outcome.[<a class="bk_pop" href="#CDR0000062698_rl_1_76">76</a>]</p></dd></dl></div></li></ul></div></div><div id="CDR0000062698_rl_1"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000062698_rl_1_1">Mirabello L, Troisi RJ, Savage SA: Osteosarcoma incidence and survival rates from 1973 to 2004: data from the Surveillance, Epidemiology, and End Results Program. Cancer 115 (7): 1531-43, 2009. [<a href="/pmc/articles/PMC2813207/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2813207</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19197972" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19197972</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_1_2">Bacci G, Longhi A, Bertoni F, et al.: Primary high-grade osteosarcoma: comparison between preadolescent and older patients. J Pediatr Hematol Oncol 27 (3): 129-34, 2005. [<a href="https://pubmed.ncbi.nlm.nih.gov/15750443" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15750443</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_1_3">Bacci G, Balladelli A, Palmerini E, et al.: Neoadjuvant chemotherapy for osteosarcoma of the extremities in preadolescent patients: the Rizzoli Institute experience. J Pediatr Hematol Oncol 30 (12): 908-12, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/19131777" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19131777</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_1_4">Link MP, Goorin AM, Miser AW, et al.: The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J Med 314 (25): 1600-6, 1986. [<a href="https://pubmed.ncbi.nlm.nih.gov/3520317" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 3520317</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_1_5">Link MP: The multi-institutional osteosarcoma study: an update. Cancer Treat Res 62: 261-7, 1993. [<a href="https://pubmed.ncbi.nlm.nih.gov/7682087" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7682087</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_1_6">Bacci G, Ferrari S, Longhi A, et al.: Nonmetastatic osteosarcoma of the extremity with pathologic fracture at presentation: local and systemic control by amputation or limb salvage after preoperative chemotherapy. Acta Orthop Scand 74 (4): 449-54, 2003. 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[<a href="https://pubmed.ncbi.nlm.nih.gov/19294672" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19294672</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_1_59">Xie L, Guo W, Li Y, et al.: Pathologic fracture does not influence local recurrence and survival in high-grade extremity osteosarcoma with adequate surgical margins. J Surg Oncol 106 (7): 820-5, 2012. [<a href="https://pubmed.ncbi.nlm.nih.gov/22740310" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22740310</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_1_60">Chung LH, Wu PK, Chen CF, et al.: Pathological fractures in predicting clinical outcomes for patients with osteosarcoma. BMC Musculoskelet Disord 17 (1): 503, 2016. [<a href="/pmc/articles/PMC5192576/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5192576</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/28031047" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28031047</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_1_61">Sun L, Li Y, Zhang J, et al.: Prognostic value of pathologic fracture in patients with high grade localized osteosarcoma: a systemic review and meta-analysis of cohort studies. J Orthop Res 33 (1): 131-9, 2015. [<a href="https://pubmed.ncbi.nlm.nih.gov/25231396" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25231396</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_1_62">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="CDR0000062698_rl_1_63">Schlegel M, Zeumer M, Prodinger PM, et al.: Impact of Pathological Fractures on the Prognosis of Primary Malignant Bone Sarcoma in Children and Adults: A Single-Center Retrospective Study of 205 Patients. Oncology 94 (6): 354-362, 2018. [<a href="https://pubmed.ncbi.nlm.nih.gov/29656296" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 29656296</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_1_64">Kelley LM, Schlegel M, Hecker-Nolting S, et al.: Pathological Fracture and Prognosis of High-Grade Osteosarcoma of the Extremities: An Analysis of 2,847 Consecutive Cooperative Osteosarcoma Study Group (COSS) Patients. J Clin Oncol 38 (8): 823-833, 2020. [<a href="https://pubmed.ncbi.nlm.nih.gov/31928458" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 31928458</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_1_65">Imran H, Enders F, Krailo M, et al.: Effect of time to resumption of chemotherapy after definitive surgery on prognosis for non-metastatic osteosarcoma. J Bone Joint Surg Am 91 (3): 604-12, 2009. [<a href="/pmc/articles/PMC2701597/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2701597</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19255220" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19255220</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_1_66">Gorlick R, Huvos AG, Heller G, et al.: Expression of HER2/erbB-2 correlates with survival in osteosarcoma. J Clin Oncol 17 (9): 2781-8, 1999. [<a href="https://pubmed.ncbi.nlm.nih.gov/10561353" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10561353</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_1_67">Onda M, Matsuda S, Higaki S, et al.: ErbB-2 expression is correlated with poor prognosis for patients with osteosarcoma. Cancer 77 (1): 71-8, 1996. [<a href="https://pubmed.ncbi.nlm.nih.gov/8630943" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8630943</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_1_68">Kilpatrick SE, Geisinger KR, King TS, et al.: Clinicopathologic analysis of HER-2/neu immunoexpression among various histologic subtypes and grades of osteosarcoma. Mod Pathol 14 (12): 1277-83, 2001. [<a href="https://pubmed.ncbi.nlm.nih.gov/11743051" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11743051</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_1_69">Look AT, Douglass EC, Meyer WH: Clinical importance of near-diploid tumor stem lines in patients with osteosarcoma of an extremity. N Engl J Med 318 (24): 1567-72, 1988. [<a href="https://pubmed.ncbi.nlm.nih.gov/3163773" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 3163773</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_1_70">Ozaki T, Schaefer KL, Wai D, et al.: Genetic imbalances revealed by comparative genomic hybridization in osteosarcomas. Int J Cancer 102 (4): 355-65, 2002. [<a href="https://pubmed.ncbi.nlm.nih.gov/12402305" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12402305</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_1_71">Feugeas O, Guriec N, Babin-Boilletot A, et al.: Loss of heterozygosity of the RB gene is a poor prognostic factor in patients with osteosarcoma. J Clin Oncol 14 (2): 467-72, 1996. [<a href="https://pubmed.ncbi.nlm.nih.gov/8636759" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8636759</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_1_72">Heinsohn S, Evermann U, Zur Stadt U, et al.: Determination of the prognostic value of loss of heterozygosity at the retinoblastoma gene in osteosarcoma. Int J Oncol 30 (5): 1205-14, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17390023" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17390023</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_1_73">Goto A, Kanda H, Ishikawa Y, et al.: Association of loss of heterozygosity at the p53 locus with chemoresistance in osteosarcomas. Jpn J Cancer Res 89 (5): 539-47, 1998. [<a href="/pmc/articles/PMC5921844/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5921844</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/9685858" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9685858</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_1_74">Serra M, Pasello M, Manara MC, et al.: May P-glycoprotein status be used to stratify high-grade osteosarcoma patients? Results from the Italian/Scandinavian Sarcoma Group 1 treatment protocol. Int J Oncol 29 (6): 1459-68, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/17088985" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17088985</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_1_75">Pakos EE, Ioannidis JP: The association of P-glycoprotein with response to chemotherapy and clinical outcome in patients with osteosarcoma. A meta-analysis. Cancer 98 (3): 581-9, 2003. [<a href="https://pubmed.ncbi.nlm.nih.gov/12879476" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12879476</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_1_76">Schwartz CL, Gorlick R, Teot L, et al.: Multiple drug resistance in osteogenic sarcoma: INT0133 from the Children's Oncology Group. J Clin Oncol 25 (15): 2057-62, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17513810" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17513810</span></a>]</div></li></ol></div></div><div id="CDR0000062698__1974"><h2 id="_CDR0000062698__1974_">Genomics of Osteosarcoma</h2><div id="CDR0000062698__sm_CDR0000777834_1"><h3>Molecular Features of Osteosarcoma</h3><p id="CDR0000062698__sm_CDR0000777834_3">The genomic landscape of osteosarcoma is distinct from that of other childhood cancers. Compared with many adult cancers, it is characterized by an exceptionally high number of structural variants with a relatively small number of single nucleotide variants.[<a class="bk_pop" href="#CDR0000062698_rl_1974_1">1</a>,<a class="bk_pop" href="#CDR0000062698_rl_1974_2">2</a>]</p><p id="CDR0000062698__sm_CDR0000777834_1911">Key observations regarding the genomic landscape of osteosarcoma are summarized below:</p><ul id="CDR0000062698__sm_CDR0000777834_1912"><li class="half_rhythm"><div class="half_rhythm">The number of structural variants observed for osteosarcoma is high, at more than 200 structural variants per genome;[<a class="bk_pop" href="#CDR0000062698_rl_1974_1">1</a>,<a class="bk_pop" href="#CDR0000062698_rl_1974_2">2</a>] thus, osteosarcoma has the most chaotic genome among childhood cancers. The Circos plots shown in Figure 1 illustrate the exceptionally high number of intra- and inter-chromosomal translocations that typify osteosarcoma genomes.</div><div class="half_rhythm"><div id="CDR0000062698__sm_CDR0000777834_1917" class="figure bk_fig"><div class="graphic"><img src="/books/NBK65736.26/bin/CDR0000777891.jpg" alt="Diagrams of osteosarcoma cases from the NCI TARGET project." /></div><div class="caption"><p>Figure 1. Circos plots of osteosarcoma cases from the National Cancer Institute's Therapeutically Applicable Research to Generate Effective Treatments (TARGET) project. The red lines in the interior circle connect chromosome regions involved in either intra- or inter-chromosomal translocations. Osteosarcoma is distinctive from other childhood cancers because it has a large number of intra- and inter-chromosomal translocations. Credit: National Cancer Institute.</p></div></div></div></li><li class="half_rhythm"><div class="half_rhythm">The number of mutations per osteosarcoma genome that affect protein sequence (approximately 25 per genome) is higher than that of some other childhood cancers (e.g., Ewing sarcoma and rhabdoid tumors) but is far below that for adult cancers such as melanoma and non-small cell lung cancer.[<a class="bk_pop" href="#CDR0000062698_rl_1974_1">1</a>,<a class="bk_pop" href="#CDR0000062698_rl_1974_2">2</a>]</div></li><li class="half_rhythm"><div class="half_rhythm">Genomic alterations in <i>TP53</i> are present in most osteosarcoma cases. A distinctive form of <i>TP53</i> inactivation occurs through structural variations in the first intron of <i>TP53</i> that lead to disruption of the <i>TP53</i> gene.[<a class="bk_pop" href="#CDR0000062698_rl_1974_1">1</a>] Other mechanisms of <i>TP53</i> inactivation are also observed, including missense and nonsense mutations and deletions of the <i>TP53</i> gene.[<a class="bk_pop" href="#CDR0000062698_rl_1974_1">1</a>,<a class="bk_pop" href="#CDR0000062698_rl_1974_2">2</a>] The combination of these various mechanisms for loss of <i>TP53</i> function leads to biallelic inactivation in most cases of osteosarcoma.</div></li><li class="half_rhythm"><div class="half_rhythm"><i>MDM2</i> amplification is observed in a minority of osteosarcoma cases (approximately 5%) and provides another mechanism for loss of <i>TP53</i> function.[<a class="bk_pop" href="#CDR0000062698_rl_1974_1">1</a>,<a class="bk_pop" href="#CDR0000062698_rl_1974_2">2</a>]</div></li><li class="half_rhythm"><div class="half_rhythm"><i>RB1</i> is commonly inactivated in osteosarcoma, sometimes by mutation but more commonly by deletion.[<a class="bk_pop" href="#CDR0000062698_rl_1974_1">1</a>,<a class="bk_pop" href="#CDR0000062698_rl_1974_2">2</a>]</div></li><li class="half_rhythm"><div class="half_rhythm">Other genes with recurrent alterations in osteosarcoma include <i>ATRX</i> and <i>DLG2</i>.[<a class="bk_pop" href="#CDR0000062698_rl_1974_1">1</a>] Additionally, pathway analysis showed that the PI3K/mammalian target of rapamycin (mTOR) pathway was altered by mutation/loss/amplification in approximately one-fourth of patients, with <i>PTEN</i> mutation/loss being the most common alteration.[<a class="bk_pop" href="#CDR0000062698_rl_1974_2">2</a>]</div></li><li class="half_rhythm"><div class="half_rhythm">A retrospective review of 71 osteosarcoma tumors from 66 patients identified theoretically targetable alterations in 14 patients (21%), including amplification of <i>CDK4</i> (n = 9) and/or <i>MDM2</i> (n = 9) and somatic truncating mutations/deletions in <i>BRCA2</i> (n = 3) and <i>PTCH1</i> (n = 1). The authors reported mutually exclusive patterns of alterations, suggesting distinct biological subsets defined by gains at 4q12 and 6p12-21. Specifically, potentially targetable gene amplifications at 4q12 involving <i>KIT</i>, <i>KDR</i>, and <i>PDGFRA</i> were identified in 13 of 66 patients (20%), which showed strong <i>PDGFRA</i> expression by immunohistochemistry. In another largely nonoverlapping subset of 14 patients (24%) with gains at 6p12-21, <i>VEGFRA</i> amplification was identified.[<a class="bk_pop" href="#CDR0000062698_rl_1974_3">3</a>]</div></li><li class="half_rhythm"><div class="half_rhythm">The range of mutations reported for osteosarcoma tumors at diagnosis do not provide obvious therapeutic targets, as they primarily reflect loss of tumor suppressor genes (e.g., <i>TP53</i>, <i>RB1</i>, <i>PTEN</i>) rather than activation of targetable oncogenes.</div></li></ul><div id="CDR0000062698__sm_CDR0000777834_1922"><h4>Genetic predisposition to osteosarcoma</h4><p id="CDR0000062698__sm_CDR0000777834_1913">Germline mutations in several genes are associated with susceptibility to osteosarcoma. Table 1 summarizes the syndromes and associated genes for these conditions. A recent multi-institutional genomic study of more than 1,200 patients with osteosarcoma revealed pathogenic or likely pathogenic germline variants in autosomal dominant cancer-susceptibility genes in 18% of patients. The frequency of these cancer-susceptibility genes was higher in children aged 10 years or younger.[<a class="bk_pop" href="#CDR0000062698_rl_1974_4">4</a>]</p><div id="CDR0000062698__sm_CDR0000777834_1923"><h5><i>TP53</i> mutations</h5><p id="CDR0000062698__sm_CDR0000777834_1919">Mutations in <i>TP53</i> are the most common germline alterations associated with osteosarcoma. Mutations in this gene are found in approximately 70% of patients with Li-Fraumeni syndrome (LFS), which is associated with increased risk of osteosarcoma, breast cancer, various brain cancers, soft tissue sarcomas, and other cancers. While rhabdomyosarcoma is the most common sarcoma arising in patients aged 5 years and younger with <i>TP53</i>-associated LFS, osteosarcoma is the most common sarcoma in children and adolescents aged 6 to 19 years.[<a class="bk_pop" href="#CDR0000062698_rl_1974_5">5</a>] One study observed a high frequency of young osteosarcoma cases (age <30 years) carrying a known LFS-associated or likely LFS-associated <i>TP53</i> mutation (3.8%) or rare exonic <i>TP53</i> variant (5.7%), with an overall <i>TP53</i> mutation frequency of 9.5%.[<a class="bk_pop" href="#CDR0000062698_rl_1974_6">6</a>] Other groups have reported lower rates (3%–7%) of <i>TP53</i> germline mutations in patients with osteosarcoma.[<a class="bk_pop" href="#CDR0000062698_rl_1974_4">4</a>,<a class="bk_pop" href="#CDR0000062698_rl_1974_7">7</a>,<a class="bk_pop" href="#CDR0000062698_rl_1974_8">8</a>]</p></div><div id="CDR0000062698__sm_CDR0000777834_1925"><h5><i>RECQL4</i> mutations</h5><p id="CDR0000062698__sm_CDR0000777834_1921">Investigators analyzed whole-exome sequencing from the germline of 4,435 pediatric cancer patients at the St. Jude Children’s Research Hospital and 1,127 patients from the National Cancer Institute's Therapeutically Applicable Research to Generate Effective Treatment (TARGET) database. They identified 24 patients (0.43%) who harbored loss-of-function <i>RECQL4</i> variants, including 5 of 249 patients (2.0%) with osteosarcoma.[<a class="bk_pop" href="#CDR0000062698_rl_1974_9">9</a>] These <i>RECQL4</i> variants were significantly overrepresented in children with osteosarcoma, the cancer most frequently observed in patients with Rothmund-Thomson syndrome, compared with 134,187 noncancer controls in the Genome Aggregation Database (gnomAD v2.1; <i>P</i> = .00087; odds ratio, 7.1; 95% confidence interval, 2.9–17). Nine of the 24 individuals (38%) possessed the same c.1573delT (p.Cys525Alafs) variant located in the highly conserved DNA helicase domain, suggesting that disruption of this domain is central to oncogenesis.</p><div id="CDR0000062698__sm_CDR0000777834_382" class="table"><h3><span class="title">Table 1. Genetic Diseases That Predispose to Osteosarcoma<sup>a</sup></span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK65736.26/table/CDR0000062698__sm_CDR0000777834_382/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__CDR0000062698__sm_CDR0000777834_382_lrgtbl__"><table class="no_margin"><thead><tr><th colspan="1" rowspan="1" style="vertical-align:top;">Syndrome </th><th colspan="1" rowspan="1" style="vertical-align:top;">Description</th><th colspan="1" rowspan="1" style="vertical-align:top;">Location </th><th colspan="1" rowspan="1" style="vertical-align:top;">Gene </th><th colspan="1" rowspan="1" style="vertical-align:top;">Function</th></tr></thead><tbody><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Bloom syndrome
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[<a class="bk_pop" href="#CDR0000062698_rl_1974_11">11</a>]</td><td colspan="1" rowspan="1" style="vertical-align:top;">Rare inherited disorder characterized by short stature and sun-sensitive skin changes. Often presents with a long, narrow face, small lower jaw, large nose, and prominent ears.</td><td colspan="1" rowspan="1" style="vertical-align:top;">15q26.1 </td><td colspan="1" rowspan="1" style="vertical-align:top;"><i>BLM</i>
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">DNA helicase</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Diamond-Blackfan anemia [<a class="bk_pop" href="#CDR0000062698_rl_1974_12">12</a>]</td><td colspan="1" rowspan="1" style="vertical-align:top;">Inherited pure red cell aplasia. Patients at risk for MDS and AML. Associated with skeletal abnormalities such as abnormal facial features (flat nasal bridge, widely spaced eyes).</td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;"> Ribosomal proteins</td><td colspan="1" rowspan="1" style="vertical-align:top;">Ribosome production [<a class="bk_pop" href="#CDR0000062698_rl_1974_12">12</a>,<a class="bk_pop" href="#CDR0000062698_rl_1974_13">13</a>]</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Li-Fraumeni syndrome [<a class="bk_pop" href="#CDR0000062698_rl_1974_14">14</a>]</td><td colspan="1" rowspan="1" style="vertical-align:top;">Inherited mutation in <i>TP53</i> gene. Affected family members at increased risk of bone tumors, breast cancer, leukemia, brain tumors, and sarcomas.</td><td colspan="1" rowspan="1" style="vertical-align:top;">17p13.1 </td><td colspan="1" rowspan="1" style="vertical-align:top;">
