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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="#__NBK65802_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK65802_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="_NBK65802_"><span class="title" itemprop="name">Childhood Rhabdomyosarcoma 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: August 5, 2015.</p></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="_abs_rndgid_" itemprop="description"><p id="CDR0000062792__761">This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood rhabdomyosarcoma. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.</p><p id="CDR0000062792__762">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="CDR0000062792__1"><h2 id="_CDR0000062792__1_">General Information</h2><p id="CDR0000062792__3">Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975.[<a class="bk_pop" href="#CDR0000062792_rl_1_1">1</a>] Children and adolescents with
|
|
cancer should be referred to medical centers that have a multidisciplinary team
|
|
of cancer specialists with experience treating the cancers that occur during
|
|
childhood and adolescence. This multidisciplinary team approach incorporates the skills
|
|
of the primary care physician, pediatric surgeon, radiation
|
|
oncologist, pediatric oncologist/hematologist, rehabilitation specialists,
|
|
pediatric nurse specialists, social workers, and others to ensure that
|
|
children receive treatment, supportive care, and rehabilitation that will
|
|
achieve optimal survival and quality of life. (Refer to the PDQ summary on <a href="/books/n/pdqcis/CDR0000595857/">Pediatric Supportive Care</a> for specific information about supportive care for children and adolescents with cancer.)</p><p id="CDR0000062792__156">Guidelines for pediatric cancer
|
|
centers and their role in the treatment of pediatric patients with cancer have
|
|
been outlined by the American Academy of Pediatrics.[<a class="bk_pop" href="#CDR0000062792_rl_1_2">2</a>] At these pediatric
|
|
cancer centers, clinical trials are available for most types of cancer
|
|
that occur in children and adolescents, and the opportunity to participate in
|
|
these trials is offered to most patients/families. Clinical trials for
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|
children and adolescents with cancer are generally designed to compare
|
|
potentially better therapy with therapy that is currently accepted as standard.
|
|
Most of the progress made in identifying curative therapies for
|
|
childhood cancers has been achieved through clinical trials. Information about
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ongoing clinical trials is available from the <a href="http://www.cancer.gov/about-cancer/treatment/clinical-trials" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCI website</a>.</p><p id="CDR0000062792__170">Dramatic improvements in survival have been achieved for children and adolescents with cancer.[<a class="bk_pop" href="#CDR0000062792_rl_1_1">1</a>] Between 1975 and 2010, childhood cancer mortality decreased by more than 50%.[<a class="bk_pop" href="#CDR0000062792_rl_1_1">1</a>] For rhabdomyosarcoma, the 5-year survival rate increased over the same time, from 53% to 67% for children younger than 15 years and from 30% to 51% for adolescents aged 15 to 19 years.[<a class="bk_pop" href="#CDR0000062792_rl_1_1">1</a>] Childhood and adolescent cancer survivors require close follow-up because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on <a href="/books/n/pdqcis/CDR0000343584/">Late Effects of Treatment for Childhood Cancer</a> for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)</p><div id="CDR0000062792__583"><h3>Incidence and Epidemiology</h3><p id="CDR0000062792__584">Childhood rhabdomyosarcoma, a soft tissue malignant tumor of mesenchymal
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origin, accounts for approximately 3.5% of the cases of cancer among children aged 0
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to 14 years and 2% of the cases among adolescents and young adults aged 15 to 19
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years.[<a class="bk_pop" href="#CDR0000062792_rl_1_3">3</a>,<a class="bk_pop" href="#CDR0000062792_rl_1_4">4</a>] The incidence is 4.5 per 1 million children and 50% of cases are seen in the first decade of life.[<a class="bk_pop" href="#CDR0000062792_rl_1_5">5</a>] </p><p id="CDR0000062792__613">Incidence may depend on the histologic subtype of rhabdomyosarcoma:</p><ul id="CDR0000062792__614"><li class="half_rhythm"><div><i>Embryonal: </i>Patients with embryonal rhabdomyosarcoma are predominantly male (M:F = 1.5) and peaks in the 0 to 4 year age group at approximately 4 cases per 1 million children, with a lower rate in adolescents, approximately 1.5 cases per 1 million adolescents.[<a class="bk_pop" href="#CDR0000062792_rl_1_5">5</a>] </div></li><li class="half_rhythm"><div><i>Alveolar: </i>The incidence of alveolar rhabdomyosarcoma does not vary by gender and is constant from ages 0 to 19 years at approximately 1 case per 1 million children and adolescents.[<a class="bk_pop" href="#CDR0000062792_rl_1_5">5</a>]</div></li><li class="half_rhythm"><div><i>Undifferentiated sarcoma: </i>Infants younger than 1 year have a higher incidence of undifferentiated sarcoma and tumors of the trunk and abdomen and a lower incidence of parameningeal tumors than do older patients.[<a class="bk_pop" href="#CDR0000062792_rl_1_6">6</a>]</div></li></ul><p id="CDR0000062792__608">The most common primary sites for rhabdomyosarcoma are the
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head, the genitourinary
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tract, and the extremities.[<a class="bk_pop" href="#CDR0000062792_rl_1_7">7</a>,<a class="bk_pop" href="#CDR0000062792_rl_1_8">8</a>] Within extremity tumors, tumors of the hand and foot occur more often in older patients and have an alveolar histology; these tumors also have a higher rate of metastatic spread.[<a class="bk_pop" href="#CDR0000062792_rl_1_9">9</a>] Other less common primary sites include the
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trunk, chest wall, perineal/anal region, and abdomen including the retroperitoneum and
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biliary tract.</p><p id="CDR0000062792__585">Most cases of rhabdomyosarcoma occur sporadically, with no
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recognized predisposing factor or risk factor.[<a class="bk_pop" href="#CDR0000062792_rl_1_10">10</a>] For patients with embryonal tumors, high birth weight and large size for gestational age are associated with an increased incidence of rhabdomyosarcoma.[<a class="bk_pop" href="#CDR0000062792_rl_1_11">11</a>] Genetic conditions associated with rhabdomyosarcoma include Li-Fraumeni
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cancer susceptibility syndrome (with germline <i>p53</i> mutations),[<a class="bk_pop" href="#CDR0000062792_rl_1_12">12</a>-<a class="bk_pop" href="#CDR0000062792_rl_1_14">14</a>] pleuropulmonary blastoma (with <i>DICER1</i> mutations),[<a class="bk_pop" href="#CDR0000062792_rl_1_15">15</a>,<a class="bk_pop" href="#CDR0000062792_rl_1_16">16</a>]
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neurofibromatosis type I,[<a class="bk_pop" href="#CDR0000062792_rl_1_17">17</a>,<a class="bk_pop" href="#CDR0000062792_rl_1_18">18</a>] Costello syndrome (with germline <i>HRAS</i> mutations),[<a class="bk_pop" href="#CDR0000062792_rl_1_19">19</a>-<a class="bk_pop" href="#CDR0000062792_rl_1_22">22</a>] Beckwith-Wiedemann syndrome (with which Wilms
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tumor and hepatoblastoma are more commonly associated),[<a class="bk_pop" href="#CDR0000062792_rl_1_23">23</a>,<a class="bk_pop" href="#CDR0000062792_rl_1_24">24</a>] and Noonan syndrome.[<a class="bk_pop" href="#CDR0000062792_rl_1_22">22</a>,<a class="bk_pop" href="#CDR0000062792_rl_1_25">25</a>,<a class="bk_pop" href="#CDR0000062792_rl_1_26">26</a>]</p></div><div id="CDR0000062792__586"><h3>Prognostic Factors</h3><p id="CDR0000062792__587">The prognosis for a child or adolescent with rhabdomyosarcoma is related to the
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age of the patient, site of origin, tumor size (widest diameter), resectability, presence of metastases, number of metastatic sites or tissues involved, presence or absence of regional lymph node involvement, histopathologic subtype (alveolar vs. embryonal), and delivery of radiation therapy in selected cases,[<a class="bk_pop" href="#CDR0000062792_rl_1_7">7</a>,<a class="bk_pop" href="#CDR0000062792_rl_1_8">8</a>,<a class="bk_pop" href="#CDR0000062792_rl_1_27">27</a>-<a class="bk_pop" href="#CDR0000062792_rl_1_33">33</a>]; [<a class="bk_pop" href="#CDR0000062792_rl_1_34">34</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335150/" class="def">Level of evidence: 3iiiA</a>] as well as unique biological characteristics of rhabdomyosarcoma tumor cells.[<a class="bk_pop" href="#CDR0000062792_rl_1_35">35</a>] It is unclear whether response to induction chemotherapy, as judged by anatomic imaging, correlates with the likelihood of survival in patients with rhabdomyosarcoma, because the Intergroup
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Rhabdomyosarcoma Study Group (IRSG) and Children's Oncology Group studies found no association.[<a class="bk_pop" href="#CDR0000062792_rl_1_36">36</a>]; [<a class="bk_pop" href="#CDR0000062792_rl_1_37">37</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335147/" class="def">Level of evidence: 3iiDi</a>] However, an Italian study found that patient response did correlate with likelihood of survival.[<a class="bk_pop" href="#CDR0000062792_rl_1_38">38</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335144/" class="def">Level of evidence: 3iiA</a>] </p><p id="CDR0000062792__615">Rhabdomyosarcoma is usually curable in most children with localized disease who
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receive combined-modality therapy, with more than 70% surviving 5 years after
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diagnosis.[<a class="bk_pop" href="#CDR0000062792_rl_1_7">7</a>,<a class="bk_pop" href="#CDR0000062792_rl_1_8">8</a>,<a class="bk_pop" href="#CDR0000062792_rl_1_39">39</a>] Relapses are uncommon after 5 years of disease-free survival, with a 9% late-event rate at 10 years. Relapses, however, are more common in patients who have gross residual disease in unfavorable sites after initial surgery and in those who have metastatic disease at diagnosis.[<a class="bk_pop" href="#CDR0000062792_rl_1_40">40</a>]</p><p id="CDR0000062792__605">Examples of both
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clinical and biological factors with proven or possible prognostic significance
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include the following:
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</p><ul id="CDR0000062792__588"><li class="half_rhythm"><div class="half_rhythm"><b>Age:</b> Children aged 1 to 9 years have the best prognosis, while those younger and older fare less well. In recent IRSG trials, 5-year failure-free survival (FFS) was 57% for patients younger than 1 year, 81% for patients aged 1 to 9 years, and 68% for patients older than 10 years. Five-year survival for these groups was 76%, 87%, and 76%, respectively.[<a class="bk_pop" href="#CDR0000062792_rl_1_6">6</a>] Historical data show that adults fare worse than children (5-year overall survival [OS] rates, 27% ± 1.4% and 61% ± 1.4%, respectively; <i>P</i> < .0001).[<a class="bk_pop" href="#CDR0000062792_rl_1_41">41</a>-<a class="bk_pop" href="#CDR0000062792_rl_1_44">44</a>]<dl id="CDR0000062792__609" class="temp-labeled-list"><dt>-</dt><dd><p class="no_top_margin"><i>Infants</i> may do poorly because their bone marrow is less tolerant of chemotherapy doses that older children can receive; thus, infants are relatively underdosed compared with older patients. In addition, infants younger than 1 year may be less likely to receive radiation therapy for local control, because of concern about the high incidence of complications in this age group. [<a class="bk_pop" href="#CDR0000062792_rl_1_28">28</a>,<a class="bk_pop" href="#CDR0000062792_rl_1_39">39</a>,<a class="bk_pop" href="#CDR0000062792_rl_1_45">45</a>] Thus, they have a relatively high rate of local failure. </p></dd><dt>-</dt><dd><p class="no_top_margin">In <i>older children</i>, vincristine and dactinomycin have upper dosage limits based on body surface area, and these patients may also require reduced vincristine doses because of neurotoxicity.[<a class="bk_pop" href="#CDR0000062792_rl_1_28">28</a>,<a class="bk_pop" href="#CDR0000062792_rl_1_46">46</a>]</p></dd><dt>-</dt><dd><p class="no_top_margin"><i>Adolescents:</i> A report from the AIEOP (Italian) Soft Tissue Sarcoma Committee suggests that adolescents may have more frequent unfavorable tumor characteristics, including alveolar histology, regional lymph node involvement, and metastatic disease involvement, accounting for their poor prognosis. This study also found that 5-year OS and progression-free survival (PFS) rates were somewhat lower in adolescents than in children, but the differences among age groups younger than 1 year and aged 10 to 19 years at diagnosis were significantly worse than those in the group aged 1 to 9 years.[<a class="bk_pop" href="#CDR0000062792_rl_1_47">47</a>]</p></dd></dl></div></li><li class="half_rhythm"><div class="half_rhythm"><b>Site of origin:</b> Primary sites with more favorable prognoses include the following:[<a class="bk_pop" href="#CDR0000062792_rl_1_7">7</a>,<a class="bk_pop" href="#CDR0000062792_rl_1_8">8</a>,<a class="bk_pop" href="#CDR0000062792_rl_1_48">48</a>,<a class="bk_pop" href="#CDR0000062792_rl_1_49">49</a>] <dl id="CDR0000062792__610" class="temp-labeled-list"><dt>-</dt><dd><p class="no_top_margin">Orbit and nonparameningeal head and neck.</p></dd><dt>-</dt><dd><p class="no_top_margin">Paratestis, vulva, vagina, uterus (nonbladder, nonprostate genitourinary tract).</p></dd><dt>-</dt><dd><p class="no_top_margin">Biliary tract.</p></dd></dl></div></li><li class="half_rhythm"><div class="half_rhythm"><b>Diameter of the tumor:</b> Patients with
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smaller tumors (≤5 cm) have improved survival compared with children with
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larger tumors.[<a class="bk_pop" href="#CDR0000062792_rl_1_7">7</a>] Both tumor volume and maximum tumor diameter are associated with outcome.[<a class="bk_pop" href="#CDR0000062792_rl_1_38">38</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335144/" class="def">Level of evidence: 3iiA</a>] </div><div class="half_rhythm">A retrospective review of soft tissue sarcomas in children and adolescents suggests that the 5 cm cutoff used for adults with soft tissue sarcoma may not be ideal for smaller children, especially infants. The review identified an interaction between tumor diameter and body surface area (BSA).[<a class="bk_pop" href="#CDR0000062792_rl_1_50">50</a>] This was not confirmed by a Children's Oncology Group study of patients with intermediate-risk rhabdomyosarcoma.[<a class="bk_pop" href="#CDR0000062792_rl_1_51">51</a>] This relationship requires prospective study to determine the therapeutic implications of the observation. </div></li><li class="half_rhythm"><div class="half_rhythm"><b>Metastases and regional lymph node involvement: </b>Children with metastatic disease at diagnosis have the
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worst prognosis. The prognostic significance of metastatic disease
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is modified by tumor histology (embryonal is more favorable than alveolar), the site of metastatic disease, and the number of metastatic sites.[<a class="bk_pop" href="#CDR0000062792_rl_1_29">29</a>,<a class="bk_pop" href="#CDR0000062792_rl_1_52">52</a>,<a class="bk_pop" href="#CDR0000062792_rl_1_53">53</a>]
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Patients with metastatic genitourinary (nonbladder, nonprostate)
|
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primary tumors have a more favorable outcome than do patients with
|
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metastatic disease from primary tumors at other sites.[<a class="bk_pop" href="#CDR0000062792_rl_1_54">54</a>]
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</div><div class="half_rhythm">Patients with otherwise localized disease but with proven regional lymph node
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involvement have a worse prognosis than do patients without regional nodal
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involvement.[<a class="bk_pop" href="#CDR0000062792_rl_1_32">32</a>,<a class="bk_pop" href="#CDR0000062792_rl_1_33">33</a>]</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Resectability: </b>The extent of disease after the primary surgical procedure (i.e., the Surgical-pathologic Group, formerly called the Clinical Group) is also correlated with outcome.[<a class="bk_pop" href="#CDR0000062792_rl_1_7">7</a>] In the IRS-III study, patients with localized, gross residual disease after
|
|
initial surgery (Surgical-pathologic Group III) had a 5-year survival rate of
|
|
approximately 70%, compared with a more than 90% 5-year survival rate for
|
|
patients without residual tumor after surgery (Group I) and an
|
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approximately 80% 5-year survival rate for patients with microscopic residual
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|
tumor after surgery (Group II).[<a class="bk_pop" href="#CDR0000062792_rl_1_7">7</a>,<a class="bk_pop" href="#CDR0000062792_rl_1_27">27</a>] Regardless, outcome is primarily related to the use of multimodality therapy; all patients require chemotherapy and at least 85% also benefit from radiation therapy, with favorable outcome even for those patients with nonresectable disease. In IRS-IV, the Group III patients with unresectable disease who were treated with chemotherapy and radiation therapy had a 5-year FFS of about 75%.[<a class="bk_pop" href="#CDR0000062792_rl_1_55">55</a>]</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Histopathologic subtype: </b>The alveolar subtype is more prevalent among patients with less favorable
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|
clinical features (e.g., younger than 1 year or older than 10 years,
|
|
extremity primary tumors, and metastatic disease at diagnosis), and is generally associated with
|
|
a worse outcome than in similar patients with embryonal rhabdomyosarcoma. In the IRS-I and IRS-II studies, the alveolar subtype was
|
|
associated with a less favorable outcome even in patients whose primary
|
|
tumor was completely resected (Group I).[<a class="bk_pop" href="#CDR0000062792_rl_1_48">48</a>] A statistically significant
|
|
difference in 5-year survival by histopathologic subtype (82% for embryonal rhabdomyosarcoma vs. 65% for alveolar rhabdomyosarcoma), was not noted
|
|
when 1,258 IRS-III and IRS-IV patients with rhabdomyosarcoma were analyzed.[<a class="bk_pop" href="#CDR0000062792_rl_1_56">56</a>] In the IRS-III study, outcome for patients with Group I alveolar subtype tumors was similar to that for other patients with
|
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Group I tumors, but the alveolar patients received more
|
|
intensive therapy.[<a class="bk_pop" href="#CDR0000062792_rl_1_7">7</a>] </div><div class="half_rhythm">Patients with alveolar rhabdomyosarcoma who have regional lymph node involvement have significantly worse outcomes (5-year FFS, 43%) than patients who do not have regional lymph node involvement (5-year FFS, 73%).[<a class="bk_pop" href="#CDR0000062792_rl_1_57">57</a>]</div><div class="half_rhythm">Anaplasia has been observed in 13% of cases of rhabdomyosarcoma and its presence may adversely influence clinical outcome in patients with intermediate-risk embryonal rhabdomyosarcoma. However, anaplasia was not shown to be an independent prognostic variable in a multivariate analysis (<i>P</i> = .081).[<a class="bk_pop" href="#CDR0000062792_rl_1_58">58</a>]</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Biological characteristics:</b> Refer to the <a href="#CDR0000062792__232">Molecular Classification</a> section of this summary for more information.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Response to therapy:</b> A retrospective analysis of 107 patients from a single institution examined positron emission tomography (PET) scans performed at baseline, after induction chemotherapy, and after local therapy.[<a class="bk_pop" href="#CDR0000062792_rl_1_59">59</a>,<a class="bk_pop" href="#CDR0000062792_rl_1_60">60</a>] Standardized uptake value measured at baseline predicted PFS and OS, but not local control. A negative scan after induction chemotherapy correlated with statistically significantly better PFS. A positive scan after local therapy predicted worse PFS, OS, and local control.</div></li></ul><p id="CDR0000062792__619">Adult patients with rhabdomyosarcoma have a high incidence of pleomorphic histology (19%). Pleomorphic histology is extremely rare in children and young adults with rhabdomyosarcoma. Adults also have a higher incidence of tumors in unfavorable sites than do children.[<a class="bk_pop" href="#CDR0000062792_rl_1_41">41</a>]</p><p id="CDR0000062792__590">Because treatment and prognosis depend, in part, on the histology and molecular genetics of the tumor,
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it is necessary that the tumor tissue be reviewed by pathologists and cytogeneticists/molecular geneticists with
|
|
experience in the evaluation and diagnosis of tumors in children.
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|
Additionally, the diversity of primary sites, the distinctive surgical and
|
|
radiation therapy treatments for each primary site, and the subsequent
|
|
site-specific rehabilitation underscore the importance of treating children
|
|
with rhabdomyosarcoma in medical centers with appropriate experience in all
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therapeutic modalities.
