Purpose of This PDQ Summary
General Information
Cellular Classification

Embryonal Rhabdomyosarcoma         Botryoid and spindle cell subtypes Alveolar Rhabdomyosarcoma Pleomorphic (Anaplastic) Rhabdomyosarcoma Chromosomal and Molecular Characteristics

Stage Information
Treatment Option Overview
Previously Untreated Childhood Rhabdomyosarcoma

Surgical Management Treatment Options         Head and neck         Extremity sites         Truncal sites         Genitourinary system         Unusual primary sites         Metastatic sites Chemotherapy Treatment Options          Low-risk patients         Intermediate-risk patients         High-risk patients Radiation Therapy Management Options         Standard treatment options         Treatment options under clinical evaluation Current Clinical Trials

Recurrent Childhood Rhabdomyosarcoma

Current Clinical Trials

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Changes to This Summary (01/02/2009)
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Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood rhabdomyosarcoma. This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board ¹.

Information about the following is included in this summary:

• Cellular classification.
• Stage information.
• Treatment options.

This summary is intended as a resource to inform and assist clinicians and other health professionals who care for pediatric cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Some of the reference citations in the 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 and Adult Treatment Editorial Boards use a formal evidence ranking system ² in developing their level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for reimbursement determinations.

This summary is also available in a patient ³ version, which is written in less-technical language, and in Spanish ⁴.

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.

Cancer in children and adolescents is rare. 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 Supportive and Palliative Care ⁵ summaries 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.[1] 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. ⁶

In recent decades, dramatic improvements in survival have been achieved for children and adolescents with cancer. 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 ⁷ 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.[2,3] It is usually curable in most children with localized disease who receive combined modality therapy, with more than 70% surviving 5 years after diagnosis.[4-6] 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.[7] The most common primary sites for rhabdomyosarcoma are the head and neck (e.g., parameningeal, orbit, pharyngeal), the genitourinary tract, and the extremities.[4,5] Other less common primary sites include the trunk, chest wall, the abdomen (including the retroperitoneum and biliary tract), and the perineal/anal region.

Most cases of rhabdomyosarcoma occur sporadically with no recognized predisposing factor or risk factor,[8] though a small proportion are associated with genetic conditions. These conditions include Li-Fraumeni cancer susceptibility syndrome (with germline p53 mutations),[9-11] neurofibromatosis type I,[12] Costello syndrome (with germline HRAS mutations),[13-15] Beckwith-Wiedemann syndrome (with which Wilms tumor and hepatoblastoma are more commonly associated),[16,17] and Noonan syndrome.[18]

The prognosis for a child or adolescent with rhabdomyosarcoma is related to the age of the patient, site of origin, resectability, presence of metastases, number of metastatic sites or tissues involved, presence or absence of lymph node involvement, histopathology,[4,5,19-26][Level of evidence: 3iiiA] and unique biological characteristics of rhabdomyosarcoma tumor cells. Response to induction chemotherapy, as judged by anatomic imaging, does not appear to correlate with the likelihood of survival in patients with rhabdomyosarcoma.[27] Examples of both clinical and biological factors with proven or possible prognostic significance are briefly described below.

• Children younger than 1 year may pose a problem in terms of the ability to deliver aggressive therapy including full-dose radiation and appropriate chemotherapy on schedule; therefore, outcome may be adversely affected.[6,28] Children aged between 1 and 9 years have the best overall survival.[20]



• Primary sites with more favorable prognoses include the orbit and nonparameningeal head and neck, paratestis and vagina (nonbladder, nonprostate genitourinary), and the biliary tract.[4,5,29-31]



• Tumor burden at diagnosis has prognostic significance. Patients with smaller tumors (<5 cm) have improved survival compared with children with larger tumors; children with metastatic disease at diagnosis have the poorest prognosis.[4,29,32] The prognostic significance of metastatic disease is modified by tumor histology (embryonal is more favorable than other histologies) and by the number of metastatic sites.[21] Similarly, patients with metastatic genitourinary (nonbladder, nonprostate) primary tumors have a more favorable outcome compared with patients with metastatic disease and primary tumors at other sites.[33] In addition, patients with otherwise localized disease but with proven regional lymph node involvement have a poorer prognosis than patients without regional nodal involvement.[24,25]



• The extent of disease following the primary surgical procedure (i.e., the clinical group) is also correlated with outcome.[4] In the Intergroup Rhabdomyosarcoma Study (IRS)-III, patients with gross residual disease after initial surgery (clinical group III) had a 5-year survival rate of approximately 70% compared with a greater than 90% 5-year survival rate for patients with no residual tumor after surgery (clinical group I) and an approximately 80% 5-year survival rate for patients with microscopic residual tumor following surgery (clinical group II).[4,19]



• 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 primaries, and metastatic disease), and is generally associated with a worse outcome. In the IRS-I and IRS-II studies, the alveolar subtype was associated with a less favorable outcome even in patients whose primary tumor was completely resected (clinical group I).[30] Statistically-significant differences in survival for histopathologic subtype were not, however, noted when all patients with rhabdomyosarcoma were analyzed,[34,35] nor were differences noted by histologic subtype in a large group of German children with rhabdomyosarcoma.[29] In the IRS-III study, outcome for patients with clinical group I alveolar subtype tumors was similar to those of other patients with clinical group I tumors, but the patients with alveolar subtype received more intensive therapy.[4]

Patients with undifferentiated sarcomas were treated in trials coordinated by the Intergroup Rhabdomyosarcoma Study Group from 1972 until 2006,[36] but are currently eligible for the nonrhabdomyosarcomatous soft tissue sarcoma protocol using agents active in adult soft tissue sarcoma such as ifosfamide and doxorubicin (COG-ARST0332 ⁸). For more information refer to the PDQ Childhood Soft Tissue Sarcoma ⁹ summary.

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 with experience in the evaluation and diagnosis of tumors in children. Additionally, the diversity of primary sites, the distinctive surgical and radiation therapy treatments for each primary site, and the subsequent site-specific rehabilitation underscore the importance of treating children with rhabdomyosarcoma in medical centers with appropriate experience in all therapeutic modalities.

References

1. Guidelines for the pediatric cancer center and role of such centers in diagnosis and treatment. American Academy of Pediatrics Section Statement Section on Hematology/Oncology. Pediatrics 99 (1): 139-41, 1997.  [PUBMED Abstract]
   
   
2. Gurney JG, Severson RK, Davis S, et al.: Incidence of cancer in children in the United States. Sex-, race-, and 1-year age-specific rates by histologic type. Cancer 75 (8): 2186-95, 1995.  [PUBMED Abstract]
   
   
3. Ries LA, Kosary CL, Hankey BF, et al., eds.: SEER Cancer Statistics Review, 1973-1996. Bethesda, Md: National Cancer Institute, 1999. Also available online ¹⁰. Last accessed April 19, 2007. 
   