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<i>P53</i>
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">DNA damage response</td></tr><tr><td colspan="1" rowspan="3" style="vertical-align:top;">Paget disease
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[<a class="bk_pop" href="#CDR0000062698_rl_1974_15">15</a>]</td><td colspan="1" rowspan="3" style="vertical-align:top;">Excessive breakdown of bone with abnormal bone formation and remodeling, resulting in pain from weak, malformed bone.</td><td colspan="1" rowspan="1" style="vertical-align:top;">18q21-qa22
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</td><td colspan="1" rowspan="3" style="vertical-align:top;">
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<i>LOH18CR1</i>
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</td><td colspan="1" rowspan="3" style="vertical-align:top;">IL-1/TNF signaling; RANKL signaling pathway
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</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">5q31</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">5q35-qter
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</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Retinoblastoma
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[<a class="bk_pop" href="#CDR0000062698_rl_1974_16">16</a>]</td><td colspan="1" rowspan="1" style="vertical-align:top;">Malignant tumor of the retina. Approximately 66% of patients are diagnosed by age 2 years and 95% of patients by age 3 years. Patients with heritable germ cell mutations at greater risk of subsequent neoplasms.</td><td colspan="1" rowspan="1" style="vertical-align:top;">13q14.2 </td><td colspan="1" rowspan="1" style="vertical-align:top;">
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<i>RB1</i>
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">Cell-cycle checkpoint</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Rothmund-Thomson syndrome (also called poikiloderma congenitale) [<a class="bk_pop" href="#CDR0000062698_rl_1974_17">17</a>,<a class="bk_pop" href="#CDR0000062698_rl_1974_18">18</a>]</td><td colspan="1" rowspan="1" style="vertical-align:top;">Autosomal recessive condition. Associated with skin findings (atrophy, telangiectasias, pigmentation), sparse hair, cataracts, small stature, and skeletal abnormalities. Increased incidence of osteosarcoma at a younger age.</td><td colspan="1" rowspan="1" style="vertical-align:top;">8q24.3 </td><td colspan="1" rowspan="1" style="vertical-align:top;"><i>RECQL4</i>
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">DNA helicase</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Werner syndrome
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[<a class="bk_pop" href="#CDR0000062698_rl_1974_19">19</a>]</td><td colspan="1" rowspan="1" style="vertical-align:top;">Patients often have short stature and in their early twenties, develop signs of aging, including graying of hair and hardening of skin. Other aging problems such as cataracts, skin ulcers, and atherosclerosis develop later.</td><td colspan="1" rowspan="1" style="vertical-align:top;">8p12-p11.2 </td><td colspan="1" rowspan="1" style="vertical-align:top;"><i>WRN</i>
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</td><td colspan="1" rowspan="1" style="vertical-align:top;"> DNA helicase; exonuclease activity
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</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">AML = acute myeloid leukemia; IL-1 = interleukin-1; MDS = myelodysplastic syndrome; RANKL = receptor activator of nuclear factor kappa beta ligand; TNF = tumor necrosis factor.</p></div></dd><dt></dt><dd><div><p class="no_margin"><sup>a</sup>Adapted from Kansara et al.[<a class="bk_pop" href="#CDR0000062698_rl_1974_10">10</a>]</p></div></dd></dl></div></div></div><p id="CDR0000062698__sm_CDR0000777834_1914">Refer to the following PDQ summaries for more information about these genetic syndromes:</p><ul id="CDR0000062698__sm_CDR0000777834_1915"><li class="half_rhythm"><div><a href="/books/n/pdqcis/CDR0000062855/">Genetics of Breast and Gynecologic Cancers</a> (<a href="/books/n/pdqcis/CDR0000062855/#CDR0000062855__144">Li-Fraumeni syndrome</a>).</div></li><li class="half_rhythm"><div><a href="/books/n/pdqcis/CDR0000552637/">Genetics of Skin Cancer</a> (<a href="/books/n/pdqcis/CDR0000552637/#CDR0000552637__155">Bloom syndrome</a>, <a href="/books/n/pdqcis/CDR0000552637/#CDR0000552637__151">Rothmund-Thomson syndrome</a>, and <a href="/books/n/pdqcis/CDR0000552637/#CDR0000552637__160">Werner syndrome</a>).</div></li></ul></div></div></div><div id="CDR0000062698_rl_1974"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000062698_rl_1974_1">Chen X, Bahrami A, Pappo A, et al.: Recurrent somatic structural variations contribute to tumorigenesis in pediatric osteosarcoma. Cell Rep 7 (1): 104-12, 2014. [<a href="/pmc/articles/PMC4096827/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4096827</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24703847" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24703847</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_1974_2">Perry JA, Kiezun A, Tonzi P, et al.: Complementary genomic approaches highlight the PI3K/mTOR pathway as a common vulnerability in osteosarcoma. Proc Natl Acad Sci U S A 111 (51): E5564-73, 2014. [<a href="/pmc/articles/PMC4280630/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4280630</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25512523" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25512523</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_1974_3">Suehara Y, Alex D, Bowman A, et al.: Clinical Genomic Sequencing of Pediatric and Adult Osteosarcoma Reveals Distinct Molecular Subsets with Potentially Targetable Alterations. Clin Cancer Res 25 (21): 6346-6356, 2019. [<a href="/pmc/articles/PMC6825534/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6825534</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/31175097" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 31175097</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_1974_4">Mirabello L, Zhu B, Koster R, et al.: Frequency of Pathogenic Germline Variants in Cancer-Susceptibility Genes in Patients With Osteosarcoma. JAMA Oncol 6 (5): 724-734, 2020. [<a href="/pmc/articles/PMC7082769/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7082769</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/32191290" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 32191290</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_1974_5">Ognjanovic S, Olivier M, Bergemann TL, et al.: Sarcomas in TP53 germline mutation carriers: a review of the IARC TP53 database. Cancer 118 (5): 1387-96, 2012. [<a href="https://pubmed.ncbi.nlm.nih.gov/21837677" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21837677</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_1974_6">Mirabello L, Yeager M, Mai PL, et al.: Germline TP53 variants and susceptibility to osteosarcoma. J Natl Cancer Inst 107 (7): , 2015. [<a href="/pmc/articles/PMC4651039/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4651039</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25896519" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25896519</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_1974_7">Toguchida J, Yamaguchi T, Dayton SH, et al.: Prevalence and spectrum of germline mutations of the p53 gene among patients with sarcoma. N Engl J Med 326 (20): 1301-8, 1992. [<a href="https://pubmed.ncbi.nlm.nih.gov/1565143" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 1565143</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_1974_8">McIntyre JF, Smith-Sorensen B, Friend SH, et al.: Germline mutations of the p53 tumor suppressor gene in children with osteosarcoma. J Clin Oncol 12 (5): 925-30, 1994. [<a href="https://pubmed.ncbi.nlm.nih.gov/8164043" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8164043</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_1974_9">Maciaszek JL, Oak N, Chen W, et al.: Enrichment of heterozygous germline RECQL4 loss-of-function variants in pediatric osteosarcoma. Cold Spring Harb Mol Case Stud 5 (5): , 2019. [<a href="/pmc/articles/PMC6824257/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6824257</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/31604778" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 31604778</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_1974_10">Kansara M, Thomas DM: Molecular pathogenesis of osteosarcoma. DNA Cell Biol 26 (1): 1-18, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17263592" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17263592</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_1974_11">German J: Bloom's syndrome. XX. The first 100 cancers. Cancer Genet Cytogenet 93 (1): 100-6, 1997. [<a href="https://pubmed.ncbi.nlm.nih.gov/9062585" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9062585</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_1974_12">Lipton JM, Federman N, Khabbaze Y, et al.: Osteogenic sarcoma associated with Diamond-Blackfan anemia: a report from the Diamond-Blackfan Anemia Registry. J Pediatr Hematol Oncol 23 (1): 39-44, 2001. [<a href="https://pubmed.ncbi.nlm.nih.gov/11196268" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11196268</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_1974_13">Idol RA, Robledo S, Du HY, et al.: Cells depleted for RPS19, a protein associated with Diamond Blackfan Anemia, show defects in 18S ribosomal RNA synthesis and small ribosomal subunit production. Blood Cells Mol Dis 39 (1): 35-43, 2007 Jul-Aug. [<a href="https://pubmed.ncbi.nlm.nih.gov/17376718" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17376718</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_1974_14">Li FP, Fraumeni JF, Mulvihill JJ, et al.: A cancer family syndrome in twenty-four kindreds. Cancer Res 48 (18): 5358-62, 1988. [<a href="https://pubmed.ncbi.nlm.nih.gov/3409256" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 3409256</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_1974_15">Grimer RJ, Cannon SR, Taminiau AM, et al.: Osteosarcoma over the age of forty. Eur J Cancer 39 (2): 157-63, 2003. [<a href="https://pubmed.ncbi.nlm.nih.gov/12509946" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12509946</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_1974_16">Wong FL, Boice JD, Abramson DH, et al.: Cancer incidence after retinoblastoma. Radiation dose and sarcoma risk. JAMA 278 (15): 1262-7, 1997. [<a href="https://pubmed.ncbi.nlm.nih.gov/9333268" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9333268</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_1974_17">Wang LL, Gannavarapu A, Kozinetz CA, et al.: Association between osteosarcoma and deleterious mutations in the RECQL4 gene in Rothmund-Thomson syndrome. J Natl Cancer Inst 95 (9): 669-74, 2003. [<a href="https://pubmed.ncbi.nlm.nih.gov/12734318" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12734318</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_1974_18">Hicks MJ, Roth JR, Kozinetz CA, et al.: Clinicopathologic features of osteosarcoma in patients with Rothmund-Thomson syndrome. J Clin Oncol 25 (4): 370-5, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17264332" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17264332</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_1974_19">Goto M, Miller RW, Ishikawa Y, et al.: Excess of rare cancers in Werner syndrome (adult progeria). Cancer Epidemiol Biomarkers Prev 5 (4): 239-46, 1996. [<a href="https://pubmed.ncbi.nlm.nih.gov/8722214" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8722214</span></a>]</div></li></ol></div></div><div id="CDR0000062698__8"><h2 id="_CDR0000062698__8_">Cellular Classification of Osteosarcoma and UPS of Bone</h2><p id="CDR0000062698__9">Osteosarcoma is a malignant tumor that is
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characterized by the direct formation of bone or osteoid tissue by the tumor
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cells. The World Health Organization’s histological classification [<a class="bk_pop" href="#CDR0000062698_rl_8_1">1</a>] of bone
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tumors separates the osteosarcomas into central (medullary) and surface
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(peripheral) tumors [<a class="bk_pop" href="#CDR0000062698_rl_8_2">2</a>,<a class="bk_pop" href="#CDR0000062698_rl_8_3">3</a>] and recognizes a number of subtypes within each group.
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</p><div id="CDR0000062698__48"><h3>Central (Medullary) Tumors</h3><ul id="CDR0000062698__46"><li class="half_rhythm"><div>
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<b>Conventional central osteosarcomas.</b> The most common pathological subtype is conventional central osteosarcoma, which
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is characterized by areas of necrosis, atypical mitoses, and malignant
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osteoid tissue and/or cartilage. The other subtypes are much less common, each occurring at a
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frequency of less than 5%. </div></li><li class="half_rhythm"><div>
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<b>Telangiectatic osteosarcomas.</b>[<a class="bk_pop" href="#CDR0000062698_rl_8_4">4</a>,<a class="bk_pop" href="#CDR0000062698_rl_8_5">5</a>] Telangiectatic osteosarcoma may be confused
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radiographically with an aneurysmal bone cyst or giant cell tumor. This
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variant should be managed the same as a conventional osteosarcoma.[<a class="bk_pop" href="#CDR0000062698_rl_8_4">4</a>,<a class="bk_pop" href="#CDR0000062698_rl_8_5">5</a>]</div></li><li class="half_rhythm"><div>
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<b>Intraosseous well-differentiated (low-grade) osteosarcomas.</b></div></li><li class="half_rhythm"><div>
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<b> Small-cell osteosarcomas.</b>
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</div></li></ul></div><div id="CDR0000062698__49"><h3>Surface (Peripheral) Tumors</h3><p id="CDR0000062698__460">The terms <i>parosteal</i> and <i>periosteal</i> osteosarcoma are embedded in the literature and widely used. They are confusing to patients and practitioners. It would be more helpful to divide osteosarcoma by location and histological grade. High-grade osteosarcoma, sometimes referred to as conventional osteosarcoma, typically arises centrally and grows outward, destroying surrounding cortex and soft tissues, but there are unequivocal cases of high-grade osteosarcoma in surface locations.[<a class="bk_pop" href="#CDR0000062698_rl_8_6">6</a>] Similarly, there are reports of low-grade osteosarcoma arising in the medullary cavity. </p><ul id="CDR0000062698__47"><li class="half_rhythm"><div class="half_rhythm">
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<b>Parosteal (juxtacortical) well-differentiated (low-grade) osteosarcomas.</b>[<a class="bk_pop" href="#CDR0000062698_rl_8_7">7</a>,<a class="bk_pop" href="#CDR0000062698_rl_8_8">8</a>] Parosteal osteosarcoma is defined as a lesion arising from the surface of the bone with a well-differentiated appearance on imaging and low-grade histological features.[<a class="bk_pop" href="#CDR0000062698_rl_8_9">9</a>] The most common site for parosteal osteosarcoma is the posterior distal femur. Parosteal osteosarcoma occurs more often in older patients than does conventional high-grade osteosarcoma and is most common in patients aged 20 to 30 years. Parosteal osteosarcoma can be treated successfully with wide excision of the primary tumor alone.[<a class="bk_pop" href="#CDR0000062698_rl_8_7">7</a>,<a class="bk_pop" href="#CDR0000062698_rl_8_10">10</a>]</div></li><li class="half_rhythm"><div class="half_rhythm">
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<b>Periosteal osteosarcomas (low-grade to intermediate-grade osteosarcomas).</b>[<a class="bk_pop" href="#CDR0000062698_rl_8_11">11</a>-<a class="bk_pop" href="#CDR0000062698_rl_8_13">13</a>] Periosteal osteosarcoma typically appears as a broad-based soft tissue mass with extrinsic erosion of the underlying bony cortex.[<a class="bk_pop" href="#CDR0000062698_rl_8_12">12</a>] Pathology shows an intermediate grade of differentiation. Wide resection is essential. </div><div class="half_rhythm">A single-institution retrospective review identified 29 patients with periosteal osteosarcoma.[<a class="bk_pop" href="#CDR0000062698_rl_8_11">11</a>] The 5-year disease-free survival rate was 83%. The authors could not make a definitive statement regarding the benefits of adjuvant chemotherapy.</div><div class="half_rhythm">Another single-institution retrospective review identified 33 patients with periosteal osteosarcoma.[<a class="bk_pop" href="#CDR0000062698_rl_8_13">13</a>] The 10-year overall survival (OS) rate was 84%. The 10-year OS rate was 83% for patients who were treated with surgery alone and 86% for patients who were treated with surgery and chemotherapy. </div><div class="half_rhythm">The European Musculoskeletal Oncology Society retrospectively analyzed 119 patients with periosteal osteosarcoma; 17 patients had metastasis.[<a class="bk_pop" href="#CDR0000062698_rl_8_12">12</a>] The OS rate was 89% at 5 years and 83% at 10 years. Eighty-one patients received chemotherapy; 50 of those patients received chemotherapy before definitive surgical resection. There was no difference in outcome between the patients who received chemotherapy and the patients who did not receive chemotherapy.</div></li><li class="half_rhythm"><div class="half_rhythm">
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<b> High-grade surface osteosarcomas.</b>
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[<a class="bk_pop" href="#CDR0000062698_rl_8_3">3</a>
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,<a class="bk_pop" href="#CDR0000062698_rl_8_6">6</a>
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,<a class="bk_pop" href="#CDR0000062698_rl_8_14">14</a>]
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</div></li></ul></div><div id="CDR0000062698__1810"><h3>Extraosseous Osteosarcoma</h3><p id="CDR0000062698__64">Extraosseous osteosarcoma is a malignant mesenchymal neoplasm without direct attachment to the skeletal system. Previously, treatment for extraosseous osteosarcoma followed soft tissue sarcoma guidelines,[<a class="bk_pop" href="#CDR0000062698_rl_8_15">15</a>] although a retrospective analysis of the cooperative German-Austrian-Swiss osteosarcoma study group identified a favorable outcome for extraosseous osteosarcoma treated with surgery and conventional osteosarcoma therapy.[<a class="bk_pop" href="#CDR0000062698_rl_8_16">16</a>] </p></div><div id="CDR0000062698__1936"><h3>Undifferentiated Pleomorphic Sarcoma (UPS) of Bone</h3><p id="CDR0000062698__1937">UPS of bone should be distinguished from angiomatoid fibrous histiocytoma, a low-grade tumor that is usually noninvasive, small, and associated with an excellent outcome using surgery alone.[<a class="bk_pop" href="#CDR0000062698_rl_8_17">17</a>] One study suggests similar event-free survival rates for UPS and osteosarcoma.[<a class="bk_pop" href="#CDR0000062698_rl_8_18">18</a>]