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</p></div><div id="CDR0000062792_rl_1"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000062792_rl_1_1">Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014. [<a href="/pmc/articles/PMC4136455/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4136455</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24853691" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24853691</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_1_2">Corrigan JJ, Feig SA; American Academy of Pediatrics: Guidelines for pediatric cancer centers. Pediatrics 113 (6): 1833-5, 2004. [<a href="https://pubmed.ncbi.nlm.nih.gov/15173520" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15173520</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_1_3">Gurney JG, Severson RK, Davis S, et al.: Incidence of cancer in children in the United States. Sex-, race-, and 1-year age-specific rates by histologic type. Cancer 75 (8): 2186-95, 1995. [<a href="https://pubmed.ncbi.nlm.nih.gov/7697611" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7697611</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_1_4">Ries LA, Kosary CL, Hankey BF, et al., eds.: SEER Cancer Statistics Review, 1973-1996. Bethesda, Md: National Cancer Institute, 1999. <a href="http://seer.cancer.gov/csr/1973_1996/" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">Also available online</a>. Last accessed August 05, 2015.</div></li><li><div class="bk_ref" id="CDR0000062792_rl_1_5">Ognjanovic S, Linabery AM, Charbonneau B, et al.: Trends in childhood rhabdomyosarcoma incidence and survival in the United States, 1975-2005. Cancer 115 (18): 4218-26, 2009. [<a href="/pmc/articles/PMC2953716/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2953716</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19536876" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19536876</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_1_6">Malempati S, Rodeberg DA, Donaldson SS, et al.: Rhabdomyosarcoma in infants younger than 1 year: a report from the Children's Oncology Group. Cancer 117 (15): 3493-501, 2011. [<a href="/pmc/articles/PMC3140625/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3140625</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21264837" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21264837</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_1_7">Crist W, Gehan EA, Ragab AH, et al.: The Third Intergroup Rhabdomyosarcoma Study. J Clin Oncol 13 (3): 610-30, 1995. [<a href="https://pubmed.ncbi.nlm.nih.gov/7884423" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7884423</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_1_8">Maurer HM, Gehan EA, Beltangady M, et al.: The Intergroup Rhabdomyosarcoma Study-II. Cancer 71 (5): 1904-22, 1993. 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NIH Pub.No. 99-4649, pp 111-123. <a href="http://seer.cancer.gov/archive/publications/childhood/childhood-monograph.pdf" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">Also available online.</a> Last accessed August 08, 2015.</div></li><li><div class="bk_ref" id="CDR0000062792_rl_1_11">Ognjanovic S, Carozza SE, Chow EJ, et al.: Birth characteristics and the risk of childhood rhabdomyosarcoma based on histological subtype. Br J Cancer 102 (1): 227-31, 2010. 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[<a href="/pmc/articles/PMC3083998/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3083998</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21357792" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21357792</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_1_58">Qualman S, Lynch J, Bridge J, et al.: Prevalence and clinical impact of anaplasia in childhood rhabdomyosarcoma : a report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group. Cancer 113 (11): 3242-7, 2008. [<a href="/pmc/articles/PMC2727712/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2727712</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18985676" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18985676</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_1_59">Dharmarajan KV, Wexler LH, Gavane S, et al.: Positron emission tomography (PET) evaluation after initial chemotherapy and radiation therapy predicts local control in rhabdomyosarcoma. Int J Radiat Oncol Biol Phys 84 (4): 996-1002, 2012. [<a href="https://pubmed.ncbi.nlm.nih.gov/22560547" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22560547</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_1_60">Casey DL, Wexler LH, Fox JJ, et al.: Predicting outcome in patients with rhabdomyosarcoma: role of [(18)f]fluorodeoxyglucose positron emission tomography. Int J Radiat Oncol Biol Phys 90 (5): 1136-42, 2014. [<a href="https://pubmed.ncbi.nlm.nih.gov/25539372" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25539372</span></a>]</div></li></ol></div></div><div id="CDR0000062792__13"><h2 id="_CDR0000062792__13_">Cellular Classification</h2><p id="CDR0000062792__14">Rhabdomyosarcoma can be divided into several histologic subsets: embryonal rhabdomyosarcoma, which has embryonal,
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botryoid, and spindle cell subtypes; alveolar rhabdomyosarcoma; and
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pleomorphic rhabdomyosarcoma.[<a class="bk_pop" href="#CDR0000062792_rl_13_1">1</a>,<a class="bk_pop" href="#CDR0000062792_rl_13_2">2</a>] </p><div id="CDR0000062792__224"><h3>Embryonal Rhabdomyosarcoma</h3><p id="CDR0000062792__225">The embryonal subtype is the most frequently observed
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subtype in children, accounting for approximately 60% to 70% of
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rhabdomyosarcomas of childhood.[<a class="bk_pop" href="#CDR0000062792_rl_13_1">1</a>] Tumors with embryonal histology typically
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arise in the head and neck region or in the genitourinary tract, although they
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may occur at any primary site. </p><div id="CDR0000062792__226"><h4>Botryoid and spindle cell subtypes</h4><p id="CDR0000062792__227">Botryoid tumors represent about 10% of all
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rhabdomyosarcoma cases and are embryonal tumors that arise under the mucosal
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surface of body orifices such as the vagina, bladder, nasopharynx, and biliary tract.
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The spindle cell variant of embryonal rhabdomyosarcoma is most frequently
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observed at the paratesticular site.[<a class="bk_pop" href="#CDR0000062792_rl_13_3">3</a>] Both the botryoid and the spindle cell
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subtypes are associated with very favorable outcomes.[<a class="bk_pop" href="#CDR0000062792_rl_13_2">2</a>]</p></div></div><div id="CDR0000062792__228"><h3>Alveolar Rhabdomyosarcoma</h3><p id="CDR0000062792__229">Approximately 20% of
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children with rhabdomyosarcoma have the alveolar subtype. An increased
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frequency of this subtype is noted in adolescents and in patients with primary
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sites involving the extremities, trunk, and perineum/perianal region.[<a class="bk_pop" href="#CDR0000062792_rl_13_1">1</a>]</p><p id="CDR0000062792__469">For current trials developed by the Soft Tissue Sarcoma Committee of the Children's Oncology Group, to be designated as alveolar, the tumor must have greater than 50% alveolar elements; if the alveolar component is 50% or less, the tumor is considered embryonal. In some earlier studies (the D series, 1997–2005), any alveolar focus was sufficient, but that criterion was later abandoned.</p></div><div id="CDR0000062792__230"><h3>Pleomorphic (Anaplastic) Rhabdomyosarcoma</h3><p id="CDR0000062792__231">Pleomorphic
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rhabdomyosarcoma occurs predominantly in adults aged 30 to 50 years and is
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rarely seen in children.[<a class="bk_pop" href="#CDR0000062792_rl_13_4">4</a>] In adults, pleomorphic rhabdomyosarcoma is associated with a worse prognosis. In children, the term <i>anaplasia</i> is preferred.[<a class="bk_pop" href="#CDR0000062792_rl_13_5">5</a>] In a retrospective review of 546 pediatric patients, the presence of anaplasia was only associated in univariate analysis with inferior clinical outcome in patients with intermediate-risk rhabdomyosarcoma.[<a class="bk_pop" href="#CDR0000062792_rl_13_6">6</a>] </p></div><div id="CDR0000062792__232"><h3>Molecular Classification</h3><p id="CDR0000062792__233">The embryonal and alveolar histologies have distinctive molecular
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characteristics that have been used for diagnostic confirmation, and may
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be useful for assigning therapy and monitoring residual disease during treatment.[<a class="bk_pop" href="#CDR0000062792_rl_13_7">7</a>-<a class="bk_pop" href="#CDR0000062792_rl_13_11">11</a>] </p><ul id="CDR0000062792__620"><li class="half_rhythm"><div class="half_rhythm"><i>Alveolar histology:</i> About 70% to 80% of alveolar tumors are characterized by translocations between
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the <i>FOXO1</i> gene on chromosome 13 and either the <i>PAX3</i> gene on chromosome 2 (t(2;13)(q35;q14)) or the
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<i>PAX7</i> gene on chromosome 1 (t(1;13)(p36;q14)).[<a class="bk_pop" href="#CDR0000062792_rl_13_7">7</a>,<a class="bk_pop" href="#CDR0000062792_rl_13_12">12</a>,<a class="bk_pop" href="#CDR0000062792_rl_13_13">13</a>] Other rare fusions include <i>PAX3-NCOA1</i> and <i>PAX3-INO80D</i>.[<a class="bk_pop" href="#CDR0000062792_rl_13_14">14</a>]
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Translocations involving the <i>PAX3</i> gene occur in approximately 59% of alveolar
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rhabdomyosarcoma cases, while the <i>PAX7</i> gene appears to be involved in about 19% of cases.[<a class="bk_pop" href="#CDR0000062792_rl_13_7">7</a>] Patients with solid-variant alveolar histology have a lower incidence of <i>PAX-FOXO1</i> gene fusions than do patients showing classical alveolar histology.[<a class="bk_pop" href="#CDR0000062792_rl_13_15">15</a>] A retrospective analysis examined the correlation between immunohistochemistry and molecular pathology for fusion genes that are used in the diagnosis of alveolar rhabdomyosarcoma.[<a class="bk_pop" href="#CDR0000062792_rl_13_16">16</a>] An algorithm that included four immunohistochemistry markers (myogenin, AP-2-beta, NOS-1, and HMGA2) had a 96% sensitivity of predicting fusion positivity, with a 91% to 92% specificity. The authors suggest that this could help characterize cases in which molecular pathology is unavailable.</div><div class="half_rhythm">Alveolar cases associated with the <i>PAX7</i> gene, with or without metastases, appear to occur in patients at a younger age, and may be associated with longer event-free survival (EFS) rates than those associated with <i>PAX3</i> gene rearrangements.[<a class="bk_pop" href="#CDR0000062792_rl_13_17">17</a>-<a class="bk_pop" href="#CDR0000062792_rl_13_22">22</a>] Alveolar cases associated with the <i>PAX3</i> gene are older and have a higher incidence of invasive tumor (T2). Around 22% of cases showing alveolar histology have no detectable <i>PAX</i> gene translocation.[<a class="bk_pop" href="#CDR0000062792_rl_13_11">11</a>,<a class="bk_pop" href="#CDR0000062792_rl_13_15">15</a>] In addition to <i>FOXO1</i> rearrangements, alveolar tumors are characterized by a lower mutational burden than are fusion-negative tumors, with fewer genes having recurring mutations.[<a class="bk_pop" href="#CDR0000062792_rl_13_14">14</a>,<a class="bk_pop" href="#CDR0000062792_rl_13_23">23</a>] <i>BCOR</i> and <i>PIK3CA</i> mutations and amplification of <i>MYCN</i>, <i>MIR17HG</i>, and <i>CDK4</i> have also been described. </div></li><li class="half_rhythm"><div class="half_rhythm"><i>Embryonal histology:</i> Embryonal tumors often show loss of heterozygosity at 11p15 and gains on chromosome 8.[<a class="bk_pop" href="#CDR0000062792_rl_13_13">13</a>,<a class="bk_pop" href="#CDR0000062792_rl_13_24">24</a>,<a class="bk_pop" href="#CDR0000062792_rl_13_25">25</a>] Embryonal tumors have a higher background mutation rate and higher single-nucleotide variant rate than do alveolar tumors, and the number of somatic mutations increases with older age at diagnosis.[<a class="bk_pop" href="#CDR0000062792_rl_13_14">14</a>,<a class="bk_pop" href="#CDR0000062792_rl_13_23">23</a>] Genes with recurring mutations include those in the RAS pathway (e.g., <i>NRAS</i>, <i>KRAS</i>, <i>HRAS</i>, and <i>NF1</i>), which together are observed in approximately one-third of cases. Other genes with recurring mutations include <i>FGFR4</i>, <i>PIK3CA</i>, <i>CTNNB1</i>, <i>FBXW7</i>, and <i>BCOR</i>, all of which are present in fewer than 10% of cases.[<a class="bk_pop" href="#CDR0000062792_rl_13_14">14</a>,<a class="bk_pop" href="#CDR0000062792_rl_13_23">23</a>]</div></li><li class="half_rhythm"><div class="half_rhythm"><i>Spindle cell/sclerosing histology: </i>Spindle cell/sclerosing rhabdomyosarcoma has been proposed as a separate entity in the WHO Classification of Tumours of Soft Tissue and Bone.[<a class="bk_pop" href="#CDR0000062792_rl_13_26">26</a>]
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For congenital/infantile spindle cell rhabdomyosarcoma, recurrent <i>NCOA2</i> gene rearrangements have been described.[<a class="bk_pop" href="#CDR0000062792_rl_13_27">27</a>] In older children and adults with spindle cell/sclerosing rhabdomyosarcoma, a specific <i>MYOD1</i> mutation (p.L122R) has been observed in a large proportion of patients.[<a class="bk_pop" href="#CDR0000062792_rl_13_28">28</a>-<a class="bk_pop" href="#CDR0000062792_rl_13_30">30</a>] The presence of the <i>MYOD1</i> mutation is associated with an increased risk of treatment failure.[<a class="bk_pop" href="#CDR0000062792_rl_13_28">28</a>,<a class="bk_pop" href="#CDR0000062792_rl_13_29">29</a>]</div></li></ul><p id="CDR0000062792__457">These findings highlight the important differences between embryonal and alveolar tumors. There are data that alveolar tumors carrying either a t(1;13) or a t(2;13) translocation (translocation-positive) are biologically and clinically different from alveolar tumors that do not have a translocation (translocation-negative) and from embryonal tumors.[<a class="bk_pop" href="#CDR0000062792_rl_13_11">11</a>,<a class="bk_pop" href="#CDR0000062792_rl_13_31">31</a>-<a class="bk_pop" href="#CDR0000062792_rl_13_34">34</a>] In a study of Intergroup
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Rhabdomyosarcoma Study Group (IRSG) cases, the outcome for patients with translocation-negative alveolar rhabdomyosarcoma was better than that observed for translocation-positive cases and was similar to that seen in patients with embryonal rhabdomyosarcoma, suggesting that fusion status is a critical factor for risk stratification in pediatric rhabdomyosarcoma.[<a class="bk_pop" href="#CDR0000062792_rl_13_32">32</a>] However, a German study of 121 patients with alveolar rhabdomyosarcoma found no significant difference in EFS at 5 years among patients who were <i>PAX-FOXO1</i>–positive compared with those who were translocation-negative.[<a class="bk_pop" href="#CDR0000062792_rl_13_35">35</a>] </p><p id="CDR0000062792__458">One study suggests that metagene expression analyses can classify patients with rhabdomyosarcoma into the three distinct risk groups and may be particularly helpful in identifying intermediate-risk patients with poor-risk features. Further studies are needed to confirm these findings.[<a class="bk_pop" href="#CDR0000062792_rl_13_31">31</a>] In another study, gene expression signature did not appear to add additional prognostic information beyond that available from the contribution of the <i>PAX3</i>/<i>FOX01</i> fusion status.[<a class="bk_pop" href="#CDR0000062792_rl_13_21">21</a>]</p></div><div id="CDR0000062792_rl_13"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000062792_rl_13_1">Parham DM, Ellison DA: Rhabdomyosarcomas in adults and children: an update. Arch Pathol Lab Med 130 (10): 1454-65, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/17090187" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17090187</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_13_2">Newton WA Jr, Gehan EA, Webber BL, et al.: Classification of rhabdomyosarcomas and related sarcomas. 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[<a href="https://pubmed.ncbi.nlm.nih.gov/9164192" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9164192</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_13_20">Barr FG, Qualman SJ, Macris MH, et al.: Genetic heterogeneity in the alveolar rhabdomyosarcoma subset without typical gene fusions. Cancer Res 62 (16): 4704-10, 2002. [<a href="https://pubmed.ncbi.nlm.nih.gov/12183429" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12183429</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_13_21">Missiaglia E, Williamson D, Chisholm J, et al.: PAX3/FOXO1 fusion gene status is the key prognostic molecular marker in rhabdomyosarcoma and significantly improves current risk stratification. J Clin Oncol 30 (14): 1670-7, 2012. [<a href="https://pubmed.ncbi.nlm.nih.gov/22454413" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22454413</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_13_22">Duan F, Smith LM, Gustafson DM, et al.: Genomic and clinical analysis of fusion gene amplification in rhabdomyosarcoma: a report from the Children's Oncology Group. Genes Chromosomes Cancer 51 (7): 662-74, 2012. [<a href="/pmc/articles/PMC3348443/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3348443</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22447499" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22447499</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_13_23">Chen X, Stewart E, Shelat AA, et al.: Targeting oxidative stress in embryonal rhabdomyosarcoma. Cancer Cell 24 (6): 710-24, 2013. [<a href="/pmc/articles/PMC3904731/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3904731</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24332040" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24332040</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_13_24">Koufos A, Hansen MF, Copeland NG, et al.: Loss of heterozygosity in three embryonal tumours suggests a common pathogenetic mechanism. Nature 316 (6026): 330-4, 1985 Jul 25-31. [<a href="https://pubmed.ncbi.nlm.nih.gov/2991766" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 2991766</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_13_25">Scrable H, Witte D, Shimada H, et al.: Molecular differential pathology of rhabdomyosarcoma. Genes Chromosomes Cancer 1 (1): 23-35, 1989. [<a href="https://pubmed.ncbi.nlm.nih.gov/2487144" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 2487144</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_13_26">Nascimento AF, Barr FG, Fletcher CD, et al., eds.: Spindle cell/sclerosing rhabdomyosarcoma. In: Fletcher CDM, Bridge JA, Hogendoorn P, et al., eds.: WHO Classification of Tumours of Soft Tissue and Bone. 4th ed. Lyon, France: IARC Press, 2013, pp 134-5.</div></li><li><div class="bk_ref" id="CDR0000062792_rl_13_27">Mosquera JM, Sboner A, Zhang L, et al.: Recurrent NCOA2 gene rearrangements in congenital/infantile spindle cell rhabdomyosarcoma. Genes Chromosomes Cancer 52 (6): 538-50, 2013. [<a href="/pmc/articles/PMC3734530/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3734530</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23463663" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23463663</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_13_28">Kohsaka S, Shukla N, Ameur N, et al.: A recurrent neomorphic mutation in MYOD1 defines a clinically aggressive subset of embryonal rhabdomyosarcoma associated with PI3K-AKT pathway mutations. Nat Genet 46 (6): 595-600, 2014. [<a href="/pmc/articles/PMC4231202/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4231202</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24793135" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24793135</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_13_29">Agaram NP, Chen CL, Zhang L, et al.: Recurrent MYOD1 mutations in pediatric and adult sclerosing and spindle cell rhabdomyosarcomas: evidence for a common pathogenesis. Genes Chromosomes Cancer 53 (9): 779-87, 2014. [<a href="/pmc/articles/PMC4108340/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4108340</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24824843" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24824843</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_13_30">Szuhai K, de Jong D, Leung WY, et al.: Transactivating mutation of the MYOD1 gene is a frequent event in adult spindle cell rhabdomyosarcoma. J Pathol 232 (3): 300-7, 2014. [<a href="https://pubmed.ncbi.nlm.nih.gov/24272621" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24272621</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_13_31">Davicioni E, Anderson JR, Buckley JD, et al.: Gene expression profiling for survival prediction in pediatric rhabdomyosarcomas: a report from the children's oncology group. J Clin Oncol 28 (7): 1240-6, 2010. [<a href="/pmc/articles/PMC3040045/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3040045</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20124188" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20124188</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_13_32">Williamson D, Missiaglia E, de Reyniès A, et al.: Fusion gene-negative alveolar rhabdomyosarcoma is clinically and molecularly indistinguishable from embryonal rhabdomyosarcoma. J Clin Oncol 28 (13): 2151-8, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/20351326" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20351326</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_13_33">Davicioni E, Finckenstein FG, Shahbazian V, et al.: Identification of a PAX-FKHR gene expression signature that defines molecular classes and determines the prognosis of alveolar rhabdomyosarcomas. Cancer Res 66 (14): 6936-46, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16849537" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16849537</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_13_34">Skapek SX, Anderson J, Barr FG, et al.: PAX-FOXO1 fusion status drives unfavorable outcome for children with rhabdomyosarcoma: a children's oncology group report. Pediatr Blood Cancer 60 (9): 1411-7, 2013. [<a href="/pmc/articles/PMC4646073/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4646073</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23526739" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23526739</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_13_35">Stegmaier S, Poremba C, Schaefer KL, et al.: Prognostic value of PAX-FKHR fusion status in alveolar rhabdomyosarcoma: a report from the cooperative soft tissue sarcoma study group (CWS). Pediatr Blood Cancer 57 (3): 406-14, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/21254373" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21254373</span></a>]</div></li></ol></div></div><div id="CDR0000062792__128"><h2 id="_CDR0000062792__128_">Stage Information</h2><p id="CDR0000062792__376">Before a biopsy of a suspected tumor mass is performed, imaging studies of the mass and baseline laboratory studies should be obtained. After the diagnosis of rhabdomyosarcoma has been made, an extensive evaluation to determine the extent of the disease should be performed before instituting therapy. This evaluation should include a chest x-ray, computed tomography (CT) scan of the chest, bilateral bone marrow aspirates and biopsies, bone scan, magnetic resonance imaging (MRI) of the base of the skull and brain (for parameningeal primary tumors only), and CT scan of the abdomen and pelvis (for lower extremity or genitourinary primary tumors). </p><p id="CDR0000062792__396">A CT or MRI scan of regional lymph nodes should be considered. Abnormal-appearing lymph nodes should be biopsied when possible. One study has demonstrated that sentinel lymph node biopsies can be safely performed in children with rhabdomyosarcoma, and tumor-positive biopsies may alter the treatment plan.[<a class="bk_pop" href="#CDR0000062792_rl_128_1">1</a>] Positron emission tomography (PET) with fluorine-18-fluorodeoxyglucose (FDG) scans can identify areas of possible metastatic disease not seen by other imaging modalities.[<a class="bk_pop" href="#CDR0000062792_rl_128_2">2</a>-<a class="bk_pop" href="#CDR0000062792_rl_128_4">4</a>] However, the efficacy of these two procedures for identifying involved lymph nodes or other sites is currently under investigation, and these procedures are not required by current treatment protocols.</p><p id="CDR0000062792__718">A retrospective study of 1,687 children with rhabdomyosarcoma enrolled in Intergroup studies from 1991 to 2004 suggests that about one-third of patients (those with localized noninvasive embryonal tumors) can have limited staging procedures that eliminate bone marrow and bone scan examinations at diagnosis.[<a class="bk_pop" href="#CDR0000062792_rl_128_5">5</a>] </p><p id="CDR0000062792__275">Terms used in this summary section are defined below in Table 1.</p><div id="CDR0000062792__276" class="table"><h3><span class="title">Table 1. Definition of Terms</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK65802.1/table/CDR0000062792__276/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__CDR0000062792__276_lrgtbl__"><table class="no_top_margin"><thead><tr><th colspan="1" rowspan="1" style="vertical-align:top;">Term</th><th colspan="1" rowspan="1" style="vertical-align:top;">Definition</th></tr></thead><tbody><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Favorable site</td><td colspan="1" rowspan="1" style="vertical-align:top;">Orbit; nonparameningeal head and neck; genitourinary tract other than kidney, bladder, and prostate; biliary tract.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Unfavorable site</td><td colspan="1" rowspan="1" style="vertical-align:top;">Any site other than favorable.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">T1</td><td colspan="1" rowspan="1" style="vertical-align:top;">Tumor confined to anatomic site of origin (noninvasive).</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">T2</td><td colspan="1" rowspan="1" style="vertical-align:top;">Tumor extension and/or fixation to surrounding tissue (invasive).</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">a</td><td colspan="1" rowspan="1" style="vertical-align:top;">Tumor ≤5 cm in maximum diameter.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">b</td><td colspan="1" rowspan="1" style="vertical-align:top;">Tumor >5 cm in maximum diameter.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">N0</td><td colspan="1" rowspan="1" style="vertical-align:top;">No clinical regional lymph node involvement.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">N1</td><td colspan="1" rowspan="1" style="vertical-align:top;">Clinical regional lymph node involvement.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">NX</td><td colspan="1" rowspan="1" style="vertical-align:top;">Regional lymph nodes not examined; no information.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">M0</td><td colspan="1" rowspan="1" style="vertical-align:top;">No metastatic disease.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">M1</td><td colspan="1" rowspan="1" style="vertical-align:top;">Metastatic disease.</td></tr></tbody></table></div></div><p id="CDR0000062792__255">Staging of rhabdomyosarcoma is relatively complex. The process includes the following steps: </p><ol id="CDR0000062792__256"><li class="half_rhythm"><div>Assigning a Stage: Determined by primary site, tumor size (widest diameter), and presence or absence of regional lymph node and/or distant metastases.</div></li><li class="half_rhythm"><div>Assigning a local tumor Group: Determined by status postsurgical resection/biopsy, with pathologic assessment of the tumor margin and of lymph node disease.</div></li><li class="half_rhythm"><div>Assigning a Risk Group: Determined by Stage, Group, and histology.</div></li></ol><p id="CDR0000062792__18">As noted previously, prognosis for children with rhabdomyosarcoma depends
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predominantly on the primary site, tumor size, Group, and histologic subtype. Favorable
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prognostic groups were identified in previous Intergroup Rhabdomyosarcoma
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Study Group (IRSG) studies, and treatment plans were designed on the basis of assignment of
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patients to different treatment groups according to prognosis. Several years ago, the IRSG merged with the National Wilms Tumor Study Group and two large cooperative pediatric cancer treatment groups to form the Children's Oncology Group (COG). New protocols for children with soft tissue sarcoma are developed by the Soft Tissue Sarcoma Committee of the COG (COG-STS).