   
4. Crist W, Gehan EA, Ragab AH, et al.: The Third Intergroup Rhabdomyosarcoma Study. J Clin Oncol 13 (3): 610-30, 1995.  [PUBMED Abstract]
   
   
5. Maurer HM, Gehan EA, Beltangady M, et al.: The Intergroup Rhabdomyosarcoma Study-II. Cancer 71 (5): 1904-22, 1993.  [PUBMED Abstract]
   
   
6. Crist WM, Anderson JR, Meza JL, et al.: Intergroup rhabdomyosarcoma study-IV: results for patients with nonmetastatic disease. J Clin Oncol 19 (12): 3091-102, 2001.  [PUBMED Abstract]
   
   
7. 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.  [PUBMED Abstract]
   
   
8. 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. ¹¹ Last accessed July 20, 2006. 
   
   
9. 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.  [PUBMED Abstract]
   
   
10. 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.  [PUBMED Abstract]
    
    
11. Trahair T, Andrews L, Cohn RJ: Recognition of Li Fraumeni syndrome at diagnosis of a locally advanced extremity rhabdomyosarcoma. Pediatr Blood Cancer 48 (3): 345-8, 2007.  [PUBMED Abstract]
    
    
12. Ferrari A, Bisogno G, Macaluso A, et al.: Soft-tissue sarcomas in children and adolescents with neurofibromatosis type 1. Cancer 109 (7): 1406-12, 2007.  [PUBMED Abstract]
    
    
13. 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.  [PUBMED Abstract]
    
    
14. Aoki Y, Niihori T, Kawame H, et al.: Germline mutations in HRAS proto-oncogene cause Costello syndrome. Nat Genet 37 (10): 1038-40, 2005.  [PUBMED Abstract]
    
    
15. Gripp KW: Tumor predisposition in Costello syndrome. Am J Med Genet C Semin Med Genet 137 (1): 72-7, 2005.  [PUBMED Abstract]
    
    
16. Samuel DP, Tsokos M, DeBaun MR: Hemihypertrophy and a poorly differentiated embryonal rhabdomyosarcoma of the pelvis. Med Pediatr Oncol 32 (1): 38-43, 1999.  [PUBMED Abstract]
    
    
17. 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.  [PUBMED Abstract]
    
    
18. 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.  [PUBMED Abstract]
    
    
19. 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.  [PUBMED Abstract]
    
    
20. 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.  [PUBMED Abstract]
    
    
21. 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.  [PUBMED Abstract]
    
    
22. 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.  [PUBMED Abstract]
    
    
23. 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.  [PUBMED Abstract]
    
    
24. 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.  [PUBMED Abstract]
    
    
25. 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.  [PUBMED Abstract]
    
    
26. 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.  [PUBMED Abstract]
    
    
27. 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.  [PUBMED Abstract]
    
    
28. 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.  [PUBMED Abstract]
    
    
29. 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.  [PUBMED Abstract]
    
    
30. 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.  [PUBMED Abstract]
    
    
31. Spunt SL, Lobe TE, Pappo AS, et al.: Aggressive surgery is unwarranted for biliary tract rhabdomyosarcoma. J Pediatr Surg 35 (2): 309-16, 2000.  [PUBMED Abstract]
    
    
32. 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.  [PUBMED Abstract]
    
    
33. 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.  [PUBMED Abstract]
    
    
34. 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.  [PUBMED Abstract]
    
    
35. 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.  [PUBMED Abstract]
    
    
36. 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.  [PUBMED Abstract]
    
    

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]

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 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]

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]

Pleomorphic rhabdomyosarcoma occurs predominantly in patients aged 30 to 50 years and is rarely seen in children. In children, the term "pleomorphic" has been replaced by the term "anaplastic."[4]

The embryonal and alveolar histologies have distinctive molecular characteristics that have been used for diagnostic confirmation and which may be useful in the future for monitoring minimal residual disease during treatment.[5-8] 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 characteristic of alveolar rhabdomyosarcoma.[5,9] 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.[5] Twenty-two percent of patients are negative for either PAX3 or PAX7 gene rearrangements. Patients with solid variant alveolar histology have a lower incidence of PAX-FKHR gene fusions compared to patients showing classical alveolar histology.[10] Among patients with alveolar histology and metastatic disease, those with PAX7 gene involvement and younger age may fare better.[11,12] In alveolar cases associated with the PAX3 gene, patients are older and have a higher incidence of invasive tumor (T2). Alveolar cases associated with the PAX7 gene appear to occur in patients at a younger age, and they may have longer event-free survival rates than those associated with PAX3 gene rearrangements.[11,13,14] Embryonal tumors, on the other hand, often show loss of specific genomic material from the short arm of chromosome 11.[9,15,16] 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.[17] Gene expression arrays identify a cluster of genes that correlate with rhabdomyosarcomas which contain the PAX-FKHR translocation. Tumors with alveolar histology which lack the translocation have a gene expression profile more similar to embryonal rhabdomyosarcomas than alveolar rhabdomyosarcomas.[18] It is controversial whether translocation-negative rhabdomyosarcomas with some histologic features of alveolar rhabdomyosarcoma should be classified as embryonal based on gene expression profile rather than as alveolar by light microscopy findings.

References

1. Parham DM, Ellison DA: Rhabdomyosarcomas in adults and children: an update. Arch Pathol Lab Med 130 (10): 1454-65, 2006.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
3. Leuschner I: Spindle cell rhabdomyosarcoma: histologic variant of embryonal rhabdomyosarcoma with association to favorable prognosis. Curr Top Pathol 89: 261-72, 1995.  [PUBMED Abstract]
   
   
4. 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.  [PUBMED Abstract]
   
   
5. 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.  [PUBMED Abstract]
   
   
6. 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.  [PUBMED Abstract]
   
   
7. 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.  [PUBMED Abstract]
   
   
8. 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.  [PUBMED Abstract]
   
   
9. Merlino G, Helman LJ: Rhabdomyosarcoma--working out the pathways. Oncogene 18 (38): 5340-8, 1999.  [PUBMED Abstract]
   
   
10. 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.  [PUBMED Abstract]
    
    
11. 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.  [PUBMED Abstract]
    
    
12. 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.  [PUBMED Abstract]
    
    
13. 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.  [PUBMED Abstract]
    
    
14. 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.  [PUBMED Abstract]
    
    
15. 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.  [PUBMED Abstract]
    
    
16. Scrable H, Witte D, Shimada H, et al.: Molecular differential pathology of rhabdomyosarcoma. Genes Chromosomes Cancer 1 (1): 23-35, 1989.  [PUBMED Abstract]
    
    
17. 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.  [PUBMED Abstract]
    
    
18. 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.  [PUBMED Abstract]
    
    

Stage Information

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

Staging of rhabdomyosarcoma is relatively complex. The process includes:

1. Assigning a local tumor group (status postsurgical resection/biopsy).



2. Assigning stage (consider site, size, group, presence/absence of metastases).



3. Assigning a risk group (consider stage, group, and histology).

As noted previously, prognosis for children with rhabdomyosarcoma is dependent on the primary site, size, group, and histologic subtype. Favorable prognostic groups have been identified by previous Intergroup Rhabdomyosarcoma Studies (IRS), and treatment plans have been designed based on assignment of patients to different groups based on prognosis. The IRS-I, IRS-II, and IRS-III studies prescribed treatment plans based on a surgicopathologic grouping 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 of these groups in the IRS-I, IRS-II, and IRS-III studies are given in Table 2 below.[1,2]

The Intergroup Rhabdomyosarcoma Study Group (IRSG) has 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 (STS-COG).

