General Information

The National Cancer Institute (NCI) provides the PDQ pediatric cancer treatment information summaries as a public service to increase the availability of evidence-based cancer information to health professionals, patients, and the public.

Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975.[1] 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 surgical subspecialists, 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 Pediatric Supportive Care for specific information about supportive care for children and adolescents with cancer.)

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.[2] 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 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 ongoing clinical trials is available from the NCI Web site.

Dramatic improvements in survival have been achieved for children and adolescents with cancer.[1] Between 1975 and 2002, childhood cancer mortality has decreased by more than 50%. For rhabdomyosarcoma, the 5-year survival rate has increased over the same time from 53% to 65% for children younger than 15 years and from 30% to 47% for adolescents aged 15 to 19 years.[1] 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 Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)

Childhood rhabdomyosarcoma, a soft tissue malignant tumor of skeletal muscle origin, accounts for approximately 3.5% of the cases of cancer among children aged 0 to 14 years and 2% of the cases among adolescents and young adults aged 15 to 19 years.[3,4] The incidence is 4.5 per million children and 50% of cases are seen in the first decade of life.[5] There is a bimodal distribution for embryonal rhabdomyosarcoma with the second, smaller peak in adolescence noted for males only. The incidence of alveolar rhabdomyosarcoma does not vary by age or gender.[5] Infants younger than 1 year have a higher incidence of undifferentiated sarcoma, a lower incidence of parameningeal tumors, and a higher incidence of tumors in the trunk and abdomen compared with older patients.[6] Rhabdomyosarcoma is usually curable in most children with localized disease who receive combined modality therapy, with more than 70% surviving 5 years after diagnosis.[7,8,9] Relapses are uncommon after 5 years of disease-free survival, with a 9% late-event rate at 10 years. Relapses, however, are more common for patients who have gross residual disease in unfavorable sites following initial surgery and those who have metastatic disease at diagnosis.[10] The most common primary sites for rhabdomyosarcoma are the head, the genitourinary tract, and the extremities.[7,8] 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.[11] Other less common primary sites include the trunk, chest wall, perineal/anal region, and abdomen including the retroperitoneum and biliary tract.

Most cases of rhabdomyosarcoma occur sporadically, with no recognized predisposing factor or risk factor.[12] For patients with embryonal tumors, high birth weight and large size for gestational age are associated with an increased incidence of rhabdomyosarcoma.[13] Genetic conditions associated with rhabdomyosarcoma include Li-Fraumeni cancer susceptibility syndrome (with germline p53 mutations),[14,15,16] neurofibromatosis type I,[17] Costello syndrome (with germline HRAS mutations),[18,19,20] Beckwith-Wiedemann syndrome (with which Wilms tumor and hepatoblastoma are more commonly associated),[21,22] Noonan syndrome,[23] and MEN2A.[24]

The prognosis for a child or adolescent with rhabdomyosarcoma is related to the age of the patient, site of origin, widest diameter of the tumor, 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 (RT) in selected cases,[7,8,25,26,27,28,29,30,31]; [32][Level of evidence: 3iiiA] as well as unique biological characteristics of rhabdomyosarcoma tumor cells.[33] It is unclear whether response to induction chemotherapy, as judged by anatomic imaging, correlates with the likelihood of survival in patients with rhabdomyosarcoma, as one study found an association and another study did not.[34][Level of evidence: 3iiA]; [35] Examples of both clinical and biological factors with proven or possible prognostic significance are briefly described below.

• Children aged 1 to 9 years have the best prognosis, while those younger and older fare less well. In recent Intergroup Rhabdomyosarcoma Study Group (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.[6]Infants may do poorly because their bone marrows are less tolerant of chemotherapy doses which older children can receive, thus infants are relatively underdosed compared to older patients. In addition, infants younger than 1 year may be less likely to receive radiation therapy for local control, because of concern for the high incidence of complications in this age group. In older children, vincristine and dactinomycin have upper dosage limits based on body surface area and these patients may also require reduced vincristine doses because of neurotoxicity.[9,26,36]Historical data show that adults fare worse than children (5-year overall survival rates, 27% ± 1.4% and 61% ± 1.4%, respectively;P< .0001).[37]
• Primary sites with more favorable prognoses include the orbit and nonparameningeal head and neck, paratestis, vulva, vagina, uterus (nonbladder, nonprostate genitourinary tract), and biliary tract.[7,8,38,39,40]
• Tumor burden at diagnosis has prognostic significance. Patients with smaller tumors (<5 cm) have improved survival compared with children with larger tumors.[7,38]Both tumor volume and maximum tumor diameter are associated with outcome.[34][Level of evidence: 3iiA] 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).[41]This was not confirmed by a Children's Oncology Group study of patients with intermediate-risk rhabdomyosarcoma.[42]This relationship requires prospective study to determine the therapeutic implications of the observation.
• Anaplasia is observed in 13% of cases of rhabdomyosarcoma and its presence may adversely influence clinical outcome in patients with intermediate-risk embryonal rhabdomyosarcoma.[43]
• Children with metastatic disease at diagnosis have the poorest prognosis. The prognostic significance of metastatic disease is modified by tumor histology (embryonal is more favorable than alveolar), the site of metastatic disease, and the number of metastatic sites.[27,44,45]Similarly, patients with metastatic genitourinary (nonbladder, nonprostate) primary tumors have a more favorable outcome than do patients with metastatic disease from primary tumors at other sites.[46]In addition, patients with otherwise localized disease but with proven regional lymph node involvement have a poorer prognosis than do patients without regional nodal involvement.[30,31]
• The extent of disease following the primary surgical procedure (i.e., the Surgico-pathologic Group, formerly called the Clinical Group) is also correlated with outcome.[7]In theIRS-IIIstudy, patients with localized, gross residual disease after initial surgery (Surgico-pathologic Group III) had a 5-year survival rate of approximately 70% compared with a more than 90% 5-year survival rate for patients with no residual tumor after surgery (Group I) and an approximate 80% 5-year survival rate for patients with microscopic residual tumor following surgery (Group II).[7,25]
• The alveolar subtype is more prevalent among patients with less favorable clinical features (e.g., younger than 1 year or older than 10 years, extremity primary tumors, and metastatic disease), and is generally associated with a worse outcome. In the IRS-I andIRS-II (POG-7898)studies, the alveolar subtype was associated with a less favorable outcome even in patients whose primary tumor was completely resected (Group I).[39]Statistically significant differences in survival for histopathologic subtype were not noted when all patients with rhabdomyosarcoma were analyzed,[47,48]and differences were not noted by histologic subtype in a large group of German children with rhabdomyosarcoma.[38]In the IRS-III study, outcome for patients with Group I alveolar subtype tumors was similar to that for other patients with Group I tumors, but the patients with alveolar subtype tumors received more intensive therapy.[7]

  Patients with alveolar rhabdomyosarcoma who have regional lymph node involvement have significantly worse outcomes (5-year failure-free survival [FFS] 43%) than patients who do not have regional lymph node involvement (5-year FFS 73%).[49]

• 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 have a higher incidence of tumors in unfavorable sites compared with children.[37]

Patients with undifferentiated sarcomas were treated in trials coordinated by the IRSG from 1972 until 2006,[50] but they are currently eligible for the nonrhabdomyosarcoma soft tissue sarcoma protocol using agents active in adult soft tissue sarcoma, ifosfamide and doxorubicin (COG-ARST0332). (Refer to the PDQ summary on Childhood Soft Tissue Sarcoma for more information.)

Because treatment and prognosis depend, in part, on the histology and molecular genetics of the tumor, 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. Additionally, the diversity of primary sites, the distinctive surgical and RT 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 therapeutic modalities.