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</p><p id="CDR0000062792__397">Current COG-STS protocols for rhabdomyosarcoma use the TNM-based pretreatment staging system that incorporates the primary tumor site, presence or absence of tumor invasion of surrounding tissues, tumor size, regional lymph node status, and the presence or absence of metastases. This staging system is described in Table 2 below.[<a class="bk_pop" href="#CDR0000062792_rl_128_6">6</a>,<a class="bk_pop" href="#CDR0000062792_rl_128_7">7</a>]</p><div id="CDR0000062792__612" class="table"><h3><span class="title">Table 2. Soft Tissue Sarcoma Committee of the Children's Oncology Group: Pretreatment Staging System</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK65802.1/table/CDR0000062792__612/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__CDR0000062792__612_lrgtbl__"><table class="no_margin"><thead><tr><th colspan="1" rowspan="1" style="vertical-align:top;">Stage </th><th colspan="1" rowspan="1" style="vertical-align:top;">Sites of Primary Tumor</th><th colspan="1" rowspan="1" style="vertical-align:top;">T Stage</th><th colspan="1" rowspan="1" style="vertical-align:top;">Tumor Size</th><th colspan="1" rowspan="1" style="vertical-align:top;">Regional Lymph Nodes</th><th colspan="1" rowspan="1" style="vertical-align:top;">Distant Metastasis</th></tr></thead><tbody><tr><td colspan="1" rowspan="1" style="vertical-align:top;">1</td><td colspan="1" rowspan="1" style="vertical-align:top;">Favorable sites</td><td colspan="1" rowspan="1" style="vertical-align:top;">T1 or T2</td><td colspan="1" rowspan="1" style="vertical-align:top;">Any size</td><td colspan="1" rowspan="1" style="vertical-align:top;">N0 or N1 or NX</td><td colspan="1" rowspan="1" style="vertical-align:top;">M0</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">2</td><td colspan="1" rowspan="1" style="vertical-align:top;">Unfavorable sites</td><td colspan="1" rowspan="1" style="vertical-align:top;">T1 or T2</td><td colspan="1" rowspan="1" style="vertical-align:top;">a, ≤ 5 cm</td><td colspan="1" rowspan="1" style="vertical-align:top;">N0 or NX</td><td colspan="1" rowspan="1" style="vertical-align:top;">M0</td></tr><tr><td colspan="1" rowspan="2" style="vertical-align:top;">3</td><td colspan="1" rowspan="2" style="vertical-align:top;">Unfavorable sites</td><td colspan="1" rowspan="2" style="vertical-align:top;">T1 or T2</td><td colspan="1" rowspan="1" style="vertical-align:top;">a, ≤ 5 cm</td><td colspan="1" rowspan="1" style="vertical-align:top;">N1</td><td colspan="1" rowspan="2" style="vertical-align:top;">M0</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">b, > 5 cm</td><td colspan="1" rowspan="1" style="vertical-align:top;">N0 or N1 or NX</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">4</td><td colspan="1" rowspan="1" style="vertical-align:top;">Any site</td><td colspan="1" rowspan="1" style="vertical-align:top;">T1 or T2</td><td colspan="1" rowspan="1" style="vertical-align:top;">Any size</td><td colspan="1" rowspan="1" style="vertical-align:top;">N0 or N1 or NX</td><td colspan="1" rowspan="1" style="vertical-align:top;">M1</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">N0 = absence of nodal spread; N1 = presence of regional nodal spread beyond the primary site; X = unknown N status; M0 = absence of metastatic spread; M1 = presence of metastatic spread beyond the primary site and regional lymph nodes; T1 = tumor confined to anatomic site of origin (noninvasive); T2a = tumor extension and/or fixation to surrounding tissue (invasive), tumor ≤5 cm in maximum diameter; T2b = tumor extension and/or fixation to surrounding tissue (invasive), tumor >5 cm in maximum diameter. </p></div></dd></dl></div></div></div><p id="CDR0000062792__391">The IRS-I, IRS-II, and IRS-III studies prescribed treatment plans based on the Surgical-pathologic Group system. In this system, Groups are defined by the
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extent of disease and by the completeness or extent of initial surgical resection after
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pathologic review of the tumor specimen(s). The definitions for these
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Groups are shown in Table 3 below.[<a class="bk_pop" href="#CDR0000062792_rl_128_8">8</a>,<a class="bk_pop" href="#CDR0000062792_rl_128_9">9</a>]</p><div id="CDR0000062792__257" class="table"><h3><span class="title">Table 3. Soft Tissue Sarcoma Committee of the Children's Oncology Group: Surgical-pathologic Group System</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK65802.1/table/CDR0000062792__257/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__CDR0000062792__257_lrgtbl__"><table class="no_top_margin"><thead><tr><th colspan="1" rowspan="1" style="vertical-align:top;">Group</th><th colspan="1" rowspan="1" style="vertical-align:top;">Incidence</th><th colspan="1" rowspan="1" style="vertical-align:top;">Definition</th></tr></thead><tbody><tr><td colspan="1" rowspan="1" style="vertical-align:top;">I</td><td colspan="1" rowspan="1" style="vertical-align:top;">Approximately 13%</td><td colspan="1" rowspan="1" style="vertical-align:top;">Localized tumor, completely removed with microscopically clear margins and no regional lymph node involvement. Lymph node biopsy or sampling is encouraged if lymph nodes are clinically or radiographically suspicious.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">II</td><td colspan="1" rowspan="1" style="vertical-align:top;">Approximately 20%</td><td colspan="1" rowspan="1" style="vertical-align:top;">Localized tumor, completely removed with: (a) microscopic disease at the margin; (b) regional disease with involved, grossly removed regional lymph nodes without microresidual disease; <b>or</b> (c) regional disease with involved nodes, grossly removed but with microscopic residual and/or histologic involvement of the most distal node from the primary tumor. </td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">III</td><td colspan="1" rowspan="1" style="vertical-align:top;">Approximately 48%</td><td colspan="1" rowspan="1" style="vertical-align:top;">Localized tumor, incompletely removed with gross, residual disease after: (a) biopsy only <b>or</b> (b) gross major resection of the primary tumor (>50%).</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">IV</td><td colspan="1" rowspan="1" style="vertical-align:top;">Approximately 18%</td><td colspan="1" rowspan="1" style="vertical-align:top;">Distant metastases are present at diagnosis. This category includes: (a) radiographically identified evidence of tumor spread <b>and</b> (b) positive tumor cells in cerebral spinal fluid, pleural, or peritoneal fluids, or implants in these regions.</td></tr></tbody></table></div></div><p id="CDR0000062792__398">After patients are categorized by Stage and Surgical-pathologic Group, a Risk Group is assigned. This takes into account Stage, Group, and histology. Patients are classified for protocol purposes as having a low risk, intermediate risk, or high risk of disease recurrence.[<a class="bk_pop" href="#CDR0000062792_rl_128_10">10</a>,<a class="bk_pop" href="#CDR0000062792_rl_128_11">11</a>] Treatment assignment is based on Risk Group, as shown in Table 4. To be designated as alveolar, the tumor must have greater than 50% alveolar elements; if the alveolar component is 50% or less, the tumor is considered embryonal.</p><div id="CDR0000062792__348" class="table"><h3><span class="title">Table 4. Soft Tissue Sarcoma Committee of the Children's Oncology Group: Rhabdomyosarcoma Risk Group Classification</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK65802.1/table/CDR0000062792__348/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__CDR0000062792__348_lrgtbl__"><table class="no_top_margin"><thead><tr><th colspan="1" rowspan="1" style="vertical-align:top;">Risk Group </th><th colspan="1" rowspan="1" style="vertical-align:top;">Histology</th><th colspan="1" rowspan="1" style="vertical-align:top;">Stage</th><th colspan="1" rowspan="1" style="vertical-align:top;">Group</th></tr></thead><tbody><tr><td colspan="1" rowspan="2" style="vertical-align:top;">Low risk </td><td colspan="1" rowspan="1" style="vertical-align:top;">Embryonal</td><td colspan="1" rowspan="1" style="vertical-align:top;">1</td><td colspan="1" rowspan="1" style="vertical-align:top;">I, II, III</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Embryonal</td><td colspan="1" rowspan="1" style="vertical-align:top;">2, 3</td><td colspan="1" rowspan="1" style="vertical-align:top;">I, II</td></tr><tr><td colspan="1" rowspan="2" style="vertical-align:top;">Intermediate risk</td><td colspan="1" rowspan="1" style="vertical-align:top;">Embryonal</td><td colspan="1" rowspan="1" style="vertical-align:top;">2, 3</td><td colspan="1" rowspan="1" style="vertical-align:top;">III</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Alveolar</td><td colspan="1" rowspan="1" style="vertical-align:top;">1, 2, 3</td><td colspan="1" rowspan="1" style="vertical-align:top;">I, II, III</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">High risk </td><td colspan="1" rowspan="1" style="vertical-align:top;">Embryonal or Alveolar</td><td colspan="1" rowspan="1" style="vertical-align:top;">4</td><td colspan="1" rowspan="1" style="vertical-align:top;">IV</td></tr></tbody></table></div></div><p id="CDR0000062792__264">[<i>Note: Since 2006, patients with undifferentiated sarcomas are treated on the COG-STS protocol for nonrhabdomyosarcomatous soft tissue sarcoma. Refer to the PDQ summary on <a href="/books/n/pdqcis/CDR0000062934/">Childhood Soft Tissue Sarcoma</a> for more information.</i>]</p><div id="CDR0000062792_rl_128"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000062792_rl_128_1">Kayton ML, Delgado R, Busam K, et al.: Experience with 31 sentinel lymph node biopsies for sarcomas and carcinomas in pediatric patients. Cancer 112 (9): 2052-9, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/18338809" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18338809</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_128_2">Völker T, Denecke T, Steffen I, et al.: Positron emission tomography for staging of pediatric sarcoma patients: results of a prospective multicenter trial. J Clin Oncol 25 (34): 5435-41, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/18048826" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18048826</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_128_3">Tateishi U, Hosono A, Makimoto A, et al.: Comparative study of FDG PET/CT and conventional imaging in the staging of rhabdomyosarcoma. Ann Nucl Med 23 (2): 155-61, 2009. [<a href="https://pubmed.ncbi.nlm.nih.gov/19225939" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19225939</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_128_4">Federico SM, Spunt SL, Krasin MJ, et al.: Comparison of PET-CT and conventional imaging in staging pediatric rhabdomyosarcoma. Pediatr Blood Cancer 60 (7): 1128-34, 2013. [<a href="/pmc/articles/PMC4266929/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4266929</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23255260" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23255260</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_128_5">Weiss AR, Lyden ER, Anderson JR, et al.: Histologic and clinical characteristics can guide staging evaluations for children and adolescents with rhabdomyosarcoma: a report from the Children's Oncology Group Soft Tissue Sarcoma Committee. J Clin Oncol 31 (26): 3226-32, 2013. [<a href="/pmc/articles/PMC3757291/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3757291</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23940218" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23940218</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_128_6">Lawrence W Jr, Gehan EA, Hays DM, et al.: Prognostic significance of staging factors of the UICC staging system in childhood rhabdomyosarcoma: a report from the Intergroup Rhabdomyosarcoma Study (IRS-II). J Clin Oncol 5 (1): 46-54, 1987. [<a href="https://pubmed.ncbi.nlm.nih.gov/3543238" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 3543238</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_128_7">Lawrence W Jr, Anderson JR, Gehan EA, et al.: Pretreatment TNM staging of childhood rhabdomyosarcoma: a report of the Intergroup Rhabdomyosarcoma Study Group. Children's Cancer Study Group. Pediatric Oncology Group. Cancer 80 (6): 1165-70, 1997. [<a href="https://pubmed.ncbi.nlm.nih.gov/9305719" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9305719</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_128_8">Crist WM, Garnsey L, Beltangady MS, et al.: Prognosis in children with rhabdomyosarcoma: a report of the intergroup rhabdomyosarcoma studies I and II. Intergroup Rhabdomyosarcoma Committee. J Clin Oncol 8 (3): 443-52, 1990. [<a href="https://pubmed.ncbi.nlm.nih.gov/2407808" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 2407808</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_128_9">Crist W, Gehan EA, Ragab AH, et al.: The Third Intergroup Rhabdomyosarcoma Study. J Clin Oncol 13 (3): 610-30, 1995. [<a href="https://pubmed.ncbi.nlm.nih.gov/7884423" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7884423</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_128_10">Raney RB, Anderson JR, Barr FG, et al.: Rhabdomyosarcoma and undifferentiated sarcoma in the first two decades of life: a selective review of intergroup rhabdomyosarcoma study group experience and rationale for Intergroup Rhabdomyosarcoma Study V. J Pediatr Hematol Oncol 23 (4): 215-20, 2001. [<a href="https://pubmed.ncbi.nlm.nih.gov/11846299" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11846299</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_128_11">Breneman JC, Lyden E, Pappo AS, et al.: Prognostic factors and clinical outcomes in children and adolescents with metastatic rhabdomyosarcoma--a report from the Intergroup Rhabdomyosarcoma Study IV. J Clin Oncol 21 (1): 78-84, 2003. [<a href="https://pubmed.ncbi.nlm.nih.gov/12506174" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12506174</span></a>]</div></li></ol></div></div><div id="CDR0000062792__129"><h2 id="_CDR0000062792__129_">Treatment Option Overview</h2><p id="CDR0000062792__39">All children with rhabdomyosarcoma require multimodality therapy with systemic chemotherapy, in conjunction with either surgery, radiation therapy (RT), or both modalities to maximize local tumor control.[<a class="bk_pop" href="#CDR0000062792_rl_129_1">1</a>-<a class="bk_pop" href="#CDR0000062792_rl_129_3">3</a>] Surgical resection may be performed before chemotherapy if it will not result in disfigurement, substantial functional compromise, or organ dysfunction. In most cases, this is not possible, and therefore, only an initial biopsy is performed. The majority of patients have Group III (gross residual) disease. After initial chemotherapy, Group III patients receive definitive RT for control of the primary tumor. Some patients with initially unresected tumors may undergo second-look surgery (delayed primary excision) to remove residual tumor. This is most appropriate if the delayed excision is deemed feasible with acceptable functional/cosmetic outcome and if a modest reduction in radiation dose is expected to significantly reduce the risk of long-term adverse effects. RT is given to clinically suspicious lymph nodes (detected by palpation or imaging) unless the suspicious lymph nodes are biopsied and shown to be free of rhabdomyosarcoma.