Current STS-COG protocols for rhabdomyosarcoma utilize a TNM-based pretreatment staging system which incorporates the surgicopathologic group, primary tumor site, regional lymph node status, and the presence or absence of metastases. This staging system is described in Table 3 below.[3,4]

Following stage assignment, a risk group is assigned. This takes into account stage, group, and histology. Patients are classified for protocol purposes as low risk, intermediate risk, or high risk.[5,6] Treatment assignment is based on risk group. Table 4 shows the current risk group classification.

 [Note: Since 2006, patients with undifferentiated sarcoma are treated on the STS-COG protocol for non-rhabdomyosarcomatous soft tissue sarcoma.]

References

1. 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.  [PUBMED Abstract]
   
   
2. Crist W, Gehan EA, Ragab AH, et al.: The Third Intergroup Rhabdomyosarcoma Study. J Clin Oncol 13 (3): 610-30, 1995.  [PUBMED Abstract]
   
   
3. 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.  [PUBMED Abstract]
   
   
4. 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.  [PUBMED Abstract]
   
   
5. Raney RB, Anderson JR, Barr FG, et al.: Rhabdomyosarcoma and undifferentiated sarcoma in the first two decades of life: a selective review of intergroup rhabdomyosarcoma study group experience and rationale for Intergroup Rhabdomyosarcoma Study V. J Pediatr Hematol Oncol 23 (4): 215-20, 2001.  [PUBMED Abstract]
   
   
6. 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.  [PUBMED Abstract]
   
   

Treatment Option Overview

All children with rhabdomyosarcoma require multimodality therapy with systemic chemotherapy, in conjunction with either surgery, radiation therapy, or both modalities for local tumor control.[1-3] This 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. Since rhabdomyosarcoma is sensitive to chemotherapy and radiation therapy, surgery is delayed if it will result in disfigurement or will interfere with organ function. Chemotherapy and possibly radiation therapy are administered in advance with the hope that subsequent surgical resection will be successful without undesirable side effects. Radiation therapy 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 radiation therapy.

Before biopsy of a suspected tumor mass, 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).

The treatment of rhabdomyosarcoma by the Children's Oncology Group and in Europe, as exemplified by the Intergroup Rhabdomyosarcoma Study Group (IRSG) trials and the International Society of Pediatric Oncology Malignant Mesenchymal Tumor (MMT) studies, respectively, differ in their management and overall treatment philosophies.[2] In the MMT trials, a primary objective is to reduce the use of local therapy, relying on initial frontline chemotherapy followed by alternate chemotherapy in the event of a poor response to initial therapy. Local therapy focused on surgical resection is then administered, reserving radiation therapy for use only after incomplete resection, documented regional lymph node involvement, or a poor clinical response to combination chemotherapy. This approach is designed to avoid major surgery and especially radiation therapy, and 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 radiation therapy. The necessity of salvage therapy for those who relapse is accepted in these trials. Conversely, the primary IRSG objective has been to employ local therapy soon after induction chemotherapy, using radiation therapy for patients with residual disease after initial surgery or biopsy only, and for all 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 result in superior EFS and better OS than the most recently published MMT (MMT 89) therapy. In some subsets of patients defined by primary site, the survival differences are greater (extremities, nonparameningeal head and neck); in others, the results are largely similar (genitourinary). Nevertheless, the overall impression is that survival for most patient subsets is superior with the use of early local therapy, including irradiation. However, in the MMT trials, some patients are spared aggressive local therapy, which may reduce the potential for morbidities associated with such therapy.[1-3]

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

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 ².)

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 and lymph node sampling of the draining nodal basin provided that major functional/cosmetic impairment is not necessary.[1][Level of evidence: 3iii] Important exceptions to the rule of normal margin 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 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 consisting of re-excision of the primary tumor bed, prior to initiation of chemotherapy, can achieve complete removal of tumor.[4] There is no evidence that debulking surgery that leaves macroscopic residual tumor improves outcome, compared with biopsy alone.[5][Level of evidence: 2A] 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 given below.

If the tumors are parameningeal (in the nasopharynx/nasal cavity, middle ear/mastoid, paranasal sinus, or parapharyngeal/infratemporal fossa region), 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. For head and neck tumors that are superficial and nonorbital, wide excision of the primary tumor (when feasible) and ipsilateral neck lymph node sampling of clinically involved nodes are appropriate. Narrower 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 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. For patients with head and neck primary tumors that are considered unresectable, chemotherapy and radiation therapy are the mainstay of primary management.[6-10] Rhabdomyosarcomas of the orbit do not require orbital exenteration at diagnosis; only a biopsy is needed to establish diagnosis.[11,12] Biopsy is followed by chemotherapy and radiation therapy, with orbital exenteration reserved for the small number of patients with locally persistent or recurrent disease.[8,13] Despite its parameningeal site, middle ear rhabdomyosarcoma has a favorable prognosis.[9]

The definitive surgical procedure involves wide local excision with en bloc removal of a cuff of normal tissue.[2] Primary re-excision may be appropriate in patients whose initial surgical procedure leaves microscopic residual disease that is resectable by a second procedure.[4] 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.[14-17] The Soft Tissue Sarcoma Committee of the Children’s Oncology Group (STS-COG) recommends systematic aggressive axillary node sampling for patients with upper-extremity primary tumors and clinically and radiographically negative nodes. The STS-COG also recommends inguinal and femoral triangle node sampling for patients with lower-extremity primary tumors. If clinically positive nodes are present, biopsy of more proximal nodes is recommended prior to sampling 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. The contribution of SLN mapping is not yet clearly defined in pediatric patients.[17-19]

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 prior to the administration of chemotherapy and/or radiation and should be followed by delayed primary resection to achieve negative margins and reconstruction. Most patients who present with large tumors in these sites have localized disease that is amenable to complete resection with negative margins after preoperative therapy and is therefore associated with excellent long-term survival.[20-22]

Intrathoracic or intra-abdominal disease may not be resectable because of the massive size of the tumor at the time of the diagnosis and extension into vital organs.[23] In two retrospective studies of children with localized retroperitoneal tumors, the outcome was somewhat better for patients who received debulking surgery initially or after chemotherapy and radiation therapy compared with those whose surgical therapy consisted only of initial biopsy.[23,24] Patients with rhabdomyosarcoma arising from tissues around the perineum or anus usually have advanced disease. These patients have a high likelihood of regional lymph node involvement, and many of the tumors have alveolar histology. The current recommendation is to sample the lymph nodes. When feasible, without unacceptable morbidity, removing all gross tumor prior to beginning chemotherapy improves the likelihood of cure. The overall survival (OS) after aggressive therapy for tumors in this location was 49%.[25] An exception is a rhabdomyosarcoma arising within the biliary tree, but even at that location, 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 and aggressive resection for biliary tract rhabdomyosarcoma are not warranted.[26] For patients with initially unresectable abdominal disease, complete surgical resection following chemotherapy offers a significant survival advantage (73% vs. 34%–44% without resection).[23]