References:

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10.	Sung L, Anderson JR, Donaldson SS, et al.: Late events occurring five years or more after successful therapy for childhood rhabdomyosarcoma: a report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group. Eur J Cancer 40 (12): 1878-85, 2004.
11.	Casanova M, Meazza C, Favini F, et al.: Rhabdomyosarcoma of the extremities: a focus on tumors arising in the hand and foot. Pediatr Hematol Oncol 26 (5): 321-31, 2009 Jul-Aug.
12.	Gurney JG, Young JL Jr, Roffers SD, et al.: Soft tissue sarcomas. In: Ries LA, Smith MA, Gurney JG, et al., eds.: Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. Bethesda, Md: National Cancer Institute, SEER Program, 1999. NIH Pub.No. 99-4649., pp 111-123. Also available online. Last accessed February 02, 2012.
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14.	Li FP, Fraumeni JF Jr: Rhabdomyosarcoma in children: epidemiologic study and identification of a familial cancer syndrome. J Natl Cancer Inst 43 (6): 1365-73, 1969.
15.	Diller L, Sexsmith E, Gottlieb A, et al.: Germline p53 mutations are frequently detected in young children with rhabdomyosarcoma. J Clin Invest 95 (4): 1606-11, 1995.
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18.	Gripp KW, Lin AE, Stabley DL, et al.: HRAS mutation analysis in Costello syndrome: genotype and phenotype correlation. Am J Med Genet A 140 (1): 1-7, 2006.
19.	Aoki Y, Niihori T, Kawame H, et al.: Germline mutations in HRAS proto-oncogene cause Costello syndrome. Nat Genet 37 (10): 1038-40, 2005.
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21.	Samuel DP, Tsokos M, DeBaun MR: Hemihypertrophy and a poorly differentiated embryonal rhabdomyosarcoma of the pelvis. Med Pediatr Oncol 32 (1): 38-43, 1999.
22.	DeBaun MR, Tucker MA: Risk of cancer during the first four years of life in children from The Beckwith-Wiedemann Syndrome Registry. J Pediatr 132 (3 Pt 1): 398-400, 1998.
23.	Moschovi M, Touliatou V, Vassiliki T, et al.: Rhabdomyosarcoma in a patient with Noonan syndrome phenotype and review of the literature. J Pediatr Hematol Oncol 29 (5): 341-4, 2007.
24.	Jones AE, Albano EA, Lovell MA, et al.: Metastatic alveolar rhabdomyosarcoma in multiple endocrine neoplasia type 2A. Pediatr Blood Cancer 55 (6): 1213-6, 2010.
25.	Smith LM, Anderson JR, Qualman SJ, et al.: Which patients with microscopic disease and rhabdomyosarcoma experience relapse after therapy? A report from the soft tissue sarcoma committee of the children's oncology group. J Clin Oncol 19 (20): 4058-64, 2001.
26.	Joshi D, Anderson JR, Paidas C, et al.: Age is an independent prognostic factor in rhabdomyosarcoma: a report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group. Pediatr Blood Cancer 42 (1): 64-73, 2004.
27.	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.
28.	La Quaglia MP, Heller G, Ghavimi F, et al.: The effect of age at diagnosis on outcome in rhabdomyosarcoma. Cancer 73 (1): 109-17, 1994.
29.	Punyko JA, Mertens AC, Baker KS, et al.: Long-term survival probabilities for childhood rhabdomyosarcoma. A population-based evaluation. Cancer 103 (7): 1475-83, 2005.
30.	Lawrence W Jr, Hays DM, Heyn R, et al.: Lymphatic metastases with childhood rhabdomyosarcoma. A report from the Intergroup Rhabdomyosarcoma Study. Cancer 60 (4): 910-5, 1987.
31.	Mandell L, Ghavimi F, LaQuaglia M, et al.: Prognostic significance of regional lymph node involvement in childhood extremity rhabdomyosarcoma. Med Pediatr Oncol 18 (6): 466-71, 1990.
32.	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.
33.	Sorensen PH, Lynch JC, Qualman SJ, et al.: PAX3-FKHR and PAX7-FKHR gene fusions are prognostic indicators in alveolar rhabdomyosarcoma: a report from the children's oncology group. J Clin Oncol 20 (11): 2672-9, 2002.
34.	Ferrari A, Miceli R, Meazza C, et al.: Comparison of the prognostic value of assessing tumor diameter versus tumor volume at diagnosis or in response to initial chemotherapy in rhabdomyosarcoma. J Clin Oncol 28 (8): 1322-8, 2010.
35.	Burke M, Anderson JR, Kao SC, et al.: Assessment of response to induction therapy and its influence on 5-year failure-free survival in group III rhabdomyosarcoma: the Intergroup Rhabdomyosarcoma Study-IV experience--a report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group. J Clin Oncol 25 (31): 4909-13, 2007.
36.	Ferrari A, Casanova M, Bisogno G, et al.: Rhabdomyosarcoma in infants younger than one year old: a report from the Italian Cooperative Group. Cancer 97 (10): 2597-604, 2003.
37.	Sultan I, Qaddoumi I, Yaser S, et al.: Comparing adult and pediatric rhabdomyosarcoma in the surveillance, epidemiology and end results program, 1973 to 2005: an analysis of 2,600 patients. J Clin Oncol 27 (20): 3391-7, 2009.
38.	Koscielniak E, Jürgens H, Winkler K, et al.: Treatment of soft tissue sarcoma in childhood and adolescence. A report of the German Cooperative Soft Tissue Sarcoma Study. Cancer 70 (10): 2557-67, 1992.
39.	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.
40.	Spunt SL, Lobe TE, Pappo AS, et al.: Aggressive surgery is unwarranted for biliary tract rhabdomyosarcoma. J Pediatr Surg 35 (2): 309-16, 2000.
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45.	Dantonello TM, Winkler P, Boelling T, et al.: Embryonal rhabdomyosarcoma with metastases confined to the lungs: report from the CWS Study Group. Pediatr Blood Cancer 56 (5): 725-32, 2011.
46.	Koscielniak E, Rodary C, Flamant F, et al.: Metastatic rhabdomyosarcoma and histologically similar tumors in childhood: a retrospective European multi-center analysis. Med Pediatr Oncol 20 (3): 209-14, 1992.
47.	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.
48.	Meza JL, Anderson J, Pappo AS, et al.: Analysis of prognostic factors in patients with nonmetastatic rhabdomyosarcoma treated on intergroup rhabdomyosarcoma studies III and IV: the Children's Oncology Group. J Clin Oncol 24 (24): 3844-51, 2006.
49.	Rodeberg DA, Garcia-Henriquez N, Lyden ER, et al.: Prognostic significance and tumor biology of regional lymph node disease in patients with rhabdomyosarcoma: a report from the Children's Oncology Group. J Clin Oncol 29 (10): 1304-11, 2011.
50.	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.

Cellular Classification

Rhabdomyosarcoma can be divided into several histologic subsets: embryonal rhabdomyosarcoma, which has embryonal, botryoid, and spindle cell subtypes; alveolar rhabdomyosarcoma; and pleomorphic rhabdomyosarcoma.[1,2]

Embryonal Rhabdomyosarcoma

The embryonal subtype is the most frequently observed subtype in children, accounting for approximately 60% to 70% of rhabdomyosarcomas of childhood.[1] Tumors with embryonal histology typically arise in the head and neck region or in the genitourinary tract, although they may occur at any primary site.

Botryoid and spindle cell subtypes

Botryoid tumors represent about 10% of all rhabdomyosarcoma cases and are embryonal tumors that arise under the mucosal surface of body orifices such as the vagina, bladder, nasopharynx, and biliary tract. The spindle cell variant of embryonal rhabdomyosarcoma is most frequently observed at the paratesticular site.[3] Both the botryoid and the spindle cell subtypes are associated with very favorable outcomes.[2]

Alveolar Rhabdomyosarcoma

Approximately 20% of children with rhabdomyosarcoma have the alveolar subtype. An increased frequency of this subtype is noted in adolescents and in patients with primary sites involving the extremities, trunk, and perineum/perianal region.[1]

To be considered alveolar histology, the tumor must have greater than 50% alveolar elements; if the alveolar component is 50% or less, the tumor is considered embryonal.

Pleomorphic (Anaplastic) Rhabdomyosarcoma

Pleomorphic rhabdomyosarcoma occurs predominantly in adults aged 30 to 50 years and is rarely seen in children.[4] In adults, pleomorphic rhabdomyosarcoma is associated with a worse prognosis. In children, the term anaplasia is preferred.[5] 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.[6]

Molecular Classification

The embryonal and alveolar histologies have distinctive molecular characteristics that have been used for diagnostic confirmation, and may be useful for assigning therapy and monitoring residual disease during treatment.[7,8,9,10,11] Unique translocations between the FKHR gene on chromosome 13 and either the PAX3 gene on chromosome 2 or the PAX7 gene on chromosome 1 are found in 70% to 80% of patients with alveolar histology tumors.[7,12] Translocations involving the PAX3 gene occur in approximately 59% of alveolar rhabdomyosarcoma cases, while the PAX7 gene appears to be involved in about 19% of cases.[7] Patients with solid variant alveolar histology have a lower incidence of PAX-FKHR gene fusions than do patients showing classical alveolar histology.[13]

Alveolar cases associated with the PAX7 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 PAX3 gene rearrangements.[14,15,16,17] Alveolar cases associated with the PAX3 gene are older and have a higher incidence of invasive tumor (T2). Around 22% of cases showing alveolar histology have no detectable PAX gene translocation.[11,13] Embryonal tumors, on the other hand, often show loss of specific genomic material from the short arm of chromosome 11.[12,18,19] The consistent loss of genomic material from the chromosome 11p15 region in embryonal tumors suggests the presence of a tumor suppressor gene, though no such gene has yet been identified. Breakpoints involving the 1p11-1q11 region are relatively common (36%) in embryonal rhabdomyosarcoma.[20]