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</p><p id="CDR0000062792__528">The discussion of treatment options for children
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with rhabdomyosarcoma is therefore divided into separate sections describing the following
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local control options:</p><ul id="CDR0000062792__594"><li class="half_rhythm"><div>Surgery.</div></li><li class="half_rhythm"><div>RT.</div></li><li class="half_rhythm"><div>Chemotherapy.</div></li></ul><p id="CDR0000062792__212">The treatment of rhabdomyosarcoma by the Children's Oncology Group (COG) and in Europe (as exemplified by trials from the Intergroup Rhabdomyosarcoma Study Group [IRSG], the Soft Tissue Sarcoma Committee of the COG [COG-STS], and the International Society of Pediatric Oncology Malignant Mesenchymal Tumor [MMT] Group) differs in management and overall treatment philosophy.[<a class="bk_pop" href="#CDR0000062792_rl_129_2">2</a>] In the MMT trials, the main objective is to reduce the use of local therapies using initial front-line chemotherapy followed by second-line therapy in the presence of poor response. Subsequent surgical resection is preferred over RT, which is used only after incomplete resection, documented regional lymph node involvement, or a poor clinical response to initial chemotherapy. This approach is designed to avoid major surgical procedures and long-term damaging effects from RT. Conversely, the primary COG-STS objective has been to employ local therapy soon after the initial operation or biopsy (except in patients with metastatic disease), using RT for patients with residual disease. Event-free survival (EFS) is the target endpoint, attempting to avoid relapse and subsequent salvage therapy.[<a class="bk_pop" href="#CDR0000062792_rl_129_3">3</a>] The MMT Group approach led to an overall survival (OS) rate of 71% in the European MMT89 study, compared with an OS rate of 84% in the IRS-IV study. Similarly, EFS rates at 5 years were 57% in the MMT89 study versus 78% in the IRS-IV study. Differences in outcome were most striking for patients with extremity and head and neck nonparameningeal tumors. Failure-free survival was lower for patients with bladder/prostate primary tumors who did not receive RT as part of their initial treatment, but there was no difference in OS between the two strategies for these patients.[<a class="bk_pop" href="#CDR0000062792_rl_129_4">4</a>] The overall impression is that survival for most patient subsets is superior with the use of early local therapy, including RT. However, in the MMT trials, some patients are spared aggressive local therapy, which may reduce the potential for morbidities associated with such therapy.[<a class="bk_pop" href="#CDR0000062792_rl_129_1">1</a>-<a class="bk_pop" href="#CDR0000062792_rl_129_3">3</a>]</p><p id="CDR0000062792__622">Patients with undifferentiated sarcomas were treated in trials coordinated by the IRSG from 1972 until 2006,[<a class="bk_pop" href="#CDR0000062792_rl_129_5">5</a>] and more recently were eligible for the nonrhabdomyosarcoma soft tissue sarcoma protocol using agents active in adult soft tissue sarcoma, ifosfamide and doxorubicin (<a href="http://cancer.gov/clinicaltrials/search/view?version=healthprofessional&cdrid=483702" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">COG-ARST0332</a>). However, this trial has now been closed. </p><div id="CDR0000062792_rl_129"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000062792_rl_129_1">Donaldson SS, Meza J, Breneman JC, et al.: Results from the IRS-IV randomized trial of hyperfractionated radiotherapy in children with rhabdomyosarcoma--a report from the IRSG. Int J Radiat Oncol Biol Phys 51 (3): 718-28, 2001. [<a href="https://pubmed.ncbi.nlm.nih.gov/11597814" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11597814</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_129_2">Stevens MC, Rey A, Bouvet N, et al.: Treatment of nonmetastatic rhabdomyosarcoma in childhood and adolescence: third study of the International Society of Paediatric Oncology--SIOP Malignant Mesenchymal Tumor 89. J Clin Oncol 23 (12): 2618-28, 2005. [<a href="https://pubmed.ncbi.nlm.nih.gov/15728225" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15728225</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_129_3">Donaldson SS, Anderson JR: Rhabdomyosarcoma: many similarities, a few philosophical differences. J Clin Oncol 23 (12): 2586-7, 2005. [<a href="https://pubmed.ncbi.nlm.nih.gov/15728222" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15728222</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_129_4">Rodeberg DA, Anderson JR, Arndt CA, et al.: Comparison of outcomes based on treatment algorithms for rhabdomyosarcoma of the bladder/prostate: combined results from the Children's Oncology Group, German Cooperative Soft Tissue Sarcoma Study, Italian Cooperative Group, and International Society of Pediatric Oncology Malignant Mesenchymal Tumors Committee. Int J Cancer 128 (5): 1232-9, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/20473932" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20473932</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_129_5">Raney RB, Anderson JR, Barr FG, et al.: Rhabdomyosarcoma and undifferentiated sarcoma in the first two decades of life: a selective review of intergroup rhabdomyosarcoma study group experience and rationale for Intergroup Rhabdomyosarcoma Study V. J Pediatr Hematol Oncol 23 (4): 215-20, 2001. [<a href="https://pubmed.ncbi.nlm.nih.gov/11846299" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11846299</span></a>]</div></li></ol></div></div><div id="CDR0000062792__130"><h2 id="_CDR0000062792__130_">Previously Untreated Childhood Rhabdomyosarcoma</h2><div id="CDR0000062792__529"><h3>Local Control Management: Surgery</h3><p id="CDR0000062792__530">In recent years, the predominant site of treatment failure in patients with initially localized rhabdomyosarcoma has been local recurrence. Both surgery and radiation therapy are primarily measures taken to produce local control, but each has risks and benefits. Surgical removal of the entire tumor should be considered initially, but only if major functional/cosmetic impairment will not result.[<a class="bk_pop" href="#CDR0000062792_rl_130_1">1</a>] With that proviso, complete resection of the primary tumor with a surrounding margin of normal tissue and sampling possibly involved lymph nodes in the draining nodal basin is recommended. Important exceptions to the rule of normal margins exist (e.g., tumors of the
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orbit and of the genitourinary region).[<a class="bk_pop" href="#CDR0000062792_rl_130_2">2</a>,<a class="bk_pop" href="#CDR0000062792_rl_130_3">3</a>] The principle of wide and
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complete resection of the primary tumor is less applicable to patients known to
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have metastatic disease at the initial operation, but it is a reasonable concept
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if easily accomplished. </p><p id="CDR0000062792__635">Patients with microscopic residual tumor after
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their initial excisional procedure appear to have improved prognoses if a
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second operative procedure (primary re-excision) to resect the primary tumor bed
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before beginning chemotherapy can achieve complete removal of the tumor.[<a class="bk_pop" href="#CDR0000062792_rl_130_4">4</a>] </p><p id="CDR0000062792__636">Clinical and/or imaging evaluation of regional lymph nodes is an important part of pretreatment staging. Pathologic evaluation of regional nodes is currently required for all patients with extremity primary rhabdomyosarcoma and boys aged 10 years and older with paratesticular rhabdomyosarcoma, because microscopic tumor is often documented even when the nodes are not enlarged. (Refer to the <a href="#CDR0000062792__552">Regional and in-transit lymph nodes</a> section of this summary for more information.)</p><p id="CDR0000062792__637">There is little evidence that debulking surgery (i.e., expected to leave macroscopic residual tumor) improves outcome, compared with biopsy alone.[<a class="bk_pop" href="#CDR0000062792_rl_130_5">5</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335132/" class="def">Level of evidence: 2A</a>] Second-look procedures (also known as delayed primary excision) can identify viable tumor that remains after initial chemotherapy; patients with viable tumor had shorter event-free survival (EFS) rates than did those without viable tumor, but there was no effect on overall survival (OS).[<a class="bk_pop" href="#CDR0000062792_rl_130_6">6</a>] Thus, the exact role of delayed primary excision remains undefined in rhabdomyosarcoma and is most appropriate if it is anticipated that a complete resection is possible and that the modest reduction in radiation dose will substantially decrease the risk for late effects. </p><p id="CDR0000062792__531">Because rhabdomyosarcoma can arise from multiple sites, surgical care decisions and radiotherapeutic options must be tailored to the specific aspects of each site, and should be discussed with a multidisciplinary team including representatives of those specialties and pediatric oncologists.
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Surgical management of the more common primary sites is provided in the <a href="#CDR0000062792__544">Local Control Management with Surgery and RT by Primary Sites of Disease</a> section of this summary.</p></div><div id="CDR0000062792__532"><h3>Local Control Management: Radiation Therapy (RT)</h3><p id="CDR0000062792__595">Only 15% of patients present with Group I, completely resected disease, so RT is used in the majority of cases.</p><p id="CDR0000062792__533">RT is an effective method for achieving local control of the tumor for patients with microscopic or gross residual disease after biopsy, initial surgical resection, or chemotherapy. Patients with completely resected embryonal rhabdomyosarcoma (Group I) do well without RT.[<a class="bk_pop" href="#CDR0000062792_rl_130_7">7</a>] An earlier study of Group I patients with alveolar rhabdomyosarcoma and undifferentiated soft tissue sarcoma found that omission of RT was followed by decreased local control.[<a class="bk_pop" href="#CDR0000062792_rl_130_8">8</a>] A subsequent review of patients with only alveolar rhabdomyosarcoma found that the improvement in outcome with RT did not reach statistical significance for patients with Stage 1 and 2 tumors. There were very few patients (n = 4) with large tumors (Stage 3, >5 cm) who did not receive RT, but their outcome was poor.[<a class="bk_pop" href="#CDR0000062792_rl_130_9">9</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335155/" class="def">Level of evidence: 3iiiDii</a>]</p><p id="CDR0000062792__638"> In more than 50% of Group II rhabdomyosarcoma patients, local recurrence was due to noncompliance with guidelines or omission of RT.[<a class="bk_pop" href="#CDR0000062792_rl_130_10">10</a>] A review of European trials conducted by the German Cooperative Weichteilsarkom Studien (CWS) Group between 1981 and 1998, in which RT was omitted for some Group II patients, demonstrated a benefit to using RT as a component of local tumor control for all Group II patient subsets, as defined by tumor histology, tumor size, and tumor site.[<a class="bk_pop" href="#CDR0000062792_rl_130_11">11</a>]</p><p id="CDR0000062792__534">The predominant type of relapse for patients with Group III disease is local failure. Patients with tumor-involved regional lymph nodes at diagnosis also have a higher risk of local and distant failure than do patients whose lymph nodes are uninvolved.[<a class="bk_pop" href="#CDR0000062792_rl_130_12">12</a>] As with the surgical management of patients with rhabdomyosarcoma, recommendations for RT depend on the site of primary tumor, the postsurgical (if performed) amount of residual disease (none vs. microscopic vs. macroscopic), and the presence of involved lymph nodes. </p><p id="CDR0000062792__596">For optimal care of pediatric patients undergoing radiation treatments, it is imperative to have available a radiation oncologist, radiation technicians, and nurses who are experienced in treating children. An anesthesiologist may be necessary to sedate and immobilize young patients. Computerized treatment planning with a 3-dimensional planning system should be available. Techniques to deliver radiation specifically to the tumor while sparing normal tissue (e.g., <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000270731/" class="def">conformal radiation therapy</a>, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000335073/" class="def">intensity-modulated radiation therapy</a> [IMRT], proton-beam therapy [<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000534234/" class="def">charged-particle radiation therapy</a>], or brachytherapy) are appropriate.[<a class="bk_pop" href="#CDR0000062792_rl_130_13">13</a>-<a class="bk_pop" href="#CDR0000062792_rl_130_17">17</a>] </p><ul id="CDR0000062792__683"><li class="half_rhythm"><div>Comparison of proton-beam and IMRT treatment plans has shown that proton-beam radiation can spare more normal tissue adjacent to the targeted volume than IMRT.[<a class="bk_pop" href="#CDR0000062792_rl_130_18">18</a>,<a class="bk_pop" href="#CDR0000062792_rl_130_19">19</a>] Follow-up remains relatively short, and there are no data available to determine if the reduction in dose to adjacent tissue will result in improved functional outcome or reduce the risk of secondary malignancy. Because patient numbers are small, it is not possible to determine if the risk of local recurrence might be increased by reducing radiation dose in tissue adjacent to the primary tumor.</div></li><li class="half_rhythm"><div>A retrospective review of patients with intermediate-risk rhabdomyosarcoma compared conformal RT and IMRT.[<a class="bk_pop" href="#CDR0000062792_rl_130_20">20</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335133/" class="def">Level of evidence: 2B</a>] IMRT improved the target coverage but did not show a difference in local failure rate or EFS.</div></li></ul><p id="CDR0000062792__597">Standard RT of children with rhabdomyosarcoma includes the following: </p><div id="CDR0000062792__643" class="table"><h3><span class="title">Table 5. Radiation Therapy (RT) Dose According to Rhabdomyosarcoma Group, Histology, and Site of Disease (Children's Oncology Group [COG])</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK65802.1/table/CDR0000062792__643/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__CDR0000062792__643_lrgtbl__"><table class="no_top_margin"><thead><tr><th colspan="1" rowspan="1" style="vertical-align:top;">Group</th><th colspan="1" rowspan="1" style="vertical-align:top;">Treatment</th></tr></thead><tbody><tr><td colspan="1" rowspan="1" style="vertical-align:top;"><b>Group I</b></td><td colspan="1" rowspan="1" style="vertical-align:top;"></td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Embryonal</td><td colspan="1" rowspan="1" style="vertical-align:top;">No RT. </td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Alveolar</td><td colspan="1" rowspan="1" style="vertical-align:top;">36 Gy to involved (prechemotherapy) site. The use of RT is under investigation.</td></tr><tr><td colspan="2" rowspan="1" style="vertical-align:top;"></td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;"><b>Group II</b></td><td colspan="1" rowspan="1" style="vertical-align:top;"></td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">N0 (microscopic residual disease after surgery) </td><td colspan="1" rowspan="1" style="vertical-align:top;">36 Gy to involved (prechemotherapy) site.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">N1 (resected regional lymph node involvement)</td><td colspan="1" rowspan="1" style="vertical-align:top;">41.4 Gy to involved (prechemotherapy) site and nodes.</td></tr><tr><td colspan="2" rowspan="1" style="vertical-align:top;"></td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;"><b>Group III</b></td><td colspan="1" rowspan="1" style="vertical-align:top;"></td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Orbital and nonorbital tumors </td><td colspan="1" rowspan="1" style="vertical-align:top;">50.4 Gy with volume reduction after 36 Gy if excellent response to chemotherapy and noninvasive pushing tumors; no volume reduction for invasive tumors.</td></tr><tr><td colspan="2" rowspan="1" style="vertical-align:top;"></td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;"><b>Group IV</b></td><td colspan="1" rowspan="1" style="vertical-align:top;"></td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;">As for other groups and including all metastatic sites, if safe and possible. <i>Exception:</i> lung (pulmonary metastases) treated with 15 Gy if aged 6 years or older, 12 Gy if younger than 6 years.</td></tr></tbody></table></div></div><ul id="CDR0000062792__598"><li class="half_rhythm"><div>The RT dose depends predominantly on the amount of residual disease, if any,
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after the primary surgical resection. In general, patients with
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microscopic residual disease (Group II) receive RT to
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36 Gy if they do not have involved lymph nodes and 41 Gy in the presence of involved nodes.[<a class="bk_pop" href="#CDR0000062792_rl_130_8">8</a>,<a class="bk_pop" href="#CDR0000062792_rl_130_21">21</a>] Low-risk patients (embryonal histology and favorable sites with microscopic residual disease) treated on a COG study had local control with 36 Gy, which was comparable to historic controls who received 41.4 Gy.[<a class="bk_pop" href="#CDR0000062792_rl_130_22">22</a>] IRS-II patients with gross residual disease (Group III) who received 40 Gy to
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more than 50 Gy had locoregional relapse rates greater than 30% but higher
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doses of radiation (>60 Gy) were associated with unacceptable
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long-term toxic effects.[<a class="bk_pop" href="#CDR0000062792_rl_130_23">23</a>,<a class="bk_pop" href="#CDR0000062792_rl_130_24">24</a>] Group III patients on the IRS-IV standard treatment
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|
arm received 50.4 Gy, with 5-year progression-free survival of 55% to 75%.[<a class="bk_pop" href="#CDR0000062792_rl_130_25">25</a>] Experience supports using a somewhat reduced dose of RT in patients with Group III disease who have delayed gross total resection with negative margins. In the recent <a href="http://cancer.gov/clinicaltrials/search/view?version=healthprofessional&cdrid=65542" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">COG-D9602</a> study, these patients had a greater than 85% likelihood of local control with 36 Gy.[<a class="bk_pop" href="#CDR0000062792_rl_130_22">22</a>]</div></li><li class="half_rhythm"><div>The treated volume should be determined by the extent of tumor at diagnosis
|
|
before surgical resection and before chemotherapy. A margin of 2 cm is
|
|
generally used, including clinically involved regional lymph nodes.[<a class="bk_pop" href="#CDR0000062792_rl_130_8">8</a>] While the volume
|
|
irradiated may be modified on the basis of guidelines for normal tissue tolerance,
|
|
gross residual disease at the time of radiation should receive full-dose
|
|
treatment.