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

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).[27] 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 Intergroup Rhabdomyosarcoma Study [IRS]-I and IRS-II studies),[14] 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 with 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.[28,29] 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.[3,30,31] In contrast, a staging ipsilateral retroperitoneal lymph node dissection is currently required for all children older than 10 years with paratesticular rhabdomyosarcoma on Intergroup Rhabdomyosarcoma Study Group (IRSG) and STS-COG studies. Node dissection is not routine in Europe for adolescents with resected paratesticular rhabdomyosarcoma. European investigators tend to rely on radiographic rather than surgical assessment of retroperitoneal lymph node involvement.[27,28] It appears, however, that the ability of the CT scan to predict the presence of lymph node involvement needs further study.[32] For patients with paratesticular tumors, repositioning the contralateral testicle prior to scrotal radiation may preserve hormone productivity.[33][Level of evidence: 3iii]

Bladder salvage is an important 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.[34] 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 radiation therapy have been used to reduce tumor bulk,[35,36] followed, when necessary, by a more limited surgical procedure, such as partial cystectomy.[37] 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 studies);[37,38] the more recent experience from IRS-III and IRS-IV studies, which used more intensive chemotherapy and radiation therapy, showed 55% of patients alive with functional bladders at 3 years from diagnosis, with 3-year OS exceeding 80%.[36,39,40] Thus, this approach to therapy remains generally accepted, with the belief that more effective chemotherapy and radiation therapy 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, cystoscopy, or by a direct-vision transanal route. For patients with biopsy-proven, residual malignant tumor following chemotherapy and radiation therapy, 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.

In patients who have been treated with chemotherapy and radiation therapy 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.[39,41,42] One study suggested that in patients with residual bladder tumors with histologic evidence of maturation, additional courses of chemotherapy should be given prior to considering cystectomy.[39] Surgery should be considered only if malignant tumor cells do not disappear over time following initial chemotherapy and radiation therapy. 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 in rhabdomyosarcoma of the vagina/vulva/uterus.[3] Conservative surgical intervention for vaginal rhabdomyosarcoma, with primary chemotherapy and adjunctive radiation when necessary, appears to result in excellent disease-free survival.[43] Because of the smaller number of patients with uterine rhabdomyosarcoma, it is difficult to make a definitive treatment decision, but chemotherapy or radiation therapy is also effective.[43] Exenteration is usually not required for primary tumors at these sites, but if needed it may be done with rectal preservation in most cases.

Rhabdomyosarcoma occasionally arises in sites other than those mentioned above. An unusual site is the diaphragm. Patients with these 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 that circumstance, chemotherapy should be initiated after diagnostic biopsy, with the intent to try to remove residual tumor at a later date.[44] Patients with laryngeal rhabdomyosarcoma will usually be treated with chemotherapy and radiation therapy after biopsy in an attempt to preserve the larynx.[45]

Primary resection of metastatic disease is rarely indicated.[46] Persistent metastatic disease in the lung following radiation and chemotherapy should be resected when possible to render patients disease free, provided that adequate pulmonary function can be preserved.[46]

All children with rhabdomyosarcoma should receive chemotherapy. The intensity and duration of the chemotherapy are dependent on the risk group assignment.[47]

Standard treatment options

• Low-risk patients have a localized embryonal histology tumor in a favorable site, or a localized embryonal rhabdomyosarcoma in an unfavorable site which has been grossly resected (groups I and II). (See Table 2 ¹⁶ in the Staging Information section of this summary.)

Certain subgroups of low-risk patients have achieved high cure rates of approximately 90% using two-drug chemotherapy with vincristine and actinomycin D. See Table 5 below:

Other subgroups of low-risk patients have achieved high cure rates using three-drug chemotherapy with vincristine, actinomycin D, and cyclophosphamide. See Table 6 below:

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 ¹⁹.

• COG-ARST0331 ²⁰ : The COG low-risk embryonal rhabdomyosarcoma regimen includes four initial courses of cyclophosphamide, using a historically modest dose of 1.2 g/m²/course, with vincristine, actinomycin-D, and cyclophosphamide administered every 3 weeks followed by radiation therapy at week 13 for patients with microscopic, locoregional, or gross residual tumor. Subsequently, patients receive 4 or 12 further courses of vincristine/dactinomycin depending on the tumor stage and clinical group. The protocol is designed to increase efficacy of treatment while shortening the duration of treatment for a subset of low-risk patients and reducing both acute toxicity (myelosuppression) and long-term toxicity (impaired fertility).

Standard treatment options

• Patients with intermediate prognosis 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 patients with intermediate prognosis, vincristine, dactinomycin, and cyclophosphamide (VAC) is the standard chemotherapy treatment.[48-50] The IRS-IV 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),[51] based on the activity of ifosfamide against rhabdomyosarcoma.[52,53] The other regimen combined vincristine with ifosfamide and etoposide (VIE).[54] The combination of ifosfamide and etoposide had previously demonstrated substantial activity against rhabdomyosarcoma in phase II trials.[55] In the IRS-IV 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.[31] A comparison of survival for patients with tumors of embryonal histology treated on IRS-IV (received higher doses of cyclophosphamide [or ifosfamide equivalent]) with similar patients treated on IRS-III (received lower doses of cyclophosphamide [or ifosfamide equivalent]) suggests a benefit with the use of higher doses for certain groups of intermediate-risk patients. The benefit may accrue 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 unresectable embryonal rhabdomyosarcoma at unfavorable sites).[56] For other groups of intermediate-risk patients, an intensification of cyclophosphamide was feasible but did not improve outcome.[57]



• 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 based on 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.[58,59] Furthermore, the combination of cyclophosphamide and topotecan demonstrated substantial activity in both the recurrent disease setting as well as in newly diagnosed patients with metastatic disease.[60,61] The COG clinical trial (COG-D9802) for newly diagnosed patients with intermediate-risk disease randomized patients to receive either VAC therapy or VAC therapy with additional courses of topotecan and cyclophosphamide. Patients randomized to receive topotecan and cyclophosphamide fared no better than those treated with VAC alone.[62]



• In a limited institution pilot study, a combination of vincristine/doxorubicin/cyclophosphamide alternating with ifosfamide/etoposide (IE) has been used to treat patients with intermediate risk rhabdomyosarcoma. The relative efficacy of this approach versus the standard approach requires further investigation.[63][Level of evidence: 3iiiA]

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 ¹⁹.

• COG-ARST0531 ²¹ : The new COG intermediate-risk rhabdomyosarcoma protocol will compare standard VAC chemotherapy versus VAC alternating with vincristine and irinotecan (VI). Radiation therapy will commence at week 4 in conjunction with VI to determine the potential benefit of early local therapy in this group of patients.

Standard treatment options

• High-risk patients have metastatic disease in one or more sites at diagnosis (stage 4). These patients continue to have a relatively poor prognosis (≤50% 5-year survival rate) with current therapy, and new approaches to treatment are needed to improve survival in this group.[50,64,65] 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 radiation therapy) 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 or bone marrow involvement, and three or more metastatic sites. The event-free survival (EFS) rate at 3 years was 50% for patients without any of these adverse prognostic factors. The EFS rates were 42%, 18%, 12% and 5% for patients with one, two, three, or four adverse prognostic factors, respectively.[66][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. For example, in the IRS-IV study, three combinations of drug pairs were studied in an up-front window: IE, vincristine/melphalan (VM),[67] and ifosfamide/doxorubicin (ID).[68] 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%).[68] However, results with VAC chemotherapy for stage 4 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 previous regimens.[60,61] An up-front window trial of topotecan in previously untreated children and adolescents with metastatic rhabdomyosarcoma gave similar results.[59] Irinotecan and irinotecan with vincristine [69] have also been evaluated as up-front windows by the STS-COG; 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.[69] 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. Four patients had progressive disease.[70]

• High-dose chemotherapy with stem cell rescue has been evaluated in a limited number of patients with rhabdomyosarcoma,[71-75][Level of evidence: 3iiiA] but has failed to improve the prognosis of patients with poor-risk rhabdomyosarcoma.