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) or embryonal tumors.[11,21,22,23] A study has shown that the clinical characteristics and gene profile of translocation-negative alveolar rhabdomyosarcoma is indistinguishable from that seen in embryonal rhabdomyosarcoma cases. In a study of Intergroup 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.[22] However, a German study of 121 patients with alveolar rhabdomyosarcoma found no significant difference in EFS at 5 years among patients who were PAX-FKHR–positive compared with those who were translocation-negative.[24]

A 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.[21]

References:

1.	Parham DM, Ellison DA: Rhabdomyosarcomas in adults and children: an update. Arch Pathol Lab Med 130 (10): 1454-65, 2006.
2.	Newton WA Jr, Gehan EA, Webber BL, et al.: Classification of rhabdomyosarcomas and related sarcomas. Pathologic aspects and proposal for a new classification--an Intergroup Rhabdomyosarcoma Study. Cancer 76 (6): 1073-85, 1995.
3.	Leuschner I: Spindle cell rhabdomyosarcoma: histologic variant of embryonal rhabdomyosarcoma with association to favorable prognosis. Curr Top Pathol 89: 261-72, 1995.
4.	Sultan I, Qaddoumi I, Yaser S, et al.: Comparing adult and pediatric rhabdomyosarcoma in the surveillance, epidemiology and end results program, 1973 to 2005: an analysis of 2,600 patients. J Clin Oncol 27 (20): 3391-7, 2009.
5.	Kodet R, Newton WA Jr, Hamoudi AB, et al.: Childhood rhabdomyosarcoma with anaplastic (pleomorphic) features. A report of the Intergroup Rhabdomyosarcoma Study. Am J Surg Pathol 17 (5): 443-53, 1993.
6.	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.
7.	Barr FG, Smith LM, Lynch JC, et al.: Examination of gene fusion status in archival samples of alveolar rhabdomyosarcoma entered on the Intergroup Rhabdomyosarcoma Study-III trial: a report from the Children's Oncology Group. J Mol Diagn 8 (2): 202-8, 2006.
8.	Kelly KM, Womer RB, Barr FG: Minimal disease detection in patients with alveolar rhabdomyosarcoma using a reverse transcriptase-polymerase chain reaction method. Cancer 78 (6): 1320-7, 1996.
9.	Edwards RH, Chatten J, Xiong QB, et al.: Detection of gene fusions in rhabdomyosarcoma by reverse transcriptase-polymerase chain reaction assay of archival samples. Diagn Mol Pathol 6 (2): 91-7, 1997.
10.	Sartori F, Alaggio R, Zanazzo G, et al.: Results of a prospective minimal disseminated disease study in human rhabdomyosarcoma using three different molecular markers. Cancer 106 (8): 1766-75, 2006.
11.	Davicioni E, Anderson MJ, Finckenstein FG, et al.: Molecular classification of rhabdomyosarcoma--genotypic and phenotypic determinants of diagnosis: a report from the Children's Oncology Group. Am J Pathol 174 (2): 550-64, 2009.
12.	Merlino G, Helman LJ: Rhabdomyosarcoma--working out the pathways. Oncogene 18 (38): 5340-8, 1999.
13.	Parham DM, Qualman SJ, Teot L, et al.: Correlation between histology and PAX/FKHR fusion status in alveolar rhabdomyosarcoma: a report from the Children's Oncology Group. Am J Surg Pathol 31 (6): 895-901, 2007.
14.	Sorensen PH, Lynch JC, Qualman SJ, et al.: PAX3-FKHR and PAX7-FKHR gene fusions are prognostic indicators in alveolar rhabdomyosarcoma: a report from the children's oncology group. J Clin Oncol 20 (11): 2672-9, 2002.
15.	Krsková L, Mrhalová M, Sumerauer D, et al.: Rhabdomyosarcoma: molecular diagnostics of patients classified by morphology and immunohistochemistry with emphasis on bone marrow and purged peripheral blood progenitor cells involvement. Virchows Arch 448 (4): 449-58, 2006.
16.	Kelly KM, Womer RB, Sorensen PH, et al.: Common and variant gene fusions predict distinct clinical phenotypes in rhabdomyosarcoma. J Clin Oncol 15 (5): 1831-6, 1997.
17.	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.
18.	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.
19.	Scrable H, Witte D, Shimada H, et al.: Molecular differential pathology of rhabdomyosarcoma. Genes Chromosomes Cancer 1 (1): 23-35, 1989.
20.	Gordon T, McManus A, Anderson J, et al.: Cytogenetic abnormalities in 42 rhabdomyosarcoma: a United Kingdom Cancer Cytogenetics Group Study. Med Pediatr Oncol 36 (2): 259-67, 2001.
21.	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.
22.	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.
23.	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.
24.	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.

Stage Information

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 done prior to 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 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).

A CT scan of regional lymph nodes should be considered. Enlarged lymph nodes should be biopsied. 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.[1] Positron emission tomography (PET) with fluorine-18-fluorodeoxyglucose (FDG) scans can identify areas of possible metastatic disease not seen by other imaging modalities.[2,3] However, the efficacy of these two procedures for identifying involved lymph nodes or other sites is under evaluation, and these procedures are not required by current treatment protocols.

Terms used in this summary section are defined below in Table 1.

Table 1. Definition of Terms

Term	Definition
Favorable site	Orbit; nonparameningeal head and neck; genitourinary tract excluding kidney, bladder, and prostate; biliary tract.
Unfavorable site	Any site other than favorable.
T1	Tumor confined to anatomic site of origin.
T2	Tumor extension and/or fixation to surrounding tissue.
a	Tumor ≤5 cm in maximum diameter.
b	Tumor >5 cm in maximum diameter.
N0	No clinical regional lymph node involvement.
N1	Clinical regional lymph node involvement.
NX	Regional lymph nodes not examined; no information.
M0	No metastatic disease.
M1	Metastatic disease.

Staging of rhabdomyosarcoma is relatively complex. The process includes the following steps:

1.	Assigning a stage (consider site, size, Surgico-pathologic Group, and presence/absence of metastases).
2.	Assigning a local tumor Surgico-pathologic Group (status postsurgical resection/biopsy, with pathologic assessment of the tumor margin).
3.	Assigning a Risk Group (classified by Stage, Group, and histology).

As noted previously, prognosis for children with rhabdomyosarcoma depends on the primary site, tumor size, Group, and histologic subtype. Favorable prognostic groups were identified in previous Intergroup Rhabdomyosarcoma Study Group (IRSG) studies, and treatment plans were designed on the basis of assignment of patients to different treatment groups according to prognosis. Several years ago, the IRSG merged with the National Wilms Tumor Study Group and with the 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).

Current COG-STS protocols for rhabdomyosarcoma use a TNM-based pretreatment staging system that incorporates the Surgico-pathologic Group, primary tumor site, regional lymph node status, and the presence or absence of metastases. This staging system is described in Table 2 below.[4,5]

Table 2. Soft Tissue Sarcoma Committee of the Children's Oncology Group Pretreatment Staging System

Stage	Sites of Primary Tumor	T Stage	Tumor Size	Regional Lymph Nodes	Distant Metastasis
I	Favorable sites	T1 or T2	Any size	N0 or N1 or NX	M0
II	Unfavorable sites	T1 or T2	a, ≤ 5 cm	N0 or NX	M0
III	Unfavorable sites	T1 or T2	a, ≤ 5 cm	N1	M0
			b, > 5 cm	N0 or N1 or NX
IV	Any site	T1 or T2	Any size	N0 or N1 or NX	M1
M0 = absence of metastatic spread; M1 = presence of metastatic spread beyond the primary site; N0 = absence of nodal spread; N1 = presence of nodal spread beyond the primary site; X = unknown N status.

The IRS-I, IRS-II (POG-7898), and IRS-III studies prescribed treatment plans based on the Surgico-pathologic Group system. In this system, Groups are defined by the extent of disease and by the extent of initial surgical resection after pathologic review of the tumor specimen(s). The definitions for these Groups are shown in Table 3 below.[6,7]

Table 3. Soft Tissue Sarcoma Committee of the Children's Oncology Group Surgico-pathologic Group System

Group	Definition
I (Approximately 13% of all patients are in this group.)	A localized tumor that is completely removed with pathologically clear margins and no regional lymph node involvement.
II (Approximately 20% of all patients are in this group.)	A localized tumor that is grossly removed with (a) microscopic disease at the margin, (b) involved, grossly removed regional lymph nodes,or(c) both (a) and (b).
III (Approximately 48% of all patients are in this group.)	A localized tumor with gross residual disease after incomplete removal or biopsy only.
IV (Approximately 18% of all patients are in this group.)	Distant metastases are present at diagnosis.