|
|
</div></li><li class="half_rhythm"><div>The timing of RT generally allows for chemotherapy to be given for 1 to 3 months before RT is initiated. RT is usually given over 5 to 6 weeks (e.g., 1.8 Gy once per day), during which time chemotherapy is usually modified to avoid the radiosensitizing agents dactinomycin and doxorubicin.</div></li></ul><p id="CDR0000062792__599">The IRS-IV trial included a randomized study that reported the administration of RT twice a day, 6 to 8 hours apart, at 1.1 Gy per dose (hyperfractionated schedule), 5 days per week, was feasible but difficult to accomplish in small children who required sedation twice daily. Patients with localized, gross residual tumors were randomly assigned to receive conventional, once-daily RT (total dose of 50.4 Gy) versus the twice-daily hyperfractionated schedule (total dose of 59.4 Gy). There was no demonstrated advantage in terms of local control.[<a class="bk_pop" href="#CDR0000062792_rl_130_26">26</a>] Conventional RT remains the standard for treating patients who have rhabdomyosarcoma with gross residual disease.[<a class="bk_pop" href="#CDR0000062792_rl_130_27">27</a>]</p><p id="CDR0000062792__600">Brachytherapy, using either intracavitary or interstitial implants, is another
|
|
method of local control and has been used in selected situations for children
|
|
with rhabdomyosarcoma, especially those with primary tumors at vaginal or
|
|
vulvar sites [<a class="bk_pop" href="#CDR0000062792_rl_130_28">28</a>-<a class="bk_pop" href="#CDR0000062792_rl_130_32">32</a>] and selected bladder/prostate sites.[<a class="bk_pop" href="#CDR0000062792_rl_130_33">33</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335150/" class="def">Level of evidence: 3iiiA</a>] In small series from one or two institutions, this treatment
|
|
approach was associated with a high survival rate and with retention of a
|
|
functional organ or tissue in most patients.[<a class="bk_pop" href="#CDR0000062792_rl_130_29">29</a>,<a class="bk_pop" href="#CDR0000062792_rl_130_34">34</a>]; [<a class="bk_pop" href="#CDR0000062792_rl_130_35">35</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335148/" class="def">Level of evidence: 3iiDii</a>] Other sites, especially
|
|
head and neck, have also been treated with brachytherapy.[<a class="bk_pop" href="#CDR0000062792_rl_130_36">36</a>]
|
|
Patients with initial Group III disease, who subsequently have microscopic
|
|
residual disease after chemotherapy with or without delayed surgery are
|
|
likely to achieve local control with RT at doses of 40 Gy or
|
|
more.[<a class="bk_pop" href="#CDR0000062792_rl_130_37">37</a>]</p><p id="CDR0000062792__601">Very young children (aged ≤36 months) diagnosed with rhabdomyosarcoma pose a therapeutic challenge because of their increased risk for treatment-related morbidity.[<a class="bk_pop" href="#CDR0000062792_rl_130_22">22</a>] As suggested above, in older children, reduced radiation doses may be appropriate if delayed surgery can provide negative margins. However, for infants who are unable to undergo surgical resection, higher doses of RT remain appropriate.[<a class="bk_pop" href="#CDR0000062792_rl_130_38">38</a>] Radiation techniques are designed to maximize normal tissue sparing, and should include conformal approaches, often with intensity-modulated techniques. </p></div><div id="CDR0000062792__544"><h3>Local Control Management with Surgery and RT by Primary Sites of Disease</h3><div id="CDR0000062792__546"><h4>Head and neck</h4><p id="CDR0000062792__591">Rhabdomyosarcomas of the <i><b>orbit </b></i>should not undergo exenteration, but biopsy is needed for diagnosis.[<a class="bk_pop" href="#CDR0000062792_rl_130_39">39</a>,<a class="bk_pop" href="#CDR0000062792_rl_130_40">40</a>] Biopsy is followed by chemotherapy and RT, with orbital
|
|
exenteration reserved for the small number of patients with locally persistent
|
|
or recurrent disease.[<a class="bk_pop" href="#CDR0000062792_rl_130_41">41</a>,<a class="bk_pop" href="#CDR0000062792_rl_130_42">42</a>] RT and chemotherapy are the standard of care, with survival in excess of 90% to 95%. For patients with orbital tumors, precautions should be taken to limit the RT dose to the lens and cornea.</p><p id="CDR0000062792__547">If the tumors are <i><b>nonorbital and cranial parameningeal</b></i> (arising in the middle ear/mastoid, nasopharynx/nasal cavity, paranasal sinus, parapharyngeal region, or pterygopalatine/infratemporal fossa), a magnetic resonance imaging (MRI) scan with contrast of the primary site and brain should be obtained to check for presence of base-of-skull erosion and possible extension onto or through the dura.[<a class="bk_pop" href="#CDR0000062792_rl_130_43">43</a>-<a class="bk_pop" href="#CDR0000062792_rl_130_45">45</a>] If skull erosion and/or transdural extension is equivocal, a computed tomography (CT) scan with contrast of the same regions is indicated. Also, if there is any suspicion of extension down the spinal cord, an MRI scan with contrast of the entire cord should be obtained. The cerebrospinal fluid (CSF) should be examined for malignant cells in all patients with parameningeal tumors. Because complete removal of these tumors is difficult, owing to their location, the initial surgical procedure for these patients is usually only a biopsy for diagnosis.</p><p id="CDR0000062792__577">Nonorbital head and neck rhabdomyosarcomas, including cranial parameningeal tumors, are optimally managed by conformal RT and chemotherapy. Patients with parameningeal disease with intracranial extension in contiguity with the primary tumor and/or signs of meningeal impingement (i.e., cranial base bone erosion, and/or cranial nerve palsy) do not require whole-brain irradiation or intrathecal therapy, unless tumor cells are present in the CSF at diagnosis.[<a class="bk_pop" href="#CDR0000062792_rl_130_43">43</a>] Patients should receive RT to the site of primary tumor with a 1.5 cm margin to include the meninges adjacent to the primary tumor and the region of intracranial extension, if present, with a 1.5 cm margin.[<a class="bk_pop" href="#CDR0000062792_rl_130_44">44</a>] In a retrospective trial, starting RT within 2 weeks of diagnosis for patients with signs of meningeal impingement was associated with lower rates of local failure but was of borderline significance. When no signs of meningeal impingement were present, delay of RT for more than 10 weeks did not impact local failure rates.[<a class="bk_pop" href="#CDR0000062792_rl_130_44">44</a>] A subsequent comparison of local control, failure-free survival (FFS), and OS rates showed no statistical difference between early irradiation (day 0) for Group III patients in IRS-IV with cranial nerve palsy and/or cranial base erosion versus later initiation of RT (week 12) for Group III patients in <a href="http://cancer.gov/clinicaltrials/search/view?version=healthprofessional&cdrid=67157" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">D9803</a> with similar evidence of meningeal involvement, suggesting that early RT for this group of patients is not necessary. However, both studies administered early irradiation to all patients with intracranial extension of the primary tumor.[<a class="bk_pop" href="#CDR0000062792_rl_130_46">46</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335132/" class="def">Level of evidence: 2A</a>] A retrospective analysis of 47 patients with parameningeal primary sites suggested that the subgroup of adolescent patients with alveolar rhabdomyosarcoma (n = 13) might benefit from the addition of prophylactic irradiation (36 Gy) to bilateral cervical nodes.[<a class="bk_pop" href="#CDR0000062792_rl_130_47">47</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335148/" class="def">Level of evidence: 3iiDii</a>] </p><p id="CDR0000062792__744">An analysis of 1,105 patients with localized parameningeal rhabdomyosarcoma treated on protocols from 1984 to 2004 in North America and Europe found that several prognostic factors could be used to define subgroups of patients with significantly differing survival rates. The OS rate at 10 years for the entire cohort was 66%. Patients with zero or one adverse factor (age <3 or >10 years at diagnosis, presence of meningeal involvement, tumor diameter >5 cm, unfavorable primary parameningeal site) had a 10-year survival rate of 80.7%; those with two factors had a 68.4% 10-year OS rate; and those with three or four factors had a 52.2% 10-year OS rate. Patients who did not receive initial RT had a poor prognosis, and their tumors were not salvaged with introduction of RT after relapse, establishing RT as a necessary component of initial treatment.[<a class="bk_pop" href="#CDR0000062792_rl_130_48">48</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335150/" class="def">Level of evidence: 3iiiA</a>]</p><p id="CDR0000062792__639">Children who present with tumor cells in the CSF (Stage 4) may or may not have other evidence of diffuse meningeal disease and/or distant metastases. In a review of experience from IRSG Protocols II though IV, eight patients had tumor cells in the CSF at diagnosis; three of four without other distant metastases were alive at 6 to 16 years after diagnosis, as was one of four who had concomitant metastases elsewhere.[<a class="bk_pop" href="#CDR0000062792_rl_130_49">49</a>] Patients may also have multiple intraparenchymal brain metastases from a distant primary tumor. They may be treated with central nervous system-directed RT in addition to treatment with chemotherapy/RT for the primary tumor. Spinal RT may also be indicated.[<a class="bk_pop" href="#CDR0000062792_rl_130_50">50</a>,<a class="bk_pop" href="#CDR0000062792_rl_130_51">51</a>]</p><p id="CDR0000062792__611">For <i><b>nonparameningeal and nonorbital head and neck tumors</b></i>, wide excision of
|
|
the primary tumor (when feasible) and ipsilateral neck lymph node sampling of
|
|
clinically involved nodes are appropriate.[<a class="bk_pop" href="#CDR0000062792_rl_130_52">52</a>] Narrow resection margins (<1 mm)
|
|
are acceptable because of anatomic restrictions. Cosmetic and functional
|
|
factors should always be considered, but with modern techniques, complete
|
|
resection in patients with superficial tumors need not be inconsistent with
|
|
good cosmetic and functional results. Specialized, multidisciplinary surgical
|
|
teams also have performed resections of anterior skull-based tumors in areas
|
|
previously considered inaccessible to definitive surgical management, including
|
|
the nasal areas, paranasal sinuses, and temporal fossa. These procedures
|
|
should only be considered, however, in children with recurrent locoregional
|
|
disease or residual disease after chemotherapy and RT.</p><p id="CDR0000062792__549">For
|
|
patients with head and neck primary tumors that are considered unresectable,
|
|
chemotherapy and RT with organ preservation are the mainstay of primary
|
|
management.[<a class="bk_pop" href="#CDR0000062792_rl_130_41">41</a>,<a class="bk_pop" href="#CDR0000062792_rl_130_45">45</a>,<a class="bk_pop" href="#CDR0000062792_rl_130_53">53</a>-<a class="bk_pop" href="#CDR0000062792_rl_130_56">56</a>] Several studies have reported excellent local control in patients with rhabdomyosarcoma of the head and neck treated with IMRT, fractionated <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044464/" class="def">stereotactic radiation therapy</a>, or protons and chemotherapy. Further study is needed, but the use of IMRT and chemotherapy in patients with head and neck rhabdomyosarcoma may result in less severe late effects.[<a class="bk_pop" href="#CDR0000062792_rl_130_57">57</a>-<a class="bk_pop" href="#CDR0000062792_rl_130_59">59</a>]; [<a class="bk_pop" href="#CDR0000062792_rl_130_60">60</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335150/" class="def">Level of evidence: 3iiiA</a>]</p></div><div id="CDR0000062792__550"><h4>Extremity sites</h4><p id="CDR0000062792__578">Intensity-modulated radiation therapy (IMRT) can be used to spare the bone, yet provide optimal soft tissue coverage, and is used for the management of extremity rhabdomyosarcoma. Complete primary tumor removal from the hand or foot is not feasible in most cases because of functional impairment.[<a class="bk_pop" href="#CDR0000062792_rl_130_61">61</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335144/" class="def">Level of evidence: 3iiA</a>] For children presenting with a primary tumor of the hands or feet, COG studies have shown 100% 10-year local control using RT along with chemotherapy, avoiding amputation in these children.[<a class="bk_pop" href="#CDR0000062792_rl_130_62">62</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335150/" class="def">Level of evidence: 3iiiA</a>]</p><p id="CDR0000062792__640">Primary re-excision before beginning chemotherapy (i.e., not delayed) may be appropriate in patients whose initial surgical procedure leaves microscopic residual disease that is deemed resectable by a second procedure.[<a class="bk_pop" href="#CDR0000062792_rl_130_4">4</a>]</p><div id="CDR0000062792__552"><h5>Regional and in-transit lymph nodes</h5><p id="CDR0000062792__554">The Soft Tissue Sarcoma Committee of the COG (COG-STS) recommends systematic aggressive axillary node sampling for patients with upper-extremity primary tumors, even with clinically and radiographically negative nodes. The COG-STS also recommends inguinal and femoral triangle node sampling for patients with lower-extremity primary tumors, even with clinically and radiographically negative nodes. If
|
|
clinically positive nodes are present, biopsy of more proximal nodes is
|
|
recommended before sampling of the involved nodal region. Sentinel
|
|
lymph node mapping is employed at some centers to identify the regional nodes
|
|
that are the most likely to be involved.[<a class="bk_pop" href="#CDR0000062792_rl_130_63">63</a>-<a class="bk_pop" href="#CDR0000062792_rl_130_66">66</a>] However, the contribution of sentinel lymph node mapping is not yet clearly defined in pediatric patients. </p><p id="CDR0000062792__592">Because of the significant incidence of regional nodal spread in patients with extremity primary tumors (often without clinical evidence of involvement) and because of the prognostic and therapeutic implications of nodal involvement, extensive pretreatment assessment of regional (and possibly in-transit) nodes is warranted.[<a class="bk_pop" href="#CDR0000062792_rl_130_63">63</a>,<a class="bk_pop" href="#CDR0000062792_rl_130_67">67</a>-<a class="bk_pop" href="#CDR0000062792_rl_130_70">70</a>]; [<a class="bk_pop" href="#CDR0000062792_rl_130_71">71</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335147/" class="def">Level of evidence: 3iiDi</a>] In-transit nodes are defined as epitrochlear and brachial for upper-extremity tumors and popliteal for lower-extremity tumors. Regional lymph nodes for those tumor sites are axillary/infraclavicular nodes and inguinal/femoral nodes, respectively. In a review of 226 patients with primary extremity rhabdomyosarcoma, 5% had tumor-involved in-transit nodes, and over 5 years, the rate of in-transit node recurrence was 12%. Very few patients (n = 11) underwent in-transit node examination at diagnosis, but five of them, all with alveolar rhabdomyosarcoma, had tumor-involved nodes. However, the EFS rates were not significantly different among those evaluated initially and those not evaluated initially for in-transit nodal disease.[<a class="bk_pop" href="#CDR0000062792_rl_130_71">71</a>]</p></div></div><div id="CDR0000062792__556"><h4>Truncal sites</h4><p id="CDR0000062792__557">The surgical management of patients with lesions of the <i><b>chest wall or abdominal
|
|
wall </b></i>should follow the same guidelines as those used for lesions of the extremities (i.e., wide local excision and an attempt to achieve negative microscopic
|
|
margins). These resections may require use of prosthetic materials. Very large
|
|
truncal masses should be biopsied initially. Chemotherapy, with or without RT, is then given. Initial surgery is performed if there is a realistic expectation of achieving negative margins. However, most patients who present with large tumors in these
|
|
sites have localized disease that becomes amenable to complete resection with
|
|
negative margins after preoperative chemoradiation therapy; those patients may have excellent long-term
|
|
survival.[<a class="bk_pop" href="#CDR0000062792_rl_130_72">72</a>-<a class="bk_pop" href="#CDR0000062792_rl_130_75">75</a>]</p><p id="CDR0000062792__558"><i><b>Intrathoracic or intra-abdominal sarcomas</b></i> may not be resectable at diagnosis because of the
|
|
massive size of the tumor and extension into vital
|
|
organs or vessels.[<a class="bk_pop" href="#CDR0000062792_rl_130_76">76</a>] For patients with initially unresectable <b><i>retroperitoneal/pelvic</i></b> tumors, complete surgical removal after chemotherapy, with or without RT, offers a significant survival advantage (73% vs. 34%–44% without removal).[<a class="bk_pop" href="#CDR0000062792_rl_130_76">76</a>] The International Society of Pediatric Oncology Malignant Mesenchymal Tumor (SIOP-MMT) group found that RT improved local control in patients with localized pelvic rhabdomyosarcoma whose initial surgical procedure was biopsy only, leaving macroscopic residual tumor. Age older than 10 years and lymph node involvement were unfavorable prognostic factors.[<a class="bk_pop" href="#CDR0000062792_rl_130_77">77</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335132/" class="def">Level of evidence: 2A</a>] A small series (N = 7) of rhabdomyosarcoma patients with peritoneal dissemination and/or malignant ascites had good outcome with whole-abdomen irradiation using IMRT with dose painting.[<a class="bk_pop" href="#CDR0000062792_rl_130_78">78</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335144/" class="def">Level of evidence: 3iiA</a>] This technique involves simultaneously irradiating the whole abdomen with a lower dose than that used for the primary tumor (or resection-bed); the larger volume receives a lower (fractional) daily dose than the high-dose target receives.</p><p id="CDR0000062792__559">With rhabdomyosarcoma of the
|
|
<i><b>biliary tree</b></i>, total resection is rarely feasible and standard treatment includes chemotherapy and RT. Outcome for patients with this primary site is
|
|
good despite residual disease after surgery. External biliary drains
|
|
significantly increase the risk of postoperative infectious complications.
|
|
Thus, external biliary drainage is not warranted.[<a class="bk_pop" href="#CDR0000062792_rl_130_79">79</a>]</p><p id="CDR0000062792__560">Patients with rhabdomyosarcoma arising from tissue around the <i><b>perineum</b></i> or <i><b>anus</b></i> usually have advanced disease. These patients have a high likelihood of regional lymph node involvement, and about half of the tumors have alveolar histology.[<a class="bk_pop" href="#CDR0000062792_rl_130_80">80</a>] The current recommendation is to sample the regional lymph nodes. When feasible and without unacceptable morbidity, removing all gross tumor before chemotherapy improves the likelihood of cure. In Intergroup Rhabdomyosarcoma Study Group (IRSG) Protocols I through IV, the OS rate after aggressive therapy for 71 patients with tumors in this location was 49%, best for patients in Stage 2 (small tumors, negative regional nodes), intermediate for those in Stage 3, and worst for those in Stage 4 at diagnosis.[<a class="bk_pop" href="#CDR0000062792_rl_130_81">81</a>] In a subsequent report from the German CWS trials, 32 patients had an EFS and OS of 47% at 5 years; in addition, patients with embryonal histology fared significantly better than did patients with alveolar histology.[<a class="bk_pop" href="#CDR0000062792_rl_130_82">82</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335150/" class="def">Level of evidence: 3iiiA</a>] However, with the goal of organ preservation, patients with tumors of the perineum/anus are preferentially managed with chemotherapy and RT without aggressive surgery, which may result in loss of sphincter control.</p></div><div id="CDR0000062792__561"><h4>Genitourinary system</h4><p id="CDR0000062792__562">Primary sites for childhood rhabdomyosarcoma within the genitourinary system
|
|
include the paratesticular area, bladder, prostate, kidney, vulva, vagina, and uterus.
|
|
Specific considerations for the surgical and radiotherapeutic management of tumors arising at each
|
|
of these sites are discussed in the paragraphs below.[<a class="bk_pop" href="#CDR0000062792_rl_130_83">83</a>]</p><p id="CDR0000062792__563">Lesions occurring adjacent to the <i><b>testis or spermatic cord</b></i> and up to the internal inguinal ring should be removed by
|
|
orchiectomy with resection of the spermatic cord, utilizing an inguinal
|
|
incision with proximal vascular control (i.e., radical orchiectomy).[<a class="bk_pop" href="#CDR0000062792_rl_130_84">84</a>] Resection of hemiscrotal skin is required when there is tumor fixation or
|
|
invasion, or when a previous transscrotal biopsy has been performed.
|
|
For patients with incompletely removed paratesticular tumors that require RT, temporarily repositioning the contralateral testicle into the adjacent thigh before scrotal radiation therapy may preserve hormone production.[<a class="bk_pop" href="#CDR0000062792_rl_130_85">85</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335152/" class="def">Level of evidence: 3iiiC</a>]</p><p id="CDR0000062792__564">Paratesticular tumors have a relatively high incidence of
|
|
lymphatic spread (26% in IRS-I and IRS-II),[<a class="bk_pop" href="#CDR0000062792_rl_130_67">67</a>] and all patients with paratesticular primary tumors should have
|
|
thin-cut abdominal and pelvic CT scans with contrast
|
|
to evaluate nodal involvement. For patients who have Group I disease, are younger than 10 years, and in whom CT scans show no evidence of lymph node enlargement,
|
|
retroperitoneal node biopsy/sampling is unnecessary, but a repeat CT scan
|
|
every 3 months is recommended.[<a class="bk_pop" href="#CDR0000062792_rl_130_86">86</a>,<a class="bk_pop" href="#CDR0000062792_rl_130_87">87</a>] For patients with suggestive or
|
|
positive CT scans, retroperitoneal lymph node sampling (but not formal node
|
|
dissection) is recommended, and treatment is based on the findings of this
|
|
procedure.[<a class="bk_pop" href="#CDR0000062792_rl_130_3">3</a>,<a class="bk_pop" href="#CDR0000062792_rl_130_27">27</a>,<a class="bk_pop" href="#CDR0000062792_rl_130_88">88</a>] A staging ipsilateral retroperitoneal lymph
|
|
node dissection is currently required for all children 10 years and older with paratesticular rhabdomyosarcoma on COG-STS studies. However, node dissection is not routine in Europe for adolescents with
|
|
resected paratesticular rhabdomyosarcoma. Many European investigators
|
|
rely on radiographic rather than surgical-pathologic assessment of retroperitoneal
|
|
lymph node involvement.[<a class="bk_pop" href="#CDR0000062792_rl_130_84">84</a>,<a class="bk_pop" href="#CDR0000062792_rl_130_86">86</a>] It appears, however, that the ability of the CT
|
|
scan to predict the presence of lymph node involvement needs further study.[<a class="bk_pop" href="#CDR0000062792_rl_130_89">89</a>]
|
|
</p><p id="CDR0000062792__565">Bladder preservation is a major goal of therapy for patients with tumors
|
|
arising in the <i><b>bladder and/or prostate</b></i>. Two important reviews provide information about the historical, current, and future treatment approaches for patients with bladder and prostate rhabdomyosarcomas.[<a class="bk_pop" href="#CDR0000062792_rl_130_90">90</a>,<a class="bk_pop" href="#CDR0000062792_rl_130_91">91</a>] </p><p id="CDR0000062792__579">In rare cases, the tumor is confined to
|
|
the dome of the bladder and can be completely resected. Otherwise, to preserve
|
|
a functional bladder in patients with gross residual disease, chemotherapy and
|
|
RT have been used in North America and some parts of Europe to reduce tumor bulk,[<a class="bk_pop" href="#CDR0000062792_rl_130_92">92</a>,<a class="bk_pop" href="#CDR0000062792_rl_130_93">93</a>] followed, when
|
|
necessary, by a more limited surgical procedure such as partial cystectomy.[<a class="bk_pop" href="#CDR0000062792_rl_130_94">94</a>]
|
|
Early experience with this approach was disappointing, with only 20% to 40% of
|
|
patients with bladder/prostate tumors remaining alive and with functional
|
|
bladders 3 years after diagnosis (3-year OS was 70% in IRS-II).[<a class="bk_pop" href="#CDR0000062792_rl_130_94">94</a>,<a class="bk_pop" href="#CDR0000062792_rl_130_95">95</a>] The later experience from IRS-III and IRS-IV, which used
|
|
more intensive chemotherapy and RT, showed 55% of patients alive
|
|
with functional bladders at 3 years postdiagnosis, with 3-year OS
|
|
exceeding 80%.[<a class="bk_pop" href="#CDR0000062792_rl_130_93">93</a>,<a class="bk_pop" href="#CDR0000062792_rl_130_96">96</a>,<a class="bk_pop" href="#CDR0000062792_rl_130_97">97</a>] Patients with a primary tumor of the bladder/prostate who present with a large pelvic mass resulting from a distended bladder caused by outlet obstruction at diagnosis receive RT to a volume defined by imaging studies after initial chemotherapy to relieve outlet obstruction. This approach to therapy remains generally
|
|
accepted, with the belief that more effective chemotherapy and RT
|
|
will continue to increase the frequency of bladder salvage. </p><p id="CDR0000062792__580">The initial
|
|
surgical procedure in most patients consists of a biopsy, which often can be
|
|
performed using ultrasound guidance or cystoscopy, or by a direct-vision transanal
|
|
route. In selected cases in one series, bladder-conserving surgery plus brachytherapy for boys with prostate or bladder-neck rhabdomyosarcoma led to excellent survival, bladder preservation, and short-term functional results.[<a class="bk_pop" href="#CDR0000062792_rl_130_33">33</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335151/" class="def">Level of evidence: 3iiiB</a>] For patients with biopsy-proven, residual malignant tumor after
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chemotherapy and RT, appropriate surgical management may include
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partial cystectomy, prostatectomy, or exenteration (usually approached anteriorly with
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preservation of the rectum).