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 ¹⁹.

• COG-ARST0431 ²² : The COG high-risk trial is currently closed and results are pending. This trial was for all patients with rhabdomyosarcoma and metastatic disease, regardless of age and histology. The trial evaluated an intensified treatment regimen which began with two courses of vincristine and irinotecan in conjunction with radiation therapy. Continuation therapy included cycles of vincristine/doxorubicin/cyclophosphamide and IE using interval dose compression. The regimen also included VAC pulses. The feasibility and toxicity of combining VI with radiation therapy was also evaluated.



• A study from the Cooperative Weichteilsarkomstudie (CWS) group demonstrated that oral maintenance chemotherapy with a trofosfamide-containing regimen might offer clinical benefit in selected patients with metastatic rhabdomyosarcoma,[75][Level of evidence: 3iiiA] and this therapeutic alternative is being investigated prospectively in one of the European Soft Tissue Sarcoma Study Group trials using oral vinorelbine and cyclophosphamide.[76]

Radiation therapy 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. Patients with completely resected tumors (group I) of embryonal histology do well without radiation therapy,[48,49] but radiation therapy benefits patients with group I tumors with alveolar or undifferentiated histology.[77] A review of European trials conducted by the Cooperative Soft Tissue Sarcoma Study Group between 1981 and 1998 in which radiation therapy was omitted for some group II patients demonstrated a benefit to using radiation therapy as a component of local tumor control for all group II patient subsets (defined by tumor histology, tumor size, and tumor site).[78] 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.[79] As with the surgical management of patients with rhabdomyosarcoma, recommendations for radiation therapy are dependent 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, two studies reported excellent local control in 28 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.[80,81]

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, IMRT, proton-beam therapy, or brachytherapy) should be considered.[82-84]

• The radiation therapy 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 radiation therapy to approximately 41 Gy,[77,85] though doses from 30 Gy to 40 Gy may be adequate in patients receiving effective multiagent chemotherapy.[86] IRS-II 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.[87,88] Group III patients on the IRS-IV standard treatment arm received 50.4 Gy.[89]



• 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.[77] While the volume irradiated may be modified based on guidelines for normal tissue tolerance, gross residual disease at the time of radiation should receive full-dose treatment.



• The timing of radiation therapy generally allows for chemotherapy to be given for 1 to 3 months prior to the initiation of radiation therapy. In current COG protocols, patients with parameningeal disease who have evidence of meningeal extension start radiation therapy at the beginning of treatment.[49,90,91] A prospective trial of 26 patients with group III parameningeal rhabdomyosarcoma achieved good local control and survival with radiation therapy administered at the conventional time.[92] Radiation therapy 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 protocol and showed that giving radiation therapy 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 radiation therapy (50.4 Gy vs. 59.4 Gy) given by the twice-daily hyperfractionated schedule. There was no demonstrated advantage in terms of local control.[93] Therefore, conventional radiation therapy remains the standard for treating patients with rhabdomyosarcoma and gross residual disease.[31]

Among the modifications of radiation therapy for specific primary sites recommended for IRS-IV patients are the following:[31,89]

• For patients with orbital tumors, precautions should be taken to limit the dose to the lens, cornea, lacrimal gland, and optic chiasm.



• Patients with bladder/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 with genitourinary primaries should have their ovaries shielded, or possibly moved, when receiving radiation to the lower abdomen and pelvis.



• Patients with parameningeal 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 nor intrathecal therapy, unless tumor cells are present in the CSF at diagnosis.[90] Patients should receive radiation to the site of primary tumor with a 2-cm margin to include the meninges adjacent to the primary tumor [91] and the region of intracranial extension, if present, again with a 2-cm margin. Patients with intracranial extension should begin receiving radiation therapy within 2 weeks after diagnosis.[91]



• Rarely, children (1) can present with tumor cells in the CSF, (2) may have other evidence of diffuse meningeal disease, and/or (3) may have multiple intraparenchymal brain metastasis from a distant primary tumor. They should be treated with central nervous system-directed irradiation in addition to chemotherapy/radiation therapy for the primary tumor. Spinal irradiation may also be indicated.

Very young children (≤36 months) diagnosed with rhabdomyosarcoma pose a therapeutic challenge because of their increased risk for treatment-related morbidity. Recent experience [94] supports using a somewhat reduced dose of radiation therapy 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 radiation therapy provides an excellent likelihood of local control. For infants with unresectable tumors, higher doses of radiation therapy remain appropriate. Radiation techniques are designed to maximize normal tissue sparing, and should include conformal approaches, often with intensity modulated techniques.

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 ¹⁹.

• Brachytherapy, using either intracavitary or interstitial implants, is another method of local control and has been used in select situations for children with rhabdomyosarcoma, especially those with primary tumors at vaginal or vulvar sites.[95-99] In a small single-institution study, this treatment approach was associated with a high survival rate (85%) and with retention of a functional vagina in most patients.[96] Other sites, especially head and neck, have also been treated with brachytherapy.[100] 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 radiation at doses of 40 Gy or more.[101]

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with previously untreated childhood rhabdomyosarcoma ²³. 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 ¹⁹.

References

1. Leaphart C, Rodeberg D: Pediatric surgical oncology: management of rhabdomyosarcoma. Surg Oncol 16 (3): 173-85, 2007.  [PUBMED Abstract]
   
   
2. Lawrence W Jr, Hays DM, Heyn R, et al.: Surgical lessons from the Intergroup Rhabdomyosarcoma Study (IRS) pertaining to extremity tumors. World J Surg 12 (5): 676-84, 1988.  [PUBMED Abstract]
   
   
3. Lawrence W Jr, Neifeld JP: Soft tissue sarcomas. Curr Probl Surg 26 (11): 753-827, 1989.  [PUBMED Abstract]
   
   
4. Hays DM, Lawrence W Jr, Wharam M, et al.: Primary reexcision for patients with 'microscopic residual' tumor following initial excision of sarcomas of trunk and extremity sites. J Pediatr Surg 24 (1): 5-10, 1989.  [PUBMED Abstract]
   
   
5. Cecchetto G, Bisogno G, De Corti F, et al.: Biopsy or debulking surgery as initial surgery for locally advanced rhabdomyosarcomas in children?: the experience of the Italian Cooperative Group studies. Cancer 110 (11): 2561-7, 2007.  [PUBMED Abstract]
   
   
6. Wharam MD, Beltangady MS, Heyn RM, et al.: Pediatric orofacial and laryngopharyngeal rhabdomyosarcoma. An Intergroup Rhabdomyosarcoma Study report. Arch Otolaryngol Head Neck Surg 113 (11): 1225-7, 1987.  [PUBMED Abstract]
   