After patients are categorized by Stage and Surgico-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.[8,9] Treatment assignment is based on Risk Group, as shown in Table 4. To be considered alveolar histology, the tumor must have greater than 50% alveolar elements; if the alveolar component is 50% or less, the tumor is considered embryonal.

Table 4. Soft Tissue Sarcoma Committee of the Children's Oncology Group Rhabdomyosarcoma Risk Group Classification

Risk Group	Histology	Stage	Group
Low risk	Embryonal	1	I, II, III
	Embryonal	2, 3	I, II
Intermediate risk	Embryonal	2, 3	III
	Alveolar	1, 2, 3	I, II, III
High risk	Embryonal or Alveolar	4	IV

Since 2006, patients with undifferentiated sarcomas are treated on the COG-STS protocol for non-rhabdomyosarcomatous soft tissue sarcoma. Refer to the PDQ summary on Childhood Soft Tissue Sarcoma for more information.

References:

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.
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.
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.
4.	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.
5.	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.
6.	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.
7.	Crist W, Gehan EA, Ragab AH, et al.: The Third Intergroup Rhabdomyosarcoma Study. J Clin Oncol 13 (3): 610-30, 1995.
8.	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.
9.	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.

Treatment Option Overview

All children with rhabdomyosarcoma require multimodality therapy with systemic chemotherapy, in conjunction with either surgery, radiation therapy (RT), or both modalities for local tumor control.[1,2,3] Treatment generally entails surgical resection, if feasible without major functional/cosmetic impairment, followed by chemotherapy. Some patients with initially unresected tumors may undergo second-look surgery to remove residual tumor. Because rhabdomyosarcoma is sensitive to chemotherapy and RT, surgery is delayed if it will result in disfigurement or if it will interfere with organ function. Chemotherapy and possibly RT are administered in advance with the hope that subsequent surgical resection will be successful without undesirable side effects. A second-look procedure is only warranted if complete resection is deemed feasible. RT is indicated for patients with microscopic residual (Group II) disease and gross residual (Group III) disease. It is also recommended for Group I patients with alveolar histology. The discussion of treatment options for children with rhabdomyosarcoma is therefore divided into separate sections describing surgery, chemotherapy, and RT.

The treatment of rhabdomyosarcoma by the Children's Oncology Group and in Europe—as exemplified by trials from the Intergroup Rhabdomyosarcoma Study Group (IRSG), the Children's Oncology Group Soft Tissue Sarcoma Committee (COG-STS), and the International Society of Pediatric Oncology Malignant Mesenchymal Tumor (MMT)—differs in management and overall treatment philosophy.[2] In the MMT trials, a primary objective is to reduce the use of radiation therapy, relying on initial chemotherapy followed by alternate chemotherapy in the event of a poor response to initial therapy and then surgical resection, reserving RT for use 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 especially RT, with their attendant morbidities. Overall survival (OS) is the primary end point, accepting the possibility of an inferior event-free survival (EFS) that might accompany nonaggressive local therapy when compared with more routine and earlier use of surgery and RT. The necessity of second-line salvage therapy for those who relapse is accepted in these trials. Conversely, the primary COG-STS objective has been to employ local therapy soon after initial chemotherapy, using RT for patients with residual disease after initial operation or biopsy only, and for patients with alveolar histology. EFS is the target end point, attempting to avoid relapse and salvage therapy. Results of these two approaches confirm that the IRSG trials resulted in superior EFS and better OS than the most recently published MMT 89 therapy. In some subsets of patients defined by primary site, the survival differences were greater (extremities, nonparameningeal head and neck); in others, the results were largely similar (genitourinary tract). Nevertheless, 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.[1,2,3]

References:

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.
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.
3.	Donaldson SS, Anderson JR: Rhabdomyosarcoma: many similarities, a few philosophical differences. J Clin Oncol 23 (12): 2586-7, 2005.

Previously Untreated Childhood Rhabdomyosarcoma

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ Editorial Boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence.)

Surgical Management Treatment Options

The basic principle for the initial surgical treatment of children with rhabdomyosarcoma is complete resection of the primary tumor with a surrounding margin of normal tissue, along with sampling lymph nodes in the draining nodal basin, provided that major functional/cosmetic impairment will not result.[1][Level of evidence: 3iii] Important exceptions to the rule of normal margins exist (e.g., tumors of the orbit and of the genitourinary region).[2,3] The principle of wide and complete resection of the primary tumor is less applicable to patients known to have metastatic disease at the initial operation, but it is a reasonable concept if easily accomplished. Patients with microscopic residual tumor following their initial excisional procedure appear to have improved prognoses if a second operative procedure to re-excise the primary tumor bed before beginning chemotherapy can achieve complete removal of tumor.[4] There is little evidence that debulking surgery that leaves macroscopic residual tumor improves outcome, compared with biopsy alone.[5][Level of evidence: 2A] Second-look procedures can show whether there is viable tumor after starting treatment; 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).[6] The exact role of second-look surgery remains undefined in rhabdomyosarcoma. Because rhabdomyosarcoma can arise from multiple sites, surgical care must be tailored to the unique aspects of each site. Surgical management of the more common primary sites is provided below.

Head and neck

If the tumors are parameningeal (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 through the dura. If skull erosion and/or transdural extension is equivocal, a computed tomography (CT) scan of the same regions with contrast is indicated. 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. Despite its parameningeal site, middle ear rhabdomyosarcoma has a favorable prognosis.[7]

Rhabdomyosarcomas of the orbit should not undergo exenteration, but biopsy is needed for diagnosis.[8,9] Biopsy is followed by chemotherapy and RT, with orbital exenteration reserved for the small number of patients with locally persistent or recurrent disease.[10,11]

For nonparameningeal and nonorbital head and neck tumors, wide excision of the primary tumor (when feasible) and ipsilateral neck lymph node sampling of clinically involved nodes are appropriate.[12] 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 following chemotherapy and radiation therapy (RT). For patients with head and neck primary tumors that are considered unresectable, chemotherapy and RT are the mainstay of primary management.[7,10,13,14,15,16]

Extremity sites

The definitive surgical procedure involves wide local excision with en bloc removal of a cuff of normal tissue.[2] Complete tumor removal from the hand or foot is not feasible in most cases because of functional impairment.[17][Level of evidence: 3iiA] Primary re-excision may be appropriate in patients whose initial surgical procedure leaves microscopic residual disease that is resectable by a second procedure.[4] Amputation should be avoided because primary RT results in excellent local control.[18][Level of evidence: 3iiiA]

Because of the significant incidence of nodal spread for extremity primary tumors (often without clinical evidence of involvement) and because of the prognostic and therapeutic implications of nodal involvement, extensive pretreatment assessment for regional nodal involvement is warranted.[19,20,21,22] The Children's Oncology Group Soft Tissue Sarcoma Committee (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 prior to sampling of the involved nodal region. Sentinel lymph node (SLN) mapping is employed at some centers to identify the regional nodes that are the most likely to be involved.[22,23,24,25] The contribution of SLN mapping is not yet clearly defined in pediatric patients.

Truncal sites

The surgical management of patients with lesions of the chest wall or abdominal wall 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 therapy and is therefore associated with excellent long-term survival.[26,27,28,29]

Intrathoracic or intraabdominal sarcomas may not be resectable at diagnosis because of the massive size of the tumor and extension into vital organs or vessels.[30] For patients with initially unresectable retroperitoneal/pelvic tumors, complete surgical removal following chemotherapy, with or without RT, offers a significant survival advantage (73% vs. 34% to 44% without removal).[30]

With rhabdomyosarcoma of the biliary tree, total resection is rarely feasible. Outcome 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.[31]

Patients with rhabdomyosarcoma arising from tissue around the perineum or anus usually have advanced disease. These patients have a high likelihood of regional lymph node involvement, and about half of the tumors have alveolar histology. The current recommendation is to sample the lymph nodes. When feasible, without unacceptable morbidity, removing all gross tumor before chemotherapy is begun improves the likelihood of cure. In Intergroup Rhabdomyosarcoma Study Group (IRSG) Protocols I through IV, the OS after aggressive therapy for tumors in this location was 49%.[32]

Genitourinary system

Primary sites for childhood rhabdomyosarcoma within the genitourinary system include the paratesticular area, bladder, prostate, kidney, vagina, uterus, and vulva. Specific considerations for the surgical management of tumors arising at each of these sites are discussed in the paragraphs below.[33]