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Very few studies have objective long-term assessments of bladder function, and urodynamic studies are important to obtain accurate evaluation of bladder function.[<a class="bk_pop" href="#CDR0000062792_rl_130_98">98</a>]</p><p id="CDR0000062792__720">An alternative strategy, used in European SIOP protocols, has been to avoid major radical surgery when possible and omit external-beam RT if complete disappearance of tumor can be achieved by chemotherapy and conservative surgical procedures. The goal is to preserve a functional bladder and prostate without incurring the late effects of RT or having to perform a total cystectomy/prostatectomy. From 1984 to 2003, 172 patients with nonmetastatic bladder and/or bladder/prostate rhabdomyosarcoma were accrued, and the 5-year overall survival rate was 77%. Fifty percent of the 119 survivors had no significant local therapy, and only 26% received RT.[<a class="bk_pop" href="#CDR0000062792_rl_130_99">99</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335144/" class="def">Level of evidence: 3iiA</a>]</p><p id="CDR0000062792__566">In patients who have been treated with chemotherapy and RT for rhabdomyosarcoma arising in the bladder/prostate region, the
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presence of well-differentiated rhabdomyoblasts in surgical specimens or
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biopsies obtained after treatment does not appear to be associated with a high
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risk of recurrence and is not an indication for a major surgical procedure such as
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total cystectomy.[<a class="bk_pop" href="#CDR0000062792_rl_130_96">96</a>,<a class="bk_pop" href="#CDR0000062792_rl_130_100">100</a>,<a class="bk_pop" href="#CDR0000062792_rl_130_101">101</a>] One study suggested that in patients with residual bladder tumors with
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histologic evidence of maturation, additional courses of chemotherapy should be given before cystectomy is considered.[<a class="bk_pop" href="#CDR0000062792_rl_130_96">96</a>]
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Surgery should be considered only if malignant tumor cells do not disappear
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over time after initial chemotherapy and RT. Because of very
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limited data, it is unclear whether this situation is analogous for patients
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with rhabdomyosarcoma arising in other parts of the body.</p><p id="CDR0000062792__606">The <i><b>kidney</b></i> is occasionally the primary site for rhabdomyosarcoma; six cases were identified from among 5,746 eligible patients enrolled on IRSG protocols. The tumors were large (mean widest diameter, 12.7 cm), and anaplasia was present in four (67%) patients. Three patients with grossly complete tumor removal at diagnosis survived; the three with incomplete removal and gross or metastatic disease died of infection or metastatic tumor.[<a class="bk_pop" href="#CDR0000062792_rl_130_102">102</a>]</p><p id="CDR0000062792__567">For patients with genitourinary primary tumors of the <i><b>vulva/vagina/uterus</b></i>, the
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initial surgical procedure is usually a vulvar or transvaginal biopsy. Initial radical surgery is not indicated for rhabdomyosarcoma of the vulva/vagina/uterus.[<a class="bk_pop" href="#CDR0000062792_rl_130_3">3</a>] Conservative
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surgical intervention for vaginal rhabdomyosarcoma, with primary chemotherapy
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and adjunctive radiation (often brachytherapy) for residual disease (Group II or III), results in excellent
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5-year survival rates.[<a class="bk_pop" href="#CDR0000062792_rl_130_103">103</a>,<a class="bk_pop" href="#CDR0000062792_rl_130_104">104</a>]; [<a class="bk_pop" href="#CDR0000062792_rl_130_105">105</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335138/" class="def">Level of evidence: 3iA</a>] </p><p id="CDR0000062792__581">In the <a href="http://cancer.gov/clinicaltrials/search/view?version=healthprofessional&cdrid=347078" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">COG-ARST0331</a> study, there was an unacceptably high rate of local recurrences in girls with Group III vaginal tumors who did not receive RT.[<a class="bk_pop" href="#CDR0000062792_rl_130_104">104</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335158/" class="def">Level of evidence: 3iiiDiii</a>] Therefore, the COG-STS recommends that RT be administered to patients with residual viable vaginal tumor, beginning at week 24.</p><p id="CDR0000062792__582">Because of the smaller number of patients with
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uterine rhabdomyosarcoma, it is difficult to make a definitive treatment
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decision, but chemotherapy with or without RT is also effective.[<a class="bk_pop" href="#CDR0000062792_rl_130_103">103</a>,<a class="bk_pop" href="#CDR0000062792_rl_130_106">106</a>] Twelve of 14 girls with primary cervical embryonal (mainly botryoid) rhabdomyosarcoma were disease-free after VAC (vincristine, dactinomycin, and cyclophosphamide) chemotherapy and conservative surgery. Of note, two girls also had a pleuropulmonary blastoma and another had Sertoli-Leydig cell tumor.[<a class="bk_pop" href="#CDR0000062792_rl_130_107">107</a>]
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Exenteration is usually not required for primary tumors at these sites, but if
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needed, it may be done, with rectal preservation possible in most cases.
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</p><p id="CDR0000062792__642">Girls with genitourinary primary tumors should have their ovaries shielded or possibly moved, in an effort to preserve fertility when they are receiving RT to the lower abdomen and pelvis. </p></div><div id="CDR0000062792__568"><h4>Unusual primary sites</h4><p id="CDR0000062792__569">Rhabdomyosarcoma occasionally arises in sites other than those discussed above. Patients with localized primary rhabdomyosarcoma of the <i><b>brain</b></i> can occasionally be cured using a combination of tumor excision, RT, and chemotherapy.[<a class="bk_pop" href="#CDR0000062792_rl_130_108">108</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335158/" class="def">Level of evidence: 3iiiDiii</a>]</p><p id="CDR0000062792__570">Patients with <i><b>laryngeal</b></i> rhabdomyosarcoma will usually be treated with chemotherapy and RT after biopsy in an attempt to preserve the larynx.[<a class="bk_pop" href="#CDR0000062792_rl_130_109">109</a>]</p><p id="CDR0000062792__571">Patients with <i><b>diaphragm</b></i> tumors often have locally advanced disease that is not grossly resectable initially because of fixation to adjacent vital structures such as the lung, great vessels, pericardium, and/or liver. In such circumstances, chemotherapy and RT should be initiated after diagnostic biopsy, with the intent to consider removal of residual tumor at a later date if feasible.[<a class="bk_pop" href="#CDR0000062792_rl_130_110">110</a>]</p><p id="CDR0000062792__573">Two well-documented cases of primary <i><b>ovarian</b></i> rhabdomyosarcoma (one Stage III and one Stage IV) have been reported to supplement the eight previously reported patients. These two patients were alive at 20 and 8 months after diagnosis. Six of the previously reported eight patients had died of their disease.[<a class="bk_pop" href="#CDR0000062792_rl_130_111">111</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335158/" class="def">Level of evidence: 3iiiDiii</a>] Treatment with combination chemotherapy followed by removal of the residual mass or masses can sometimes be successful.[<a class="bk_pop" href="#CDR0000062792_rl_130_111">111</a>]</p></div><div id="CDR0000062792__574"><h4>Metastatic sites</h4><p id="CDR0000062792__575">Primary resection of metastatic disease at diagnosis (Stage 4, M1, Group IV) is rarely indicated.</p><p id="CDR0000062792__604"> The CWS Group
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reviewed four consecutive trials and identified 29 patients with M1 embryonal rhabdomyosarcoma and metastasis limited to the lung at diagnosis. They reported approximately 38% 5-year EFS for the cohort and did not identify any benefit for local control of pulmonary metastasis, whether by lung irradiation (n = 9), pulmonary metastasectomy (n = 3), or no targeted pulmonary therapy (n = 19).[<a class="bk_pop" href="#CDR0000062792_rl_130_112">112</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335150/" class="def">Level of evidence: 3iiiA</a>]</p><p id="CDR0000062792__576">The IRSG reviewed 46 IRS-IV (1991–1997) patients with metastatic disease at diagnosis confined to the lungs. Only 11 (24%) had a biopsy of the lung, including six at the time of primary diagnosis. They were compared with 234 patients with single non-lung metastatic sites or multiple other sites of metastases. The lung-only patients were more likely to have embryonal rhabdomyosarcoma and parameningeal primary tumors than the larger group of 234 patients, and were less likely to have regional lymph node disease at diagnosis. FFS and OS rates at 4 years were 35% and 42%, respectively, better than for those with two or more sites of metastases (<i>P</i> = .005 and .002, respectively). Being younger than 10 years at diagnosis was also a favorable prognostic factor. Lung irradiation was recommended by the protocols for the lung-only group, but many did not receive it. Those who did receive lung irradiation had better FFS and OS at 4 years than those who did not (<i>P</i> = .01 and <i>P</i> = .039, respectively).[<a class="bk_pop" href="#CDR0000062792_rl_130_113">113</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335151/" class="def">Level of evidence: 3iiiB</a>]</p></div></div><div id="CDR0000062792__133"><h3>Chemotherapy Treatment Options</h3><p id="CDR0000062792__134"> All children with rhabdomyosarcoma should receive
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chemotherapy. The intensity and duration of the chemotherapy are dependent on
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the Risk Group assignment.[<a class="bk_pop" href="#CDR0000062792_rl_130_114">114</a>] See <a class="figpopup" href="/books/NBK65802.1/table/CDR0000062792__348/?report=objectonly" target="object" rid-figpopup="figCDR0000062792348" rid-ob="figobCDR0000062792348">Table 4</a> in the <a href="#CDR0000062792__128">Stage Information</a> section for more information about Risk Groups.</p><p id="CDR0000062792__634">Adolescents treated with therapy for rhabdomyosarcoma experience less hematologic toxicity and more peripheral nerve toxicity than do younger patients.[<a class="bk_pop" href="#CDR0000062792_rl_130_115">115</a>]</p><div id="CDR0000062792__137"><h4> Low-risk patients</h4><h5><span class="title"> Standard treatment options </span></h5><ul id="CDR0000062792__116"><li class="half_rhythm"><div> Low-risk patients have localized (nonmetastatic) embryonal histology tumors in favorable sites that have been grossly resected (Groups I and II), embryonal tumors in the orbit that have not been completely resected (Group III), and localized tumors in an unfavorable site that have been grossly resected (Groups I and II). (See <a class="figpopup" href="/books/NBK65802.1/table/CDR0000062792__257/?report=objectonly" target="object" rid-figpopup="figCDR0000062792257" rid-ob="figobCDR0000062792257">Table 3</a> in the <a href="#CDR0000062792__128">Stage Information</a> section of this summary.) Certain subgroups of low-risk patients have achieved survival rates higher than 90% when treated with a two-drug chemotherapy regimen that includes vincristine and dactinomycin (VA) plus RT for residual tumor. See Table 6 below.</div></li></ul><div id="CDR0000062792__278" class="table"><h3><span class="title">Table 6. Characteristics of Low-Risk Patients with High Survival Rates Using Two-Drug Therapy with Vincristine and Dactinomycin With or Without Radiation Therapy (Subset A)</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK65802.1/table/CDR0000062792__278/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__CDR0000062792__278_lrgtbl__"><table class="no_margin"><thead><tr><th colspan="1" rowspan="1" style="vertical-align:top;">Site</th><th colspan="1" rowspan="1" style="vertical-align:top;">Size</th><th colspan="1" rowspan="1" style="vertical-align:top;">Group</th><th colspan="1" rowspan="1" style="vertical-align:top;">Nodes</th></tr></thead><tbody><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Favorable</td><td colspan="1" rowspan="1" style="vertical-align:top;">Any</td><td colspan="1" rowspan="1" style="vertical-align:top;">I, IIA</td><td colspan="1" rowspan="1" style="vertical-align:top;">N0</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Orbital</td><td colspan="1" rowspan="1" style="vertical-align:top;">Any</td><td colspan="1" rowspan="1" style="vertical-align:top;">I, II, III</td><td colspan="1" rowspan="1" style="vertical-align:top;">N0</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Unfavorable</td><td colspan="1" rowspan="1" style="vertical-align:top;">≤5 cm</td><td colspan="1" rowspan="1" style="vertical-align:top;">I</td><td colspan="1" rowspan="1" style="vertical-align:top;">N0</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">N0 = absence of nodal spread.</p></div></dd></dl></div></div></div><p id="CDR0000062792__507">The <a href="http://cancer.gov/clinicaltrials/search/view?version=healthprofessional&cdrid=65542" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">COG-D9602</a> study stratified 388 patients with low-risk embryonal rhabdomyosarcoma into two groups.[<a class="bk_pop" href="#CDR0000062792_rl_130_116">116</a>] Treatment for subgroup A patients (n = 264; Stage 1 Group I/IIA, Stage 2 Group I, and Stage 1 Group III orbit) consisted of VA with or without RT for 48 weeks. Patients with subgroup B disease (n = 78; Stage 1 Group IIB/C, Stage I Group III nonorbit, Stage 2 Group II, and Stage 3 Group I/II disease) received VAC (total cumulative dose of 28.6 g/m<sup>2</sup>). Radiation doses were reduced from 41.4 Gy to 36 Gy for Stage 1 Group IIA patients and from 50 Gy or 59 Gy to 45 Gy for Group III orbit patients. For subgroup A patients, the 5-year overall FFS rate was 89% and the OS rate was 97%. For subgroup B patients, the 5-year FFS rate was 85% and the OS rate was 93%.</p><p id="CDR0000062792__279">Other subgroups of low-risk patients have achieved survival rates of at least 90% with three-drug chemotherapy with VAC (total cyclophosphamide dose of 28.6 g/m<sup>2</sup>) plus RT for residual tumor. See Table 7 below.</p><div id="CDR0000062792__280" class="table"><h3><span class="title">Table 7. Characteristics of Low-Risk Patients with High Survival Rates Using Three-Drug Therapy with Vincristine, Dactinomycin, and Cyclophosphamide With or Without
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Radiation Therapy (Subset B)</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK65802.1/table/CDR0000062792__280/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__CDR0000062792__280_lrgtbl__"><table class="no_margin"><thead><tr><th colspan="1" rowspan="1" style="vertical-align:top;">Site</th><th colspan="1" rowspan="1" style="vertical-align:top;">Size</th><th colspan="1" rowspan="1" style="vertical-align:top;">Group</th><th colspan="1" rowspan="1" style="vertical-align:top;">Nodes</th></tr></thead><tbody><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Favorable (orbital or non-orbital)</td><td colspan="1" rowspan="1" style="vertical-align:top;">Any</td><td colspan="1" rowspan="1" style="vertical-align:top;">IIB, IIC, III</td><td colspan="1" rowspan="1" style="vertical-align:top;">N0, N1</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Unfavorable</td><td colspan="1" rowspan="1" style="vertical-align:top;">≤5 cm</td><td colspan="1" rowspan="1" style="vertical-align:top;">II </td><td colspan="1" rowspan="1" style="vertical-align:top;">N0</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Unfavorable</td><td colspan="1" rowspan="1" style="vertical-align:top;">>5 cm</td><td colspan="1" rowspan="1" style="vertical-align:top;">I, II</td><td colspan="1" rowspan="1" style="vertical-align:top;">N0, N1</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">N0 = absence of nodal spread; N1 = presence of regional nodal spread beyond the primary site.</p></div></dd></dl></div></div></div><p id="CDR0000062792__745">The <a href="http://cancer.gov/clinicaltrials/search/view?version=healthprofessional&cdrid=347078" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">COG-ARST0331</a> trial treated 271 newly diagnosed patients with low-risk rhabdomyosarcoma, defined as patients with Stage 1 or Stage 2 tumors; Group I or Group II embryonal tumors; and Stage 1, Group III orbital embryonal tumors, with a shorter duration chemotherapy regimen that included four cycles of VAC chemotherapy followed by 10 weeks of therapy with vincristine and dactinomycin. The 3-year FFS rate was 89% and the OS rate was 98%. Thus, shorter duration of therapy did not appear to compromise outcome in these patients.[<a class="bk_pop" href="#CDR0000062792_rl_130_117">117</a>] </p></div><div id="CDR0000062792__234"><h4>Intermediate-risk patients</h4><h5><span class="title">Standard treatment options</span></h5><ul id="CDR0000062792__235"><li class="half_rhythm"><div class="half_rhythm">In IRS-IV, intermediate-risk patients had survival
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rates at 3 years from 84% to 88%. This category includes patients with embryonal
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rhabdomyosarcoma at unfavorable sites (Stages 2 and 3) with gross residual disease (i.e.,
|
|
Group III), and patients with nonmetastatic alveolar
|
|
rhabdomyosarcoma (Stages 2 and 3) at any site (Groups I, II, and III). The IRS-IV study randomly assigned intermediate-risk patients to receive either standard VAC therapy or one of two other
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chemotherapy regimens using ifosfamide as the alkylating agent. Outcomes with VAC were as good as the other two regimens and easier to administer. Because
|
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there was no difference in outcome between these three treatments, confirming VAC as the standard chemotherapy combination for children with intermediate-risk
|
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rhabdomyosarcoma.[<a class="bk_pop" href="#CDR0000062792_rl_130_27">27</a>] </div><div class="half_rhythm">A comparison of survival in patients with tumors of embryonal
|
|
histology treated on IRS-IV (who received higher doses of alkylating agents) compared with similar patients treated on IRS-III (who received lower
|
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doses of alkylating agents) suggested a benefit with the use of higher doses of cyclophosphamide for certain groups of
|
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intermediate-risk patients. These included patients with tumors at favorable
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sites and positive lymph nodes, patients with gross residual disease, or patients with tumors at unfavorable sites who underwent grossly complete
|
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resections, but not patients with unresected embryonal rhabdomyosarcoma at
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unfavorable sites.[<a class="bk_pop" href="#CDR0000062792_rl_130_118">118</a>] For other groups of intermediate-risk patients, an intensification of cyclophosphamide was feasible but did not improve outcome.[<a class="bk_pop" href="#CDR0000062792_rl_130_119">119</a>]</div></li><li class="half_rhythm"><div class="half_rhythm">The COG has also evaluated whether the addition of topotecan and cyclophosphamide to standard VAC therapy improved outcome for children with intermediate-risk rhabdomyosarcoma. Topotecan was prioritized for evaluation on the basis of its preclinical activity in rhabdomyosarcoma xenograft models as well as its single-agent activity in previously untreated children with rhabdomyosarcoma, particularly those with alveolar rhabdomyosarcoma.[<a class="bk_pop" href="#CDR0000062792_rl_130_120">120</a>,<a class="bk_pop" href="#CDR0000062792_rl_130_121">121</a>] Furthermore, the combination of cyclophosphamide and topotecan demonstrated substantial activity both in patients with recurrent disease and in newly diagnosed patients with metastatic disease.[<a class="bk_pop" href="#CDR0000062792_rl_130_122">122</a>,<a class="bk_pop" href="#CDR0000062792_rl_130_123">123</a>] The <a href="http://cancer.gov/clinicaltrials/search/view?version=healthprofessional&cdrid=67157" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">COG-D9803</a> clinical trial for newly diagnosed patients with intermediate-risk disease randomly assigned patients to receive either VAC therapy or VAC therapy with additional courses of topotecan and cyclophosphamide. However, patients who received topotecan and cyclophosphamide fared no better than those treated with VAC alone; 4-year FFS was 73% with VAC and 68% with VAC/VTC (vincristine, topotecan, and cyclophosphamide).[<a class="bk_pop" href="#CDR0000062792_rl_130_122">122</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335125/" class="def">Level of evidence: 1iiA</a>] Thus, VAC is still the standard form of multiagent chemotherapy for intermediate-risk patients.</div></li><li class="half_rhythm"><div class="half_rhythm"> In a limited-institution pilot study, a combination of vincristine/doxorubicin/cyclophosphamide (VDC) alternating with ifosfamide/etoposide (IE) was used to treat patients with intermediate-risk rhabdomyosarcoma. The relative efficacy of this approach versus the standard approach would require further investigation.[<a class="bk_pop" href="#CDR0000062792_rl_130_124">124</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000561227/" class="def">Level of evidence: 3iiiA</a>] </div></li><li class="half_rhythm"><div class="half_rhythm">Approximately 20% of Group III patients will have a residual mass at the completion of therapy. The presence of a residual mass had no adverse prognostic significance.[<a class="bk_pop" href="#CDR0000062792_rl_130_125">125</a>,<a class="bk_pop" href="#CDR0000062792_rl_130_126">126</a>] Aggressive alternative therapy may not be warranted for rhabdomyosarcoma patients with a residual mass at the end of planned therapy. For Group III patients, best response to initial chemotherapy had no impact on overall outcome.[<a class="bk_pop" href="#CDR0000062792_rl_130_126">126</a>] While induction chemotherapy is commonly administered for 9 to 12 weeks, 2.2% of patients with intermediate-risk rhabdomyosarcoma on the IRS-IV and <a href="http://cancer.gov/clinicaltrials/search/view?version=healthprofessional&cdrid=67157" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">COG-D9803</a> studies were found to have early disease progression and did not receive their planned course of RT.[<a class="bk_pop" href="#CDR0000062792_rl_130_127">127</a>] COG investigators are now studying the value of early administration of RT in patients of intermediate risk.</div></li><li class="half_rhythm"><div class="half_rhythm">In a European trial (<a href="http://cancer.gov/clinicaltrials/search/view?version=healthprofessional&cdrid=65228" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">SIOP-MMT-95</a>) of 457 patients with incompletely resected embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma, undifferentiated sarcoma, or soft tissue primitive neuroectodermal tumor, the addition of carboplatin, epirubicin, and etoposide to standard ifosfamide, vincristine, and dactinomycin (IVA) therapy did not improve outcome (3-year OS for IVA was 82%; 3-year OS for IVA plus carboplatin, epirubicin, and etoposide was 80%).