   
7. Pappo AS, Meza JL, Donaldson SS, et al.: Treatment of localized nonorbital, nonparameningeal head and neck rhabdomyosarcoma: lessons learned from intergroup rhabdomyosarcoma studies III and IV. J Clin Oncol 21 (4): 638-45, 2003.  [PUBMED Abstract]
   
   
8. Raney RB, Anderson JR, Kollath J, et al.: Late effects of therapy in 94 patients with localized rhabdomyosarcoma of the orbit: Report from the Intergroup Rhabdomyosarcoma Study (IRS)-III, 1984-1991. Med Pediatr Oncol 34 (6): 413-20, 2000.  [PUBMED Abstract]
   
   
9. Hawkins DS, Anderson JR, Paidas CN, et al.: Improved outcome for patients with middle ear rhabdomyosarcoma: a children's oncology group study. J Clin Oncol 19 (12): 3073-9, 2001.  [PUBMED Abstract]
   
   
10. Meazza C, Ferrari A, Casanova M, et al.: Evolving treatment strategies for parameningeal rhabdomyosarcoma: the experience of the Istituto Nazionale Tumori of Milan. Head Neck 27 (1): 49-57, 2005.  [PUBMED Abstract]
    
    
11. Wharam M, Beltangady M, Hays D, et al.: Localized orbital rhabdomyosarcoma. An interim report of the Intergroup Rhabdomyosarcoma Study Committee. Ophthalmology 94 (3): 251-4, 1987.  [PUBMED Abstract]
    
    
12. Oberlin O, Rey A, Anderson J, et al.: Treatment of orbital rhabdomyosarcoma: survival and late effects of treatment--results of an international workshop. J Clin Oncol 19 (1): 197-204, 2001.  [PUBMED Abstract]
    
    
13. Mannor GE, Rose GE, Plowman PN, et al.: Multidisciplinary management of refractory orbital rhabdomyosarcoma. Ophthalmology 104 (7): 1198-201, 1997.  [PUBMED Abstract]
    
    
14. 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.  [PUBMED Abstract]
    
    
15. 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.  [PUBMED Abstract]
    
    
16. Andrassy RJ, Corpron CA, Hays D, et al.: Extremity sarcomas: an analysis of prognostic factors from the Intergroup Rhabdomyosarcoma Study III. J Pediatr Surg 31 (1): 191-6, 1996.  [PUBMED Abstract]
    
    
17. Neville HL, Andrassy RJ, Lobe TE, et al.: Preoperative staging, prognostic factors, and outcome for extremity rhabdomyosarcoma: a preliminary report from the Intergroup Rhabdomyosarcoma Study IV (1991-1997). J Pediatr Surg 35 (2): 317-21, 2000.  [PUBMED Abstract]
    
    
18. Neville HL, Andrassy RJ, Lally KP, et al.: Lymphatic mapping with sentinel node biopsy in pediatric patients. J Pediatr Surg 35 (6): 961-4, 2000.  [PUBMED Abstract]
    
    
19. Neville HL, Raney RB, Andrassy RJ, et al.: Multidisciplinary management of pediatric soft-tissue sarcoma. Oncology (Huntingt) 14 (10): 1471-81; discussion 1482-6, 1489-90, 2000.  [PUBMED Abstract]
    
    
20. Saenz NC, Ghavimi F, Gerald W, et al.: Chest wall rhabdomyosarcoma. Cancer 80 (8): 1513-7, 1997.  [PUBMED Abstract]
    
    
21. Beech TR, Moss RL, Anderson JA, et al.: What comprises appropriate therapy for children/adolescents with rhabdomyosarcoma arising in the abdominal wall? A report from the Intergroup Rhabdomyosarcoma Study Group. J Pediatr Surg 34 (5): 668-71, 1999.  [PUBMED Abstract]
    
    
22. Chui CH, Billups CA, Pappo AS, et al.: Predictors of outcome in children and adolescents with rhabdomyosarcoma of the trunk--the St Jude Children's Research Hospital experience. J Pediatr Surg 40 (11): 1691-5, 2005.  [PUBMED Abstract]
    
    
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24. Raney RB, Stoner JA, Walterhouse DO, et al.: Results of treatment of fifty-six patients with localized retroperitoneal and pelvic rhabdomyosarcoma: a report from The Intergroup Rhabdomyosarcoma Study-IV, 1991-1997. Pediatr Blood Cancer 42 (7): 618-25, 2004.  [PUBMED Abstract]
    
    
25. Blakely ML, Andrassy RJ, Raney RB, et al.: Prognostic factors and surgical treatment guidelines for children with rhabdomyosarcoma of the perineum or anus: a report of Intergroup Rhabdomyosarcoma Studies I through IV, 1972 through 1997. J Pediatr Surg 38 (3): 347-53, 2003.  [PUBMED Abstract]
    
    
26. Spunt SL, Lobe TE, Pappo AS, et al.: Aggressive surgery is unwarranted for biliary tract rhabdomyosarcoma. J Pediatr Surg 35 (2): 309-16, 2000.  [PUBMED Abstract]
    
    
27. Stewart RJ, Martelli H, Oberlin O, et al.: Treatment of children with nonmetastatic paratesticular rhabdomyosarcoma: results of the Malignant Mesenchymal Tumors studies (MMT 84 and MMT 89) of the International Society of Pediatric Oncology. J Clin Oncol 21 (5): 793-8, 2003.  [PUBMED Abstract]
    
    
28. Ferrari A, Bisogno G, Casanova M, et al.: Paratesticular rhabdomyosarcoma: report from the Italian and German Cooperative Group. J Clin Oncol 20 (2): 449-55, 2002.  [PUBMED Abstract]
    
    
29. Ferrari A, Casanova M, Massimino M, et al.: The management of paratesticular rhabdomyosarcoma: a single institutional experience with 44 consecutive children. J Urol 159 (3): 1031-4, 1998.  [PUBMED Abstract]
    
    
30. Wiener ES, Lawrence W, Hays D, et al.: Retroperitoneal node biopsy in paratesticular rhabdomyosarcoma. J Pediatr Surg 29 (2): 171-7; discussion 178, 1994.  [PUBMED Abstract]
    
    
31. Crist WM, Anderson JR, Meza JL, et al.: Intergroup rhabdomyosarcoma study-IV: results for patients with nonmetastatic disease. J Clin Oncol 19 (12): 3091-102, 2001.  [PUBMED Abstract]
    
    
32. Wiener ES, Anderson JR, Ojimba JI, et al.: Controversies in the management of paratesticular rhabdomyosarcoma: is staging retroperitoneal lymph node dissection necessary for adolescents with resected paratesticular rhabdomyosarcoma? Semin Pediatr Surg 10 (3): 146-52, 2001.  [PUBMED Abstract]
    
    
33. Grüschow K, Kyank U, Stuhldreier G, et al.: Surgical repositioning of the contralateral testicle before irradiation of a paratesticular rhabdomyosarcoma for preservation of hormone production. Pediatr Hematol Oncol 24 (5): 371-7, 2007 Jul-Aug.  [PUBMED Abstract]
    
    
34. Ferrer FA, Isakoff M, Koyle MA: Bladder/prostate rhabdomyosarcoma: past, present and future. J Urol 176 (4 Pt 1): 1283-91, 2006.  [PUBMED Abstract]
    