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</p></div><div id="CDR0000062698_rl_8"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000062698_rl_8_1">Schajowicz F, Sissons HA, Sobin LH: The World Health Organization's histologic classification of bone tumors. A commentary on the second edition. Cancer 75 (5): 1208-14, 1995. [<a href="https://pubmed.ncbi.nlm.nih.gov/7850721" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7850721</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_8_2">Antonescu CR, Huvos AG: Low-grade osteogenic sarcoma arising in medullary and surface osseous locations. Am J Clin Pathol 114 (Suppl): S90-103, 2000. [<a href="https://pubmed.ncbi.nlm.nih.gov/11996175" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11996175</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_8_3">Kaste SC, Fuller CE, Saharia A, et al.: Pediatric surface osteosarcoma: clinical, pathologic, and radiologic features. Pediatr Blood Cancer 47 (2): 152-62, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16123997" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16123997</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_8_4">Bacci G, Ferrari S, Ruggieri P, et al.: Telangiectatic osteosarcoma of the extremity: neoadjuvant chemotherapy in 24 cases. Acta Orthop Scand 72 (2): 167-72, 2001. [<a href="https://pubmed.ncbi.nlm.nih.gov/11372948" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11372948</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_8_5">Weiss A, Khoury JD, Hoffer FA, et al.: Telangiectatic osteosarcoma: the St. Jude Children's Research Hospital's experience. Cancer 109 (8): 1627-37, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17351949" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17351949</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_8_6">Okada K, Unni KK, Swee RG, et al.: High grade surface osteosarcoma: a clinicopathologic study of 46 cases. Cancer 85 (5): 1044-54, 1999. [<a href="https://pubmed.ncbi.nlm.nih.gov/10091787" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10091787</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_8_7">Hoshi M, Matsumoto S, Manabe J, et al.: Oncologic outcome of parosteal osteosarcoma. Int J Clin Oncol 11 (2): 120-6, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16622746" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16622746</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_8_8">Han I, Oh JH, Na YG, et al.: Clinical outcome of parosteal osteosarcoma. J Surg Oncol 97 (2): 146-9, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/18050289" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18050289</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_8_9">Kumar VS, Barwar N, Khan SA: Surface osteosarcomas: Diagnosis, treatment and outcome. Indian J Orthop 48 (3): 255-61, 2014. [<a href="/pmc/articles/PMC4052023/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4052023</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24932030" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24932030</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_8_10">Schwab JH, Antonescu CR, Athanasian EA, et al.: A comparison of intramedullary and juxtacortical low-grade osteogenic sarcoma. Clin Orthop Relat Res 466 (6): 1318-22, 2008. [<a href="/pmc/articles/PMC2384019/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2384019</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18425560" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18425560</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_8_11">Rose PS, Dickey ID, Wenger DE, et al.: Periosteal osteosarcoma: long-term outcome and risk of late recurrence. Clin Orthop Relat Res 453: 314-7, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16906092" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16906092</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_8_12">Grimer RJ, Bielack S, Flege S, et al.: Periosteal osteosarcoma--a European review of outcome. Eur J Cancer 41 (18): 2806-11, 2005. [<a href="https://pubmed.ncbi.nlm.nih.gov/16290134" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16290134</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_8_13">Cesari M, Alberghini M, Vanel D, et al.: Periosteal osteosarcoma: a single-institution experience. Cancer 117 (8): 1731-5, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/21472720" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21472720</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_8_14">Staals EL, Bacchini P, Bertoni F: High-grade surface osteosarcoma: a review of 25 cases from the Rizzoli Institute. Cancer 112 (7): 1592-9, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/18300258" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18300258</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_8_15">Wodowski K, Hill DA, Pappo AS, et al.: A chemosensitive pediatric extraosseous osteosarcoma: case report and review of the literature. J Pediatr Hematol Oncol 25 (1): 73-7, 2003. [<a href="https://pubmed.ncbi.nlm.nih.gov/12544778" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12544778</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_8_16">Goldstein-Jackson SY, Gosheger G, Delling G, et al.: Extraskeletal osteosarcoma has a favourable prognosis when treated like conventional osteosarcoma. J Cancer Res Clin Oncol 131 (8): 520-6, 2005. [<a href="https://pubmed.ncbi.nlm.nih.gov/15918046" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15918046</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_8_17">Daw NC, Billups CA, Pappo AS, et al.: Malignant fibrous histiocytoma and other fibrohistiocytic tumors in pediatric patients: the St. Jude Children's Research Hospital experience. Cancer 97 (11): 2839-47, 2003. [<a href="https://pubmed.ncbi.nlm.nih.gov/12767098" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12767098</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_8_18">Picci P, Bacci G, Ferrari S, et al.: Neoadjuvant chemotherapy in malignant fibrous histiocytoma of bone and in osteosarcoma located in the extremities: analogies and differences between the two tumors. Ann Oncol 8 (11): 1107-15, 1997. [<a href="https://pubmed.ncbi.nlm.nih.gov/9426330" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9426330</span></a>]</div></li></ol></div></div><div id="CDR0000062698__21"><h2 id="_CDR0000062698__21_">Staging and Site Information for Osteosarcoma and UPS of Bone</h2><p id="CDR0000062698__354">Historically, the Enneking staging system for skeletal malignancies was used.[<a class="bk_pop" href="#CDR0000062698_rl_21_1">1</a>] This system inferred the aggressiveness of the primary tumor by the descriptors <i>intracompartmental</i> or <i>extracompartmental</i>. The American Joint Committee on Cancer's tumor-node-metastasis (TNM) staging system for malignant bone tumors is not widely used for pediatric osteosarcoma, and patients are not stratified on the basis of prognostic stage groups.</p><p id="CDR0000062698__384">For the purposes of treatment, osteosarcoma is described as one of the following: </p><ul id="CDR0000062698__1812"><li class="half_rhythm"><div><a href="#CDR0000062698__22">Localized</a>. Patients without clinically detectable metastatic disease are considered to have localized osteosarcoma. </div></li><li class="half_rhythm"><div><a href="#CDR0000062698__24">Metastatic</a>. Patients with any site of metastasis at the time of initial presentation detected by routine clinical studies are considered to have metastatic osteosarcoma.</div></li></ul><div id="CDR0000062698__22"><h3>Localized Osteosarcoma </h3><p id="CDR0000062698__23">Localized tumors are limited to the bone of origin. Patients with skip lesions confined to the bone that includes the primary tumor are considered to have localized disease if the skip lesions can be included in the planned surgical resection.[<a class="bk_pop" href="#CDR0000062698_rl_21_2">2</a>] Approximately one-half of the tumors arise in the femur; of these, 80% are in the distal femur. Other primary sites, in
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descending order of frequency, are the proximal tibia, proximal humerus, pelvis, jaw, fibula, and
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ribs.[<a class="bk_pop" href="#CDR0000062698_rl_21_3">3</a>]
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Osteosarcoma of the head and neck is more likely to be low grade [<a class="bk_pop" href="#CDR0000062698_rl_21_4">4</a>] and to arise in older patients than is osteosarcoma of the appendicular skeleton. </p></div><div id="CDR0000062698__24"><h3>Metastatic Osteosarcoma </h3><p id="CDR0000062698__25">Radiologic evidence of metastatic tumor deposits is found in approximately 20% of patients at diagnosis, with 85% to 90% of
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metastatic disease presenting in the lungs. The second most common site of metastasis
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is another bone, which may be solitary or multiple.[<a class="bk_pop" href="#CDR0000062698_rl_21_5">5</a>] </p><p id="CDR0000062698__1948">The syndrome of multifocal osteosarcoma refers to a presentation with multiple foci of osteosarcoma without a clear primary tumor, often with symmetrical metaphyseal involvement.[<a class="bk_pop" href="#CDR0000062698_rl_21_3">3</a>]
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</p></div><div id="CDR0000062698__1813"><h3>Staging Evaluation</h3><p id="CDR0000062698__296">For patients with confirmed osteosarcoma, in addition to plain radiographs of the primary site that include a single-plane view of the entire affected bone to assess for skip metastasis, pretreatment staging studies should include the following:[<a class="bk_pop" href="#CDR0000062698_rl_21_6">6</a>] </p><ul id="CDR0000062698__1814"><li class="half_rhythm"><div>Magnetic resonance imaging (MRI) of the primary site to include the entire bone.</div></li><li class="half_rhythm"><div>Computed tomography (CT) scan, if MRI is not available.</div></li><li class="half_rhythm"><div>Bone scan.</div></li><li class="half_rhythm"><div>Posteroanterior and lateral chest radiograph.</div></li><li class="half_rhythm"><div>CT scan of the chest.</div></li></ul><p id="CDR0000062698__1815">Positron emission tomography (PET) using fluorine F 18-fludeoxyglucose is an optional staging modality.</p><p id="CDR0000062698__1816">A retrospective review of 206 patients with osteosarcoma compared bone scan, PET scan, and PET-CT scan for the detection of bone metastases.[<a class="bk_pop" href="#CDR0000062698_rl_21_7">7</a>] PET-CT was more sensitive and accurate than bone scan, and the combined use of both imaging studies achieved the highest sensitivity for diagnosing bone metastases in osteosarcoma.</p></div><div id="CDR0000062698_rl_21"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000062698_rl_21_1">Enneking WF: A system of staging musculoskeletal neoplasms. Clin Orthop Relat Res (204): 9-24, 1986. [<a href="https://pubmed.ncbi.nlm.nih.gov/3456859" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 3456859</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_21_2">Kager L, Zoubek A, Kastner U, et al.: Skip metastases in osteosarcoma: experience of the Cooperative Osteosarcoma Study Group. J Clin Oncol 24 (10): 1535-41, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16575004" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16575004</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_21_3">Longhi A, Fabbri N, Donati D, et al.: Neoadjuvant chemotherapy for patients with synchronous multifocal osteosarcoma: results in eleven cases. J Chemother 13 (3): 324-30, 2001. [<a href="https://pubmed.ncbi.nlm.nih.gov/11450892" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11450892</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_21_4">Patel SG, Meyers P, Huvos AG, et al.: Improved outcomes in patients with osteogenic sarcoma of the head and neck. Cancer 95 (7): 1495-503, 2002. [<a href="https://pubmed.ncbi.nlm.nih.gov/12237918" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12237918</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_21_5">Harris MB, Gieser P, Goorin AM, et al.: Treatment of metastatic osteosarcoma at diagnosis: a Pediatric Oncology Group Study. J Clin Oncol 16 (11): 3641-8, 1998. [<a href="https://pubmed.ncbi.nlm.nih.gov/9817286" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9817286</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_21_6">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="CDR0000062698_rl_21_7">Byun BH, Kong CB, Lim I, et al.: Comparison of (18)F-FDG PET/CT and (99 m)Tc-MDP bone scintigraphy for detection of bone metastasis in osteosarcoma. Skeletal Radiol 42 (12): 1673-81, 2013. [<a href="https://pubmed.ncbi.nlm.nih.gov/23995264" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23995264</span></a>]</div></li></ol></div></div><div id="CDR0000062698__26"><h2 id="_CDR0000062698__26_">Treatment Option Overview for Osteosarcoma and UPS of Bone</h2><div id="CDR0000062698__1949"><h3>Treatment Overview for Osteosarcoma and UPS of Bone</h3><p id="CDR0000062698__1819">It is imperative that patients with proven or suspected
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osteosarcoma have an initial evaluation by an orthopedic oncologist familiar
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with the surgical management of this disease. This evaluation, which includes imaging studies, should be done
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before the initial biopsy, because an inappropriately performed biopsy may
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jeopardize a limb-sparing procedure. Additionally, protective weight bearing is recommended for patients with tumors of weight-bearing bones to prevent pathological fractures that could preclude limb-preserving surgery.</p><p id="CDR0000062698__151">Successful treatment generally requires the combination of effective systemic chemotherapy and complete resection of all clinically detectable disease.</p><p id="CDR0000062698__27">Randomized clinical trials have established that both neoadjuvant and adjuvant
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chemotherapy are effective in preventing relapse in patients with clinically nonmetastatic tumors.[<a class="bk_pop" href="#CDR0000062698_rl_26_1">1</a>]; [<a class="bk_pop" href="#CDR0000062698_rl_26_2">2</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335125/" class="def">Level of evidence: 1iiA</a>] The Pediatric Oncology Group (POG) conducted a study in which patients were randomly assigned to either immediate amputation or amputation after neoadjuvant therapy. A large percentage of patients declined to be assigned randomly, and the study was terminated without approaching the stated accrual goals. In the small number of patients treated, there was no difference in outcome between those who received preoperative chemotherapy and those who received postoperative chemotherapy.[<a class="bk_pop" href="#CDR0000062698_rl_26_3">3</a>]</p><p id="CDR0000062698__1820">The treatment of osteosarcoma also depends on the histologic grade, as follows:</p><ul id="CDR0000062698__480"><li class="half_rhythm"><div class="half_rhythm"><b>Low-grade osteosarcoma.</b> Patients with low-grade osteosarcoma can be treated successfully by wide surgical resection alone, regardless of site of origin.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Intermediate-grade osteosarcoma.</b> Pathologists sometimes characterize tumors as intermediate-grade osteosarcoma. It is difficult to make treatment decisions for patients with intermediate-grade tumors. When a tumor biopsy suggests an intermediate-grade osteosarcoma, an option is to proceed with wide resection. The availability of the entire tumor allows the pathologist to examine more tissue and evaluate soft tissue and lymphovascular invasion, which can often clarify the nature of the lesion.</div><div class="half_rhythm">If the lesion proves to have high-grade elements, systemic chemotherapy is indicated, just as it would be for any high-grade osteosarcoma. The POG performed a study in which patients with high-grade osteosarcoma were randomly assigned to either immediate definitive surgery followed by adjuvant chemotherapy or to an initial period of chemotherapy followed by definitive surgery.[<a class="bk_pop" href="#CDR0000062698_rl_26_3">3</a>] The outcome was the same for both groups. Although the strategy of initial chemotherapy followed by definitive surgery has become an almost universally applied approach for osteosarcoma, this study suggests that there is no increased risk of treatment failure if definitive surgery is done before chemotherapy begins; this can help to clarify equivocal diagnoses of intermediate-grade osteosarcoma.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>High-grade osteosarcoma.</b> Patients with high-grade osteosarcoma require surgery and systemic chemotherapy whether the tumor arises in the conventional central location or on a bone surface.</div></li></ul><p id="CDR0000062698__385">Recognition of
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intraosseous well-differentiated osteosarcoma and parosteal osteosarcoma is
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important because patients with these tumor types have the most favorable prognosis and
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can be treated successfully with wide excision of the primary tumor alone.[<a class="bk_pop" href="#CDR0000062698_rl_26_4">4</a>,<a class="bk_pop" href="#CDR0000062698_rl_26_5">5</a>] Patients with periosteal osteosarcoma have a generally good prognosis [<a class="bk_pop" href="#CDR0000062698_rl_26_6">6</a>] and treatment is
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guided by histologic grade.[<a class="bk_pop" href="#CDR0000062698_rl_26_5">5</a>,<a class="bk_pop" href="#CDR0000062698_rl_26_7">7</a>]</p><p id="CDR0000062698__1817">Patients with undifferentiated pleomorphic sarcoma (UPS) of bone are treated according to
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osteosarcoma treatment protocols.[<a class="bk_pop" href="#CDR0000062698_rl_26_8">8</a>] </p><p id="CDR0000062698__353">Imaging modalities such as dynamic magnetic resonance imaging or positron emission tomography scanning are under investigation as noninvasive methods to assess response.[<a class="bk_pop" href="#CDR0000062698_rl_26_9">9</a>-<a class="bk_pop" href="#CDR0000062698_rl_26_17">17</a>]</p><p id="CDR0000062698__1886"><a class="figpopup" href="/books/NBK65736.26/table/CDR0000062698__1880/?report=objectonly" target="object" rid-figpopup="figCDR00000626981880" rid-ob="figobCDR00000626981880">Table 2</a> describes the treatment options for localized, metastatic, and recurrent osteosarcoma and UPS of bone.</p><div id="CDR0000062698__1880" class="table"><h3><span class="title">Table 2. Treatment Options for Osteosarcoma and Undifferentiated Pleomorphic Sarcoma (UPS) of Bone</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK65736.26/table/CDR0000062698__1880/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__CDR0000062698__1880_lrgtbl__"><table class="no_top_margin"><thead><tr><th colspan="2" rowspan="1" style="vertical-align:top;">Treatment Group</th><th colspan="1" rowspan="1" style="vertical-align:top;">Treatment Options</th></tr></thead><tbody><tr><td colspan="2" rowspan="3" style="vertical-align:top;">Localized osteosarcoma and UPS of bone</td><td colspan="1" rowspan="1" style="vertical-align:top;"><a href="#CDR0000062698__248">Surgical removal of primary tumor</a>.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;"><a href="#CDR0000062698__252">Chemotherapy</a>.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;"><a href="#CDR0000062698__1829">Radiation therapy, if surgery is not feasible or surgical margins are inadequate</a>.</td></tr><tr><td colspan="2" rowspan="1" style="vertical-align:top;">Osteosarcoma and UPS of bone with metastatic disease at diagnosis:</td><td colspan="1" rowspan="1" style="vertical-align:top;"><a href="#CDR0000062698__1846">Chemotherapy</a>.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;">Lung-only metastases</td><td colspan="1" rowspan="1" style="vertical-align:top;"><a href="#CDR0000062698__1852">Preoperative chemotherapy followed by surgery to remove the tumor followed by postoperative combination chemotherapy</a>.</td></tr><tr><td colspan="1" rowspan="4" style="vertical-align:top;"></td><td colspan="1" rowspan="4" style="vertical-align:top;">Bone metastases with or without lung metastases</td><td colspan="1" rowspan="1" style="vertical-align:top;"><a href="#CDR0000062698__1854">Preoperative chemotherapy followed by surgery to remove the primary tumor and all metastatic disease followed by postoperative combination chemotherapy</a>.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;"><a href="#CDR0000062698__1854">Surgery to remove the primary tumor followed by chemotherapy and then surgical resection of metastatic disease followed by postoperative combination chemotherapy</a>.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;"><a href="#CDR0000062698__1854">Resection of metastatic bone lesions if possible</a>.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;"><a href="#CDR0000062698__1854">Radiation therapy to the extremities (may offer some local control)</a>.</td></tr><tr><td colspan="2" rowspan="3" style="vertical-align:top;">Recurrent osteosarcoma and UPS of bone:</td><td colspan="1" rowspan="1" style="vertical-align:top;"><a href="#CDR0000062698__1943">Surgery to remove all sites of metastatic disease</a>.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">