Lesions occurring adjacent to the testis or spermatic cord and up to the internal inguinal ring should be removed by orchiectomy with resection of the entire spermatic cord, utilizing an inguinal incision with proximal vascular control (i.e., radical orchiectomy).[34] Resection of hemiscrotal skin is required when there is tumor fixation or invasion, or when a previous transscrotal biopsy has been performed. Paratesticular tumors have been found to have a relatively high incidence of lymphatic spread (26% in IRS-I and IRS-II [POG-7898]),[19] 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 are younger than 10 years and who have Group I disease, and whose 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.[35,36] 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.[3,37,38] A staging ipsilateral retroperitoneal lymph node dissection is currently required for all children 10 years and older with paratesticular rhabdomyosarcoma on IRSG and COG-STS studies. Node dissection is not routine in Europe for adolescents with resected paratesticular rhabdomyosarcoma. European investigators tend to rely on radiographic rather than surgico-pathologic assessment of retroperitoneal lymph node involvement.[34,35] It appears, however, that the ability of the CT scan to predict the presence of lymph node involvement needs further study.[39] For patients with incompletely removed paratesticular tumors that require radiation therapy, temporarily repositioning the contralateral testicle into the adjacent thigh prior to scrotal radiation therapy may preserve hormone production.[40][Level of evidence: 3iiiC]

Bladder salvage is a major goal of therapy for patients with tumors arising in the prostate and bladder. An important review providing information about historical, current, and future treatment approaches for prostate and bladder rhabdomyosarcomas has been published.[41] 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 to reduce tumor bulk,[42,43] followed, when necessary, by a more limited surgical procedure such as partial cystectomy.[44] 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 following diagnosis (3-year OS was 70% in IRS-II [POG-7898]).[44,45] The more recent experience from IRS-III and IRS-IV-STAGE- 1, 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%.[43,46,47] Thus, 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. 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. For patients with biopsy-proven, residual malignant tumor following chemotherapy and RT, appropriate surgical management may include partial cystectomy, prostatectomy, or exenteration (usually approached anteriorly with preservation of the rectum). Very few studies have objective long-term assessments of bladder function, and urodynamic studies are important to obtain accurate evaluation of bladder function.[48]

In patients who have been treated with chemotherapy and RT for rhabdomyosarcoma arising in the bladder/prostate region, the presence of well-differentiated rhabdomyoblasts in surgical specimens or biopsies obtained after treatment does not appear to be associated with a high risk of recurrence and is not an indication for a surgical procedure such as total cystectomy.[46,49,50] One study suggested that in patients with residual bladder tumors with histologic evidence of maturation, additional courses of chemotherapy should be given before cystectomy is considered.[46] Surgery should be considered only if malignant tumor cells do not disappear over time following initial chemotherapy and RT. Because of very limited data, it is unclear whether this situation is analogous for patients with rhabdomyosarcoma arising in other parts of the body.

For patients with genitourinary primary tumors of the vagina/vulva/uterus, the initial surgical procedure is usually a transvaginal biopsy. Initial radical surgery is not indicated for rhabdomyosarcoma of the vagina/vulva/uterus.[3] Conservative surgical intervention for vaginal rhabdomyosarcoma, with primary chemotherapy and adjunctive radiation (often brachytherapy) for residual disease (Group IIA or III), results in excellent disease-free survival.[51,52] Because of the smaller number of patients with uterine rhabdomyosarcoma, it is difficult to make a definitive treatment decision, but chemotherapy or RT is also effective.[51,53] Exenteration is usually not required for primary tumors at these sites, but if needed it may be done, with rectal preservation possible in most cases.

Unusual primary sites

Rhabdomyosarcoma occasionally arises in sites other than those discussed above. Patients with localized primary rhabdomyosarcoma of the brain can occasionally be cured using a combination of tumor excision, RT, and chemotherapy.[54][Level of evidence: 3iiiDiii]

Patients with laryngeal rhabdomyosarcoma will usually be treated with chemotherapy and RT after biopsy in an attempt to preserve the larynx.[55]

Patients with diaphragm 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 should be initiated after diagnostic biopsy, with the intent to try to remove residual tumor at a later date.[56]

The kidney is occasionally the primary site for rhabdomyosarcoma or undifferentiated sarcoma; ten cases have been identified from among 5,746 eligible patients (0.17%) enrolled on IRSG protocols. The tumors were large (median diameter, 12 cm), and anaplasia was present in 60% of patients. Six patients with grossly complete tumor removal at diagnosis survived; the four with incomplete removal and gross or metastatic disease died of infection or metastatic tumor.[57]

Two well-documented cases of primary ovarian rhabdomyosarcoma (one stage III and one stage IV) have been reported to supplement the eight previously reported patients. These two cases were alive at 20 and 8 months after diagnosis. Six of the previously reported eight patients had died of their disease.[58][Level of evidence: 3iiiDiii] Treatment with combination chemotherapy followed by removal of the residual mass or masses can sometimes be successful.[58]

Metastatic sites

Primary resection of metastatic disease is rarely indicated.[59] The European Cooperative Rhabdomyosarcoma Study Group reviewed four consecutive trials and identified 29 patients with embryonal rhabdomyosarcoma and metastasis limited to the lung. They reported approximately 40% 5-year EFS for the cohort and did not identify any benefit for local control of the pulmonary metastasis.[60][Level of evidence: 3iiiA]

Chemotherapy Treatment Options

All children with rhabdomyosarcoma should receive chemotherapy. The intensity and duration of the chemotherapy are dependent on the Risk Group assignment.[61]See Table 4 in the Staging Information section for more information on Risk Groups.

Low-risk patients

Standard treatment options

• Low-risk patients have localized (nonmetastatic) embryonal histology tumors in favorable sites that have been grossly resected (Groups I and II), embryonal tumors that have not been completely resected in the orbit (Group III), and localized tumors in an unfavorable site that have been grossly resected (Groups I and II). (SeeTable 3in the Staging Information 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 5 below.

Table 5. Characteristics of Low-Risk Patients with High Survival Rates Using Two-Drug Therapy with VA ± RT (Stratum I)

Site	Size	Group	Nodes
Favorable	Any	I, IIA	N0
Orbital	Any	I, II, III	N0
Unfavorable	≤5 cm	I, IIA	N0

The COG-D9602 study of the Children's Oncology Group stratified 388 patients with low-risk embryonal rhabdomyosarcoma into two groups.[62] 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 VA plus cyclophosphamide (total dose 28.6 g/m²). 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. At 5 years for subgroup A patients, the overall failure-free survival (FFS) rate was 88% and the OS rate was 97%. For subgroup B patients, the 5-year FFS rate was 85% and the OS rate was 93%.

Other subgroups of low-risk patients have achieved survival rates higher than 90% by undergoing three-drug chemotherapy with VA and cyclophosphamide (VAC) plus RT for residual tumor. The total cyclophosphamide dose used in completed COG protocols was 28.6 g/m². See Table 6 below.

Table 6. Characteristics of Low-Risk Patients with High Survival Rates Using Three-Drug Therapy with VAC ± RT (Stratum II)

Site	Size	Group	Nodes
Favorable (orbital or non-orbital)	Any	IIB, IIC, III	N0, N1
Unfavorable	≤5 cm	II	N0
Unfavorable	>5 cm	I, II	N0, N1

Intermediate-risk patients

Standard treatment options

• Intermediate-risk patients have survival rates ranging from 55% to 70%. This category includes patients with embryonal rhabdomyosarcoma at unfavorable sites who have gross residual disease (i.e., Group III), and patients with nonmetastatic alveolar rhabdomyosarcoma at any site. For intermediate-risk patients, vincristine, dactinomycin, and cyclophosphamide (VAC) is the standard chemotherapy treatment.[63,64,65]TheIRS-IV-STAGE-1study randomly assigned patients to receive either standard VAC therapy or one of two other chemotherapy regimens. One regimen combined vincristine and dactinomycin with ifosfamide (VAI),[66]based on the activity of ifosfamide against rhabdomyosarcoma.[67,68]The other regimen combined vincristine with ifosfamide and etoposide.[69]The combination of ifosfamide and etoposide had previously demonstrated substantial activity against rhabdomyosarcoma in phase II trials.[70]In the IRS-IV-STAGE-1 study, there was no difference in outcome between these three treatments, confirming that VAC remains the standard chemotherapy combination for children with intermediate-prognosis rhabdomyosarcoma.[38]

  A comparison of survival in patients with tumors of embryonal histology treated on IRS-IV-STAGE-1 (who received higher doses of alkylating agents) compared with similar patients treated on IRS-III (who received lower doses of alkylating agents) suggested a benefit with the use of higher doses of cyclophosphamide for certain groups of intermediate-risk patients. These included patients with tumors at favorable sites and positive lymph nodes, patients with gross residual disease, or patients with tumors at unfavorable sites who underwent grossly complete resections, but not patients with unresected embryonal rhabdomyosarcoma at unfavorable sites.[71] For other groups of intermediate-risk patients, an intensification of cyclophosphamide was feasible but did not improve outcome.[72]

• The COG has also evaluated whether the addition of topotecan and cyclophosphamide to standard VAC therapy improves 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.[73,74]Furthermore, the combination of cyclophosphamide and topotecan demonstrated substantial activity both in the recurrent disease setting and in newly diagnosed patients with metastatic disease.[75,76]The COG 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.[77][Level of evidence: 1A]
• 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.[78][Level of evidence: 3iiiA]
• For Group III patients, approximately 20% of patients will have a residual mass at the completion of therapy. The presence of a residual mass had no adverse prognostic significance. 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.[79]

Treatment options under clinical evaluation

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 NCI Web site.