    
35. Hays DM, Raney RB, Wharam MD, et al.: Children with vesical rhabdomyosarcoma (RMS) treated by partial cystectomy with neoadjuvant or adjuvant chemotherapy, with or without radiotherapy. A report from the Intergroup Rhabdomyosarcoma Study (IRS) Committee. J Pediatr Hematol Oncol 17 (1): 46-52, 1995.  [PUBMED Abstract]
    
    
36. Lobe TE, Wiener E, Andrassy RJ, et al.: The argument for conservative, delayed surgery in the management of prostatic rhabdomyosarcoma. J Pediatr Surg 31 (8): 1084-7, 1996.  [PUBMED Abstract]
    
    
37. Pappo AS, Shapiro DN, Crist WM, et al.: Biology and therapy of pediatric rhabdomyosarcoma. J Clin Oncol 13 (8): 2123-39, 1995.  [PUBMED Abstract]
    
    
38. Raney RB Jr, Gehan EA, Hays DM, et al.: Primary chemotherapy with or without radiation therapy and/or surgery for children with localized sarcoma of the bladder, prostate, vagina, uterus, and cervix. A comparison of the results in Intergroup Rhabdomyosarcoma Studies I and II. Cancer 66 (10): 2072-81, 1990.  [PUBMED Abstract]
    
    
39. Heyn R, Newton WA, Raney RB, et al.: Preservation of the bladder in patients with rhabdomyosarcoma. J Clin Oncol 15 (1): 69-75, 1997.  [PUBMED Abstract]
    
    
40. Arndt C, Rodeberg D, Breitfeld PP, et al.: Does bladder preservation (as a surgical principle) lead to retaining bladder function in bladder/prostate rhabdomyosarcoma? Results from intergroup rhabdomyosarcoma study iv. J Urol 171 (6 Pt 1): 2396-403, 2004.  [PUBMED Abstract]
    
    
41. Godbole P, Outram A, Wilcox DT, et al.: Myogenin and desmin immunohistochemistry in the assessment of post-chemotherapy genitourinary embryonal rhabdomyosarcoma: prognostic and management implications. J Urol 176 (4 Pt 2): 1751-4, 2006.  [PUBMED Abstract]
    
    
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43. Arndt CA, Donaldson SS, Anderson JR, et al.: What constitutes optimal therapy for patients with rhabdomyosarcoma of the female genital tract? Cancer 91 (12): 2454-68, 2001.  [PUBMED Abstract]
    
    
44. Raney RB, Anderson JR, Andrassy RJ, et al.: Soft-tissue sarcomas of the diaphragm: a report from the Intergroup Rhabdomyosarcoma Study Group from 1972 to 1997. J Pediatr Hematol Oncol 22 (6): 510-4, 2000 Nov-Dec.  [PUBMED Abstract]
    
    
45. Kato MA, Flamant F, Terrier-Lacombe MJ, et al.: Rhabdomyosarcoma of the larynx in children: a series of five patients treated in the Institut Gustave Roussy (Villejuif, France). Med Pediatr Oncol 19 (2): 110-4, 1991.  [PUBMED Abstract]
    
    
46. La Quaglia MP: The surgical management of metastases in pediatric cancer. Semin Pediatr Surg 2 (1): 75-82, 1993.  [PUBMED Abstract]
    
    
47. Mandell LR: Ongoing progress in the treatment of childhood rhabdomyosarcoma. Oncology (Huntingt) 7 (1): 71-83; discussion 84-6, 89-90, 1993.  [PUBMED Abstract]
    
    
48. Maurer HM, Beltangady M, Gehan EA, et al.: The Intergroup Rhabdomyosarcoma Study-I. A final report. Cancer 61 (2): 209-20, 1988.  [PUBMED Abstract]
    
    
49. Maurer HM, Gehan EA, Beltangady M, et al.: The Intergroup Rhabdomyosarcoma Study-II. Cancer 71 (5): 1904-22, 1993.  [PUBMED Abstract]
    
    
50. Crist W, Gehan EA, Ragab AH, et al.: The Third Intergroup Rhabdomyosarcoma Study. J Clin Oncol 13 (3): 610-30, 1995.  [PUBMED Abstract]
    
    
51. Otten J, Flamant F, Rodary C, et al.: Treatment of rhabdomyosarcoma and other malignant mesenchymal tumours of childhood with ifosfamide + vincristine + dactinomycin (IVA) as front-line therapy (a SIOP study). Cancer Chemother Pharmacol 24 (Suppl 1): S30, 1989.  [PUBMED Abstract]
    
    
52. Pappo AS, Etcubanas E, Santana VM, et al.: A phase II trial of ifosfamide in previously untreated children and adolescents with unresectable rhabdomyosarcoma. Cancer 71 (6): 2119-25, 1993.  [PUBMED Abstract]
    
    
53. Magrath I, Sandlund J, Raynor A, et al.: A phase II study of ifosfamide in the treatment of recurrent sarcomas in young people. Cancer Chemother Pharmacol 18 (Suppl 2): S25-8, 1986.  [PUBMED Abstract]
    
    
54. Arndt C, Tefft M, Gehan E, et al.: A feasibility, toxicity, and early response study of etoposide, ifosfamide, and vincristine for the treatment of children with rhabdomyosarcoma: a report from the Intergroup Rhabdomyosarcoma Study (IRS) IV pilot study. J Pediatr Hematol Oncol 19 (2): 124-9, 1997 Mar-Apr.  [PUBMED Abstract]
    
    
55. Miser JS, Kinsella TJ, Triche TJ, et al.: Ifosfamide with mesna uroprotection and etoposide: an effective regimen in the treatment of recurrent sarcomas and other tumors of children and young adults. J Clin Oncol 5 (8): 1191-8, 1987.  [PUBMED Abstract]
    
    
56. Baker KS, Anderson JR, Link MP, et al.: Benefit of intensified therapy for patients with local or regional embryonal rhabdomyosarcoma: results from the Intergroup Rhabdomyosarcoma Study IV. J Clin Oncol 18 (12): 2427-34, 2000.  [PUBMED Abstract]
    
    
57. Spunt SL, Smith LM, Ruymann FB, et al.: Cyclophosphamide dose intensification during induction therapy for intermediate-risk pediatric rhabdomyosarcoma is feasible but does not improve outcome: a report from the soft tissue sarcoma committee of the children's oncology group. Clin Cancer Res 10 (18 Pt 1): 6072-9, 2004.  [PUBMED Abstract]
    
    
58. Houghton PJ, Cheshire PJ, Myers L, et al.: Evaluation of 9-dimethylaminomethyl-10-hydroxycamptothecin against xenografts derived from adult and childhood solid tumors. Cancer Chemother Pharmacol 31 (3): 229-39, 1992.  [PUBMED Abstract]
    
    
59. Pappo AS, Lyden E, Breneman J, et al.: Up-front window trial of topotecan in previously untreated children and adolescents with metastatic rhabdomyosarcoma: an intergroup rhabdomyosarcoma study. J Clin Oncol 19 (1): 213-9, 2001.  [PUBMED Abstract]
    
    
60. 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.  [PUBMED Abstract]
    
    
61. 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.  [PUBMED Abstract]
    
    
62. Arndt CA, Hawkins DS, Stoner JA, et al.: Randomized phase III trial comparing vincristine, actinomycin, cyclophosphamide (VAC) with VAC/V topotecan/cyclophosphamide (TC) for intermediate risk rhabdomyosarcoma (IRRMS). D9803, COG study. [Abstract] J Clin Oncol 25 (Suppl 18): A-9509, 528s, 2007. 
    