[<a class="bk_pop" href="#CDR0000062792_rl_130_128">128</a>]</div></li></ul></div><div id="CDR0000062792__239"><h4>High-risk patients</h4><h5><span class="title">Standard treatment options</span></h5><ul id="CDR0000062792__240"><li class="half_rhythm"><div class="half_rhythm"> High-risk patients have metastatic disease in one or more sites at diagnosis (Stage IV). These patients continue to have a relatively poor prognosis (5-year survival rate of 50% or lower) with current therapy, and new approaches to treatment are needed to improve survival in this group.[<a class="bk_pop" href="#CDR0000062792_rl_130_113">113</a>,<a class="bk_pop" href="#CDR0000062792_rl_130_129">129</a>,<a class="bk_pop" href="#CDR0000062792_rl_130_130">130</a>] Two retrospective studies have looked at patients who present with metastases limited to the lungs;[<a class="bk_pop" href="#CDR0000062792_rl_130_112">112</a>,<a class="bk_pop" href="#CDR0000062792_rl_130_113">113</a>] results are summarized in the <a href="#CDR0000062792__574">Metastatic sites</a> section of this summary.</div><div class="half_rhythm">A pooled analysis of 788 high-risk rhabdomyosarcoma patients treated with multiagent chemotherapy (all regimens used cyclophosphamide or ifosfamide plus dactinomycin and vincristine with or without additional chemotherapeutic agents), followed by local therapy (surgery with or without RT) within 3 to 5 months of starting chemotherapy, identified several adverse prognostic factors. These were age younger than 1 year, age 10 years or older, unfavorable primary site, bone and/or bone marrow involvement, and three or more different metastatic sites. The EFS rate at 3 years was 50% for patients without any of these adverse prognostic factors. The EFS rates were 42% for patients with one adverse prognostic factor, 18% for patients with two adverse prognostic factors, 12% for patients three adverse prognostic factors, and 5% for patients with four adverse prognostic factors (<i>P</i> < .0001).[<a class="bk_pop" href="#CDR0000062792_rl_130_131">131</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335150/" class="def">Level of evidence: 3iiiA</a>]</div><div class="half_rhythm">The standard systemic therapy for children with metastatic rhabdomyosarcoma is the three-drug combination of VAC. Despite many clinical trials attempting to improve outcome by adding additional agents to standard VAC chemotherapy (or substituting new agents for one or more components of VAC chemotherapy), to date, no chemotherapy regimens have been shown to be more effective than VAC, including the following: <dl id="CDR0000062792__471" class="temp-labeled-list"><dt>-</dt><dd><p class="no_top_margin">In the IRS-IV study, three combinations of drug pairs were studied in an <i>up-front window</i>—IE, vincristine/melphalan (VM),[<a class="bk_pop" href="#CDR0000062792_rl_130_132">132</a>] and ifosfamide/doxorubicin (ID).[<a class="bk_pop" href="#CDR0000062792_rl_130_133">133</a>] These patients received VAC after the up-front window agents were evaluated at weeks 6 and 12. OS rates for patients treated with IE and ID were comparable (31% and 34%, respectively) and better than for those treated with VM (22%).[<a class="bk_pop" href="#CDR0000062792_rl_130_133">133</a>] However, results with VAC chemotherapy for Stage IV rhabdomyosarcoma in the North American experience are similar. </p></dd><dt>-</dt><dd><p class="no_top_margin">Results from a phase II window trial of patients with metastatic disease at presentation and treated with topotecan and cyclophosphamide showed activity for this two-drug combination, but survival was not different from that seen with previous regimens.[<a class="bk_pop" href="#CDR0000062792_rl_130_122">122</a>,<a class="bk_pop" href="#CDR0000062792_rl_130_123">123</a>] An up-front window trial of topotecan in previously untreated children and adolescents with metastatic rhabdomyosarcoma gave similar results.[<a class="bk_pop" href="#CDR0000062792_rl_130_121">121</a>]</p></dd><dt>-</dt><dd><p class="no_top_margin"> Irinotecan and irinotecan with vincristine [<a class="bk_pop" href="#CDR0000062792_rl_130_134">134</a>] have also been evaluated as up-front windows by the COG-STS; the response rates were better when irinotecan was administered with vincristine than without it, but again, survival in a preliminary analysis was not improved
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over prior experience.[<a class="bk_pop" href="#CDR0000062792_rl_130_134">134</a>]</p></dd><dt>-</dt><dd><p class="no_top_margin">In a French study, 20 patients with metastatic disease at diagnosis received window therapy with doxorubicin for two courses. Thirteen of 20 patients responded to therapy, and four patients had progressive disease.[<a class="bk_pop" href="#CDR0000062792_rl_130_135">135</a>]</p></dd><dt>-</dt><dd><p class="no_top_margin">A study from the International Society of Pediatric Oncology (SIOP) demonstrated continued poor outcome for patients with high-risk features such as age 10 years and older or bone/bone marrow involvement. This study compared a standard six-drug combination followed by vincristine, doxorubicin, cyclophosphamide (VDC) maintenance versus an arm that evaluated a window of single-agent doxorubicin or carboplatin followed by sequential high-dose monotherapy courses including cyclophosphamide, etoposide, and carboplatin followed by maintenance VAC. No benefit was seen for the high-dose therapy arm.[<a class="bk_pop" href="#CDR0000062792_rl_130_136">136</a>]</p></dd></dl></div></li></ul><div id="CDR0000062792__349"><h5>Alternative Therapies</h5><ul id="CDR0000062792__350"><li class="half_rhythm"><div> High-dose chemotherapy with autologous and allogeneic stem cell rescue has been evaluated in a limited number of patients with rhabdomyosarcoma.[<a class="bk_pop" href="#CDR0000062792_rl_130_137">137</a>-<a class="bk_pop" href="#CDR0000062792_rl_130_139">139</a>]; [<a class="bk_pop" href="#CDR0000062792_rl_130_140">140</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335150/" class="def">Level of evidence: 3iiiA</a>] The use of this modality has failed to improve the outcomes of patients with newly diagnosed or recurrent rhabdomyosarcoma.[<a class="bk_pop" href="#CDR0000062792_rl_130_139">139</a>]</div></li></ul></div><div id="CDR0000062792__241"><h5>Treatment options under clinical evaluation</h5><p id="CDR0000062792__242">The following is an example of a national and/or institutional clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the <a href="http://www.cancer.gov/about-cancer/treatment/clinical-trials" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCI website</a>.</p><ul id="CDR0000062792__243"><li class="half_rhythm"><div>The NCI's intramural Pediatric Oncology Branch conducted a study of consolidative immunotherapy incorporating T-cell reconstitution followed by a dendritic-cell plus tumor-peptide vaccine that was given with little toxicity to patients with translocation-positive metastatic or recurrent Ewing sarcoma and alveolar rhabdomyosarcoma.[<a class="bk_pop" href="#CDR0000062792_rl_130_141">141</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335150/" class="def">Level of evidence: 3iiiA</a>] </div></li></ul></div></div></div><div id="CDR0000062792__TrialSearch_130_sid_5"><h3>Current Clinical Trials</h3><p id="CDR0000062792__TrialSearch_130_20">Check the list of NCI-supported cancer clinical trials that are now accepting patients with
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<a href="http://www.cancer.gov/search/ClinicalTrialsLink.aspx?Diagnosis=41431&tt=1&format=2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">previously untreated childhood rhabdomyosarcoma</a>. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.</p><p id="CDR0000062792__TrialSearch_130_21">General information about clinical trials is also available from the <a href="http://www.cancer.gov/about-cancer/treatment/clinical-trials" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCI website</a>.</p></div><div id="CDR0000062792_rl_130"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000062792_rl_130_1">Leaphart C, Rodeberg D: Pediatric surgical oncology: management of rhabdomyosarcoma. Surg Oncol 16 (3): 173-85, 2007. 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[<a href="/pmc/articles/PMC3020959/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3020959</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19470937" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19470937</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_130_127">Minn AY, Lyden ER, Anderson JR, et al.: Early treatment failure in intermediate-risk rhabdomyosarcoma: results from IRS-IV and D9803--a report from the Children's Oncology Group. J Clin Oncol 28 (27): 4228-32, 2010. [<a href="/pmc/articles/PMC2953975/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2953975</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20713850" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20713850</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_130_128">Oberlin O, Rey A, Sanchez de Toledo J, et al.: Randomized comparison of intensified six-drug versus standard three-drug chemotherapy for high-risk nonmetastatic rhabdomyosarcoma and other chemotherapy-sensitive childhood soft tissue sarcomas: long-term results from the International Society of Pediatric Oncology MMT95 study. J Clin Oncol 30 (20): 2457-65, 2012. [<a href="https://pubmed.ncbi.nlm.nih.gov/22665534" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22665534</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_130_129">Crist W, Gehan EA, Ragab AH, et al.: The Third Intergroup Rhabdomyosarcoma Study. J Clin Oncol 13 (3): 610-30, 1995. [<a href="https://pubmed.ncbi.nlm.nih.gov/7884423" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7884423</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_130_130">Breneman JC, Lyden E, Pappo AS, et al.: Prognostic factors and clinical outcomes in children and adolescents with metastatic rhabdomyosarcoma--a report from the Intergroup Rhabdomyosarcoma Study IV. J Clin Oncol 21 (1): 78-84, 2003. [<a href="https://pubmed.ncbi.nlm.nih.gov/12506174" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12506174</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_130_131">Oberlin O, Rey A, Lyden E, et al.: Prognostic factors in metastatic rhabdomyosarcomas: results of a pooled analysis from United States and European cooperative groups. J Clin Oncol 26 (14): 2384-9, 2008. [<a href="/pmc/articles/PMC4558625/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4558625</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18467730" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18467730</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_130_132">Breitfeld PP, Lyden E, Raney RB, et al.: Ifosfamide and etoposide are superior to vincristine and melphalan for pediatric metastatic rhabdomyosarcoma when administered with irradiation and combination chemotherapy: a report from the Intergroup Rhabdomyosarcoma Study Group. J Pediatr Hematol Oncol 23 (4): 225-33, 2001. [<a href="https://pubmed.ncbi.nlm.nih.gov/11846301" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11846301</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_130_133">Sandler E, Lyden E, Ruymann F, et al.: Efficacy of ifosfamide and doxorubicin given as a phase II "window" in children with newly diagnosed metastatic rhabdomyosarcoma: a report from the Intergroup Rhabdomyosarcoma Study Group. Med Pediatr Oncol 37 (5): 442-8, 2001. [<a href="https://pubmed.ncbi.nlm.nih.gov/11745872" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11745872</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_130_134">Pappo AS, Lyden E, Breitfeld P, et al.: Two consecutive phase II window trials of irinotecan alone or in combination with vincristine for the treatment of metastatic rhabdomyosarcoma: the Children's Oncology Group. J Clin Oncol 25 (4): 362-9, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17264331" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17264331</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_130_135">Bergeron C, Thiesse P, Rey A, et al.: Revisiting the role of doxorubicin in the treatment of rhabdomyosarcoma: an up-front window study in newly diagnosed children with high-risk metastatic disease. Eur J Cancer 44 (3): 427-31, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/18215514" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18215514</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_130_136">McDowell HP, Foot AB, Ellershaw C, et al.: Outcomes in paediatric metastatic rhabdomyosarcoma: results of The International Society of Paediatric Oncology (SIOP) study MMT-98. Eur J Cancer 46 (9): 1588-95, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/20338746" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20338746</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_130_137">Admiraal R, van der Paardt M, Kobes J, et al.: High-dose chemotherapy for children and young adults with stage IV rhabdomyosarcoma. Cochrane Database Syst Rev (12): CD006669, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/21154373" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21154373</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_130_138">Peinemann F, Kröger N, Bartel C, et al.: High-dose chemotherapy followed by autologous stem cell transplantation for metastatic rhabdomyosarcoma--a systematic review. PLoS One 6 (2): e17127, 2011. [<a href="/pmc/articles/PMC3044147/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3044147</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21373200" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21373200</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_130_139">Thiel U, Koscielniak E, Blaeschke F, et al.: Allogeneic stem cell transplantation for patients with advanced rhabdomyosarcoma: a retrospective assessment. Br J Cancer 109 (10): 2523-32, 2013. [<a href="/pmc/articles/PMC3833217/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3833217</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24149176" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24149176</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_130_140">Klingebiel T, Boos J, Beske F, et al.: Treatment of children with metastatic soft tissue sarcoma with oral maintenance compared to high dose chemotherapy: report of the HD CWS-96 trial. Pediatr Blood Cancer 50 (4): 739-45, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/18286501" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18286501</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_130_141">Mackall CL, Rhee EH, Read EJ, et al.: A pilot study of consolidative immunotherapy in patients with high-risk pediatric sarcomas. Clin Cancer Res 14 (15): 4850-8, 2008. [<a href="/pmc/articles/PMC2497450/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2497450</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18676758" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18676758</span></a>]</div></li></ol></div></div><div id="CDR0000062792__85"><h2 id="_CDR0000062792__85_">Recurrent Childhood Rhabdomyosarcoma</h2><p id="CDR0000062792__86">Although patients with recurrent or progressive rhabdomyosarcoma sometimes
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achieve complete remission with secondary therapy, the long-term prognosis
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is usually poor.[<a class="bk_pop" href="#CDR0000062792_rl_85_1">1</a>,<a class="bk_pop" href="#CDR0000062792_rl_85_2">2</a>] The prognosis is most
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favorable (5-year survival rates, 50%–70%) for children who initially
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present with Stage 1 or Group I disease and embryonal histology and who have small tumors, and for those who have a local or regional nodal recurrence.[<a class="bk_pop" href="#CDR0000062792_rl_85_1">1</a>-<a class="bk_pop" href="#CDR0000062792_rl_85_3">3</a>] A retrospective analysis of children with recurrence after initial presentation with localized rhabdomyosarcoma of the orbit reported 80% survival 5 years after recurrence with aggressive retrieval therapy.[<a class="bk_pop" href="#CDR0000062792_rl_85_4">4</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335144/" class="def">Level of evidence: 3iiA</a>] The small number of children with botryoid
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histology who relapse have a similarly favorable prognosis.[<a class="bk_pop" href="#CDR0000062792_rl_85_1">1</a>] Most other
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children who relapse have an extremely poor prognosis.[<a class="bk_pop" href="#CDR0000062792_rl_85_1">1</a>] A retrospective review of rhabdomyosarcoma patients from German soft tissue sarcoma trials identified time to recurrence as an important independent prognostic factor. Shorter time to recurrence was associated with higher risk of mortality from recurrent rhabdomyosarcoma.[<a class="bk_pop" href="#CDR0000062792_rl_85_5">5</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335145/" class="def">Level of evidence: 3iiB</a>] European investigators performed a retrospective review of patients with rhabdomyosarcoma enrolled on cooperative group trials who experienced recurrence. They identified metastatic (as opposed to local) recurrence, prior radiation therapy, initial tumor size (>5 cm), and time to relapse (<18 months) as unfavorable prognostic features for survival after recurrence.[<a class="bk_pop" href="#CDR0000062792_rl_85_6">6</a>] In a retrospective review from the German Cooperative Soft Tissue Sarcoma Group, patients with alveolar rhabdomyosarcoma who relapsed with a single-disease focus and who received subsequent multiagent chemotherapy plus adequate local-relapse therapy (complete resection or gross resection with radiation therapy) had a better probability of long-term disease control than did patients with disseminated recurrences and/or tumors treated without adequate local-relapse therapy.[<a class="bk_pop" href="#CDR0000062792_rl_85_7">7</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335144/" class="def">Level of evidence: 3iiA</a>] </p><p id="CDR0000062792__263">The selection of
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further treatment depends on many factors, including the site(s) of recurrence,
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previous treatment, and individual patient considerations. Treatment for local or regional recurrence may include wide local excision or aggressive surgical removal of tumor, particularly in the absence of widespread bony metastases.[<a class="bk_pop" href="#CDR0000062792_rl_85_8">8</a>,<a class="bk_pop" href="#CDR0000062792_rl_85_9">9</a>] Some survivors have also been reported after surgical removal of only one or a few metastases in the lung.[<a class="bk_pop" href="#CDR0000062792_rl_85_8">8</a>] Radiation therapy should be considered for patients who have not already received radiation therapy in the area of recurrence, or rarely for those who have received radiation therapy but for whom surgical excision is not possible. Previously unused, active, single agents or combinations of drugs may also enhance the likelihood of disease control.</p><p id="CDR0000062792__248"><b>The following standard chemotherapy regimens have been used to treat recurrent rhabdomyosarcoma: </b></p><ul id="CDR0000062792__249"><li class="half_rhythm"><div>Carboplatin/etoposide.[<a class="bk_pop" href="#CDR0000062792_rl_85_10">10</a>]</div></li><li class="half_rhythm"><div>Ifosfamide, carboplatin, and etoposide.[<a class="bk_pop" href="#CDR0000062792_rl_85_11">11</a>,<a class="bk_pop" href="#CDR0000062792_rl_85_12">12</a>]</div></li><li class="half_rhythm"><div>Cyclophosphamide/topotecan.[<a class="bk_pop" href="#CDR0000062792_rl_85_13">13</a>]</div></li><li class="half_rhythm"><div>Irinotecan with or without vincristine.[<a class="bk_pop" href="#CDR0000062792_rl_85_14">14</a>-<a class="bk_pop" href="#CDR0000062792_rl_85_17">17</a>] A Children's Oncology Group (COG) prospective, randomized, up-front window trial, <a href="http://cancer.gov/clinicaltrials/search/view?version=healthprofessional&cdrid=68954" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">COG-ARST0121</a>, showed no difference between vincristine plus irinotecan (20 mg/m<sup>2</sup>/d) daily × 5 days for 4 weeks per 6-week treatment cycle (Regimen 1A) and irinotecan (50 mg/m<sup>2</sup>/d) daily × 5 days for 2 weeks per 6-week treatment cycle (Regimen 1B) in poor-risk patients with relapsed or progressive rhabdomyosarcoma. At 1 year after initiation of treatment for recurrence, the failure-free survival (FFS) rate was 37% and the overall survival rate (OS) was 55% for Regimen 1A; the FFS rate was 38% and OS rate was 60% for Regimen 1B. The Soft Tissue Sarcoma Committee of the COG recommended the more convenient Regimen 1B for further investigation.[<a class="bk_pop" href="#CDR0000062792_rl_85_18">18</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335125/" class="def">Level of evidence: 1iiA</a>]</div></li><li class="half_rhythm"><div>Single-agent vinorelbine. In one phase II trial, four of eleven patients with recurrent rhabdomyosarcoma responded to single-agent vinorelbine.[<a class="bk_pop" href="#CDR0000062792_rl_85_19">19</a>] In another trial, 6 of 12 young patients (aged 9–29 years) had a partial response.[<a class="bk_pop" href="#CDR0000062792_rl_85_20">20</a>]</div></li><li class="half_rhythm"><div>Vinorelbine and cyclophosphamide. In a pilot study, three of nine patients with rhabdomyosarcoma had an objective response.[<a class="bk_pop" href="#CDR0000062792_rl_85_21">21</a>] In a phase II study in France (N = 50), children with recurrent or refractory rhabdomyosarcoma were treated with vinorelbine and low-dose oral cyclophosphamide. Four complete responses and 14 partial responses were observed, for an objective response rate of 36%.[<a class="bk_pop" href="#CDR0000062792_rl_85_22">22</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000587991/" class="def">Level of evidence: 3iiiDiv</a>]</div></li><li class="half_rhythm"><div>Gemcitabine and docetaxel. In a single institution trial, two patients (N = 5) with recurrent rhabdomyosarcoma achieved an objective response.[<a class="bk_pop" href="#CDR0000062792_rl_85_23">23</a>]</div></li><li class="half_rhythm"><div>Rapamycin.[<a class="bk_pop" href="#CDR0000062792_rl_85_24">24</a>]</div></li><li class="half_rhythm"><div>Topotecan, vincristine, and doxorubicin.[<a class="bk_pop" href="#CDR0000062792_rl_85_25">25</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000587991/" class="def">Level of evidence: 3iiiDiv</a>]</div></li><li class="half_rhythm"><div>Vincristine, irinotecan, and temozolomide. One of four patients with recurrent alveolar rhabdomyosarcoma had a complete radiographic response sustained for 27 weeks with no grade 3 or 4 toxicities.[<a class="bk_pop" href="#CDR0000062792_rl_85_26">26</a>]; [<a class="bk_pop" href="#CDR0000062792_rl_85_27">27</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335158/" class="def">Level of evidence: 3iiiDiii</a>]</div></li></ul><p id="CDR0000062792__250"><b>Treatment options under clinical evaluation for recurrent rhabdomyosarcoma: </b></p><p id="CDR0000062792__719">The following are examples of national and/or institutional clinical trials that are currently being conducted. Information about ongoing clinical trials is available from the <a href="http://www.cancer.gov/about-cancer/treatment/clinical-trials" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCI website</a>.</p><ul id="CDR0000062792__251"><li class="half_rhythm"><div>Intensive chemotherapy followed by autologous bone marrow transplantation. Very intensive chemotherapy followed by autologous bone marrow reinfusion is also under investigation for patients with recurrent rhabdomyosarcoma. However, a review of the published data did not determine a significant benefit for patients who underwent this salvage treatment approach.[<a class="bk_pop" href="#CDR0000062792_rl_85_28">28</a>-<a class="bk_pop" href="#CDR0000062792_rl_85_30">30</a>]</div></li><li class="half_rhythm"><div>New agents under
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clinical evaluation in phase I and phase II trials should be considered for