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<a href="#CDR0000062698__1945">Chemotherapy and targeted therapy</a>.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;"><a href="#CDR0000062698__1946">Radiopharmaceuticals and radiation therapy</a>.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;">Local recurrence</td><td colspan="1" rowspan="1" style="vertical-align:top;"><a href="#CDR0000062698__1959">Surgery to remove the tumor</a>.</td></tr><tr><td colspan="1" rowspan="2" style="vertical-align:top;"></td><td colspan="1" rowspan="2" style="vertical-align:top;">Lung-only recurrence</td><td colspan="1" rowspan="1" style="vertical-align:top;"><a href="#CDR0000062698__1963">Surgery to remove the tumor</a>.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;"><a href="#CDR0000062698__1963">Targeted therapy (sorafenib and regorafenib)</a>.</td></tr><tr><td colspan="1" rowspan="4" style="vertical-align:top;"></td><td colspan="1" rowspan="4" style="vertical-align:top;">Recurrence with bone-only metastases</td><td colspan="1" rowspan="1" style="vertical-align:top;"><a href="#CDR0000062698__1873">Surgery to remove the tumor</a>.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;"><a href="#CDR0000062698__1873">153Sm-EDTMP with or without stem cell support</a>.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;"><a href="#CDR0000062698__1873">Targeted therapy (sorafenib and regorafenib)</a>.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;"></td></tr><tr><td colspan="1" rowspan="2" style="vertical-align:top;"></td><td colspan="1" rowspan="2" style="vertical-align:top;">Second recurrence of osteosarcoma</td><td colspan="1" rowspan="1" style="vertical-align:top;"><a href="#CDR0000062698__1877">Surgery to remove the tumor and/or chemotherapy</a>.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;"><a href="#CDR0000062698__1877">Targeted therapy (sorafenib and regorafenib)</a>.</td></tr><tr><td colspan="3" rowspan="1" style="vertical-align:top;">153Sm-EDTMP = samarium Sm 153-ethylenediamine tetramethylene phosphonic acid.</td></tr></tbody></table></div></div></div><div id="CDR0000062698_rl_26"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000062698_rl_26_1">Link MP, Goorin AM, Miser AW, et al.: The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J Med 314 (25): 1600-6, 1986. [<a href="https://pubmed.ncbi.nlm.nih.gov/3520317" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 3520317</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_26_2">Bernthal NM, Federman N, Eilber FR, et al.: Long-term results (>25 years) of a randomized, prospective clinical trial evaluating chemotherapy in patients with high-grade, operable osteosarcoma. Cancer 118 (23): 5888-93, 2012. [<a href="https://pubmed.ncbi.nlm.nih.gov/22648705" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22648705</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_26_3">Goorin AM, Schwartzentruber DJ, Devidas M, et al.: Presurgical chemotherapy compared with immediate surgery and adjuvant chemotherapy for nonmetastatic osteosarcoma: Pediatric Oncology Group Study POG-8651. J Clin Oncol 21 (8): 1574-80, 2003. [<a href="https://pubmed.ncbi.nlm.nih.gov/12697883" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12697883</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_26_4">Hoshi M, Matsumoto S, Manabe J, et al.: Oncologic outcome of parosteal osteosarcoma. Int J Clin Oncol 11 (2): 120-6, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16622746" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16622746</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_26_5">Schwab JH, Antonescu CR, Athanasian EA, et al.: A comparison of intramedullary and juxtacortical low-grade osteogenic sarcoma. Clin Orthop Relat Res 466 (6): 1318-22, 2008. [<a href="/pmc/articles/PMC2384019/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2384019</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18425560" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18425560</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_26_6">Rose PS, Dickey ID, Wenger DE, et al.: Periosteal osteosarcoma: long-term outcome and risk of late recurrence. Clin Orthop Relat Res 453: 314-7, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16906092" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16906092</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_26_7">Grimer RJ, Bielack S, Flege S, et al.: Periosteal osteosarcoma--a European review of outcome. Eur J Cancer 41 (18): 2806-11, 2005. [<a href="https://pubmed.ncbi.nlm.nih.gov/16290134" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16290134</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_26_8">Picci P, Bacci G, Ferrari S, et al.: Neoadjuvant chemotherapy in malignant fibrous histiocytoma of bone and in osteosarcoma located in the extremities: analogies and differences between the two tumors. Ann Oncol 8 (11): 1107-15, 1997. [<a href="https://pubmed.ncbi.nlm.nih.gov/9426330" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9426330</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_26_9">Reddick WE, Wang S, Xiong X, et al.: Dynamic magnetic resonance imaging of regional contrast access as an additional prognostic factor in pediatric osteosarcoma. Cancer 91 (12): 2230-7, 2001. [<a href="https://pubmed.ncbi.nlm.nih.gov/11413510" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11413510</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_26_10">Hawkins DS, Conrad EU, Butrynski JE, et al.: [F-18]-fluorodeoxy-D-glucose-positron emission tomography response is associated with outcome for extremity osteosarcoma in children and young adults. Cancer 115 (15): 3519-25, 2009. [<a href="/pmc/articles/PMC2716419/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2716419</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19517457" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19517457</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_26_11">Cheon GJ, Kim MS, Lee JA, et al.: Prediction model of chemotherapy response in osteosarcoma by 18F-FDG PET and MRI. J Nucl Med 50 (9): 1435-40, 2009. [<a href="https://pubmed.ncbi.nlm.nih.gov/19690035" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19690035</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_26_12">Costelloe CM, Macapinlac HA, Madewell JE, et al.: 18F-FDG PET/CT as an indicator of progression-free and overall survival in osteosarcoma. J Nucl Med 50 (3): 340-7, 2009. [<a href="https://pubmed.ncbi.nlm.nih.gov/19258257" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19258257</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_26_13">Hamada K, Tomita Y, Inoue A, et al.: Evaluation of chemotherapy response in osteosarcoma with FDG-PET. Ann Nucl Med 23 (1): 89-95, 2009. [<a href="https://pubmed.ncbi.nlm.nih.gov/19205843" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19205843</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_26_14">Bajpai J, Kumar R, Sreenivas V, et al.: Prediction of chemotherapy response by PET-CT in osteosarcoma: correlation with histologic necrosis. J Pediatr Hematol Oncol 33 (7): e271-8, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/22193290" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22193290</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_26_15">Kong CB, Byun BH, Lim I, et al.: ¹⁸F-FDG PET SUVmax as an indicator of histopathologic response after neoadjuvant chemotherapy in extremity osteosarcoma. Eur J Nucl Med Mol Imaging 40 (5): 728-36, 2013. [<a href="https://pubmed.ncbi.nlm.nih.gov/23361860" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23361860</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_26_16">Byun BH, Kong CB, Lim I, et al.: Combination of 18F-FDG PET/CT and diffusion-weighted MR imaging as a predictor of histologic response to neoadjuvant chemotherapy: preliminary results in osteosarcoma. J Nucl Med 54 (7): 1053-9, 2013. [<a href="https://pubmed.ncbi.nlm.nih.gov/23670899" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23670899</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_26_17">Davis JC, Daw NC, Navid F, et al.: 18F-FDG Uptake During Early Adjuvant Chemotherapy Predicts Histologic Response in Pediatric and Young Adult Patients with Osteosarcoma. J Nucl Med 59 (1): 25-30, 2018. [<a href="/pmc/articles/PMC5750521/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5750521</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/28611244" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28611244</span></a>]</div></li></ol></div></div><div id="CDR0000062698__532"><h2 id="_CDR0000062698__532_">Special Considerations for the Treatment of Children With Cancer</h2><p id="CDR0000062698__533">Cancer in children and adolescents is rare, although the overall incidence has been slowly increasing since 1975.[<a class="bk_pop" href="#CDR0000062698_rl_532_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
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of the following health care professionals and
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others to ensure that children receive treatment, supportive care, and
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rehabilitation that will achieve optimal survival and quality of life:</p><ul id="CDR0000062698__1881"><li class="half_rhythm"><div>Primary care physicians.</div></li><li class="half_rhythm"><div>Orthopedic surgeon experienced in bone
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tumors.</div></li><li class="half_rhythm"><div>Pathologists.</div></li><li class="half_rhythm"><div>Radiation oncologists.</div></li><li class="half_rhythm"><div>Pediatric oncologists.</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="CDR0000062698__1882">(Refer to the PDQ summaries on <a href="https://www.cancer.gov/publications/pdq/information-summaries/supportive-care" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Supportive and Palliative Care</a> for specific information about supportive care for children and adolescents with cancer.)</p><p id="CDR0000062698__534"> The American Academy of
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Pediatrics has outlined guidelines for pediatric cancer centers and their role in the treatment of
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pediatric patients with cancer.[<a class="bk_pop" href="#CDR0000062698_rl_532_2">2</a>] At these centers, clinical trials are
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available for most types of cancer that occur in children and
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adolescents, and the opportunity to participate is offered to
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most patients and their families. Clinical trials for children and adolescents with
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cancer are generally designed to compare potentially better therapy with
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current standard therapy. Most of the progress
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in identifying curative therapies for childhood cancers has been achieved
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through clinical trials. Information about ongoing clinical trials is
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available from the <a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">National Cancer Institute's website</a>.</p><p id="CDR0000062698__1799"> Childhood and adolescent cancer survivors require close monitoring because side effects of cancer therapy may persist or develop months or years after treatment. (Refer to the PDQ summary on <a href="/books/n/pdqcis/CDR0000343584/">Late Effects of Treatment for Childhood Cancer</a> for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)</p><div id="CDR0000062698_rl_532"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000062698_rl_532_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="CDR0000062698_rl_532_2">American Academy of Pediatrics: Standards for pediatric cancer centers. Pediatrics 134 (2): 410-4, 2014. <a href="https://pediatrics.aappublications.org/content/134/2/410" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">Also available online</a>. Last accessed February 1, 2022.</div></li></ol></div></div><div id="CDR0000062698__29"><h2 id="_CDR0000062698__29_">Treatment of Localized Osteosarcoma and UPS of Bone</h2><p id="CDR0000062698__30">Patients with localized osteosarcoma who undergo surgery and chemotherapy have a 5-year overall survival (OS) rate of 62% to 65%.[<a class="bk_pop" href="#CDR0000062698_rl_29_1">1</a>] Complete surgical resection is crucial for patients with localized osteosarcoma; however, at least 80% of patients treated with surgery alone will develop metastatic disease.[<a class="bk_pop" href="#CDR0000062698_rl_29_2">2</a>] Randomized clinical trials have established that adjuvant chemotherapy is
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effective in preventing relapse or recurrence in patients with localized
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resectable primary tumors.[<a class="bk_pop" href="#CDR0000062698_rl_29_2">2</a>]; [<a class="bk_pop" href="#CDR0000062698_rl_29_3">3</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335125/" class="def">Level of evidence: 1iiA</a>] </p><p id="CDR0000062698__355">Undifferentiated pleomorphic sarcoma (UPS) of bone is seen more commonly in older adults. Patients with UPS of bone are treated according to osteosarcoma treatment protocols, and the outcome for patients with resectable UPS is similar to the outcome for patients with osteosarcoma.[<a class="bk_pop" href="#CDR0000062698_rl_29_4">4</a>] As with osteosarcoma, patients with favorable necrosis (≥90% necrosis) have a longer survival than do those with an inferior necrosis (<90% necrosis).[<a class="bk_pop" href="#CDR0000062698_rl_29_5">5</a>] Many patients with UPS will need preoperative chemotherapy to achieve a wide local excision.[<a class="bk_pop" href="#CDR0000062698_rl_29_6">6</a>]</p><div id="CDR0000062698__1887"><h3>Treatment Options for Localized Osteosarcoma and UPS of Bone</h3><p id="CDR0000062698__1823">Treatment options for patients with localized osteosarcoma or UPS of bone include the following:</p><ol id="CDR0000062698__1824"><li class="half_rhythm"><div><a href="#CDR0000062698__248">Surgical removal of primary tumor</a>.</div></li><li class="half_rhythm"><div><a href="#CDR0000062698__252">Chemotherapy</a> (may start before or after definitive surgical resection of the primary tumor).</div></li><li class="half_rhythm"><div><a href="#CDR0000062698__1829">Radiation therapy, if surgery is not feasible or surgical margins are inadequate</a>.</div></li></ol><div id="CDR0000062698__248"><h4>Surgical removal of primary tumor</h4><p id="CDR0000062698__249">Surgical resection of the primary tumor with adequate margins is an essential component of the curative strategy for patients with localized osteosarcoma. The type of surgery required for complete ablation of the primary tumor depends on a number of factors that must be evaluated on a case-by-case basis.[<a class="bk_pop" href="#CDR0000062698_rl_29_7">7</a>]</p><div id="CDR0000062698__1950"><h5>Limb-sparing procedures</h5><p id="CDR0000062698__356">In general, more than 80% of patients with extremity osteosarcoma can be treated using a limb-sparing procedure and do not require amputation.[<a class="bk_pop" href="#CDR0000062698_rl_29_8">8</a>] Limb-sparing procedures are planned only when the preoperative staging indicates that it would be possible to achieve wide surgical margins. In one study, patients who underwent limb-salvage procedures who had poor histologic response and close surgical margins had a high rate of local recurrence.[<a class="bk_pop" href="#CDR0000062698_rl_29_9">9</a>] </p><p id="CDR0000062698__1825">Reconstruction after limb-sparing surgery can be accomplished with many options, including metallic endoprosthesis, allograft, vascularized autologous bone graft, and rotationplasty. An additional option, osteogenesis distraction bone transport, is available for patients whose tumors do not involve the epiphysis of long bones.[<a class="bk_pop" href="#CDR0000062698_rl_29_10">10</a>] This procedure results in a stable reconstruction that functionally restores the normal limb. </p><p id="CDR0000062698__1826">The choice of optimal surgical reconstruction involves many factors, including the following:[<a class="bk_pop" href="#CDR0000062698_rl_29_11">11</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335125/" class="def">Level of evidence: 1iiA]</a></p><ul id="CDR0000062698__1827"><li class="half_rhythm"><div>Site and size of the primary tumor.</div></li><li class="half_rhythm"><div>Ability to preserve the neurovascular supply of the distal extremity.</div></li><li class="half_rhythm"><div>Age of the patient and potential for additional growth.</div></li><li class="half_rhythm"><div>Needs and desires of the patient and family for specific functions such as sports participation. </div></li></ul><p id="CDR0000062698__1828">If a complicated reconstruction delays or prohibits the resumption of systemic chemotherapy, limb preservation may endanger the chance for cure. In retrospective analyses of 703 patients with localized osteosarcoma, the resumption of chemotherapy 21 days or more after definitive surgery was associated with an increased risk of death and adverse events (hazard ratio [HR], 1.57; 1.04–2.36).[<a class="bk_pop" href="#CDR0000062698_rl_29_11">11</a>] Delays in total time to completion of chemotherapy have also been associated with inferior OS and event-free survival (EFS). In a retrospective multivariate analysis of 113 patients with localized osteosarcoma, a delay of time to completion of chemotherapy greater than 4 weeks was associated with an OS HR of 2.70 (1.11–6.76, <i>P</i> = .003) and an EFS HR of 1.13 (1.00–1.26, <i>P</i> = .016).[<a class="bk_pop" href="#CDR0000062698_rl_29_12">12</a>]</p></div><div id="CDR0000062698__1951"><h5>Amputation</h5><p id="CDR0000062698__357">For some patients, amputation remains the optimal choice for management of the primary tumor. A pathological fracture noted at diagnosis or during preoperative chemotherapy does not preclude limb-salvage surgery if wide surgical margins can be achieved.[<a class="bk_pop" href="#CDR0000062698_rl_29_13">13</a>] If the pathological examination of the surgical specimen shows inadequate margins, an immediate amputation should be considered, especially if the histologic necrosis after preoperative chemotherapy was poor.[<a class="bk_pop" href="#CDR0000062698_rl_29_14">14</a>]</p></div><div id="CDR0000062698__1952"><h5>Factors associated with an increased risk of local recurrence</h5><p id="CDR0000062698__250">Patients who undergo amputation have lower local recurrence rates than do patients who undergo limb-salvage procedures.[<a class="bk_pop" href="#CDR0000062698_rl_29_15">15</a>] There is no difference in OS between patients initially treated with amputation and those treated with a limb-sparing procedure.