    
63. 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.  [PUBMED Abstract]
    
    
64. 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.  [PUBMED Abstract]
    
    
65. 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.  [PUBMED Abstract]
    
    
66. 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.  [PUBMED Abstract]
    
    
67. 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.  [PUBMED Abstract]
    
    
68. 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.  [PUBMED Abstract]
    
    
69. 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.  [PUBMED Abstract]
    
    
70. 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.  [PUBMED Abstract]
    
    
71. Koscielniak E, Klingebiel TH, Peters C, et al.: Do patients with metastatic and recurrent rhabdomyosarcoma benefit from high-dose therapy with hematopoietic rescue? Report of the German/Austrian Pediatric Bone Marrow Transplantation Group. Bone Marrow Transplant 19 (3): 227-31, 1997.  [PUBMED Abstract]
    
    
72. Horowitz ME, Kinsella TJ, Wexler LH, et al.: Total-body irradiation and autologous bone marrow transplant in the treatment of high-risk Ewing's sarcoma and rhabdomyosarcoma. J Clin Oncol 11 (10): 1911-8, 1993.  [PUBMED Abstract]
    
    
73. Boulad F, Kernan NA, LaQuaglia MP, et al.: High-dose induction chemoradiotherapy followed by autologous bone marrow transplantation as consolidation therapy in rhabdomyosarcoma, extraosseous Ewing's sarcoma, and undifferentiated sarcoma. J Clin Oncol 16 (5): 1697-706, 1998.  [PUBMED Abstract]
    
    
74. Carli M, Colombatti R, Oberlin O, et al.: European intergroup studies (MMT4-89 and MMT4-91) on childhood metastatic rhabdomyosarcoma: final results and analysis of prognostic factors. J Clin Oncol 22 (23): 4787-94, 2004.  [PUBMED Abstract]
    
    
75. 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.  [PUBMED Abstract]
    
    
76. 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.  [PUBMED Abstract]
    
    
77. 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.  [PUBMED Abstract]
    
    
78. 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.  [PUBMED Abstract]
    
    
79. 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.  [PUBMED Abstract]
    
    
80. 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.  [PUBMED Abstract]
    
    
81. 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.  [PUBMED Abstract]
    
    
82. 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.  [PUBMED Abstract]
    
    
83. 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.  [PUBMED Abstract]
    
    
84. Laskar S, Bahl G, Ann Muckaden M, et al.: Interstitial brachytherapy for childhood soft tissue sarcoma. Pediatr Blood Cancer 49 (5): 649-55, 2007.  [PUBMED Abstract]
    
    
85. 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. 
    
    
86. 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.  [PUBMED Abstract]
    
    
87. 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.  [PUBMED Abstract]
    
    
88. 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.  [PUBMED Abstract]
    
    
89. 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.  [PUBMED Abstract]
    
    
90. 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.  [PUBMED Abstract]
    
    
91. 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.  [PUBMED Abstract]
    
    
92. 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.  [PUBMED Abstract]
    
    
93. 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.  [PUBMED Abstract]
    
    
94. 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.  [PUBMED Abstract]
    
    
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101. 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.  [PUBMED Abstract]
     
     

Recurrent Childhood Rhabdomyosarcoma

Although patients with recurrent or progressive rhabdomyosarcoma can sometimes achieve complete remission with secondary therapy, the long-term prognosis for most is poor.[1,2] The prognosis is most favorable (50%–70%, 5-year survival rates) for children who initially presented with stage 1 or group I disease and embryonal histology and who have local or regional recurrence.[1,2] 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] The selection of further treatment depends on many factors, including the site of recurrence and 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.[3] Some survivors have also been reported after surgical removal of only one or a few metastases in the lung.[3] Radiation therapy should be considered for patients who have not already been irradiated to the area of recurrence, or rarely for those who have been previously irradiated but 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. [4]



• Ifosfamide, carboplatin, and etoposide. [5,6]



• Cyclophosphamide/topotecan. [7]



• Irinotecan with or without vincristine. [8-11]

Treatment options under clinical evaluation for recurrent rhabdomyosarcoma:

• Based on historical relapse data from the Intergroup Rhabdomyosarcoma Studies Group,[1] the Children’s Oncology Group is currently 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.[12]



• Single agent vinorelbine. [13]



• Combination vinorelbine and low-dose cyclophosphamide. [14]



• Rapamycin.[15]



• New agents under clinical evaluation in phase I and phase II trials should be considered for relapsed patients.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with recurrent childhood rhabdomyosarcoma ²⁴. 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 ¹⁹.

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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
3. 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.  [PUBMED Abstract]
   
   
4. 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.  [PUBMED Abstract]
   
   
5. 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.  [PUBMED Abstract]
   
   
6. 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.  [PUBMED Abstract]
   
   
7. Saylors RL 3rd, Stine KC, Sullivan J, et al.: Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: a Pediatric Oncology Group phase II study. J Clin Oncol 19 (15): 3463-9, 2001.  [PUBMED Abstract]
   
   
8. 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.  [PUBMED Abstract]
   
   
9. 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.  [PUBMED Abstract]
   
   
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Changes to This Summary (01/02/2009)

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 ²⁸

Added text ²⁹ to state that for patients with paratesticular tumors, repositioning the contralateral testicle prior to scrotal radiation may preserve hormone productivity (cited Grüschow et al. as reference 33 and added level of evidence 3iii).

Added text ³⁰ to state that in a French study, 20 patients with metastatic disease at diagnosis received window therapy with doxorubicin for two courses; 13 of 20 patients responded to therapy while four patients had progressive disease (cited Bergeron et al. as reference 70).

More Information

About PDQ

• PDQ® - NCI's Comprehensive Cancer Database ³¹.

  Full description of the NCI PDQ database.

Additional PDQ Summaries

• PDQ® Cancer Information Summaries: Adult Treatment ³²

  Treatment options for adult cancers.

• PDQ® Cancer Information Summaries: Pediatric Treatment ³³

  Treatment options for childhood cancers.

• PDQ® Cancer Information Summaries: Supportive and Palliative Care ⁵

  Side effects of cancer treatment, management of cancer-related complications and pain, and psychosocial concerns.

• PDQ® Cancer Information Summaries: Screening/Detection (Testing for Cancer) ³⁴

  Tests or procedures that detect specific types of cancer.

• PDQ® Cancer Information Summaries: Prevention ³⁵

  Risk factors and methods to increase chances of preventing specific types of cancer.

• PDQ® Cancer Information Summaries: Genetics ³⁶

  Genetics of specific cancers and inherited cancer syndromes, and ethical, legal, and social concerns.

• PDQ® Cancer Information Summaries: Complementary and Alternative Medicine ³⁷

  Information about complementary and alternative forms of treatment for patients with cancer.

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Glossary Terms

Nonrandomized, controlled clinical trial with total mortality as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.

Nonconsecutive case series. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.

Nonconsecutive case series with total mortality as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.