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relapsed patients.</div></li></ul><div id="CDR0000062792__TrialSearch_85_sid_6"><h3>Current Clinical Trials</h3><p id="CDR0000062792__TrialSearch_85_20">Check the list of NCI-supported cancer clinical trials that are now accepting patients with
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<a href="http://www.cancer.gov/search/ClinicalTrialsLink.aspx?Diagnosis=43196&tt=1&format=2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">recurrent childhood rhabdomyosarcoma</a>. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.</p><p id="CDR0000062792__TrialSearch_85_21">General information about clinical trials is also available from the <a href="http://www.cancer.gov/about-cancer/treatment/clinical-trials" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCI website</a>.</p></div><div id="CDR0000062792_rl_85"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000062792_rl_85_1">Pappo AS, Anderson JR, Crist WM, et al.: Survival after relapse in children and adolescents with rhabdomyosarcoma: A report from the Intergroup Rhabdomyosarcoma Study Group. J Clin Oncol 17 (11): 3487-93, 1999. [<a href="https://pubmed.ncbi.nlm.nih.gov/10550146" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10550146</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_85_2">Mazzoleni S, Bisogno G, Garaventa A, et al.: Outcomes and prognostic factors after recurrence in children and adolescents with nonmetastatic rhabdomyosarcoma. Cancer 104 (1): 183-90, 2005. [<a href="https://pubmed.ncbi.nlm.nih.gov/15895378" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15895378</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_85_3">Dantonello TM, Int-Veen C, Winkler P, et al.: Initial patient characteristics can predict pattern and risk of relapse in localized rhabdomyosarcoma. J Clin Oncol 26 (3): 406-13, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/18202417" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18202417</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_85_4">Raney B, Huh W, Hawkins D, et al.: Outcome of patients with localized orbital sarcoma who relapsed following treatment on Intergroup Rhabdomyosarcoma Study Group (IRSG) Protocols-III and -IV, 1984-1997: a report from the Children's Oncology Group. Pediatr Blood Cancer 60 (3): 371-6, 2013. [<a href="/pmc/articles/PMC5140272/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5140272</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22961750" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22961750</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_85_5">Mattke AC, Bailey EJ, Schuck A, et al.: Does the time-point of relapse influence outcome in pediatric rhabdomyosarcomas? Pediatr Blood Cancer 52 (7): 772-6, 2009. [<a href="https://pubmed.ncbi.nlm.nih.gov/19165889" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19165889</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_85_6">Chisholm JC, Marandet J, Rey A, et al.: Prognostic factors after relapse in nonmetastatic rhabdomyosarcoma: a nomogram to better define patients who can be salvaged with further therapy. J Clin Oncol 29 (10): 1319-25, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/21357778" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21357778</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_85_7">Dantonello TM, Int-Veen C, Schuck A, et al.: Survival following disease recurrence of primary localized alveolar rhabdomyosarcoma. Pediatr Blood Cancer 60 (8): 1267-73, 2013. [<a href="https://pubmed.ncbi.nlm.nih.gov/23418028" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23418028</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_85_8">Hayes-Jordan A, Doherty DK, West SD, et al.: Outcome after surgical resection of recurrent rhabdomyosarcoma. J Pediatr Surg 41 (4): 633-8; discussion 633-8, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16567168" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16567168</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_85_9">De Corti F, Bisogno G, Dall'Igna P, et al.: Does surgery have a role in the treatment of local relapses of non-metastatic rhabdomyosarcoma? Pediatr Blood Cancer 57 (7): 1261-5, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/21826783" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21826783</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_85_10">Klingebiel T, Pertl U, Hess CF, et al.: Treatment of children with relapsed soft tissue sarcoma: report of the German CESS/CWS REZ 91 trial. Med Pediatr Oncol 30 (5): 269-75, 1998. [<a href="https://pubmed.ncbi.nlm.nih.gov/9544222" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9544222</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_85_11">Kung FH, Desai SJ, Dickerman JD, et al.: Ifosfamide/carboplatin/etoposide (ICE) for recurrent malignant solid tumors of childhood: a Pediatric Oncology Group Phase I/II study. J Pediatr Hematol Oncol 17 (3): 265-9, 1995. [<a href="https://pubmed.ncbi.nlm.nih.gov/7620926" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7620926</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_85_12">Van Winkle P, Angiolillo A, Krailo M, et al.: Ifosfamide, carboplatin, and etoposide (ICE) reinduction chemotherapy in a large cohort of children and adolescents with recurrent/refractory sarcoma: the Children's Cancer Group (CCG) experience. Pediatr Blood Cancer 44 (4): 338-47, 2005. [<a href="https://pubmed.ncbi.nlm.nih.gov/15503297" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15503297</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_85_13">Saylors RL 3rd, Stine KC, Sullivan J, et al.: Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: a Pediatric Oncology Group phase II study. J Clin Oncol 19 (15): 3463-9, 2001. [<a href="https://pubmed.ncbi.nlm.nih.gov/11481351" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11481351</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_85_14">Cosetti M, Wexler LH, Calleja E, et al.: Irinotecan for pediatric solid tumors: the Memorial Sloan-Kettering experience. J Pediatr Hematol Oncol 24 (2): 101-5, 2002. [<a href="https://pubmed.ncbi.nlm.nih.gov/11990694" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11990694</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_85_15">Pappo AS, Lyden E, Breitfeld P, et al.: Two consecutive phase II window trials of irinotecan alone or in combination with vincristine for the treatment of metastatic rhabdomyosarcoma: the Children's Oncology Group. J Clin Oncol 25 (4): 362-9, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17264331" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17264331</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_85_16">Vassal G, Couanet D, Stockdale E, et al.: Phase II trial of irinotecan in children with relapsed or refractory rhabdomyosarcoma: a joint study of the French Society of Pediatric Oncology and the United Kingdom Children's Cancer Study Group. J Clin Oncol 25 (4): 356-61, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17264330" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17264330</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_85_17">Furman WL, Stewart CF, Poquette CA, et al.: Direct translation of a protracted irinotecan schedule from a xenograft model to a phase I trial in children. J Clin Oncol 17 (6): 1815-24, 1999. [<a href="https://pubmed.ncbi.nlm.nih.gov/10561220" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10561220</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_85_18">Mascarenhas L, Lyden ER, Breitfeld PP, et al.: Randomized phase II window trial of two schedules of irinotecan with vincristine in patients with first relapse or progression of rhabdomyosarcoma: a report from the Children's Oncology Group. J Clin Oncol 28 (30): 4658-63, 2010. [<a href="/pmc/articles/PMC2974343/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2974343</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20837952" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20837952</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_85_19">Kuttesch JF Jr, Krailo MD, Madden T, et al.: Phase II evaluation of intravenous vinorelbine (Navelbine) in recurrent or refractory pediatric malignancies: a Children's Oncology Group study. Pediatr Blood Cancer 53 (4): 590-3, 2009. [<a href="/pmc/articles/PMC2754403/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2754403</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19533657" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19533657</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_85_20">Casanova M, Ferrari A, Spreafico F, et al.: Vinorelbine in previously treated advanced childhood sarcomas: evidence of activity in rhabdomyosarcoma. Cancer 94 (12): 3263-8, 2002. [<a href="https://pubmed.ncbi.nlm.nih.gov/12115359" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12115359</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_85_21">Casanova M, Ferrari A, Bisogno G, et al.: Vinorelbine and low-dose cyclophosphamide in the treatment of pediatric sarcomas: pilot study for the upcoming European Rhabdomyosarcoma Protocol. Cancer 101 (7): 1664-71, 2004. [<a href="https://pubmed.ncbi.nlm.nih.gov/15378498" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15378498</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_85_22">Minard-Colin V, Ichante JL, Nguyen L, et al.: Phase II study of vinorelbine and continuous low doses cyclophosphamide in children and young adults with a relapsed or refractory malignant solid tumour: good tolerance profile and efficacy in rhabdomyosarcoma--a report from the Société Française des Cancers et leucémies de l'Enfant et de l'adolescent (SFCE). Eur J Cancer 48 (15): 2409-16, 2012. [<a href="https://pubmed.ncbi.nlm.nih.gov/22633624" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22633624</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_85_23">Rapkin L, Qayed M, Brill P, et al.: Gemcitabine and docetaxel (GEMDOX) for the treatment of relapsed and refractory pediatric sarcomas. Pediatr Blood Cancer 59 (5): 854-8, 2012. [<a href="https://pubmed.ncbi.nlm.nih.gov/22302783" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22302783</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_85_24">Houghton PJ, Morton CL, Kolb EA, et al.: Initial testing (stage 1) of the mTOR inhibitor rapamycin by the pediatric preclinical testing program. Pediatr Blood Cancer 50 (4): 799-805, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/17635004" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17635004</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_85_25">Meazza C, Casanova M, Zaffignani E, et al.: Efficacy of topotecan plus vincristine and doxorubicin in children with recurrent/refractory rhabdomyosarcoma. Med Oncol 26 (1): 67-72, 2009. [<a href="https://pubmed.ncbi.nlm.nih.gov/18679836" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18679836</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_85_26">McNall-Knapp RY, Williams CN, Reeves EN, et al.: Extended phase I evaluation of vincristine, irinotecan, temozolomide, and antibiotic in children with refractory solid tumors. Pediatr Blood Cancer 54 (7): 909-15, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/20405511" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20405511</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_85_27">Mixon BA, Eckrich MJ, Lowas S, et al.: Vincristine, irinotecan, and temozolomide for treatment of relapsed alveolar rhabdomyosarcoma. J Pediatr Hematol Oncol 35 (4): e163-6, 2013. [<a href="https://pubmed.ncbi.nlm.nih.gov/22735885" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22735885</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_85_28">Weigel BJ, Breitfeld PP, Hawkins D, et al.: Role of high-dose chemotherapy with hematopoietic stem cell rescue in the treatment of metastatic or recurrent rhabdomyosarcoma. J Pediatr Hematol Oncol 23 (5): 272-6, 2001 Jun-Jul. [<a href="https://pubmed.ncbi.nlm.nih.gov/11464981" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11464981</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_85_29">Admiraal R, van der Paardt M, Kobes J, et al.: High-dose chemotherapy for children and young adults with stage IV rhabdomyosarcoma. Cochrane Database Syst Rev (12): CD006669, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/21154373" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21154373</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062792_rl_85_30">Peinemann F, Kröger N, Bartel C, et al.: High-dose chemotherapy followed by autologous stem cell transplantation for metastatic rhabdomyosarcoma--a systematic review. PLoS One 6 (2): e17127, 2011. [<a href="/pmc/articles/PMC3044147/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3044147</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21373200" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21373200</span></a>]</div></li></ol></div></div><div id="CDR0000062792__148"><h2 id="_CDR0000062792__148_">Changes to This Summary (08/05/2015)</h2><p id="CDR0000062792__154">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="CDR0000062792__755"><b><a href="#CDR0000062792__1">General Information</a></b></p><p id="CDR0000062792__756">Added Crucis et al. as <a href="#CDR0000062792__585">reference 18</a>.</p><p id="CDR0000062792__757">Added <a href="/books/NBK65802.1/#CDR0000062792__588">text</a> about a retrospective analysis of 107 patients from a single institution that examined positron emission tomography scans performed at baseline, after induction chemotherapy, and after local therapy. Standardized uptake value measured at baseline predicted progression-free survival and overall survival, but not local control (cited Casey et al. as reference 60).</p><p id="CDR0000062792__758"><b><a href="#CDR0000062792__130">Previously Untreated Childhood Rhabdomyosarcoma</a></b></p><p id="CDR0000062792__759">Added Ladra et al. as <a href="#CDR0000062792__596">reference 17</a>.</p><p id="CDR0000062792__760">Added <a href="#CDR0000062792__558">text</a> to state that the dose painting technique involves simultaneously irradiating the whole abdomen with a lower dose than that used for the primary tumor (or resection-bed); the larger volume receives a lower (fractional) daily dose than the high-dose target receives.</p><p id="CDR0000062792__disclaimerHP_3">This summary is written and maintained by the <a href="http://www.cancer.gov/publications/pdq/editorial-boards/pediatric-treatment" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PDQ Pediatric Treatment Editorial Board</a>, which is
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editorially independent of NCI. The summary reflects an independent review of
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the literature and does not represent a policy statement of NCI or NIH. More
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information about summary policies and the role of the PDQ Editorial Boards in
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maintaining the PDQ summaries can be found on the <a href="#CDR0000062792__AboutThis_1">About This PDQ Summary</a> and <a href="http://www.cancer.gov/publications/pdq" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PDQ® - NCI's Comprehensive Cancer Database</a> pages.
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</p></div><div id="CDR0000062792__AboutThis_1"><h2 id="_CDR0000062792__AboutThis_1_">About This PDQ Summary</h2><div id="CDR0000062792__AboutThis_2"><h3>Purpose of This Summary</h3><p id="CDR0000062792__AboutThis_3">This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood rhabdomyosarcoma. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.</p></div><div id="CDR0000062792__AboutThis_4"><h3>Reviewers and Updates</h3><p id="CDR0000062792__AboutThis_5">This summary is reviewed regularly and updated as necessary by the <a href="http://www.cancer.gov/publications/pdq/editorial-boards/pediatric-treatment" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PDQ Pediatric Treatment Editorial Board</a>, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).</p><p id="CDR0000062792__AboutThis_22"> Board members review recently published articles each month to determine whether an article should:</p><ul id="CDR0000062792__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="CDR0000062792__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 Childhood Rhabdomyosarcoma Treatment are:</p><ul><li class="half_rhythm"><div>Louis S. Constine, MD (James P. Wilmot Cancer Center at University of Rochester Medical Center)</div></li><li class="half_rhythm"><div>Holcombe Edwin Grier, MD (Dana-Farber Cancer Institute/Boston Children's Hospital)</div></li><li class="half_rhythm"><div>Michael P. LaQuaglia, MD (Memorial Sloan-Kettering Cancer Center)</div></li><li class="half_rhythm"><div>Paul A. Meyers, MD (Memorial Sloan-Kettering Cancer Center)</div></li><li class="half_rhythm"><div>Alberto S. Pappo, MD (St. Jude Children's Research Hospital)</div></li><li class="half_rhythm"><div>R Beverly Raney, MD (Consultant)</div></li><li class="half_rhythm"><div>Stephen J. Shochat, MD (St. Jude Children's Research Hospital)</div></li></ul><p id="CDR0000062792__AboutThis_9">Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's <a href="http://www.cancer.gov/contact/email-us" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Email Us</a>. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.</p></div><div id="CDR0000062792__AboutThis_10"><h3>Levels of Evidence</h3><p id="CDR0000062792__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="CDR0000062792__AboutThis_12"><h3>Permission to Use This Summary</h3><p id="CDR0000062792__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="CDR0000062792__AboutThis_14">The preferred citation for this PDQ summary is:</p><p id="CDR0000062792__AboutThis_15">PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Rhabdomyosarcoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: <a href="http://www.cancer.gov/types/soft-tissue-sarcoma/hp/rhabdomyosarcoma-treatment-pdq" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">http://www.cancer.gov/types/soft-tissue-sarcoma/hp/rhabdomyosarcoma-treatment-pdq</a>. Accessed <MM/DD/YYYY>. [PMID: 26389243]</p><p id="CDR0000062792__AboutThis_16">Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in <a href="http://visualsonline.cancer.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Visuals Online</a>, a collection of over 2,000 scientific images.
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</p></div><div id="CDR0000062792__AboutThis_17"><h3>Disclaimer</h3><p id="CDR0000062792__AboutThis_18">Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the <a href="http://www.cancer.gov/about-cancer/managing-care" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Managing Cancer Care</a> page.</p></div><div id="CDR0000062792__AboutThis_20"><h3>Contact Us</h3><p id="CDR0000062792__AboutThis_21">More information about contacting us or receiving help with the Cancer.gov website can be found on our <a href="http://www.cancer.gov/contact" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Contact Us for Help</a> page. Questions can also be submitted to Cancer.gov through the website’s <a href="http://www.cancer.gov/contact/email-us" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Email Us</a>.</p></div></div></div></div>
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Childhood Rhabdomyosarcoma Treatment (PDQ®): Health Professional Version. 2015 Aug 5. In: PDQ Cancer Information Summaries [Internet]. 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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="#CDR0000062792__1" ref="log$=inpage&link_id=inpage">General Information</a></li><li><a href="#CDR0000062792__13" ref="log$=inpage&link_id=inpage">Cellular Classification</a></li><li><a href="#CDR0000062792__128" ref="log$=inpage&link_id=inpage">Stage Information</a></li><li><a href="#CDR0000062792__129" ref="log$=inpage&link_id=inpage">Treatment Option Overview</a></li><li><a href="#CDR0000062792__130" ref="log$=inpage&link_id=inpage">Previously Untreated Childhood Rhabdomyosarcoma</a></li><li><a href="#CDR0000062792__85" ref="log$=inpage&link_id=inpage">Recurrent Childhood Rhabdomyosarcoma</a></li><li><a href="#CDR0000062792__148" ref="log$=inpage&link_id=inpage">Changes to This Summary (08/05/2015)</a></li><li><a href="#CDR0000062792__AboutThis_1" ref="log$=inpage&link_id=inpage">About This PDQ Summary</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Related publications</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="document-links" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="/books/NBK65839/">Patient Version</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Related information</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="discovery_db_links" 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href="/pubmed/26389330" ref="ordinalpos=1&linkpos=1&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Childhood Craniopharyngioma Treatment (PDQ®): Health Professional Version.</a><span class="source">[PDQ Cancer Information Summari...]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Childhood Craniopharyngioma Treatment (PDQ®): Health Professional Version.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">PDQ Pediatric Treatment Editorial Board. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">PDQ Cancer Information Summaries. 2002</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/29337483" ref="ordinalpos=1&linkpos=2&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Childhood Esthesioneuroblastoma Treatment (PDQ®): Health Professional Version.</a><span class="source">[PDQ Cancer Information Summari...]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Childhood Esthesioneuroblastoma Treatment (PDQ®): Health Professional Version.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">PDQ Pediatric Treatment Editorial Board. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">PDQ Cancer Information Summaries. 2002</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/31593397" ref="ordinalpos=1&linkpos=3&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Childhood Mesothelioma Treatment (PDQ®): Health Professional Version.</a><span class="source">[PDQ Cancer Information Summari...]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Childhood Mesothelioma Treatment (PDQ®): Health Professional Version.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">PDQ Pediatric Treatment Editorial Board. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">PDQ Cancer Information Summaries. 2002</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/38630971" ref="ordinalpos=1&linkpos=4&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Childhood Myelodysplastic Neoplasms Treatment (PDQ®): Health Professional Version.</a><span class="source">[PDQ Cancer Information Summari...]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Childhood Myelodysplastic Neoplasms Treatment (PDQ®): Health Professional Version.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">PDQ Pediatric Treatment Editorial Board. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">PDQ Cancer Information Summaries. 2002</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/31909942" ref="ordinalpos=1&linkpos=5&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Childhood Pheochromocytoma and Paraganglioma Treatment (PDQ®): Health Professional Version.</a><span class="source">[PDQ Cancer Information Summari...]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Childhood Pheochromocytoma and Paraganglioma Treatment (PDQ®): Health Professional Version.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">PDQ Pediatric Treatment Editorial Board. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">PDQ Cancer Information Summaries. 2002</em></div></div></li></ul><a class="seemore" href="/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed_reviews&uid=26389243" ref="ordinalpos=1&log$=relatedreviews_seeall&logdbfrom=pubmed">See reviews...</a><a class="seemore" href="/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed&uid=26389243" ref="ordinalpos=1&log$=relatedarticles_seeall&logdbfrom=pubmed">See all...</a></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Recent Activity</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" 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