• COG-ARST0531(Combination Chemotherapy and Radiation Therapy in Treating Patients With Newly Diagnosed Rhabdomyosarcoma): The COG intermediate-risk rhabdomyosarcoma protocol is comparing standard VAC chemotherapy versus VAC alternating with vincristine and irinotecan (VI). RT begins at week 4 in conjunction with VI to determine the potential benefit of early local therapy in this group of patients.

High-risk patients

Standard treatment options

• 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.[65,80,81]

  In a pooled analysis of high-risk rhabdomyosarcoma patients treated with multiagent chemotherapy (all chemotherapy regimens used a cyclophosphamide or ifosfamide plus dactinomycin and vincristine-based backbone with variation as to the use of additional chemotherapy agents) followed by local therapy (surgery with or without RT) within 3 to 5 months of starting chemotherapy, adverse prognostic factors in patients presenting with metastatic disease included: age younger than 1 year or age 10 years or older, unfavorable primary site, bone and/or bone marrow involvement, and three or more 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.[82][Level of evidence: 3iiiA]

  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:

  • In theIRS-IV-STAGE-1study, three combinations of drug pairs were studied in an up-front window: IE, vincristine/melphalan (VM),[83]and ifosfamide/doxorubicin (ID).[84]These patients received VAC after the up-front window agents were evaluated at weeks 6 and 12. OS for patients treated with IE and ID was comparable (31% and 34%, respectively) and better than those treated with VM (22%).[84]However, results with VAC chemotherapy for stage IV rhabdomyosarcoma in the North American experience are similar.
  • 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.[75,76]An up-front window trial of topotecan in previously untreated children and adolescents with metastatic rhabdomyosarcoma gave similar results.[74]
  • Irinotecan and irinotecan with vincristine[85]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 over prior experience.[85]
  • 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.[86]
  • 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 (VAC) 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.[87]

Alternative Therapies

• High-dose chemotherapy with stem cell rescue has been evaluated in a limited number of patients with rhabdomyosarcoma.[88,89];[90][Level of evidence: 3iiiA] The use of high-dose chemotherapy with stem cell rescue has failed to improve the outcome of patients with newly diagnosed or recurrent rhabdomyosarcoma.

Treatment options under clinical evaluation

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 NCI Web site.

• COG-ARST08P1(Temozolomide, Cixutumumab, and Combination Chemotherapy in Treating Patients With Metastatic Rhabdomyosarcoma): COG-ARST08P1 evaluates the addition of novel therapeutic agents to the intensive chemotherapy used in the COG studyCOG-ARST0431. Newly diagnosed patients with metastatic rhabdomyosarcoma (excluding patients younger than 10 years with embryonal rhabdomyosarcoma) who have an expected FFS of less than 20% are eligible. The study consists of the following three sequential pilots:
  • Pilot 1 assesses the feasibility of adding IMC-A12, a fully human IgG1 monoclonal antibody targeting the insulin-like growth factor-I receptor (IGF-IR), to most known effective chemotherapy agents in rhabdomyosarcoma.
  • Pilot 2 assesses the feasibility of adding temozolomide, an alkylating agent, to vincristine/irinotecan cycles, based on the synergistic activity of temozolomide when added to irinotecan.
  • Pilot 3 will assess the feasibility of adding both agents to the COG-ARST0431 backbone, provided that pilot studies 1 and 2 have not shown unexpected toxicity.
• The NCI's intramural Pediatric Oncology Branch is conducting a study of consolidative immunotherapy incorporating T-cell reconstitution followed by a dendritic-cell plus tumor-peptide vaccine that could be given with little toxicity to patients with translocation-positive metastatic or recurrent Ewing sarcoma and alveolar rhabdomyosarcoma.[91][Level of evidence: 3iiiA]

Radiation Therapy Management Options

RT is an effective method for achieving local control of tumor for patients with microscopic or gross residual disease following biopsy, initial surgical resection, or chemotherapy. In Group II rhabdomyosarcoma patients, over 50% experienced local recurrence associated with noncompliance or omission of RT.[92] Patients with completely resected tumors (Group I) of embryonal histology do well without RT,[63,64] but RT benefits patients with Group I tumors with alveolar or undifferentiated histology.[93] A review of European trials conducted by the Cooperative Soft Tissue Sarcoma Study 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 (defined by tumor histology, tumor size, and tumor site).[94] Local failure is the predominant type of relapse for patients with Group III disease. Patients with tumor-involved regional lymph nodes at diagnosis have a higher risk of local and distant failure compared with patients whose lymph nodes are negative.[95] As with the surgical management of patients with rhabdomyosarcoma, recommendations for RT depend on the site of primary tumor and on the amount of residual disease, if any, following surgical resection. For patients with head and neck rhabdomyosarcoma, four studies reported excellent local control in patients treated with intensity-modulated radiation therapy (IMRT) or fractionated stereotactic radiation therapy and chemotherapy over a 4-year period. 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.[96,97,98,99]; [100][Level of evidence: 3iiiA]

For optimal care of pediatric patients undergoing radiation treatments, it is imperative to have a radiation oncologist, radiation technicians, and nurses who are experienced in treating children. An anesthesiologist may be necessary to help sedate and immobilize young patients. The facility should be equipped with a linear accelerator and have the capabilities to administer electron beam therapy. Computerized treatment planning with a three-dimensional planning system should be available. Techniques to deliver radiation specifically to the tumor while sparing normal tissue (e.g., conformal radiation therapy , IMRT, proton-beam therapy [charged-particle radiation therapy], or brachytherapy) should be considered (see below).[101,102,103]

Standard treatment options

• The RT dose depends predominantly on the amount of residual disease, if any, following the primary surgical resection. In general, patients with microscopic residual disease (Group II) receive RT to approximately 41 Gy,[93,104]though doses from 30 Gy to 40 Gy may be adequate in patients receiving effective multiagent chemotherapy.[105]IRS-II (POG-7898)study patients with gross residual disease (Group III) who received 40 Gy to more than 50 Gy had locoregional relapse rates greater than 30%; higher doses of radiation (>60 Gy) have been associated with unacceptable long-term toxic effects.[106,107]Group III patients on theIRS-IV-STAGE-1standard treatment arm received 50.4 Gy.[108]
• The treated volume should be determined by the extent of tumor at diagnosis prior to surgical resection and prior to chemotherapy. A margin of 2 cm is generally used, including clinically involved regional lymph nodes.[93]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.
• The timing of RT generally allows for chemotherapy to be given for 1 to 3 months before RT is initiated. In COG protocols, patients with parameningeal disease who have evidence of intracranial extension start radiation therapy at the beginning of treatment.[64,109,110]A prospective trial of 26 patients with Group III parameningeal rhabdomyosarcoma achieved good local control and survival with RT administered at the conventional time.[111]RT is usually given for 5 to 6 weeks (e.g., 1.8 Gy per day for 28 treatment days), during which time chemotherapy is usually modified to avoid the radiosensitizing agents dactinomycin and doxorubicin.