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Patients with tumors of the femur have a higher local recurrence rate than do patients with primary tumors of the tibia or fibula. Rotationplasty and other limb-salvage procedures have been evaluated for both their functional outcome and their effect on survival. While limb-sparing resection is the current practice for local control at most pediatric institutions, there are few data to indicate that salvage of the lower limb is substantially superior to amputation with regard to patient quality of life.[<a class="bk_pop" href="#CDR0000062698_rl_29_16">16</a>]</p><p id="CDR0000062698__343">The German Cooperative Osteosarcoma Study Group performed a retrospective analysis of 1,802 patients with localized and metastatic osteosarcoma who underwent surgical resection of all clinically detectable disease.[<a class="bk_pop" href="#CDR0000062698_rl_29_17">17</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335144/" class="def">Level of evidence: 3iiA</a>] Local recurrence (n = 76) was associated with a high risk of death from osteosarcoma. Factors associated with an increased risk of local recurrence included nonparticipation in a clinical trial, pelvic primary site, limb-preserving surgery, soft tissue infiltration beyond the periosteum, poor pathological response to initial chemotherapy, failure to complete planned chemotherapy, and performing the biopsy at an institution different from where the definitive surgery is being performed.</p></div></div><div id="CDR0000062698__252"><h4>Chemotherapy</h4><div id="CDR0000062698__1830"><h5>Preoperative chemotherapy</h5><p id="CDR0000062698__253">Almost all patients receive intravenous preoperative chemotherapy as initial treatment. However, a standard chemotherapy regimen has not been determined. Current chemotherapy protocols
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include combinations of the following agents: high-dose methotrexate,
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doxorubicin, cyclophosphamide, cisplatin, ifosfamide, etoposide, and
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carboplatin.[<a class="bk_pop" href="#CDR0000062698_rl_29_18">18</a>-<a class="bk_pop" href="#CDR0000062698_rl_29_26">26</a>]</p><p id="CDR0000062698__1831">Evidence (preoperative chemotherapy):</p><ol id="CDR0000062698__1832"><li class="half_rhythm"><div class="half_rhythm"> A meta-analysis of protocols for the treatment of osteosarcoma concluded the following:[<a class="bk_pop" href="#CDR0000062698_rl_29_27">27</a>]<ul id="CDR0000062698__1888"><li class="half_rhythm"><div>Regimens containing three active chemotherapy agents were superior to regimens containing two active agents.</div></li><li class="half_rhythm"><div>Regimens with four active agents were not superior to regimens with three active agents.</div></li><li class="half_rhythm"><div>Three-drug regimens that did not include high-dose methotrexate were inferior to three-drug regimens that did include high-dose methotrexate.</div></li></ul></div></li><li class="half_rhythm"><div class="half_rhythm">An Italian study that used regimens containing fewer courses of high-dose methotrexate observed the following results:[<a class="bk_pop" href="#CDR0000062698_rl_29_28">28</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335132/" class="def">Level of evidence: 2A</a>]<ul id="CDR0000062698__1942"><li class="half_rhythm"><div>There was a lower probability for EFS than found in earlier studies that used regimens containing more courses of high-dose methotrexate.</div></li></ul></div></li><li class="half_rhythm"><div class="half_rhythm">The Children's Oncology Group (COG) performed a prospective randomized trial in newly diagnosed children and young adults with localized osteosarcoma. All patients received cisplatin, doxorubicin, and high-dose methotrexate. One-half of the patients were randomly assigned to receive ifosfamide. In a second randomization, one-half of the patients were assigned to receive the biological compound muramyl tripeptide-phosphatidyl ethanolamine encapsulated in liposomes (L-MTP-PE) beginning after definitive surgical resection. Results showed that:[<a class="bk_pop" href="#CDR0000062698_rl_29_29">29</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335125/" class="def">Level of evidence: 1iiA</a>]<ul id="CDR0000062698__1833"><li class="half_rhythm"><div> The addition of ifosfamide did not improve outcome.</div></li><li class="half_rhythm"><div>The addition of L-MTP-PE produced improvement in the EFS rate, which did not meet the conventional test for statistical significance (<i>P</i> = .08), and a significant improvement in the OS rate (78% vs. 70%; <i>P</i> = .03).</div></li><li class="half_rhythm"><div>There has been speculation regarding the potential contribution of postrelapse treatment, although there were no differences in the postrelapse surgical approaches in the relapsed patients. The appropriate role of L-MTP-PE in the treatment of osteosarcoma remains under discussion.[<a class="bk_pop" href="#CDR0000062698_rl_29_30">30</a>]</div></li></ul></div></li><li class="half_rhythm"><div class="half_rhythm">The COG performed a series of pilot studies in patients with newly diagnosed localized osteosarcoma.[<a class="bk_pop" href="#CDR0000062698_rl_29_31">31</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335132/" class="def">Level of evidence: 2A</a>] <ol id="CDR0000062698__1834" class="lower-alpha"><li class="half_rhythm"><div>In pilot study 1, patients with lower degrees of necrosis after three-drug initial therapy received subsequent therapy with a higher cumulative dose of doxorubicin of 600 mg/m<sup>2</sup>. </div></li><li class="half_rhythm"><div>In pilot study 2, all patients received four-drug initial chemotherapy with cisplatin, doxorubicin, high-dose methotrexate, and ifosfamide. Patients with lower degrees of necrosis received subsequent chemotherapy with a higher cumulative dose of doxorubicin of 600 mg/m<sup>2</sup>. </div></li><li class="half_rhythm"><div>In pilot study 3, all patients received the same four-drug initial chemotherapy as pilot study 2. Patients with lower degrees of necrosis received higher doses of ifosfamide with the addition of etoposide in subsequent therapy.</div></li></ol></div><div class="half_rhythm">The results of these pilot studies were as follows:<ul id="CDR0000062698__1835"><li class="half_rhythm"><div>Outcomes for all three pilot studies were similar to each other and to historical controls. </div></li><li class="half_rhythm"><div>All patients received dexrazoxane before each dose of doxorubicin. The addition of dexrazoxane did not appear to decrease the rate of good necrosis after initial therapy or EFS.</div></li><li class="half_rhythm"><div>Left ventricular fractional shortening, as measured by echocardiography, was minimally affected at 78 weeks from study entry.</div></li><li class="half_rhythm"><div>There was no evidence for an increased risk of secondary leukemia.</div></li></ul></div></li><li class="half_rhythm"><div class="half_rhythm">The international European and American Osteosarcoma Study (EURAMOS) Group consortium was formed to conduct a large, prospective, randomized trial to help determine whether modifying the chemotherapy regimen on the basis of the degree of necrosis would improve EFS. All patients received initial therapy with cisplatin, doxorubicin, and high-dose methotrexate (MAP). Patients with more than 90% necrosis were randomly assigned to continue the same chemotherapy after surgery or to receive the same chemotherapy with the addition of interferon alpha-2B. Patients with less than 90% necrosis were randomly assigned to continue the same chemotherapy or to receive the same chemotherapy with the addition of high-dose ifosfamide and etoposide (MAPIE).[<a class="bk_pop" href="#CDR0000062698_rl_29_32">32</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335125/" class="def">Level of evidence: 1iiA</a>]<ul id="CDR0000062698__1927"><li class="half_rhythm"><div> At a median follow-up of 54 months for all registered patients (N = 2,260), the 3-year EFS rate was 59% (95% confidence interval [CI], 57%–61%), and the 5-year EFS rate was 54% (95% CI, 52%–56%).</div></li><li class="half_rhythm"><div> The 3-year OS rate was 79% (95% CI, 77%–81%), and the 5-year OS rate was 71% (95% CI, 68%–73%).</div></li><li class="half_rhythm"><div> Patients with localized disease at diagnosis (M0) who underwent complete surgical resection (n = 1,549) had 3-year EFS and OS rates from surgery of 70% and 88%, respectively; the 5-year EFS and OS rates from surgery were 64% and 79%, respectively.</div></li><li class="half_rhythm"><div>Forty percent of patients/families who participated in the study declined randomization after definitive surgical resection, making interpretation of the outcome of the randomized study questions more difficult and challenging the generalizability of the results.</div></li><li class="half_rhythm"><div>Of patients with more than 90% necrosis, 716 were randomly assigned to continue the same chemotherapy after surgery with or without the addition of interferon alpha-2B. The 3-year EFS rates were 74% (95% CI, 69%–79%) for patients who received MAP and 77% (95% CI, 72%–81%) for patients who received MAP plus interferon alpha-2B. The HR was 0.83 (95% CI, 0.61–1.12; <i>P</i> = .2).[<a class="bk_pop" href="#CDR0000062698_rl_29_33">33</a>]</div></li><li class="half_rhythm"><div>Of patients with less than 90% necrosis, 618 were randomly assigned to continue MAP chemotherapy or to receive MAPIE chemotherapy. The 3-year EFS estimates for patients with localized disease were 60% (95% CI, 54%–66%) for the MAP group and 57% (95% CI, 51%–63%) for the MAPIE group. The HR was 1.03 (0.81–1.33, <i>P</i> = .80).[<a class="bk_pop" href="#CDR0000062698_rl_29_34">34</a>]</div></li></ul></div></li></ol></div><div id="CDR0000062698__1836"><h5>Postoperative chemotherapy</h5><p id="CDR0000062698__535">Historically, the extent of tumor necrosis was used in some clinical trials to determine what type of postoperative chemotherapy would be given. In general, if tumor necrosis exceeded 90%, the preoperative chemotherapy regimen was continued. If tumor necrosis was less than 90%, some groups incorporated drugs not previously utilized in the preoperative therapy.</p><p id="CDR0000062698__511">Patients with less necrosis after initial chemotherapy have a prognosis that is inferior to the prognosis for patients with more necrosis. The prognosis is still substantially better than the prognosis for patients treated with surgery alone and no adjuvant chemotherapy. </p><p id="CDR0000062698__1954">Based on the following evidence, it is inappropriate to conclude that patients with less necrosis have not responded to chemotherapy and that adjuvant chemotherapy should be withheld for these patients. Chemotherapy after definitive surgery should include the agents used in the initial phase of treatment unless there is clear and unequivocal progressive disease during the initial phase of therapy.</p><p id="CDR0000062698__1837">Evidence (using the same agents for postoperative chemotherapy):</p><ol id="CDR0000062698__1838"><li class="half_rhythm"><div>Early reports from the Memorial Sloan Kettering Cancer Center (MSKCC) that suggested that adding cisplatin to postoperative chemotherapy improved the outcome for patients with less than 90% tumor necrosis.[<a class="bk_pop" href="#CDR0000062698_rl_29_35">35</a>] <ul id="CDR0000062698__1955"><li class="half_rhythm"><div>With longer follow-up, the outcome for patients with less than 90% tumor necrosis treated at MSKCC was the same whether they did or did not receive cisplatin in the postoperative phase of treatment.[<a class="bk_pop" href="#CDR0000062698_rl_29_36">36</a>]</div></li></ul></div></li><li class="half_rhythm"><div>In an early experience, the German cooperative osteosarcoma group performed a trial in which the chemotherapy regimen for patients with poor necrosis was changed after initial treatment.[<a class="bk_pop" href="#CDR0000062698_rl_29_37">37</a>] The agents used before surgery were discontinued and other agents were substituted. <ul id="CDR0000062698__1839"><li class="half_rhythm"><div>The results were substantially poorer for these patients than for patients who continued to receive the same agents.</div></li></ul></div></li><li class="half_rhythm"><div>Subsequent trials performed by other groups failed to demonstrate improved EFS when drugs not included in the preoperative regimen (cisplatin) were added to postoperative therapy.[<a class="bk_pop" href="#CDR0000062698_rl_29_19">19</a>,<a class="bk_pop" href="#CDR0000062698_rl_29_38">38</a>]</div></li><li class="half_rhythm"><div>A limited-institution pilot trial tested the strategy of discontinuing the agents used in the initial phase of therapy for patients with poorer necrosis; postoperative therapy consisted of melphalan with autologous stem cell reconstitution.[<a class="bk_pop" href="#CDR0000062698_rl_29_39">39</a>] <ul id="CDR0000062698__1840"><li class="half_rhythm"><div>The 5-year EFS rate for this group was 28%, which was lower than the EFS rates observed in many large series in which agents were continued despite a lesser degree of necrosis.</div></li></ul></div></li><li class="half_rhythm"><div>The international European and American Osteosarcoma Study (EURAMOS) group consortium was formed to conduct a large, prospective, randomized trial to help determine whether modifying the chemotherapy regimen on the basis of the degree of necrosis would improve EFS. All patients received initial therapy with cisplatin, doxorubicin, and high-dose methotrexate (MAP). Patients with more than 90% necrosis were randomly assigned to continue the same chemotherapy after surgery or to receive the same chemotherapy with the addition of interferon alpha-2b.[<a class="bk_pop" href="#CDR0000062698_rl_29_33">33</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335128/" class="def">Level of evidence: 1iiDi</a>] In the same EURAMOS trial, patients with less than 90% necrosis were randomly assigned to continue the same chemotherapy or to receive the same chemotherapy with the addition of high-dose ifosfamide and etoposide (MAPIE).[<a class="bk_pop" href="#CDR0000062698_rl_29_34">34</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335128/" class="def">Level of evidence: 1iiDi</a>]<ul id="CDR0000062698__1956"><li class="half_rhythm"><div> The addition of interferon alpha-2b did not improve the probability of EFS.</div></li><li class="half_rhythm"><div>With a median follow-up of over 61 months, the EFS did not differ between the two groups. </div></li><li class="half_rhythm"><div>The intensification of treatment in the MAPIE group resulted in greater toxicity than did the treatment in the standard MAP arm.</div></li></ul></div></li></ol></div><div id="CDR0000062698__1843"><h5>Other chemotherapy approaches not considered effective</h5><p id="CDR0000062698__461">The Italian Sarcoma Group and the Scandinavian Sarcoma Group performed a clinical trial in patients with osteosarcoma who presented with clinically detectable metastatic disease.[<a class="bk_pop" href="#CDR0000062698_rl_29_40">40</a>] Consolidation with high-dose etoposide and carboplatin followed by autologous stem cell reconstitution did not appear to improve outcome and the investigators did not recommend this strategy for the treatment of osteosarcoma.</p><p id="CDR0000062698__514">Laboratory studies using cell lines and xenografts suggested that bisphosphonates had activity against osteosarcoma.[<a class="bk_pop" href="#CDR0000062698_rl_29_41">41</a>] A single-institution clinical trial demonstrated that pamidronate could safely be administered along with multiagent chemotherapy to patients with newly diagnosed osteosarcoma.[<a class="bk_pop" href="#CDR0000062698_rl_29_41">41</a>] The French pediatric and adult sarcoma cooperative groups performed a prospective trial for the treatment of osteosarcoma.[<a class="bk_pop" href="#CDR0000062698_rl_29_42">42</a>] All patients received multiagent chemotherapy, and patients were randomly assigned to receive or not to receive zoledronate. The addition of zoledronate did not improve EFS.</p></div></div><div id="CDR0000062698__1829"><h4>Radiation therapy</h4><p id="CDR0000062698__251">If complete surgical resection is not feasible or if surgical margins are inadequate, radiation therapy may improve the local control rate.[<a class="bk_pop" href="#CDR0000062698_rl_29_43">43</a>,<a class="bk_pop" href="#CDR0000062698_rl_29_44">44</a>]; [<a class="bk_pop" href="#CDR0000062698_rl_29_45">45</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335144/" class="def">Level of evidence: 3iiA</a>] Radiation therapy should be considered in patients with osteosarcoma of the head and neck who have positive or uncertain resection margins.[<a class="bk_pop" href="#CDR0000062698_rl_29_46">46</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335144/" class="def">Level of evidence: 3iiA</a>] </p><p id="CDR0000062698__1933">Evidence (radiation therapy for local control):</p><ol id="CDR0000062698__1934"><li class="half_rhythm"><div>While it is accepted that the standard approach is primary surgical resection, a retrospective analysis of a small group of highly selective patients reported long-term EFS with external-beam radiation therapy for local control in some patients.[<a class="bk_pop" href="#CDR0000062698_rl_29_47">47</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335150/" class="def">Level of evidence: 3iiiA</a>] </div></li><li class="half_rhythm"><div>Investigators from a single institution reported on 28 children and young adults with osteosarcoma who were treated with radiation therapy for local control. Sixteen patients received radiation therapy during the primary treatment course, and 12 patients received radiation therapy as part of therapy after recurrence.[<a class="bk_pop" href="#CDR0000062698_rl_29_48">48</a>]<ul id="CDR0000062698__1935"><li class="half_rhythm"><div>For patients who received radiation therapy during primary treatment, the cumulative incidence of local failure at 5 years was 25%.</div></li><li class="half_rhythm"><div>For patients with recurrent disease, the cumulative incidence of local failure at 5 years was 44%.</div></li><li class="half_rhythm"><div>Local tumor progression was observed in 3 of 13 patients (23%) who were treated with adjuvant radiation therapy after resection, while three of six patients (50%) who received definitive radiation therapy as a sole modality of local control experienced local progression.</div></li></ul></div></li></ol></div></div><div id="CDR0000062698__321"><h3>Osteosarcoma of the Head and Neck</h3><p id="CDR0000062698__322">Osteosarcoma of the head and neck occurs in an older population than does osteosarcoma of the extremities.[<a class="bk_pop" href="#CDR0000062698_rl_29_46">46</a>,<a class="bk_pop" href="#CDR0000062698_rl_29_49">49</a>-<a class="bk_pop" href="#CDR0000062698_rl_29_52">52</a>] In the pediatric age group, osteosarcomas of the head and neck are more likely to be low-grade or intermediate-grade tumors than are osteosarcomas of the extremities.[<a class="bk_pop" href="#CDR0000062698_rl_29_53">53</a>,<a class="bk_pop" href="#CDR0000062698_rl_29_54">54</a>] All reported series emphasize the need for complete surgical resection.[<a class="bk_pop" href="#CDR0000062698_rl_29_46">46</a>,<a class="bk_pop" href="#CDR0000062698_rl_29_49">49</a>-<a class="bk_pop" href="#CDR0000062698_rl_29_54">54</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335150/" class="def">Level of evidence: 3iiiA</a>] The probability for cure with surgery alone is higher for osteosarcoma of the head and neck than it is for extremity osteosarcoma. When surgical margins are positive, there is a trend for improved survival with adjuvant radiation therapy.[<a class="bk_pop" href="#CDR0000062698_rl_29_46">46</a>,<a class="bk_pop" href="#CDR0000062698_rl_29_51">51</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335150/" class="def">Level of evidence: 3iiiA</a>] </p><p id="CDR0000062698__1844">There are no randomized trials to assess the efficacy of chemotherapy in patients with osteosarcoma of the head and neck, but several series suggest a benefit.[<a class="bk_pop" href="#CDR0000062698_rl_29_49">49</a>,<a class="bk_pop" href="#CDR0000062698_rl_29_55">55</a>] Chemotherapy should be considered for younger patients with high-grade osteosarcoma of the head and neck.[<a class="bk_pop" href="#CDR0000062698_rl_29_53">53</a>,<a class="bk_pop" href="#CDR0000062698_rl_29_56">56</a>]</p><p id="CDR0000062698__1845">Patients with osteosarcoma of the head and neck have a higher risk of developing a local recurrence and a lower risk of having distant metastasis than do patients with osteosarcoma of the extremities.[<a class="bk_pop" href="#CDR0000062698_rl_29_49">49</a>,<a class="bk_pop" href="#CDR0000062698_rl_29_51">51</a>,<a class="bk_pop" href="#CDR0000062698_rl_29_52">52</a>,<a class="bk_pop" href="#CDR0000062698_rl_29_57">57</a>] </p></div><div id="CDR0000062698__TrialSearch_29_sid_7"><h3>Current Clinical Trials</h3><p id="CDR0000062698__TrialSearch_29_22">Use our <a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials/advanced-search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">advanced clinical trial search</a> to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. <a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">General information</a> about clinical trials is also available.</p></div><div id="CDR0000062698_rl_29"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000062698_rl_29_1">Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014. 