The IRSG conducted a randomized study within the IRS-IV-STAGE-1 protocol and showed that giving 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 RT (50.4 Gy vs. 59.4 Gy) given by the twice-daily hyperfractionated schedule. There was no demonstrated advantage in terms of local control.[112] Therefore, conventional RT remains the standard for treating patients with rhabdomyosarcoma and gross residual disease.[38]

Among the modifications of RT for specific primary sites recommended for IRS-IV-STAGE-1 patients were the following:[38,108]

• For patients withorbital tumors, precautions should be taken to limit the dose to the lens, cornea, lacrimal gland, and optic chiasm.
• Patients withbladder/prostate primary tumors who present with a large pelvic mass resulting from a distended bladder caused by outlet obstruction receive treatment to a volume defined by imaging studies following initial chemotherapy.
• Girls withgenitourinary 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. In a retrospective review of 41 patients on two sequential studies for patients with low-risk embryonal rhabdomyosarcoma conducted by IRSG/COG, 33 girls with Group IIA or III N0 localized vaginal tumors received no primary irradiation and 12 (36%) recurred locally after VA (4 out of 6), VAC (2 out of 14), or VAc ([c, low-dose cyclophosphamide] 6 out of 13) chemotherapy. All survived. For the 25 patients with vaginal rhabdomyosarcoma treated onCOG-D9602, the estimated 5-year FFS was 70% and OS rate was 100%. However, for the 16 patients with Group III vaginal tumors treated onCOG-ARST0331, the estimated 2-year FFS rate was 42% and OS rate was 88%. Thus, a response-based approach that eliminates RT in children with vaginal tumors treated with VA or low-dose VAC appears to increase the rate of local recurrences. Based on this evidence, patients choosing to not undergo therapy have a 50% chance risk of needing intensive chemotherapy followed by RT.[52][Level of evidence: 3iiiDiii]
• Patients withparameningeal disease with intracranial extension in contiguity with the primary tumor, and/or 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.[109]Patients should receive RT to the site of primary tumor with a 2-cm margin to include the meninges adjacent to the primary tumor[110]and the region of intracranial extension, if present, again with a 2-cm margin. Patients with intracranial extension should begin receiving RT within 2 weeks after diagnosis.[110]
• Rarely, children can present withtumor cells in the CSF, have other evidence of diffuse meningeal disease, and/or have multiple intraparenchymal brain metastases from a distant primary tumor. They should be treated with central nervous system-directed irradiation in addition to chemotherapy/RT for the primary tumor. Spinal irradiation may also be indicated.

Very young children (age <36 months or younger) diagnosed with rhabdomyosarcoma pose a therapeutic challenge because of their increased risk for treatment-related morbidity. Recent experience [113] supports using a somewhat reduced dose of RT in settings where surgery alone is insufficient to provide a high likelihood of local control. For children with initially unresectable tumors, delayed gross total resection followed by 36 Gy beam RT provides an excellent likelihood of local control. For infants with unresectable tumors, higher doses of RT remain appropriate. Radiation techniques are designed to maximize normal tissue sparing, and should include conformal approaches, often with intensity-modulated techniques.

Treatment options under clinical evaluation

The following are examples of national and/or institutional clinical trials involving RT that are currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.

• Brachytherapy: 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,[114,115,116,117,118]and selected bladder/prostate sites.[100]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.[115,119]Other sites, especially head and neck, have also been treated with brachytherapy.[120]Patients with initial Group III disease who later 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.[121]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with previously untreated childhood rhabdomyosarcoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

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76.	Walterhouse DO, Lyden ER, Breitfeld PP, et al.: Efficacy of topotecan and cyclophosphamide given in a phase II window trial in children with newly diagnosed metastatic rhabdomyosarcoma: a Children's Oncology Group study. J Clin Oncol 22 (8): 1398-403, 2004.
77.	Arndt CA, Stoner JA, Hawkins DS, et al.: Vincristine, actinomycin, and cyclophosphamide compared with vincristine, actinomycin, and cyclophosphamide alternating with vincristine, topotecan, and cyclophosphamide for intermediate-risk rhabdomyosarcoma: children's oncology group study D9803. J Clin Oncol 27 (31): 5182-8, 2009.
78.	Arndt CA, Hawkins DS, Meyer WH, et al.: Comparison of results of a pilot study of alternating vincristine/doxorubicin/cyclophosphamide and etoposide/ifosfamide with IRS-IV in intermediate risk rhabdomyosarcoma: a report from the Children's Oncology Group. Pediatr Blood Cancer 50 (1): 33-6, 2008.
79.	Rodeberg DA, Stoner JA, Hayes-Jordan A, et al.: Prognostic significance of tumor response at the end of therapy in group III rhabdomyosarcoma: a report from the children's oncology group. J Clin Oncol 27 (22): 3705-11, 2009.
80.	Rodeberg D, Arndt C, Breneman J, et al.: Characteristics and outcomes of rhabdomyosarcoma patients with isolated lung metastases from IRS-IV. J Pediatr Surg 40 (1): 256-62, 2005.
81.	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.
82.	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.
83.	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.
84.	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.
85.	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.
86.	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.
87.	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.
88.	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.
89.	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.
90.	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.
91.	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.
92.	Million L, Anderson J, Breneman J, et al.: Influence of noncompliance with radiation therapy protocol guidelines and operative bed recurrences for children with rhabdomyosarcoma and microscopic residual disease: a report from the Children's Oncology Group. Int J Radiat Oncol Biol Phys 80 (2): 333-8, 2011.
93.	Wolden SL, Anderson JR, Crist WM, et al.: Indications for radiotherapy and chemotherapy after complete resection in rhabdomyosarcoma: A report from the Intergroup Rhabdomyosarcoma Studies I to III. J Clin Oncol 17 (11): 3468-75, 1999.
94.	Schuck A, Mattke AC, Schmidt B, et al.: Group II rhabdomyosarcoma and rhabdomyosarcomalike tumors: is radiotherapy necessary? J Clin Oncol 22 (1): 143-9, 2004.
95.	Wharam MD, Meza J, Anderson J, et al.: Failure pattern and factors predictive of local failure in rhabdomyosarcoma: a report of group III patients on the third Intergroup Rhabdomyosarcoma Study. J Clin Oncol 22 (10): 1902-8, 2004.
96.	Wolden SL, Wexler LH, Kraus DH, et al.: Intensity-modulated radiotherapy for head-and-neck rhabdomyosarcoma. Int J Radiat Oncol Biol Phys 61 (5): 1432-8, 2005.
97.	Combs SE, Behnisch W, Kulozik AE, et al.: Intensity Modulated Radiotherapy (IMRT) and Fractionated Stereotactic Radiotherapy (FSRT) for children with head-and-neck-rhabdomyosarcoma. BMC Cancer 7: 177, 2007.
98.	McDonald MW, Esiashvili N, George BA, et al.: Intensity-modulated radiotherapy with use of cone-down boost for pediatric head-and-neck rhabdomyosarcoma. Int J Radiat Oncol Biol Phys 72 (3): 884-91, 2008.
99.	Curtis AE, Okcu MF, Chintagumpala M, et al.: Local control after intensity-modulated radiotherapy for head-and-neck rhabdomyosarcoma. Int J Radiat Oncol Biol Phys 73 (1): 173-7, 2009.
100.	Martelli H, Haie-Meder C, Branchereau S, et al.: Conservative surgery plus brachytherapy treatment for boys with prostate and/or bladder neck rhabdomyosarcoma: a single team experience. J Pediatr Surg 44 (1): 190-6, 2009.
101.	Hug EB, Adams J, Fitzek M, et al.: Fractionated, three-dimensional, planning-assisted proton-radiation therapy for orbital rhabdomyosarcoma: a novel technique. Int J Radiat Oncol Biol Phys 47 (4): 979-84, 2000.
102.	Yock T, Schneider R, Friedmann A, et al.: Proton radiotherapy for orbital rhabdomyosarcoma: clinical outcome and a dosimetric comparison with photons. Int J Radiat Oncol Biol Phys 63 (4): 1161-8, 2005.
103.	Laskar S, Bahl G, Ann Muckaden M, et al.: Interstitial brachytherapy for childhood soft tissue sarcoma. Pediatr Blood Cancer 49 (5): 649-55, 2007.
104.	Raney R, Hays D, Tefft M, et al.: Rhabdomyosarcoma and the undifferentiated sarcomas. In: Pizzo PA, Poplack DG, eds.: Principles and Practice of Pediatric Oncology. Philadelphia: JB Lippincott, 1989, pp 635-658.
105.	Mandell L, Ghavimi F, Peretz T, et al.: Radiocurability of microscopic disease in childhood rhabdomyosarcoma with radiation doses less than 4,000 cGy. J Clin Oncol 8 (9): 1536-42, 1990.
106.	Heyn R, Ragab A, Raney RB Jr, et al.: Late effects of therapy in orbital rhabdomyosarcoma in children. A report from the Intergroup Rhabdomyosarcoma Study. Cancer 57 (9): 1738-43, 1986.
107.	Tefft M, Lattin PB, Jereb B, et al.: Acute and late effects on normal tissues following combined chemo- and radiotherapy for childhood rhabdomyosarcoma and Ewing's sarcoma. Cancer 37 (2 Suppl): 1201-17, 1976.
108.	Donaldson SS, Asmar L, Breneman J, et al.: Hyperfractionated radiation in children with rhabdomyosarcoma--results of an Intergroup Rhabdomyosarcoma Pilot Study. Int J Radiat Oncol Biol Phys 32 (4): 903-11, 1995.
109.	Raney RB, Meza J, Anderson JR, et al.: Treatment of children and adolescents with localized parameningeal sarcoma: experience of the Intergroup Rhabdomyosarcoma Study Group protocols IRS-II through -IV, 1978-1997. Med Pediatr Oncol 38 (1): 22-32, 2002.
110.	Michalski JM, Meza J, Breneman JC, et al.: Influence of radiation therapy parameters on outcome in children treated with radiation therapy for localized parameningeal rhabdomyosarcoma in Intergroup Rhabdomyosarcoma Study Group trials II through IV. Int J Radiat Oncol Biol Phys 59 (4): 1027-38, 2004.
111.	Douglas JG, Arndt CA, Hawkins DS: Delayed radiotherapy following dose intensive chemotherapy for parameningeal rhabdomyosarcoma (PM-RMS) of childhood. Eur J Cancer 43 (6): 1045-50, 2007.
112.	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.
113.	Puri DR, Wexler LH, Meyers PA, et al.: The challenging role of radiation therapy for very young children with rhabdomyosarcoma. Int J Radiat Oncol Biol Phys 65 (4): 1177-84, 2006.
114.	Curran WJ Jr, Littman P, Raney RB: Interstitial radiation therapy in the treatment of childhood soft-tissue sarcomas. Int J Radiat Oncol Biol Phys 14 (1): 169-74, 1988.
115.	Flamant F, Gerbaulet A, Nihoul-Fekete C, et al.: Long-term sequelae of conservative treatment by surgery, brachytherapy, and chemotherapy for vulval and vaginal rhabdomyosarcoma in children. J Clin Oncol 8 (11): 1847-53, 1990.
116.	Flamant F, Chassagne D, Cosset JM, et al.: Embryonal rhabdomyosarcoma of the vagina in children: conservative treatment with curietherapy and chemotherapy. Eur J Cancer 15 (4): 527-32, 1979.
117.	Nag S, Shasha D, Janjan N, et al.: The American Brachytherapy Society recommendations for brachytherapy of soft tissue sarcomas. Int J Radiat Oncol Biol Phys 49 (4): 1033-43, 2001.
118.	Magné N, Haie-Meder C: Brachytherapy for genital-tract rhabdomyosarcomas in girls: technical aspects, reports, and perspectives. Lancet Oncol 8 (8): 725-9, 2007.
119.	Magné N, Oberlin O, Martelli H, et al.: Vulval and vaginal rhabdomyosarcoma in children: update and reappraisal of Institut Gustave Roussy brachytherapy experience. Int J Radiat Oncol Biol Phys 72 (3): 878-83, 2008.
120.	Nag S, Fernandes PS, Martinez-Monge R, et al.: Use of brachytherapy to preserve function in children with soft-tissue sarcomas. Oncology (Huntingt) 13 (3): 361-69; discussion 369-70, 373-4, 1999.
121.	Regine WF, Fontanesi J, Kumar P, et al.: Local tumor control in rhabdomyosarcoma following low-dose irradiation: comparison of group II and select group III patients. Int J Radiat Oncol Biol Phys 31 (3): 485-91, 1995.

Recurrent Childhood Rhabdomyosarcoma

Although patients with recurrent or progressive rhabdomyosarcoma sometimes achieve complete remission with secondary therapy, the long-term prognosis is usually poor.[1,2] The prognosis is most favorable (50% to 70% 5-year survival rates) for children who initially present with stage I or Group I disease and embryonal histology and who have smaller tumors or present with a local or regional recurrence.[1,2,3] The small number of children with botryoid histology who relapse have a similarly favorable prognosis.[1] Most other children who relapse have an extremely poor prognosis.[1] 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.[4][Level of evidence: 3iiB] 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 post recurrence.[5]

The selection of further treatment depends on many factors, including the site(s) of recurrence, 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.[6] Some survivors have also been reported after surgical removal of only one or a few metastases in the lung.[6] RT should be considered for patients who have not already received RT in the area of recurrence, or rarely for those who have received RT 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.

The following standard chemotherapy regimens have been used to treat recurrent rhabdomyosarcoma:

• Carboplatin/etoposide.[7]
• Ifosfamide, carboplatin, and etoposide.[8,9]
• Cyclophosphamide/topotecan.[10]
• Irinotecan with or without vincristine.[11,12,13,14]Results of a prospective randomized trial showed no difference between irinotecan (20 mg/m² /d) daily x 5 days for 4 weeks per treatment cycle and irinotecan (50 mg/m² /d) daily x 5 days for 2 weeks per treatment cycle in relapsed rhabdomyosarcoma and recommended the shorter regimen for further investigation.[15][Level of evidence: 1iiDiv]

Treatment options under clinical evaluation for recurrent rhabdomyosarcoma:

• On the basis of historical relapse data from the Intergroup Rhabdomyosarcoma Study Group,[1]the Children's Oncology Group is analyzing a risk-based approach to salvage treatment for rhabdomyosarcoma patients experiencing a first relapse or progressive disease. Relapsed patients with a favorable prognosis received doxorubicin/cyclophosphamide alternating with ifosfamide/etoposide. For patients with a poor prognosis and measurable disease, a randomized study of two administration schedules of irinotecan (five daily doses for 1 week vs. five daily doses for 2 weeks) in combination with vincristine preceded treatment with doxorubicin/cyclophosphamide alternating with ifosfamide/etoposide. Poor-prognosis patients without measurable disease received doxorubicin/cyclophosphamide with the addition of an investigational agent, tirapazamine, alternating with ifosfamide/etoposide.
• 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. A review of the published data did not determine a significant benefit for patients who underwent this salvage treatment approach.[16,17,18]
• Single-agent vinorelbine.[19]
• Combination vinorelbine and low-dose cyclophosphamide.[20]
• Rapamycin.[21]
• Topotecan, vincristine, and doxorubicin.[22][Level of evidence: 3iiiDiii]
• New agents under clinical evaluation in phase I and phase II trials should be considered for relapsed patients.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent childhood rhabdomyosarcoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

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.
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.
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.
4.	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.
5.	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.
6.	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.
7.	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.
8.	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.
9.	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.
10.	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.
11.	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.
12.	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.
13.	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.
14.	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.
15.	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.
16.	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.
17.	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.
18.	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.
19.	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.
20.	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.
21.	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.
22.	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.

Changes to This Summary (02 / 03 / 2012)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Previously Untreated Childhood Rhabdomyosarcoma

Added text to state that in Group II rhabdomyosarcoma patients, over 50% experienced local recurrence associated with noncompliance or omission of radiation therapy (RT) (cited Million et al. as reference 92).

Added text about how in a retrospective review of 41 patients on two sequential studies for patients with low-risk embryonal rhabdomyosarcoma conducted by IRSG/COG, 33 girls with Group IIA or III N0 localized vaginal tumors received no primary irradiation and 12 (36%) recurred locally after vincristine and dactinomycin (VA), VA and cyclophosphamide (VAC), or VAc (low-dose cyclophosphamide) chemotherapy. A response-based approach that eliminates RT in children with vaginal tumors treated with VA or low-dose VAC appears to increase the rate of local recurrences; patients choosing to not undergo therapy have a 50% chance risk of needing intensive chemotherapy followed by RT (added level of evidence 3iiiDiii).

About This PDQ Summary

Purpose of This Summary

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.

Reviewers and Updates

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).

Board members review recently published articles each month to determine whether an article should:

• be discussed at a meeting,
• be cited with text, or
• replace or update an existing article that is already cited.

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.

The lead reviewers for Childhood Rhabdomyosarcoma Treatment are:

• Louis S. Constine, MD (James P. Wilmot Cancer Center at University of Rochester Medical Center)
• Holcombe Edwin Grier, MD (Dana-Farber Cancer Institute/Boston Children's Hospital)
• Michael P. LaQuaglia, MD (Memorial Sloan-Kettering Cancer Center)
• Paul A. Meyers, MD (Memorial Sloan-Kettering Cancer Center)
• Alberto S. Pappo, MD (St. Jude Children's Research Hospital)
• R. Beverly Raney, MD (Consultant)
• Stephen J. Shochat, MD (St. Jude Children's Research Hospital)

Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's Contact Form. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

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 formal evidence ranking system in developing its level-of-evidence designations.

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The preferred citation for this PDQ summary is:

National Cancer Institute: PDQ® Childhood Rhabdomyosarcoma Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/treatment/childrhabdomyosarcoma/HealthProfessional. Accessed <MM/DD/YYYY>.

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Last Revised: 2012-02-03