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For patients with metastatic disease at initial presentation, roughly 20% will remain continuously free of disease, and roughly 30% will survive 5 years from diagnosis.[<a class="bk_pop" href="#CDR0000062698_rl_38_1">1</a>] </p><p id="CDR0000062698__358">The lung is the most common site of initial metastatic disease.[<a class="bk_pop" href="#CDR0000062698_rl_38_2">2</a>] Patients with metastases limited to the lungs have a better outcome than do patients with metastases to other sites or to the lungs combined with other sites.[<a class="bk_pop" href="#CDR0000062698_rl_38_1">1</a>,<a class="bk_pop" href="#CDR0000062698_rl_38_3">3</a>]</p><div id="CDR0000062698__1889"><h3>Treatment Options for Osteosarcoma and UPS of Bone With Metastatic Disease at Diagnosis</h3><p id="CDR0000062698__1846">Treatment options for patients with osteosarcoma or undifferentiated pleomorphic sarcoma (UPS) of bone with metastatic disease at diagnosis include the following:</p><ol id="CDR0000062698__1847"><li class="half_rhythm"><div>Chemotherapy.</div></li></ol><p id="CDR0000062698__1848">The chemotherapeutic agents used include high-dose methotrexate, doxorubicin, cisplatin, high-dose ifosfamide, etoposide, and, in some reports, carboplatin or cyclophosphamide.</p><p id="CDR0000062698__1849">Evidence (chemotherapy):</p><ol id="CDR0000062698__1850"><li class="half_rhythm"><div class="half_rhythm">In a trial that investigated high-dose ifosfamide (17.5 g per course) in combination with etoposide for patients with newly diagnosed metastatic osteosarcoma, the following was observed:[<a class="bk_pop" href="#CDR0000062698_rl_38_4">4</a>]<ul id="CDR0000062698__1957"><li class="half_rhythm"><div>The combination produced a complete response in 10% of the patients and a partial response in 49% of the patients.</div></li></ul></div><div class="half_rhythm"> However, similar to localized disease, there is no evidence that the addition of ifosfamide or etoposide contributes to improved event-free survival (EFS) or overall survival (OS) in patients with metastatic disease.</div></li><li class="half_rhythm"><div class="half_rhythm">A study using a factorial design in patients with metastatic osteosarcoma (n = 91) evaluated the addition of either muramyl tripeptide or ifosfamide to a standard chemotherapy regimen that included cisplatin, high-dose methotrexate, and doxorubicin.[<a class="bk_pop" href="#CDR0000062698_rl_38_5">5</a>] <ul id="CDR0000062698__1851"><li class="half_rhythm"><div>There was a nominal advantage for the addition of muramyl tripeptide (but not for ifosfamide) in terms of EFS and OS, but criteria for statistical significance were not met.</div></li></ul></div></li><li class="half_rhythm"><div class="half_rhythm">In the international European and American Osteosarcoma Study (EURAMOS) group consortium, 362 of 2,186 patients (17%) presented with metastasis at diagnosis. Patients were randomly assigned to receive either treatment with cisplatin, doxorubicin, and high-dose methotrexate or cisplatin, doxorubicin, high-dose methotrexate, and ifosfamide.[<a class="bk_pop" href="#CDR0000062698_rl_38_6">6</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335125/" class="def">Level of evidence: 1iiA</a>]<ul id="CDR0000062698__1928"><li class="half_rhythm"><div> At a median follow-up of 47 months, the 3-year EFS rate was 32% (95% confidence interval [CI], 27%–37%), and the 5-year EFS rate was 28% (95% CI, 23%–33%).</div></li><li class="half_rhythm"><div> The 3-year OS rate was 56% (95% CI, 50%–61%), and the 5-year OS rate was 45% (95% CI, 39%–50%). </div></li></ul></div></li></ol><p id="CDR0000062698__361">The treatment options for UPS of bone with metastasis at initial presentation are the same as the treatment for osteosarcoma with metastasis. Patients with unresectable or metastatic UPS have a very poor outcome.[<a class="bk_pop" href="#CDR0000062698_rl_38_7">7</a>]</p></div><div id="CDR0000062698__256"><h3>Treatment Options for Lung-Only Metastases at Diagnosis</h3><p id="CDR0000062698__1852">Treatment options for patients with metastatic lung lesions at diagnosis include the following:</p><ol id="CDR0000062698__1853"><li class="half_rhythm"><div>Preoperative chemotherapy followed by surgery to remove the tumor followed by postoperative combination chemotherapy.</div></li></ol><p id="CDR0000062698__257">Patients with metastatic lung lesions as the sole site of metastatic disease should have the lung lesions resected if possible. Generally, this is performed after the administration of preoperative chemotherapy. After definitive surgical resection of the primary tumor, most clinicians resume systemic chemotherapy before initiating lung surgery to avoid longer delays in the resumption of chemotherapy. In approximately 10% of patients, all lung lesions disappear after preoperative chemotherapy.[<a class="bk_pop" href="#CDR0000062698_rl_38_3">3</a>] Complete resection of pulmonary metastatic disease can be achieved in a high percentage of patients with residual lung nodules after preoperative chemotherapy. The long-term survival is poor for patients who do not undergo complete surgical resection of pulmonary metastatic disease.[<a class="bk_pop" href="#CDR0000062698_rl_38_8">8</a>,<a class="bk_pop" href="#CDR0000062698_rl_38_9">9</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335132/" class="def">Level of evidence: 2A</a>]</p><p id="CDR0000062698__258">For patients who present with primary osteosarcoma and metastases limited to the lungs and who achieve complete surgical remission, the 5-year EFS rate is approximately 20% to 25%. Multiple metastatic nodules confer a worse prognosis than do one or two nodules, and bilateral lung involvement is worse than unilateral.[<a class="bk_pop" href="#CDR0000062698_rl_38_1">1</a>] Patients with peripheral lung lesions may have a better prognosis than patients with central lesions.[<a class="bk_pop" href="#CDR0000062698_rl_38_10">10</a>] Patients with fewer than three nodules confined to one lung may achieve a 5-year EFS rate of approximately 40% to 50%.[<a class="bk_pop" href="#CDR0000062698_rl_38_1">1</a>]</p></div><div id="CDR0000062698__259"><h3>Treatment Options for Bone Metastases With or Without Lung Metastases</h3><p id="CDR0000062698__260">The second most common site of metastasis is another bone that is distant from the primary tumor. Patients with metastasis to other bones distant from the primary tumor experience EFS and OS rates of approximately 10%.[<a class="bk_pop" href="#CDR0000062698_rl_38_1">1</a>] In a study of patients who presented with primary extremity tumors and synchronous metastasis to other bones, only 3 of 46 patients remained continuously disease-free 5 years later.[<a class="bk_pop" href="#CDR0000062698_rl_38_11">11</a>] Patients with transarticular skip lesions have a poor prognosis.[<a class="bk_pop" href="#CDR0000062698_rl_38_12">12</a>]</p><p id="CDR0000062698__261">Multifocal osteosarcoma is different from osteosarcoma that presents with a clearly delineated primary lesion and limited bone metastasis. Multifocal osteosarcoma classically presents with symmetrical, metaphyseal lesions, and it may be difficult to determine the primary lesion. Patients with multifocal bone disease at presentation have an extremely poor prognosis, but treatment with systemic chemotherapy and aggressive surgical resection may significantly prolong life.[<a class="bk_pop" href="#CDR0000062698_rl_38_13">13</a>,<a class="bk_pop" href="#CDR0000062698_rl_38_14">14</a>]</p><p id="CDR0000062698__1854">Treatment options for patients with bone metastases with or without lung metastases include the following:</p><ol id="CDR0000062698__1855"><li class="half_rhythm"><div class="half_rhythm">Preoperative chemotherapy followed by surgery to remove the primary tumor. After definitive surgical resection of the primary tumor, most clinicians resume systemic chemotherapy. The timing of surgery to remove metastatic tumors is not well defined. It is usually not attempted at the time of primary surgery because delays of more than 21 days until resumption of chemotherapy can increase the risk of adverse events and death.[<a class="bk_pop" href="#CDR0000062698_rl_38_15">15</a>]</div></li><li class="half_rhythm"><div class="half_rhythm">Surgery to remove the primary tumor followed by chemotherapy and then surgical resection of metastatic disease followed by postoperative combination chemotherapy.</div><div class="half_rhythm"> When the usual treatment course of preoperative chemotherapy followed by surgical ablation of the primary tumor and resection of all overt metastatic disease followed by postoperative combination chemotherapy cannot be used, an alternative treatment approach may be used. This alternative treatment approach begins with surgery for the primary tumor, followed by chemotherapy, and then surgical resection of metastatic disease. This approach may be appropriate in patients with intractable pain, pathological fracture, or uncontrolled infection of the tumor when initiation of chemotherapy could create risk of sepsis.[<a class="bk_pop" href="#CDR0000062698_rl_38_16">16</a>]</div></li><li class="half_rhythm"><div class="half_rhythm">Resection of metastatic bone lesions if possible. </div></li><li class="half_rhythm"><div class="half_rhythm">Radiation therapy to the extremities. There is some evidence that radiation therapy to the extremities may offer some local control.[<a class="bk_pop" href="#CDR0000062698_rl_38_17">17</a>]</div></li></ol></div><div id="CDR0000062698__TrialSearch_38_sid_8"><h3>Current Clinical Trials</h3><p id="CDR0000062698__TrialSearch_38_22">Use our <a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials/advanced-search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">advanced clinical trial search</a> to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. <a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">General information</a> about clinical trials is also available.</p></div><div id="CDR0000062698_rl_38"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000062698_rl_38_1">Kager L, Zoubek A, Pötschger U, et al.: Primary metastatic osteosarcoma: presentation and outcome of patients treated on neoadjuvant Cooperative Osteosarcoma Study Group protocols. J Clin Oncol 21 (10): 2011-8, 2003. [<a href="https://pubmed.ncbi.nlm.nih.gov/12743156" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12743156</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_38_2">Kempf-Bielack B, Bielack SS, Jürgens H, et al.: Osteosarcoma relapse after combined modality therapy: an analysis of unselected patients in the Cooperative Osteosarcoma Study Group (COSS). J Clin Oncol 23 (3): 559-68, 2005. [<a href="https://pubmed.ncbi.nlm.nih.gov/15659502" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15659502</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_38_3">Bacci G, Rocca M, Salone M, et al.: High grade osteosarcoma of the extremities with lung metastases at presentation: treatment with neoadjuvant chemotherapy and simultaneous resection of primary and metastatic lesions. J Surg Oncol 98 (6): 415-20, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/18792969" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18792969</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_38_4">Goorin AM, Harris MB, Bernstein M, et al.: Phase II/III trial of etoposide and high-dose ifosfamide in newly diagnosed metastatic osteosarcoma: a pediatric oncology group trial. J Clin Oncol 20 (2): 426-33, 2002. [<a href="https://pubmed.ncbi.nlm.nih.gov/11786570" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11786570</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_38_5">Chou AJ, Kleinerman ES, Krailo MD, et al.: Addition of muramyl tripeptide to chemotherapy for patients with newly diagnosed metastatic osteosarcoma: a report from the Children's Oncology Group. Cancer 115 (22): 5339-48, 2009. [<a href="/pmc/articles/PMC2783515/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2783515</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19637348" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19637348</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_38_6">Smeland S, Bielack SS, Whelan J, et al.: Survival and prognosis with osteosarcoma: outcomes in more than 2000 patients in the EURAMOS-1 (European and American Osteosarcoma Study) cohort. Eur J Cancer 109: 36-50, 2019. [<a href="/pmc/articles/PMC6506906/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6506906</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/30685685" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30685685</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_38_7">Daw NC, Billups CA, Pappo AS, et al.: Malignant fibrous histiocytoma and other fibrohistiocytic tumors in pediatric patients: the St. Jude Children's Research Hospital experience. Cancer 97 (11): 2839-47, 2003. [<a href="https://pubmed.ncbi.nlm.nih.gov/12767098" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12767098</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_38_8">Yamamoto Y, Kanzaki R, Kanou T, et al.: Long-term outcomes and prognostic factors of pulmonary metastasectomy for osteosarcoma and soft tissue sarcoma. Int J Clin Oncol 24 (7): 863-870, 2019. [<a href="https://pubmed.ncbi.nlm.nih.gov/30806840" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30806840</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_38_9">Slade AD, Warneke CL, Hughes DP, et al.: Effect of concurrent metastatic disease on survival in children and adolescents undergoing lung resection for metastatic osteosarcoma. J Pediatr Surg 50 (1): 157-60; discussion 160, 2015. [<a href="https://pubmed.ncbi.nlm.nih.gov/25598115" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25598115</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_38_10">Letourneau PA, Xiao L, Harting MT, et al.: Location of pulmonary metastasis in pediatric osteosarcoma is predictive of outcome. J Pediatr Surg 46 (7): 1333-7, 2011. [<a href="/pmc/articles/PMC3768269/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3768269</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21763830" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21763830</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_38_11">Bacci G, Fabbri N, Balladelli A, et al.: Treatment and prognosis for synchronous multifocal osteosarcoma in 42 patients. J Bone Joint Surg Br 88 (8): 1071-5, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16877608" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16877608</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_38_12">Kager L, Zoubek A, Kastner U, et al.: Skip metastases in osteosarcoma: experience of the Cooperative Osteosarcoma Study Group. J Clin Oncol 24 (10): 1535-41, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16575004" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16575004</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_38_13">Harris MB, Gieser P, Goorin AM, et al.: Treatment of metastatic osteosarcoma at diagnosis: a Pediatric Oncology Group Study. J Clin Oncol 16 (11): 3641-8, 1998. [<a href="https://pubmed.ncbi.nlm.nih.gov/9817286" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9817286</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_38_14">Longhi A, Fabbri N, Donati D, et al.: Neoadjuvant chemotherapy for patients with synchronous multifocal osteosarcoma: results in eleven cases. J Chemother 13 (3): 324-30, 2001. [<a href="https://pubmed.ncbi.nlm.nih.gov/11450892" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11450892</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_38_15">Imran H, Enders F, Krailo M, et al.: Effect of time to resumption of chemotherapy after definitive surgery on prognosis for non-metastatic osteosarcoma. J Bone Joint Surg Am 91 (3): 604-12, 2009. [<a href="/pmc/articles/PMC2701597/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2701597</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19255220" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19255220</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_38_16">Marina NM, Smeland S, Bielack SS, et al.: Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international, randomised controlled trial. Lancet Oncol 17 (10): 1396-1408, 2016. [<a href="/pmc/articles/PMC5052459/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5052459</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/27569442" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27569442</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_38_17">Tinkle CL, Lu J, Han Y, et al.: Curative-intent radiotherapy for pediatric osteosarcoma: The St. Jude experience. Pediatr Blood Cancer 66 (8): e27763, 2019. [<a href="/pmc/articles/PMC6588458/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6588458</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/31012273" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 31012273</span></a>]</div></li></ol></div></div><div id="CDR0000062698__44"><h2 id="_CDR0000062698__44_">Treatment of Recurrent Osteosarcoma and UPS of Bone</h2><p id="CDR0000062698__45"> Approximately 50% of relapses in patients with recurrent osteosarcoma occur within 18 months of therapy termination, and only 5% of recurrences develop beyond 5 years.[<a class="bk_pop" href="#CDR0000062698_rl_44_1">1</a>-<a class="bk_pop" href="#CDR0000062698_rl_44_4">4</a>] </p><div id="CDR0000062698__1958"><h3>Prognostic Factors for Recurrence</h3><p id="CDR0000062698__1856">Prognostic factors for recurrent osteosarcoma or undifferentiated pleomorphic sarcoma (UPS) of bone include the following:</p><ul id="CDR0000062698__1857"><li class="half_rhythm"><div class="half_rhythm"><b>Time from diagnosis.</b> In 564 patients with a recurrence, patients whose disease recurred within 2 years of diagnosis had a worse prognosis than patients whose disease recurred after 2 years.[<a class="bk_pop" href="#CDR0000062698_rl_44_1">1</a>] In another series of 431 patients, recurrences occurring less than 2 years from diagnosis were also associated with worse outcomes.[<a class="bk_pop" href="#CDR0000062698_rl_44_5">5</a>]</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Age at initial diagnosis.</b> Older age at initial study enrollment was associated with a worse prognosis.[<a class="bk_pop" href="#CDR0000062698_rl_44_5">5</a>]</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Presence of metastatic disease at diagnosis.</b> The presence of metastatic disease at initial presentation was associated with a worse prognosis.[<a class="bk_pop" href="#CDR0000062698_rl_44_5">5</a>]</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Tumor response to preoperative chemotherapy.</b> Patients with a good histologic response to initial preoperative chemotherapy had a better overall survival (OS) after recurrence than did poor initial responders.[<a class="bk_pop" href="#CDR0000062698_rl_44_1">1</a>]</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Site of metastases.</b> The probability of developing lung metastases at 5 years is 28% in patients presenting with localized disease.[<a class="bk_pop" href="#CDR0000062698_rl_44_6">6</a>] In two large series, the incidence of recurrence by site was as follows: lung only (65%–80%), bone only (8%–10%), local recurrence only (4%–7%), and combined relapse (10%–15%).[<a class="bk_pop" href="#CDR0000062698_rl_44_4">4</a>,<a class="bk_pop" href="#CDR0000062698_rl_44_7">7</a>] Abdominal metastases are rare but may occur as late as 4 years after diagnosis.[<a class="bk_pop" href="#CDR0000062698_rl_44_8">8</a>] The Children's Oncology Group (COG) reported the outcomes of 431 young patients with recurrent osteosarcoma.[<a class="bk_pop" href="#CDR0000062698_rl_44_5">5</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000587990/" class="def">Level of evidence: 3iiDiv</a>] Patients with recurrences in both lung and bone had worse outcomes than did patients with recurrences in lung only (<i>P</i> = .005).</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Surgical resectability.</b> Patients with recurrent
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osteosarcoma should be assessed for surgical
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resectability because they may sometimes be cured with aggressive surgical
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resection with or without chemotherapy.[<a class="bk_pop" href="#CDR0000062698_rl_44_9">9</a> ,<a class="bk_pop" href="#CDR0000062698_rl_44_7">7</a>,<a class="bk_pop" href="#CDR0000062698_rl_44_10">10</a>-<a class="bk_pop" href="#CDR0000062698_rl_44_13">13</a>] </div><div class="half_rhythm">Control of osteosarcoma after recurrence depends on complete surgical resection of all sites of clinically detectable metastatic disease. If surgical resection is not attempted or cannot be performed, progression and death are certain. The ability to achieve a complete
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resection of recurrent disease is the most important prognostic factor at first
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relapse, with a 5-year survival rate of 20% to 45% after complete
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resection of metastatic pulmonary tumors and a 20% survival rate after complete resection of metastases at other sites.[<a class="bk_pop" href="#CDR0000062698_rl_44_4">4</a>,<a class="bk_pop" href="#CDR0000062698_rl_44_7">7</a>,<a class="bk_pop" href="#CDR0000062698_rl_44_13">13</a>,<a class="bk_pop" href="#CDR0000062698_rl_44_14">14</a>]</div></li></ul></div><div id="CDR0000062698__1890"><h3>Treatment Options for Recurrent Osteosarcoma and UPS of Bone</h3><p id="CDR0000062698__1859">Treatment options for patients with recurrent osteosarcoma or UPS of bone include the following:</p><ol id="CDR0000062698__1860"><li class="half_rhythm"><div><a href="#CDR0000062698__1943">Surgery</a> to remove all sites of metastatic disease.</div></li><li class="half_rhythm"><div><a href="#CDR0000062698__1945">Chemotherapy and targeted therapy</a>.</div></li><li class="half_rhythm"><div><a href="#CDR0000062698__1946">Radiopharmaceuticals and radiation therapy</a>.</div></li></ol><div id="CDR0000062698__1943"><h4>Surgery</h4><p id="CDR0000062698__1944">Control of osteosarcoma after recurrence depends on complete surgical resection of all sites of clinically detectable metastatic disease. </p></div><div id="CDR0000062698__1945"><h4>Chemotherapy and targeted therapy</h4><p id="CDR0000062698__155">The role of systemic chemotherapy for the treatment of patients with recurrent osteosarcoma is not well defined. The selection of further systemic treatment
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depends on many factors, including the site of recurrence, the patient’s
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previous primary treatment, and individual patient considerations.</p><p id="CDR0000062698__1898">The COG reported the outcomes of patients with recurrent osteosarcoma from seven phase II trials, all of which were assessed to have shown no treatment benefit.[<a class="bk_pop" href="#CDR0000062698_rl_44_15">15</a>] </p><ul id="CDR0000062698__1979"><li class="half_rhythm"><div>The event-free survival (EFS) rate for 96 patients with osteosarcoma and measurable disease was 12% at 4 months (95% confidence interval [CI], 6%–19%). </div></li><li class="half_rhythm"><div>There was no significant difference in EFS between the trials according to the number of previous treatment regimens or patient age, sex, and ethnicity.</div></li></ul><p id="CDR0000062698__1980">One additional phase II trial with a different study design was reported. In this trial, patients with osteosarcoma and metastases to the lung underwent surgical resection of all lung nodules and then were treated with adjuvant inhaled granulocyte-macrophage colony-stimulating factor (GM-CSF).[<a class="bk_pop" href="#CDR0000062698_rl_44_15">15</a>]</p><ul id="CDR0000062698__1981"><li class="half_rhythm"><div>The 12-month EFS rate for the 42 evaluable patients enrolled in this study was 20% (95% CI, 10%–34%).</div></li></ul><p id="CDR0000062698__1861">The following chemotherapy and targeted therapy agents have been studied to treat recurrent osteosarcoma and UPS of bone:</p><ul id="CDR0000062698__1862"><li class="half_rhythm"><div><b>Ifosfamide
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alone with mesna uroprotection, or in combination with etoposide.</b> Ifosfamide
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alone with mesna uroprotection, or in combination with etoposide, has been active in as many as one-third of patients with recurrent osteosarcoma who have
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not previously received this drug.[<a class="bk_pop" href="#CDR0000062698_rl_44_16">16</a>-<a class="bk_pop" href="#CDR0000062698_rl_44_20">20</a>]</div></li><li class="half_rhythm"><div><b>Gemcitabine and docetaxel.</b> A nonrandomized comparison of two doses of gemcitabine, both given with docetaxel, suggested that a higher dose of gemcitabine (900 mg/m<sup>2</sup>) was associated with a better response rate and longer survival than was a lower dose of gemcitabine (675 mg/m<sup>2</sup>) for recurrent or refractory osteosarcoma.[<a class="bk_pop" href="#CDR0000062698_rl_44_21">21</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335144/" class="def">Level of evidence: 3iiA</a>] The combination of gemcitabine (at a dose of 900 mg/m<sup>2</sup>) and docetaxel has also been reported to have activity in some studies that included patients with unresectable disease.[<a class="bk_pop" href="#CDR0000062698_rl_44_22">22</a>-<a class="bk_pop" href="#CDR0000062698_rl_44_24">24</a>]; [<a class="bk_pop" href="#CDR0000062698_rl_44_25">25</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000587990/" class="def">Level of evidence: 3iiDiv</a>]</div></li><li class="half_rhythm"><div><b>Cyclophosphamide and etoposide.</b> Cyclophosphamide and etoposide have been shown to have activity in recurrent osteosarcoma.[<a class="bk_pop" href="#CDR0000062698_rl_44_22">22</a>]</div></li><li class="half_rhythm"><div><b>Sorafenib.</b> The Italian Sarcoma Group reported rare objective responses and disease stabilization with sorafenib in patients with recurrent osteosarcoma.[<a class="bk_pop" href="#CDR0000062698_rl_44_26">26</a>]</div></li><li class="half_rhythm"><div><b>Sorafenib and everolimus.</b> The Italian Sarcoma Group also reported the outcome of patients with metastatic recurrent osteosarcoma treated with the combination of sorafenib and everolimus. They observed two partial responses and two minor responses in 38 patients; 17 of 38 patients were progression free at 6 months from study entry but toxicity was greater than with sorafenib monotherapy.[<a class="bk_pop" href="#CDR0000062698_rl_44_27">27</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335137/" class="def">Level of evidence: 2Diii</a>]</div></li><li class="half_rhythm"><div><b>Regorafenib.</b> Two prospective, randomized, double-blind trials have evaluated the role of regorafenib in the treatment of metastatic recurrent osteosarcoma. Both studies used the approved treatment regimen of 160 mg by mouth daily for 21 days followed by 7 days without treatment. The French trial randomly assigned patients 2:1 between regorafenib and placebo and allowed crossover for patients assigned to placebo.[<a class="bk_pop" href="#CDR0000062698_rl_44_28">28</a>] Seventeen of 26 patients (65%; one-sided 95% CI, 47%) in the regorafenib group did not have disease progression at 8 weeks, compared with 0 of 12 patients in the placebo group. The Sarcoma Alliance for Research Collaboration (SARC) group randomly assigned adult patients 1:1 between regorafenib and placebo.[<a class="bk_pop" href="#CDR0000062698_rl_44_29">29</a>] Median progression-free survival was significantly improved with regorafenib versus placebo: 3.6 months (95% CI, 2.0–7.6 months) versus 1.7 months (95% CI, 1.2–1.8 months), respectively (hazard ratio, 0.42; 95% CI, 0.21–0.85; <i>P</i> = .017).</div></li></ul></div><div id="CDR0000062698__1946"><h4>Radiopharmaceuticals and radiation therapy</h4><p id="CDR0000062698__1864">High-dose samarium Sm 153-ethylenediamine tetramethylene phosphonic acid (153Sm-EDTMP) coupled with peripheral blood stem
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cell support may provide significant pain palliation in patients with bone
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metastases.[<a class="bk_pop" href="#CDR0000062698_rl_44_30">30</a>-<a class="bk_pop" href="#CDR0000062698_rl_44_33">33</a>] Toxicity of 153Sm-EDTMP is primarily hematologic.[<a class="bk_pop" href="#CDR0000062698_rl_44_34">34</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335149/" class="def">Level of evidence: 3iiDiii</a>]</p><p id="CDR0000062698__1915">A single-institution retrospective review reported that high-dose fraction radiation therapy (2 Gy/fraction) was a useful form of palliation for patients with recurrent osteosarcoma.[<a class="bk_pop" href="#CDR0000062698_rl_44_35">35</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000587991/" class="def">Level of evidence: 3iiiDiv</a>] Thirty-two courses of palliative radiation therapy were given to 20 patients with symptomatic metastatic and/or locally recurrent primary disease. Twenty-four of the 32 courses (75%) were associated with symptom improvement. Higher doses of radiation therapy correlated with longer durations of symptom response.</p></div></div><div id="CDR0000062698__275"><h3>Treatment Options for Local Recurrence</h3><p id="CDR0000062698__1959">Treatment options for patients with osteosarcoma or UPS of bone that has recurred locally include the following:</p><ol id="CDR0000062698__1960"><li class="half_rhythm"><div>Surgery to remove the tumor.</div></li></ol><p id="CDR0000062698__276"> The postrelapse outcome of
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patients who have a local recurrence is quite poor,[<a class="bk_pop" href="#CDR0000062698_rl_44_36">36</a>-<a class="bk_pop" href="#CDR0000062698_rl_44_38">38</a>] and survival of patients with local recurrences and either previous or concurrent systemic metastases is poor.[<a class="bk_pop" href="#CDR0000062698_rl_44_39">39</a>]</p><p id="CDR0000062698__1961">Two retrospective, single-institution series reported a survival rate of 10% to 40% after local recurrence without associated systemic metastasis.[<a class="bk_pop" href="#CDR0000062698_rl_44_39">39</a>-<a class="bk_pop" href="#CDR0000062698_rl_44_42">42</a>]</p><p id="CDR0000062698__1962"> A retrospective review from the Italian Sarcoma Group identified 62 patients (median age, 21 years) with local recurrences.[<a class="bk_pop" href="#CDR0000062698_rl_44_43">43</a>] With a median follow-up of 43 months (range, 5–235 months), the 5-year post–local relapse survival rate was 37%, significantly better for patients with a longer local recurrence–free interval (≤24 months, 31% vs. >24 months, 61.5%; <i>P</i> = .03), absence of distant metastases (no distant metastases, 56% vs. distant metastases, 11.5%; <i>P</i> = .0001), and achievement of second complete remission (CR2) by surgical resection (no CR2, 0% vs. CR2, 58.5%; <i>P</i> = .0001). No difference in post–local relapse survival was found according to age, and there was no benefit from chemotherapy administration.</p><p id="CDR0000062698__1876">The incidence of local relapse was higher
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in patients who had a poor pathologic response to
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chemotherapy in the primary tumor and in patients with inadequate surgical margins.[<a class="bk_pop" href="#CDR0000062698_rl_44_36">36</a>,<a class="bk_pop" href="#CDR0000062698_rl_44_41">41</a>]</p></div><div id="CDR0000062698__271"><h3>Treatment Options for Lung-Only Recurrence</h3><p id="CDR0000062698__1963">Treatment options for patients with osteosarcoma and UPS of bone that has recurred in the lung only include the following:</p><ol id="CDR0000062698__1964"><li class="half_rhythm"><div>Surgery to remove the tumor.</div></li><li class="half_rhythm"><div>Targeted therapy (sorafenib and regorafenib).</div></li></ol><p id="CDR0000062698__272">Repeated resections of pulmonary recurrences can lead to extended disease control and possibly cure for some patients.[<a class="bk_pop" href="#CDR0000062698_rl_44_14">14</a>,<a class="bk_pop" href="#CDR0000062698_rl_44_44">44</a>] Survival for patients with unresectable metastatic disease is less than 5%.[<a class="bk_pop" href="#CDR0000062698_rl_44_7">7</a>,<a class="bk_pop" href="#CDR0000062698_rl_44_45">45</a>] The 5-year EFS rate for patients who have complete surgical resection of all pulmonary metastases ranges from 20% to 45%.[<a class="bk_pop" href="#CDR0000062698_rl_44_4">4</a>,<a class="bk_pop" href="#CDR0000062698_rl_44_13">13</a>,<a class="bk_pop" href="#CDR0000062698_rl_44_14">14</a>]; [<a class="bk_pop" href="#CDR0000062698_rl_44_46">46</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335150/" class="def">Level of evidence: 3iiiA</a>]</p><p id="CDR0000062698__1865">Factors associated with a
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better outcome include the following:[<a class="bk_pop" href="#CDR0000062698_rl_44_4">4</a>,<a class="bk_pop" href="#CDR0000062698_rl_44_6">6</a>,<a class="bk_pop" href="#CDR0000062698_rl_44_7">7</a>,<a class="bk_pop" href="#CDR0000062698_rl_44_47">47</a>,<a class="bk_pop" href="#CDR0000062698_rl_44_48">48</a>] </p><ul id="CDR0000062698__1965"><li class="half_rhythm"><div> Fewer pulmonary nodules.</div></li><li class="half_rhythm"><div>Unilateral pulmonary
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metastases.</div></li><li class="half_rhythm"><div>Longer intervals between primary tumor resection and
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metastases.</div></li><li class="half_rhythm"><div>Tumor location in the periphery of the lung.</div></li></ul><p id="CDR0000062698__1966">Approximately 50% of patients with one isolated pulmonary lesion more than 1 year after diagnosis were long-term survivors after metastasectomy. Chemotherapy did not appear to offer an advantage.[<a class="bk_pop" href="#CDR0000062698_rl_44_49">49</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335150/" class="def">Level of evidence: 3iiiA</a>]</p><p id="CDR0000062698__455">Control of osteosarcoma requires surgical resection of all macroscopic tumors; however, recommendations are conflicting regarding the surgical approach to the treatment of pulmonary metastases in osteosarcoma. Several options are available to resect pulmonary nodules in a patient with osteosarcoma, including thoracoscopy and thoracotomy with palpation of the collapsed lung. When patients have nodules identified only in one lung, some surgeons advocate thoracoscopy, some advocate unilateral thoracotomy, and some advocate bilateral thoracotomy. Bilateral thoracotomy can be performed as a single surgical procedure with a median sternotomy or a clamshell approach, or by staged bilateral thoracotomies.</p><p id="CDR0000062698__1869">Evidence (surgical approach for lung-only recurrence of osteosarcoma and UPS of bone):</p><ol id="CDR0000062698__1870"><li class="half_rhythm"><div>The St. Jude Children’s Research Hospital reported on 81 patients who had pulmonary nodules identified at initial presentation in only one lung by computed tomography (CT) scan.[<a class="bk_pop" href="#CDR0000062698_rl_44_50">50</a>] They performed unilateral thoracotomy and did not explore the contralateral hemithorax. At the time of thoracotomy, 44 of 81 patients had a solitary nodule identified; 15 of 81 patients had two nodules identified; 16 of 81 patients had three to five nodules identified; and 6 of 81 patients had more than five nodules identified. Additional patients who were considered unresectable were not included in the analysis. <ul id="CDR0000062698__1871"><li class="half_rhythm"><div>Thirty-nine of 81 patients had subsequent pulmonary recurrence; for most patients, recurrence occurred within 6 months.</div></li><li class="half_rhythm"><div>Within the first 6 months, 9 of 81 patients had ipsilateral recurrence, and 10 of 81 patients had a contralateral recurrence. By 2 years after initial thoracotomy, 13 of 81 patients had ipsilateral recurrence; 19 of 81 patients had contralateral recurrence; and 2 of 81 patients had bilateral recurrence.</div></li><li class="half_rhythm"><div>OS was similar for patients with ipsilateral and bilateral recurrence.</div></li></ul></div></li><li class="half_rhythm"><div>The Memorial Sloan Kettering Cancer Center reported on pulmonary metastatic disease recurrence after initial therapy for osteosarcoma. Fourteen patients had pulmonary nodules identified in only one lung by CT scan; nine patients were identified less than 2 years from initial diagnosis (early metastases), and five patients were identified more than 2 years from initial diagnosis (late metastases).[<a class="bk_pop" href="#CDR0000062698_rl_44_47">47</a>] Seven of nine patients with early metastases had staged contralateral thoracotomies, and six of seven had nodules removed from the contralateral lung, despite negative CT scan findings. <ul id="CDR0000062698__1872"><li class="half_rhythm"><div>The lack of a comparison group precludes evaluation of the impact of the contralateral thoracotomy on subsequent EFS or OS.</div></li><li class="half_rhythm"><div>The same group expanded their analysis to include a retrospective review of 161 thoracotomies performed in 88 patients with osteosarcoma metastatic to the lung.[<a class="bk_pop" href="#CDR0000062698_rl_44_51">51</a>] In this expanded series, CT failed to identify one-third of pulmonary metastases confirmed by pathological examination.</div></li></ul></div></li></ol></div><div id="CDR0000062698__273"><h3>Treatment Options for Recurrence With Bone-Only Metastases</h3><p id="CDR0000062698__1873">Treatment options for patients with osteosarcoma or UPS of bone that has recurred in the bone only include the following:</p><ol id="CDR0000062698__1874"><li class="half_rhythm"><div>Surgery to remove the tumor.</div></li><li class="half_rhythm"><div>153Sm-EDTMP with or without stem cell support.</div></li><li class="half_rhythm"><div>Targeted therapy (sorafenib and regorafenib).</div></li></ol><p id="CDR0000062698__274">Patients with osteosarcoma who develop bone metastases have a poor prognosis. In one large series, the 5-year EFS rate was 11%.[<a class="bk_pop" href="#CDR0000062698_rl_44_52">52</a>] Patients with late solitary bone relapse have a 5-year EFS rate of approximately 30%.[<a class="bk_pop" href="#CDR0000062698_rl_44_52">52</a>-<a class="bk_pop" href="#CDR0000062698_rl_44_55">55</a>]</p><p id="CDR0000062698__1875">For patients with multiple unresectable bone lesions, 153Sm-EDTMP with or without stem cell support may produce stable disease and/or provide pain relief.[<a class="bk_pop" href="#CDR0000062698_rl_44_34">34</a>]</p></div><div id="CDR0000062698__278"><h3>Treatment Options for Second Recurrence of Osteosarcoma</h3><p id="CDR0000062698__1877">Treatment options for patients with osteosarcoma or UPS of bone that has recurred twice include the following:</p><ol id="CDR0000062698__1878"><li class="half_rhythm"><div>Surgery to remove the tumor and/or chemotherapy.</div></li><li class="half_rhythm"><div>Targeted therapy (sorafenib and regorafenib).</div></li></ol><p id="CDR0000062698__1967">Evidence (surgery and/or chemotherapy):</p><ol id="CDR0000062698__1968"><li class="half_rhythm"><div>The cooperative German-Austrian-Swiss osteosarcoma study group reported on 249 patients who had a second recurrence of osteosarcoma. The main feature of therapy was repeated surgical resection of recurrent disease.[<a class="bk_pop" href="#CDR0000062698_rl_44_56">56</a>]<ul id="CDR0000062698__1969"><li class="half_rhythm"><div> Of these patients, 197 died and 37 were alive in CR (24 patients after a third complete response and 13 patients after a fourth or subsequent complete response).</div></li><li class="half_rhythm"><div> Fifteen patients who did not achieve surgical remission remained alive, but follow-up for these patients was extremely short.</div></li></ul></div></li><li class="half_rhythm"><div>The Spanish Group for Research on Sarcoma reported the results of a phase II trial of patients with relapsed or refractory osteosarcoma who were treated with gemcitabine and sirolimus.[<a class="bk_pop" href="#CDR0000062698_rl_44_57">57</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000587990/" class="def">Level of evidence: 3iiDiv</a>] <ul id="CDR0000062698__1970"><li class="half_rhythm"><div>The progression-free survival (PFS) rate at 4 months was 44%. </div></li><li class="half_rhythm"><div>After central radiologic review of 33 assessable patients, 2 partial responses and 14 disease stabilizations (48.5%) were reported.</div></li></ul></div></li><li class="half_rhythm"><div> The COG reported the outcomes of patients with recurrent osteosarcoma from seven phase II trials, all of which were assessed to have shown no treatment benefit.[<a class="bk_pop" href="#CDR0000062698_rl_44_15">15</a>]<ul id="CDR0000062698__1971"><li class="half_rhythm"><div> The EFS rate for 96 patients with osteosarcoma and measurable disease was 12% at 4 months (95% CI, 6%–19%).</div></li><li class="half_rhythm"><div> There was no significant difference in EFS between the trials according to the number of previous treatment regimens or patient age, sex, and ethnicity. </div></li></ul></div></li><li class="half_rhythm"><div>One additional phase II trial with a different study design was reported. In this trial, patients with osteosarcoma and metastases to the lung underwent surgical resection of all lung nodules and then were treated with adjuvant inhaled GM-CSF.[<a class="bk_pop" href="#CDR0000062698_rl_44_15">15</a>]<ul id="CDR0000062698__1972"><li class="half_rhythm"><div> The 12-month EFS rate for the 42 evaluable patients enrolled in this study was 20% (95% CI, 10%–34%).</div></li></ul></div></li></ol></div><div id="CDR0000062698__502"><h3>Treatment Options Under Clinical Evaluation</h3><p id="CDR0000062698__503">Information about National Cancer Institute (NCI)–supported clinical trials can be found on the <a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials/search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCI website</a>. For information about clinical trials sponsored by other organizations, refer to the <a href="https://clinicaltrials.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ClinicalTrials.gov website</a>.</p><p id="CDR0000062698__1798">The following are examples of national and/or institutional clinical trials that are currently being conducted:</p><ul id="CDR0000062698__504"><li class="half_rhythm"><div class="half_rhythm"><b><a href="https://www.cancer.gov/clinicaltrials/NCT03155620" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">APEC1621 (NCT03155620)</a></b> (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders)<b>:</b> NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified in a patient's tumor (refractory or recurrent). Children and adolescents aged 1 to 21 years are eligible for the trial.</div><div class="half_rhythm">Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the <a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials/nci-supported/pediatric-match" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCI website</a> and <a href="https://clinicaltrials.gov/ct2/show/NCT03155620" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ClinicalTrials.gov website</a>.
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</div></li><li class="half_rhythm"><div class="half_rhythm"><b><a href="https://www.cancer.gov/clinicaltrials/NCT04154189" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCT04154189</a></b> (A Study to Compare the Efficacy and Safety of Ifosfamide and Etoposide With or Without Lenvatinib in Children, Adolescents, and Young Adults With Relapsed and Refractory Osteosarcoma)<b>:</b>
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The aim of this study is to evaluate whether lenvatinib in combination with ifosfamide and etoposide (Arm A) is superior to ifosfamide and etoposide (Arm B) in improving the PFS rate at 4 months (by independent imaging review using Response Evaluation Criteria In Solid Tumors [RECIST 1.1]), in children, adolescents, and young adults with relapsed or refractory osteosarcoma.</div></li></ul><div id="CDR0000062698__TrialSearch_502_sid_10"><h4>Current Clinical Trials</h4><p id="CDR0000062698__TrialSearch_502_22">Use our <a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials/advanced-search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">advanced clinical trial search</a> to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. <a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">General information</a> about clinical trials is also available.</p></div></div><div id="CDR0000062698_rl_44"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000062698_rl_44_1">Gelderblom H, Jinks RC, Sydes M, et al.: Survival after recurrent osteosarcoma: data from 3 European Osteosarcoma Intergroup (EOI) randomized controlled trials. Eur J Cancer 47 (6): 895-902, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/21216138" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21216138</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_44_2">Hauben EI, Bielack S, Grimer R, et al.: Clinico-histologic parameters of osteosarcoma patients with late relapse. Eur J Cancer 42 (4): 460-6, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16426841" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16426841</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_44_3">Ferrari S, Briccoli A, Mercuri M, et al.: Late relapse in osteosarcoma. J Pediatr Hematol Oncol 28 (7): 418-22, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16825986" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16825986</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_44_4">Kempf-Bielack B, Bielack SS, Jürgens H, et al.: Osteosarcoma relapse after combined modality therapy: an analysis of unselected patients in the Cooperative Osteosarcoma Study Group (COSS). J Clin Oncol 23 (3): 559-68, 2005. [<a href="https://pubmed.ncbi.nlm.nih.gov/15659502" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15659502</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_44_5">Spraker-Perlman HL, Barkauskas DA, Krailo MD, et al.: Factors influencing survival after recurrence in osteosarcoma: A report from the Children's Oncology Group. Pediatr Blood Cancer 66 (1): e27444, 2019. [<a href="/pmc/articles/PMC6249072/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6249072</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/30255612" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30255612</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_44_6">Aljubran AH, Griffin A, Pintilie M, et al.: Osteosarcoma in adolescents and adults: survival analysis with and without lung metastases. Ann Oncol 20 (6): 1136-41, 2009. [<a href="https://pubmed.ncbi.nlm.nih.gov/19153114" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19153114</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_44_7">Bacci G, Briccoli A, Longhi A, et al.: Treatment and outcome of recurrent osteosarcoma: experience at Rizzoli in 235 patients initially treated with neoadjuvant chemotherapy. Acta Oncol 44 (7): 748-55, 2005. [<a href="https://pubmed.ncbi.nlm.nih.gov/16227167" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16227167</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_44_8">Rejin K, Aykan OA, Omer G, et al.: Intra-abdominal metastasis in osteosarcoma: survey and literature review. Pediatr Hematol Oncol 28 (7): 609-15, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/21875322" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21875322</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_44_9">Goorin AM, Shuster JJ, Baker A, et al.: Changing pattern of pulmonary metastases with adjuvant chemotherapy in patients with osteosarcoma: results from the multiinstitutional osteosarcoma study. J Clin Oncol 9 (4): 600-5, 1991. [<a href="https://pubmed.ncbi.nlm.nih.gov/2066757" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 2066757</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_44_10">Harting MT, Blakely ML: Management of osteosarcoma pulmonary metastases. Semin Pediatr Surg 15 (1): 25-9, 2006. 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[<a href="https://pubmed.ncbi.nlm.nih.gov/27197055" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27197055</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_44_22">Massimo B, Giovanni G, Stefano F, et al.: Phase 2 trial of two courses of cyclophosphamide and etoposide for relapsed high-risk osteosarcoma patients. Cancer 115 (13): 2980-7, 2009. [<a href="https://pubmed.ncbi.nlm.nih.gov/19452540" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19452540</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_44_23">Navid F, Willert JR, McCarville MB, et al.: Combination of gemcitabine and docetaxel in the treatment of children and young adults with refractory bone sarcoma. Cancer 113 (2): 419-25, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/18484657" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18484657</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_44_24">Qi WX, He AN, Tang LN, et al.: Efficacy and safety of gemcitabine-docetaxel combination therapy for recurrent or refractory high-grade osteosarcoma in China: a retrospective study of 18 patients. Jpn J Clin Oncol 42 (5): 427-31, 2012. [<a href="https://pubmed.ncbi.nlm.nih.gov/22450929" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22450929</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_44_25">Palmerini E, Jones RL, Marchesi E, et al.: Gemcitabine and docetaxel in relapsed and unresectable high-grade osteosarcoma and spindle cell sarcoma of bone. BMC Cancer 16: 280, 2016. [<a href="/pmc/articles/PMC4839113/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4839113</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/27098543" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27098543</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_44_26">Grignani G, Palmerini E, Dileo P, et al.: A phase II trial of sorafenib in relapsed and unresectable high-grade osteosarcoma after failure of standard multimodal therapy: an Italian Sarcoma Group study. Ann Oncol 23 (2): 508-16, 2012. [<a href="https://pubmed.ncbi.nlm.nih.gov/21527590" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21527590</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_44_27">Grignani G, Palmerini E, Ferraresi V, et al.: Sorafenib and everolimus for patients with unresectable high-grade osteosarcoma progressing after standard treatment: a non-randomised phase 2 clinical trial. Lancet Oncol 16 (1): 98-107, 2015. [<a href="https://pubmed.ncbi.nlm.nih.gov/25498219" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25498219</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_44_28">Duffaud F, Mir O, Boudou-Rouquette P, et al.: Efficacy and safety of regorafenib in adult patients with metastatic osteosarcoma: a non-comparative, randomised, double-blind, placebo-controlled, phase 2 study. Lancet Oncol 20 (1): 120-133, 2019. [<a href="https://pubmed.ncbi.nlm.nih.gov/30477937" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30477937</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_44_29">Davis LE, Bolejack V, Ryan CW, et al.: Randomized Double-Blind Phase II Study of Regorafenib in Patients With Metastatic Osteosarcoma. J Clin Oncol 37 (16): 1424-1431, 2019. [<a href="/pmc/articles/PMC7799443/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7799443</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/31013172" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 31013172</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_44_30">Anderson PM, Wiseman GA, Dispenzieri A, et al.: High-dose samarium-153 ethylene diamine tetramethylene phosphonate: low toxicity of skeletal irradiation in patients with osteosarcoma and bone metastases. J Clin Oncol 20 (1): 189-96, 2002. [<a href="https://pubmed.ncbi.nlm.nih.gov/11773169" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11773169</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_44_31">Franzius C, Bielack S, Flege S, et al.: High-activity samarium-153-EDTMP therapy followed by autologous peripheral blood stem cell support in unresectable osteosarcoma. Nuklearmedizin 40 (6): 215-20, 2001. [<a href="https://pubmed.ncbi.nlm.nih.gov/11797510" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11797510</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_44_32">Sauerbrey A, Bielack S, Kempf-Bielack B, et al.: High-dose chemotherapy (HDC) and autologous hematopoietic stem cell transplantation (ASCT) as salvage therapy for relapsed osteosarcoma. Bone Marrow Transplant 27 (9): 933-7, 2001. [<a href="https://pubmed.ncbi.nlm.nih.gov/11436103" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11436103</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_44_33">Fagioli F, Aglietta M, Tienghi A, et al.: High-dose chemotherapy in the treatment of relapsed osteosarcoma: an Italian sarcoma group study. J Clin Oncol 20 (8): 2150-6, 2002. [<a href="https://pubmed.ncbi.nlm.nih.gov/11956277" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11956277</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_44_34">Loeb DM, Garrett-Mayer E, Hobbs RF, et al.: Dose-finding study of 153Sm-EDTMP in patients with poor-prognosis osteosarcoma. Cancer 115 (11): 2514-22, 2009. [<a href="/pmc/articles/PMC2974628/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2974628</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19338063" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19338063</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_44_35">Chen EL, Yoo CH, Gutkin PM, et al.: Outcomes for pediatric patients with osteosarcoma treated with palliative radiotherapy. Pediatr Blood Cancer 67 (1): e27967, 2020. [<a href="https://pubmed.ncbi.nlm.nih.gov/31407520" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 31407520</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_44_36">Weeden S, Grimer RJ, Cannon SR, et al.: The effect of local recurrence on survival in resected osteosarcoma. Eur J Cancer 37 (1): 39-46, 2001. [<a href="https://pubmed.ncbi.nlm.nih.gov/11165128" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11165128</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_44_37">Bacci G, Ferrari S, Lari S, et al.: Osteosarcoma of the limb. Amputation or limb salvage in patients treated by neoadjuvant chemotherapy. J Bone Joint Surg Br 84 (1): 88-92, 2002. [<a href="https://pubmed.ncbi.nlm.nih.gov/11837839" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11837839</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_44_38">Rodriguez-Galindo C, Shah N, McCarville MB, et al.: Outcome after local recurrence of osteosarcoma: the St. Jude Children's Research Hospital experience (1970-2000). Cancer 100 (9): 1928-35, 2004. [<a href="https://pubmed.ncbi.nlm.nih.gov/15112274" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15112274</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_44_39">Bacci G, Longhi A, Cesari M, et al.: Influence of local recurrence on survival in patients with extremity osteosarcoma treated with neoadjuvant chemotherapy: the experience of a single institution with 44 patients. Cancer 106 (12): 2701-6, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16691623" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16691623</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_44_40">Grimer RJ, Sommerville S, Warnock D, et al.: Management and outcome after local recurrence of osteosarcoma. Eur J Cancer 41 (4): 578-83, 2005. [<a href="https://pubmed.ncbi.nlm.nih.gov/15737563" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15737563</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_44_41">Bacci G, Forni C, Longhi A, et al.: Local recurrence and local control of non-metastatic osteosarcoma of the extremities: a 27-year experience in a single institution. J Surg Oncol 96 (2): 118-23, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17577221" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17577221</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_44_42">Nathan SS, Gorlick R, Bukata S, et al.: Treatment algorithm for locally recurrent osteosarcoma based on local disease-free interval and the presence of lung metastasis. Cancer 107 (7): 1607-16, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16933325" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16933325</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_44_43">Palmerini E, Torricelli E, Cascinu S, et al.: Is there a role for chemotherapy after local relapse in high-grade osteosarcoma? Pediatr Blood Cancer 66 (8): e27792, 2019. [<a href="https://pubmed.ncbi.nlm.nih.gov/31058424" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 31058424</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_44_44">Briccoli A, Rocca M, Salone M, et al.: Resection of recurrent pulmonary metastases in patients with osteosarcoma. Cancer 104 (8): 1721-5, 2005. [<a href="https://pubmed.ncbi.nlm.nih.gov/16155943" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16155943</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_44_45">Tabone MD, Kalifa C, Rodary C, et al.: Osteosarcoma recurrences in pediatric patients previously treated with intensive chemotherapy. J Clin Oncol 12 (12): 2614-20, 1994. [<a href="https://pubmed.ncbi.nlm.nih.gov/7989936" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7989936</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_44_46">Briccoli A, Rocca M, Salone M, et al.: High grade osteosarcoma of the extremities metastatic to the lung: long-term results in 323 patients treated combining surgery and chemotherapy, 1985-2005. Surg Oncol 19 (4): 193-9, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/19515554" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19515554</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_44_47">Su WT, Chewning J, Abramson S, et al.: Surgical management and outcome of osteosarcoma patients with unilateral pulmonary metastases. J Pediatr Surg 39 (3): 418-23; discussion 418-23, 2004. [<a href="https://pubmed.ncbi.nlm.nih.gov/15017563" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15017563</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_44_48">Letourneau PA, Xiao L, Harting MT, et al.: Location of pulmonary metastasis in pediatric osteosarcoma is predictive of outcome. J Pediatr Surg 46 (7): 1333-7, 2011. [<a href="/pmc/articles/PMC3768269/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3768269</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21763830" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21763830</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_44_49">Daw NC, Chou AJ, Jaffe N, et al.: Recurrent osteosarcoma with a single pulmonary metastasis: a multi-institutional review. Br J Cancer 112 (2): 278-82, 2015. [<a href="/pmc/articles/PMC4453448/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4453448</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25422914" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25422914</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_44_50">Karplus G, McCarville MB, Smeltzer MP, et al.: Should contralateral exploratory thoracotomy be advocated for children with osteosarcoma and early unilateral pulmonary metastases? J Pediatr Surg 44 (4): 665-71, 2009. [<a href="/pmc/articles/PMC3646508/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3646508</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19361624" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19361624</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_44_51">Heaton TE, Hammond WJ, Farber BA, et al.: A 20-year retrospective analysis of CT-based pre-operative identification of pulmonary metastases in patients with osteosarcoma: A single-center review. J Pediatr Surg 52 (1): 115-119, 2017. [<a href="/pmc/articles/PMC5384104/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5384104</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/27836366" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27836366</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_44_52">Bacci G, Longhi A, Bertoni F, et al.: Bone metastases in osteosarcoma patients treated with neoadjuvant or adjuvant chemotherapy: the Rizzoli experience in 52 patients. Acta Orthop 77 (6): 938-43, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/17260205" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17260205</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_44_53">Aung L, Gorlick R, Healey JH, et al.: Metachronous skeletal osteosarcoma in patients treated with adjuvant and neoadjuvant chemotherapy for nonmetastatic osteosarcoma. J Clin Oncol 21 (2): 342-8, 2003. [<a href="https://pubmed.ncbi.nlm.nih.gov/12525528" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12525528</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_44_54">Jaffe N, Pearson P, Yasko AW, et al.: Single and multiple metachronous osteosarcoma tumors after therapy. Cancer 98 (11): 2457-66, 2003. [<a href="https://pubmed.ncbi.nlm.nih.gov/14635081" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14635081</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_44_55">Franke M, Hardes J, Helmke K, et al.: Solitary skeletal osteosarcoma recurrence. Findings from the Cooperative Osteosarcoma Study Group. Pediatr Blood Cancer 56 (5): 771-6, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/21370409" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21370409</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_44_56">Bielack SS, Kempf-Bielack B, Branscheid D, et al.: Second and subsequent recurrences of osteosarcoma: presentation, treatment, and outcomes of 249 consecutive cooperative osteosarcoma study group patients. J Clin Oncol 27 (4): 557-65, 2009. [<a href="https://pubmed.ncbi.nlm.nih.gov/19075282" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19075282</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062698_rl_44_57">Martin-Broto J, Redondo A, Valverde C, et al.: Gemcitabine plus sirolimus for relapsed and progressing osteosarcoma patients after standard chemotherapy: a multicenter, single-arm phase II trial of Spanish Group for Research on Sarcoma (GEIS). Ann Oncol 28 (12): 2994-2999, 2017. [<a href="https://pubmed.ncbi.nlm.nih.gov/29045512" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 29045512</span></a>]</div></li></ol></div></div><div id="CDR0000062698__65"><h2 id="_CDR0000062698__65_">Changes to This Summary (03/03/2022)</h2><p id="CDR0000062698__70">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="CDR0000062698__2393">Editorial changes were made to this summary.</p><p id="CDR0000062698__disclaimerHP_3">This summary is written and maintained by the <a href="https://www.cancer.gov/publications/pdq/editorial-boards/pediatric-treatment" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PDQ Pediatric Treatment Editorial Board</a>, which is
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editorially independent of NCI. The summary reflects an independent review of
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the literature and does not represent a policy statement of NCI or NIH. More
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information about summary policies and the role of the PDQ Editorial Boards in
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maintaining the PDQ summaries can be found on the <a href="#CDR0000062698__AboutThis_1">About This PDQ Summary</a> and <a href="https://www.cancer.gov/publications/pdq" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PDQ® - NCI's Comprehensive Cancer Database</a> pages.
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</p></div><div id="CDR0000062698__AboutThis_1"><h2 id="_CDR0000062698__AboutThis_1_">About This PDQ Summary</h2><div id="CDR0000062698__AboutThis_2"><h3>Purpose of This Summary</h3><p id="CDR0000062698__AboutThis_3">This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of osteosarcoma and undifferentiated pleomorphic sarcoma of bone. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.</p></div><div id="CDR0000062698__AboutThis_4"><h3>Reviewers and Updates</h3><p id="CDR0000062698__AboutThis_5">This summary is reviewed regularly and updated as necessary by the <a href="https://www.cancer.gov/publications/pdq/editorial-boards/pediatric-treatment" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PDQ Pediatric Treatment Editorial Board</a>, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).</p><p id="CDR0000062698__AboutThis_22"> Board members review recently published articles each month to determine whether an article should:</p><ul id="CDR0000062698__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="CDR0000062698__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 Osteosarcoma and Undifferentiated Pleomorphic Sarcoma of Bone Treatment are:</p><ul><li class="half_rhythm"><div>Holcombe Edwin Grier, MD</div></li><li class="half_rhythm"><div>Karen J. Marcus, MD, FACR (Dana-Farber Cancer Institute/Boston Children's Hospital)</div></li><li class="half_rhythm"><div>William H. Meyer, MD (University of Oklahoma Health Sciences Center)</div></li><li class="half_rhythm"><div>Paul A. Meyers, MD (Memorial Sloan-Kettering Cancer Center)</div></li><li class="half_rhythm"><div>Thomas A. Olson, MD (Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta - Egleston Campus)</div></li><li class="half_rhythm"><div>Nita Louise Seibel, MD (National Cancer Institute)</div></li></ul><p id="CDR0000062698__AboutThis_9">Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's <a href="https://www.cancer.gov/contact/email-us" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Email Us</a>. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.</p></div><div id="CDR0000062698__AboutThis_10"><h3>Levels of Evidence</h3><p id="CDR0000062698__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="CDR0000062698__AboutThis_12"><h3>Permission to Use This Summary</h3><p id="CDR0000062698__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="CDR0000062698__AboutThis_14">The preferred citation for this PDQ summary is:</p><p id="CDR0000062698__AboutThis_15">PDQ® Pediatric Treatment Editorial Board. PDQ Osteosarcoma and Undifferentiated Pleomorphic Sarcoma of Bone Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: <a href="https://www.cancer.gov/types/bone/hp/osteosarcoma-treatment-pdq" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">https://www.cancer.gov/types/bone/hp/osteosarcoma-treatment-pdq</a>. Accessed <MM/DD/YYYY>. [PMID: 26389179]</p><p id="CDR0000062698__AboutThis_16">Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in <a href="https://visualsonline.cancer.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Visuals Online</a>, a collection of over 2,000 scientific images.
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</p></div><div id="CDR0000062698__AboutThis_17"><h3>Disclaimer</h3><p id="CDR0000062698__AboutThis_18">Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the <a href="https://www.cancer.gov/about-cancer/managing-care" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Managing Cancer Care</a> page.</p></div><div id="CDR0000062698__AboutThis_20"><h3>Contact Us</h3><p id="CDR0000062698__AboutThis_21">More information about contacting us or receiving help with the Cancer.gov website can be found on our <a href="https://www.cancer.gov/contact" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Contact Us for Help</a> page. Questions can also be submitted to Cancer.gov through the website’s <a href="https://www.cancer.gov/contact/email-us" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Email Us</a>.</p></div></div></div></div>
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<div class="post-content"><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright Notice</a></div><div class="small"><span class="label">Bookshelf ID: NBK65736</span><span class="label">PMID: <a href="https://pubmed.ncbi.nlm.nih.gov/26389179" title="PubMed record of this page" ref="pagearea=meta&targetsite=entrez&targetcat=link&targettype=pubmed">26389179</a></span></div></div></div>
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2015</li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>In this Page</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="page-toc" 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="#CDR0000062698__1" ref="log$=inpage&link_id=inpage">General Information About Osteosarcoma and Undifferentiated Pleomorphic Sarcoma (UPS) (Formerly Called Malignant Fibrous Histiocytoma [MFH]) of Bone</a></li><li><a href="#CDR0000062698__1974" ref="log$=inpage&link_id=inpage">Genomics of Osteosarcoma</a></li><li><a href="#CDR0000062698__8" ref="log$=inpage&link_id=inpage">Cellular Classification of Osteosarcoma and UPS of Bone</a></li><li><a href="#CDR0000062698__21" ref="log$=inpage&link_id=inpage">Staging and Site Information for Osteosarcoma and UPS of Bone</a></li><li><a href="#CDR0000062698__26" ref="log$=inpage&link_id=inpage">Treatment Option Overview for Osteosarcoma and UPS of Bone</a></li><li><a href="#CDR0000062698__532" ref="log$=inpage&link_id=inpage">Special Considerations for the Treatment of Children With Cancer</a></li><li><a href="#CDR0000062698__29" ref="log$=inpage&link_id=inpage">Treatment of Localized Osteosarcoma and UPS of Bone</a></li><li><a href="#CDR0000062698__38" ref="log$=inpage&link_id=inpage">Treatment of Osteosarcoma and UPS of Bone With Metastatic Disease at Diagnosis</a></li><li><a href="#CDR0000062698__44" ref="log$=inpage&link_id=inpage">Treatment of Recurrent Osteosarcoma and UPS of Bone</a></li><li><a href="#CDR0000062698__65" ref="log$=inpage&link_id=inpage">Changes to This Summary (03/03/2022)</a></li><li><a href="#CDR0000062698__AboutThis_1" ref="log$=inpage&link_id=inpage">About This PDQ Summary</a></li></ul></div></div><div class="portlet"><div 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